WO2008134047A1

WO2008134047A1 - Methods of treating hypertension

Info

Publication number: WO2008134047A1
Application number: PCT/US2008/005451
Authority: WO
Inventors: Robert L. Rolleri; Charles L. Pamplin Iii
Original assignee: King Pharmaceuticals Research And Development, Inc.
Priority date: 2007-04-27
Filing date: 2008-04-28
Publication date: 2008-11-06

Abstract

The present invention is directed to pharmaceutical compositions and methods of treating cardiovascular disorders by administering pharmaceutical compositions comprising ramipril in combination with other active agents, such as a tablet comprising ramipril and hydrochlorothiazide. The compositions of the present invention have improved stability of ramipril which is less susceptible to degradation relative to other compositions comprising ramipril alone or in combination with another active agent.

Description

METHODS OF TREATING HYPERTENSION

1.0 References to Related Applications

[0001] This application claims the benefit of U.S. Provisional Applications

60/926,796 filed April 27, 2007, 60/930,783 filed May 17, 2007, and 60/930,992 filed May 18, 2007.

2.0 Field of the Invention

[0002] The present invention relates to novel pharmaceutical compositions comprising ramipril in combination with other active agents. More particularly, the present invention is directed to a tablet comprising ramipril and hydrochlorothiazide. The compositions of the present invention have improved stability of ramipril which is less susceptible to degradation relative to other compositions comprising ramipril alone or in combination with another active agent. The present invention also relates to methods of making and methods of manufacturing such compositions. The present invention also relates to methods of treating cardiovascular disorders such as hypertension by administering to a patient in need thereof a tablet formulation comprising a therapeutically effective amount of ramipril and hydrochlorothiazide, or administering to a patient a multi daily dose of ramipril that is more effective in treating hypertension than the equivalent amount of ramipril administered in a single daily dose.

3.0 Background

[0003] Cardiovascular disease treatment has evolved rapidly over the last few decades to include agents that range in diversity from diuretics and natural products such as rauwolfia serpentina to agents such as angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers (CCB). In efforts to achieve improved therapy (primarily for the treatment of hypertension, its sequelae, reversible conditions secondary to hypertension, and hypertension secondary to other conditions), a number of agents have been tested both alone as well as in combination with other agents. Some of the conditions for which at least one of these agents has been used or is believed useful include, without limitation, hypertension, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache. Indeed, many agents useful for the treatment of cardiovascular disease and related conditions are apparent to those of ordinary skill in the art based on knowledge of the underlying mechanisms involved in certain conditions as well as on general clinical and pre-clinical experience (U.S. Patent No. 6,162,802, issued December 19, 2000 to Papa, et al.).

[0004] Treatment of cardiovascular disease has become complex and can often entail the administration of multiple agents or one agent multiple times a day. Therefore, there is a need for combination products. The incorporation of two or more agents useful in the treatment of cardiovascular disease into one single unit dosage form can eliminate the need to take multiple single agent dosage forms. Combination products can simplify the dosing schedule and thereby improve patent compliance and diminish the need for multiple administrations or multiple single agent dosage forms. Even though taking one single unit dosage form is more convenient, in certain circumstances taking multiple daily doses of a single agent may increase the efficacy and bioavailability of the agent, which can outweigh the convenience of a single unit dosage form. Therefore, there is a need for dosing regimes that include multiple daily doses of a single agent which yield better patient response compared to single daily doses of an equivalent amount of the same agent. [0005] Although it is generally recognized that combination therapy can be more efficiently affected using combination products that incorporate two or more active agents, there are practical hurdles to formulating active agents into a single combination product. [0006] For example, although the usefulness of having a combination product containing an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof and another antihypertensive, a cholesterol lowering agent, a diuretic or aspirin for the use in the prevention of cardiovascular events is suggested in U.S. Patent Application Publication No. 2005/0101658, published May 12, 2005 (Scholkens et al.), the publication does not teach or suggest any tablets containing ramipril in combination with another active agent.

[0007] Likewise, although the combination of an angiotensin II antagonist with drugs selected from among the remedies for hypertension, hypoglycemics, hyperlipemia, antithromboties, menopause and anticancer drugs is suggested in U.S. Patent Application Publication No. 2004/0219208, published November 4, 2004 (Kawamura, et al.) the publication does not teach or suggest any tablets containing ramipril in combination with another active agent.

[0008] Also, even though the combination of ramipril and hydrochlorothiazide has been tested, as described in Scholze et al. "Shot Repot: Ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design," J. of Hypertension, 1993, 1 1 :217-221, each drug was administered individually and not in a combination tablet formulation.

[0009] In general, drug stability is an important consideration during the design, manufacture and storage of pharmaceutical compositions. Drugs that lack stability can degrade into degradant products which can cause side effects or, in some instances, can cause a decrease in the efficacy and bioavailability of the drug itself, making it difficult for doctors to prescribe consistent and effective treatments. This is applicable to the formulation of combination products and can be even more complex because of the inherent difficulties that accompany formulating combination products.

[0010] Oftentimes, the incompatibility of active agents can make the process of formulating the agents into a single unit dosage form very difficult. In certain instances, the potency, stability, and/or bioavailability of one or more of the agents is adversely affected in comparison to the single agent counterparts. Indeed, it is known that ACE inhibitors, a class of drugs that is extremely useful in the treatment of cardiovascular disease, are susceptible to degradation, particularly when subjected to the stresses inherent to formulation processes. [0011] Ramipril is an ACE inhibitor used in the treatment of cardiovascular disease, especially hypertension, and it is one of the most frequently prescribed drugs for congestive heart failure. In hypertensive patients, ramipril is known to reduce peripheral arterial resistance causing a reduction in blood pressure without a compensatory rise in heart rate. Ramipril has also been shown to reduce mortality in patients with clinical signs of congestive heart failure after surviving an acute myocardial infarction. Ramipril may have an added advantage over many other ACE inhibitors due to its pronounced inhibition of the ACE enzymes in tissues resulting in organ protective effects in such organs as the heart, kidney, and blood vessels.

[0012] Even though ramipril is without question one of the most important ACE inhibitors available today, like other ACE inhibitors, ramipril is susceptible to degradation. Indeed, current ramipril formulations show a considerable degree of instability. To date, the leading formulation of ramipril is a capsule. The degradation of ramipril is believed to occur mainly via two pathways: (a) hydrolysis to ramipril-diacid; and (b) cyclization or condensation to ramipril-diketopiperazine, also referred herein as ramipril-DKP. These ramipril-diacid and ramipril-DKP compounds form, as indicated above, as a result of cyclization, condensation and/or breakdown arising from exposure to heat, air, moisture, stress, compaction or other interactions or events.

[0013] Indeed, ramipril needs special care when formulating into pharmaceutical preparations due the physical stress associated with the formulation process. Factors that influence the stability of ramipril formulations are mechanical stress, compression, manufacturing processes, excipients, storage conditions, heat and moisture. In particular, the physical stress associated with formulating tablets can increase the decomposition of ramipril into degradant products. Moreover, addition of other active agents to a ramipril tablet formulation could further increase the rate of ramipril decomposition and affect the potency or bioavailability of ramipril. In certain instances, the potency or bioavailability of the other active agent can be adversely affected by the presence of ramipril in the formulation or during the formulation process.

[0014] Attempts to overcome ramipril stability have been reported in

PCT/EP2004/00456 and PCT/CA2002/01379.

[0015] PCT/EP2004/00456 describes solid ramipril compositions having suitably low water content and a process that utilizes excipients with low water content, in combination with processing parameters and packaging material that prohibit water or moisture uptake to formulate ramipril compositions and even though some formulations use glyceryl dibehenate, the rate of ramipril-DKP formulation is much higher than that in present invention. After one month the percent weight of ramipril-DKP is 2.14% at 40° C and at 75% humidity. [0016] PCT/CA2002/01379 describes solid ramipril compositions that comprise a mixture of ramipril and lactose monohydrate as the diluent. According to PCT/EP2004/000456, the process includes lactose monohydrate as the major excipient to formulate ramipril compositions in its attempt to improve ramipril stability. However, with the lactose monohydrate, the lowest rate of ramipril-DKP formation shows the presence of ramipril-DKP at 1.10%, immediately after formation of the capsule. [0017] U. S. Patent Application Publication No. 2005/0069586, published March 31,

2005 (Hrakovsky, et al.) describes ramipril tablets that have an admixture of ramipril and sodium stearyl fumarate with reduced ramipril-DKP formation, but does not teach pre- blending or co-milling the ramipril with glyceryl behenate or substantially coating the ramipril with any blending agent.

[0018] As such, there remains a need for formulations, in particular oral dosage forms such as tablets that contain ramipril in combination with at least one other active agent, such as hydrochlorothiazide wherein the ramipril does not degrade and maintains its potency under formulation and storage conditions. There also remains a need for tablet formulations that contain ramipril in combination with one or more active agents, such as hydrochlorothiazide wherein the bioavailability of ramipril and the other agent is the same or improved in comparison to the single agent forms.

[0019] Citations of any reference in the Background section of this application is not an admission that the reference is prior art to the application.

4.0 Summary of the Invention

[0020] The present invention is directed to a tablet formulation comprising a therapeutically effective amount of ramipril and another active agent, such as a diuretic. In certain embodiments the present invention is directed to a tablet comprising a therapeutically effective amount of ramipril and hydrochlorothiazide. The combination tablet comprising ramipril and hydrochlorothiazide can be formulated for once-a-day dosing. Once-a-day dosing allows for greater patient compliance since a patient would only have to take a tablet once daily instead of multiple times throughout the day. In other embodiments, the combination tablet comprising ramipril and hydrochlorothiazide is formulated for twice-a- day dosing. In certain embodiments, the ramipril contained in the tablets of the present invention is stable against decomposition into such degradation products as ramipril-diacid or ramipril-diketopiperazine.

[0021] The present invention is based in part on the discovery that stable oral dosage forms comprising ramipril and at least one other active agent can be achieved by first pre- blending or co-milling a blending agent such as glyceryl behenate with ramipril during manufacture of oral dosage forms that contain ramipril and another active agent. In particular, the inventors have made the surprising discovery that by combining ramipril with a blending agent such as glyceryl behenate, prior to formulation of ramipril and a diuretic into a tablet dosage form, the rate of ramipril degradant production is extremely low. In fact, it is particularly surprising that even when the formulation contains another active agent, the potency and stability of ramipril in the compositions of the subject invention is improved compared to current ramipril formulations. The inventors have also discovered that the bioavailability of the ramipril and the other agent of the combination tablet remain effectively the same as compared to the bioavailability of single agent tablets. Without being limited to one particular theory, the inventors of the present invention believe that the blending agent such as glyceryl behenate coats the ramipril and is able to protect the ramipril from physical and environmental stress that, under normal conditions, cause the ramipril to degrade into degradant products such as ramipril-DKP and ramipril-diacid.

[0022] In particular, the inventors have demonstrated that by utilizing glyceryl behenate as a blending agent, ramipril decomposition into degradant products, such as ramipril-DKP and ramipril diacid, can be significantly reduced. Indeed, the inventors have demonstrated that the rate of decomposition of ramipril in compositions of the invention is less than 0.05% of the total weight of ramipril on average per month for at least 36 months from the date that the ramipril compositions are first formulated. Moreover, the inventors have demonstrated that the ramipril in the tablets of the invention containing ramipril and chlorthalidone is as bioavailable as ramipril formulated alone [0023] As such, the pharmaceutical compositions contemplated by the present invention comprise ramipril in combination with at least one other active ingredient, wherein the ramipril has a low rate of degradation and is substantially free of ramipril-DKP and ramipril-diacid. Moreover, the pharmaceutical compositions of the present invention have increased stability, bioavailability and shelf-life compared to current formulations comprising ramipril alone. Additionally, the pharmaceutical compositions of the present invention allow ramipril to maintain potency, assuring health care providers and patients that they are giving and receiving consistent and exact treatment. The invention also contemplates reducing the rate of ramipril-DKP formation, especially under formulation and extended storage conditions.

[0024] The present invention also relates to methods of making the pharmaceutical compositions, of the present invention. Such methods comprise first pre-blending and/or co- milling ramipril with a blending agent before combining with other active agents and excipients. The methods of the present invention also comprise first coating ramipril with a blending agent prior to formulation of ramipril into a dosage form that includes one or more additional active agents.

[0025] The present invention is also directed to methods of treating cardiovascular disorders such as hypertension. In accordance with the present invention cardiovascular disorders such as hypertension can be treated by administering to a patient in need thereof a tablet comprising an effective amount of ramipril and hydrochlorothiazide. In certain embodiments the present invention is directed to methods of treating hypertension in a patient requiring a reduction in systolic blood pressure of > 20 mm Hg or a reduction in diastolic blood pressure of > 10 mm Hg comprising orally administering to the patient a tablet comprising a therapeutically effective amount of ramipril and a therapeutically effective amount of hydrochlorothiazide.

[0026] Also, the present invention is directed to methods of treating cardiovascular disorders, such as hypertension in specific patient populations such as individuals of African- American descent, males, females, and individuals 65 years and older. The present invention includes methods of treating hypertension in a patient in need thereof comprising orally administering to a patient an effective amount of ramipril and an effective amount of hydrochlorothiazide, wherein response to the administration of ramipril and hydrochlorothiazide was the same of similar in an African- American and a non African- American patient.

[0027] The present invention also includes methods of treating hypertension in a patient in need thereof comprising administering to a patient diagnosed with hypertension or diagnosed to be at risk for hypertension a daily oral dose of 20 mg of ramipril, wherein the oral dose is administered in the from of at least two tablets, each tablet comprising 10 mg of ramipril. For example, the present invention includes methods of treating hypertension in a female in need thereof by administering to the female a tablet comprising at least 10 mg of ramipril at least twice a day and methods of treating hypertension in a patient in need thereof, wherein the patient is 65 years or older by orally administering to the patient a tablet comprising at least 10 mg of ramipril at least twice a day.

[0028] In still other embodiments the present invention includes method of treating hypertension comprising orally administering to a patient in need thereof at least twice daily a tablet comprising ramipril or a pharmaceutically acceptable salt, wherein the at least twice daily administration of the tablet is more effective in lowering blood pressure as a once daily dosage form having an equivalent amount of ramipril as well as, methods for the treatment of hypertension comprising administering twice daily to a patient in need thereof a tablet comprising ramipril, wherein the increase in ambulatory trough blood pressure is less than the increase in ambulatory blood pressure when the patient is administered a once daily dosage form with the equivalent amount of ramipril.

[0029] The present invention is also directed to methods of reducing blood pressure in a patient. In certain embodiments, the present invention includes comprising orally administering to a patient in need thereof at least twice daily a tablet comprising ramipril or a pharmaceutically acceptable salt, wherein the reduction in blood pressure of the patient is greater than the reduction of blood pressure in the patient if the patient is administered a once daily dosage form with the equivalent amount of ramipril. For example, the present invention includes methods of reducing the sitting systolic blood pressure of an individual who has a sitting systolic blood pressure between about 140 and 180 mm Hg by orally administering to the individual at least 10 mg of ramipril at least twice daily and methods of reducing the sitting diastolic blood pressure of an individual who has a sitting diastolic blood pressure between about 100 and 1 15 mm Hg by orally administering to the individual at least 10 mg of ramipril at least twice a day.

[0030] The present invention is also directed to methods of improving the therapeutic efficacy and/or bioavailability of ramipril in females, individuals 65 years of age or older, individuals of non- African decent, naϊve and non-naϊve individuals by administering to such individuals at least 10 mg of ramipril at least twice a day.

[0031] The present invention is also directed to dosing regimens wherein a total daily dose of a therapeutically effective amount of ramipril is administered to a patient in multiple daily doses such that the administration of multiple daily dosages of ramipril is more effective than a single daily dose containing an equivalent amount of ramipril. This embodiment of the invention is based on the discovery that administration of multiple daily doses of ramipril was more effective in lowering blood pressure and treating hypertension than a single daily dose of ramipril containing an amount of ramipril that is equal to the amount contained in the multiple daily doses of ramipril. For example the present invention is directed to a twice-a-day dosing regime for the treatment of hypertension comprising twice daily administration of an oral dosage form comprising 10 mg of ramipril or a pharmaceutically acceptable salt. 5.0 Brief Description of the Figures

[0032] Figure 1 - Method of making tablets

[0033] Figure 2 - Mean Whole Blood Chlorthalidone Concentrations Versus Time

(Linear Scale), Group I of Example 2

[0034] Figure 3 - Mean Whole Blood Chlorthalidone Concentrations Versus Time

(Linear Scale), Group II of Example 2

[0035] Figure 4 - Mean Whole Blood Chlorthalidone Concentrations Versus Time

(Linear Scale), Group III of Example 2

[0036] Figure 5 - Mean (SD) Plasma Ramipril Concentrations Versus Time for

Group I of Example 3 (Linear Scale)

[0037] Figure 6 - Mean (SD) Plasma Ramipril Concentrations Versus Time for

Group II of Example 3 (Linear Scale)

[0038] Figure 7 - Mean (SD) Plasma Ramipril Concentrations Versus Time for

Group III of Example 3 (Linear Scale)

[0039] Figure 8 - Mean (SD) Plasma Ramipril Concentrations Versus Time for

Group IV of Example 3 (Linear Scale)

[0040] Figure 9 - Mean (SD) Plasma Ramipril Concentrations Versus Time for

Groups I-IV of Example 3 (Linear Scale)

[0041] Figure 10.1 - Boxplot of Change from Baseline to End of Treatment (Visit 7) in Mean Sitting Diastolic Blood Pressure (mm Hg).

[0042] Figure 10.2 - Boxplot of Change from Baseline to End of Treatment (Visit 7) in Mean Sitting Systolic Blood Pressure (mm Hg).

[0043] Figure 10.3 - Boxplot of Change from Baseline to End of Treatment (Visit 7) in Mean Standing Diastolic Blood Pressure (mm Hg).

[0044] Figure 10.4 - Boxplot of Change from Baseline to End of Treatment (Visit 7) in Mean Standing Systolic Blood Pressure (mm Hg).

[0045] Figure 10.5 - Boxplot of Change from Baseline to Visit 4 in Mean Sitting

Diastolic Blood Pressure (mm Hg).

[0046] Figure 10.6 - Boxplot of Change from Baseline to Visit 4 in Mean Sitting

Systolic Blood Pressure (mm Hg).

[0047] Figure 10.7 - Boxplot of Change from Baseline to Visit 4 in Mean Standing

Diastolic Blood Pressure (mm Hg). [0048] Figure 10.8 - Boxplot of Change from Baseline to Visit 4 in Mean Standing

Systolic Blood Pressure (mm Hg).

[0049] Figure 10.9 - Boxplot of Change from Baseline to End of Treatment (Visit 7) in Mean Ambulatory Diastolic Blood Pressure (mm Hg).

[0050] Figure 10.10 - Boxplot of Change from Baseline to End of Treatment (Visit

7) in Mean Ambulatory Systolic Blood Pressure (mm Hg).

[0051] Figure 10.11.1 - Plot of Mean Sitting Diastolic Blood Pressure Over Time by

Treatment Group.

[0052] Figure 10.11.2 - Plot of Change from Baseline in Mean Sitting Diastolic

Blood Pressure Over Time by Treatment Group.

[0053] Figure 10.12.1 - Plot of Mean Sitting Systolic Blood Pressure Over Time by

Treatment Group.

[0054] Figure 10.12.2 - Plot of Change from Baseline in Mean Sitting Systolic Blood

Pressure Over Time by Treatment Group.

[0055] Figure 10.13 - Plot of Mean Ambulatory Diastolic Blood Pressure (mm Hg) at Visit 3 (Baseline) by Hour and Treatment Group.

[0056] Figure 10.14 - Plot of Mean Ambulatory Systolic Blood Pressure (mm Hg) at

Visit 3 (Baseline) by Hour and Treatment Group.

[0057] Figure 10.15 - Plot of Mean Ambulatory Diastolic Blood Pressure (mm Hg) at Visit 7 by Hour and Treatment Group.

[0058] Figure 10.16 - Plot of Mean Ambulatory Systolic Blood Pressure (mm Hg) at

Visit 7 by Hour and Treatment Group.

[0059] Figure 10.17 - Plot of Change from Baseline to End of Treatment (Visit 7) in

Mean Ambulatory Diastolic Blood Pressure (mm Hg) by Hour and Treatment Group.

[0060] Figure 10.18 - Plot of Change from Baseline to End of Treatment (Visit 7) in

Mean Ambulatory Systolic Blood Pressure (mm Hg) by Hour and Treatment Group.

[0061] Figure 11.1- Plot of mean HCTZ dissolution results for ramipril/HCTZ tablets (2.5/12.5 mg) for exemplary tablets A9.

[0062] Figure 11.2- Plot of mean HCTZ dissolution results for ramipril/HCTZ tablets

(10/25 mg) for exemplary tablets B4.

[0063] Figure 11.3- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (2.5/12.5 mg) for exemplary tablets Al . [0064] Figure 11.4- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (2.5/12.5 mg) for exemplary tablets A2.

[0065] Figure 11.5- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (2.5/12.5 mg) for exemplary tablets A7.

[0066] Figure 11.6- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (2.5/12.5 mg) for exemplary tablets A9.

[0067] Figure 11.7- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (5/25 mg) in bottles of 100.

[0068] Figure 11.8- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (5/25 mg) in blisters of 10.

[0069] Figure 11.9- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (10/12.5 mg) in bottles of 100.

[0070] Figure 11.10- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (10/12.5 mg) in blisters of 10.

[0071] Figure 11.11- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (10/25 mg) in bottles of 100.

[0072] Figure 11.12- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (10/25 mg) in blisters of 10.

[0073] Figure 11.13- Plot of minimum HCTZ dissolution results for ramipril/HCTZ tablets (10/25 mg) for exemplary tablets B4.

6.0 Detailed Description 6.1 Definitions

[0074] The terms "stabilized", "stability", "improved stability" or "stable" as applied to ramipril, can encompass products that are substantially free of breakdown products or degradants. Such products or degradants include, but are not limited to, ramipril-diacid and ramipril-DKP.

[0075] The term "substantially free" refers to the ramipril formulations described herein that have significantly reduced levels of detectable breakdown products; e.g., ramipril- diacid and/or ramipril-DKP. [0076] The term "cardiovascular disorder(s)" as used herein means and broadly encompasses any disease, illness, sickness, disorder, condition, symptom or issue involving or concerning any part or portion of the heart or blood vessels of an animal, including a human. The term "blood vessel", as used herein, is defined to include any vessel in which blood circulates. Such cardiovascular disorders include, for example, arterial enlargements, arterial narrowings, peripheral artery disease, atherosclerotic cardiovascular disease, high blood pressure, angina, irregular heart rates, inappropriate rapid heart rate, inappropriate slow heart rate, angina pectoris, heart attack, myocardial infarction, transient ischemic attacks, heart enlargement, heart failure, congested heart failure, heart muscle weakness, inflammation of the heart muscle, overall heart pumping weakness, heart valve leaks, heart valve stenosis (failure-to-open fully), infection of the heart valve leaflets, heart stoppage, asymptomatic left ventricular dysfunction, cerebrovascular incidents, strokes, chronic renal insufficiency, and diabetic or hypertensive nephropathy. These above-listed conditions commonly arise in healthy, pre-disposed or critically ill patients, and may or may not be accompanied by hypertension, angina, light-headedness, dizziness, fatigue or other symptoms.

[0077] The terms "treat(s)", "treated", "treating" or "treatment" are used herein interchangeably and refer to any treatment of a disorder in an animal diagnosed or inflicted with such disorder and includes, but is not limited to: (a) caring for an animal diagnosed or inflicted with a disorder; (b) curing or healing an animal diagnosed or inflicted with a disorder; (c) causing regression of a disorder in an animal; (d) arresting further development or progression of a disorder in an animal; (e) slowing the course of a disorder in an animal; (f) relieving, improving, decreasing or stopping the conditions of a disorder in a animal; (g) relieving, decreasing or stopping the symptoms caused by or associated with a disorder in an animal; or (h) reducing the frequency, number or severity of episodes caused by or associated with a disorder in an animal.

[0078] The terms "prevent(s)", "prevented", "preventing" or "prevention" are used herein interchangeably and refer to any prevention or any contribution to the prevention of a disorder in an animal or the development of a disorder if none has occurred in an animal which may be predisposed to such disorder but has not yet been inflicted with or diagnosed as having such disorder. [0079] The phrase "safe and effective amount(s)", as used herein, means any amount of a drug which, when administered to a subject to be treated, will achieve a beneficial pharmacological effect or therapeutic improvement consistent with the objectives of the present invention without causing serious, adverse or otherwise treatment-limiting side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. [0080] The term "about" as used herein means approximately or near or around. For example, when the term "about" is used in relation to a specified dosage amount or range, the term "about" indicates that the dosage amount or range specified is an approximate dosage amount or range and that it includes not only the amount or range actually specified, but those amounts or ranges that may also be safe and effective amounts that are somewhat outside the cited amount or range.

[0081] As used herein, the terms "comprising," "comprises", "comprised of,"

"including," "includes," "included," "involving," "involves," "involved," and "such as" are used in their open, non-limiting sense.

[0082] It should be understood that the phrase "pharmaceutically acceptable" is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product.

[0083] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and/or base of the specified compound. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycollates, tartarates, methane- sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates. Several of the officially approved salts are listed in Remington: The Science and Practice of Pharmacy, Mack Publ. Co., Easton. Additional examples of pharmaceutically acceptable salts are besylate, edisylate, and mesylate salts (Gould, Philip L, 1986, "Salt selection for basic drugs", Int. J. Pharmaceutics, 33, pp 201 - 217). [0084] The term "derivative" as used herein means a chemically modified compound wherein the chemical modification takes place at one or more functional groups of the compound and/or on an aromatic ring, when present. The derivative may or may not retain the pharmacological activity of the compound from which it is derived. [0085] The term "pharmaceutical grade" as used herein, means that a substance meets pharmaceutical standards, and that its purity is superior as compared to the purity of the same such substance when classified as food grade, which is less pure. 6.2 Pharmaceutical Compositions

[0086] In general, the pharmaceutical compositions of the present invention relate to compositions comprising a combination of two or more drugs wherein at least one of the drugs is susceptible to degradation when exposed to the environment or exposed to physical stresses during the manufacturing process and wherein the rate of degradation of the compound is extremely low.

[0087] The present invention encompasses pharmaceutical compositions that comprise a combination of two or more drugs wherein at least one of the drugs is susceptible to degradation when exposed to the environment or exposed to physical stresses during the manufacturing process; and a blending agent.

6.2.1 ACE Inhibitors

[0088] In certain preferred embodiments, the drug susceptible to degradation is an

ACE inhibitor. Suitable ACE inhibitors include, but are not limited to, captopril, benazepril, enalapril, lisinopril, fosinopril, ramipril, perindopril, quinapril, moexipril, and trandolapril. [0089] Of the ACE inhibitors, ramipril, its derivatives and salts are of special interest.

Suitable ramipril derivatives and salts include, but are not limited to, the esters and those common salts known to be substantially equivalent to ramipril. Suitable ramipril esters include, but are not limited to, hexahydroramipril, ramipril benzyl ester, isopropyl ester, ethyl ester or methyl ester. Pharmaceutically acceptable salts of ramipril include, but are not limited to, salts with pharmaceutically acceptable amines or inorganic or organic acids such as, HCl, HBr, H₂SO₄, maleic acid, fumaric acid, tartaric acid and citric acid. Additional examples of pharmaceutically acceptable salts are besylate, edisylate, and mesylate salts. [0090] Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative with five chiral centers, and 32 different enantiomeric forms. The chemical name of ramipril is (2S,3aS,6aS)-l [(S)-N-[(S)-l-carboxy-3-phenylpropyl]alanyl]octahydrocyclo-penta[b]pyrrole- 2-carboxylic acid, 1 -ethyl ester is most preferred and has the following chemical structure:

[0091] Ramipril is converted to ramiprilat in the body by hepatic cleavage of the ester group. Ramiprilat, the diacid or free acid metabolite of ramipril, is obtained in vivo upon administration of ramipril but ramiprilat is not absorbed appreciably in- vivo from the GI tract.

[0092] In preferred embodiments of the present invention the percent of ramiprilat does not exceed 20% after 8 weeks at 40°C and 75% relative humidity. Preferably, the percent of ramiprilat does not exceed 1.0% during the life of the composition. Most preferably, the percent of ramiprilat does not exceed 0.5% during the life of the composition. [0093] Ramipril is marketed in the United States under the brand name Altace® and abroad under the brand name Delix®. Altace® (ramipril) is supplied as hard shell capsules for oral administration containing 1.25 mg, 2.5 mg, 5 mg or 10 mg of ramipril. [0094] Ramipril compositions of the present invention can be formulated with any form of ramipril known in the art. Ramipril suitable for the present invention can be uncoated or be coated with a coat forming material. Ramipril and processes for making and using ramipril are described and claimed in U.S. Patent Nos. 4,587,258, 5,061,722 and 5,403,856, all of which are incorporated herein by reference in their entirety. The preparation of ramipril has also been described in EP 0 079 022 A2, EP 0 317 878 Al and DE 44 20 102 A, which are incorporated herein by reference in their entirety.

[0095] Uncoated ramipril suitable for the present invention includes ramipril. Coated ramipril suitable for the present invention can be any coated ramipril known in the art. For example, coated ramipril suitable for the present invention can include ramipril particles that are coated with a suitable coat forming material. Coated ramipril suitable for the present invention can be partially, substantially or completely covered with a coat forming material. Ramipril particles can include but are not limited to, coated ramipril micro- or nanoparticles, coated ramipril crystalline particles, coated individual ramipril crystals and coated ramipril agglomerates, granules or beads. One preferred type of ramipril agglomerates is the GEcoated ramipril agglomerates, manufactured by Aventis Pharma Deutschland GmbH (Frankfurt on Main, Germany). Such GEcoated ramipril agglomerates are ramipril agglomerates coated with a hydroxypropyl methylcellulose polymer coating (1.192 mg GEcoated granules = 1.0 mg ramipril). Coated ramipril particles, suitable for the present invention, can also be made according to the methods disclosed in U.S. Patent Nos. 5,061,722; 5,151,433; 5,403,856; and 5,442,008, U.S. Provisional Application No. 60/625,270 and co-pending U.S. applications U.S. Serial No. 11/269,387, filed November 7, 2005 (published as U.S. Patent Application Publication No. 2006-0159742) and U.S. Serial No. 1 1/269,388, filed November 7, 2005 (published as U.S. Patent Application Publication No. 2006-0134213), herein incorporated by reference. The compositions of the present invention can also contain anhydrous, pharmaceutical grade ramipril powder comprising coated ramipril particles.

6.2.2 Additional Active Agents

[0096] Accordingly, the pharmaceutical compositions of the present invention comprise ramipril in combination with at least one other active agent, wherein the ramipril is substantially stable against decomposition into degradant products, such as ramipril-diacid and ramipril-DKP. Additionally, the ramipril compositions of the present invention have improved stability and shelf-life. This improved stability allows the ramipril compositions to maintain potency and improve effectiveness and bioavailability of ramipril compared to other ramipril formulations.

[0097] In the various embodiments contemplated, non-limiting examples of the active agents that can be formulated in combination with ramipril include: diuretics such as but not limited to chlorthalidone, furosemide, bumetanide, torsemide, hydrochlorothiazide, metolazone, and spironolactone; angiotensin receptor blockers such as but not limited to candesartan, eprosartan, irbesartan, telmisartan, valsartan and losartan; other ACE inhibitors such as but not limited to captopril, benazepril, enalapril, lisinopril, fosinopril, perindopril, quinapril, moexipril and trandolapril; cholesterol lowering drugs such as but not limited to atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin; calcium channel blockers such as but not limited to amlodipine, felodipine, dilitiazem, verapamil, nifedipine, nicardipine, nisoldpine and bepridil; beta blockers; glucose lowering agents such as but not limited to insulin, and oral hypoglycemics such as but not limited to the sulfonylurea class (i.e., metformin).

[0098] In preferred embodiments, the diuretics contemplated in the present invention are chlorthalidone and/or hydrochlorthiazide.

[0099] Chlorthalidone is a monosulfamyl diuretic that differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is 2-chloro-5- (l-hydroxy-3-oxo-l-isoindolinyl) benzenesulfonamide with an molecular formula of Ci₄H_I iClN₂O₄S, a molecular weight of 338.76 and the following structural formula:

Ci₄H_{1 1}CI N₂O₄S M.W. 338.76

[0100] Hydrochlorothiazide is a diuretic and antihypertensive. It is the 3, 4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3, 4-dihydro-2H-l, 2, 4- benzothiadiazine-7-sulfonamide 1, 1 -dioxide. Its empirical formula is C₇H₈ClN₃O₄S₂ and its structural formula is:

[0101] A therapeutically effective amount of hydrochlorothiazide can be formulated into a dosage form such as a tablet suitable for once-a-day or twice-a-day dosing. [0102] In various embodiments of the invention, the compositions comprise ramipril and a diuretic, wherein the bioavailability of the ramipril is the same as the bioavailability of ramipril when formulated alone. In certain preferred embodiments, the potency and stability of ramipril is improved when compared to current ramipril formulations. Moreover, in certain embodiments, the bioavailability or potency of the diuretic is improved or the same when compared to current single agent diuretic formulations. 6.2.3 Stability of the ACE Inhibitor

[0103] The rate of decomposition of ramipril to ramipril-DKP is typically monitored at conditions of 25⁰C and 60% relative humidity (R.H.). These conditions may also be described as room temperature conditions. The rate of decomposition of ramipril to ramipril- DKP, in the compositions of the present invention is between 0.00-0.12% of the total weight of ramipril per month. Preferably the rate of decomposition of ramipril in the compositions of the present invention is 0.00-0.1 1 % of the total weight of ramipril; more preferably the rate of decomposition is 0.04-0.095% of the total weight of ramipril per month. [0104] For example, the ramipril compositions of the present invention result in ramipril-DKP formation of between about 0.0-0.6 % or 0.0-0.6 % of the total weight of ramipril during about the first three months or the first three months after the compositions are formed and between about 0-4 % or 0-4% of the total weight of ramipril during a period of at least about 36 months or 36 months after the composition are formed. [0105] In one embodiment, the pharmaceutical compositions of the present invention have a rate of decomposition of ramipril of less than about 0.04% to about 0.095% of the total weight of ramipril at room temperature or less than 0.04% to 0.095% of the total weight of ramipril at room temperature, on average per month for at least about 36 months or at least 36 months from the date that the ramipril compositions are first formulated. Preferred pharmaceutical compositions have ramipril-DKP formation of less than about 0.04% to about 0.085% or less than 0.04% to 0.085% of the total weight of ramipril at room temperature, on average per month for an extended period, more preferred the pharmaceutical compositions have ramipril-DKP formation of less than about 0.04% to about 0.055% or less than 0.04% to 0.055% of the total weight of ramipril at room temperature, per month on average for such an extended period, and even more preferred pharmaceutical compositions have ramipril-DKP formation of less than about 0.04% to about 0. 042% or less than 0.04% to 0.042% of the total weight of ramipril at room temperature, per month on average for an extended period of time.

[0106] Preferably the compositions of the present invention result in ramipril-DKP formation of less than about 0.4% or less than 0.4% during about the first three months of the total weight of ramipril and less than about 2.0% or less than 2.0% of the total weight of ramipril during a period of at least about 36 months after the first three month period. Preferred compositions result in ramipril-DKP formation of less than about 0.4% or less than 0.4% of the total weight of ramipril during about the first three months and less than about

1.5% or less than 1.5% of the total weight of ramipril during a period of at least about 36 months after the first three month period.

[0107] More preferably the compositions of the present invention result in ramipril-

DKP formation of less than about 0.3% or less than 0.3% during about the first three months of the total weight of ramipril and less than about 2.0% or less than 2.0% of the total weight of ramipril during a period of at least about 36 months after the first three month period.

Preferred compositions result in ramipril-DKP formation of less than about 0.3% or less than

0.3% of the total weight of ramipril during about the first three months and less than about

[0108] In one preferred embodiment, the compositions of the present invention comprise ramipril alone or in combination with at least one other active agent, wherein the rate ramipril decomposition to ramipril-DKP, is less than about 0.4% or less than 0.4% of the total weight of the ramipril during about the first three months after the compositions are formed.

[0109] In another preferred embodiment, the compositions of the present invention comprise ramipril alone or in combination with at least one other active agent, wherein the rate ramipril decomposition to ramipril-DKP, is less than about 0.3% or less than 0.3% of the total weight of the ramipril during about the first three months after the compositions are formed.

[0110] In another preferred embodiment, the compositions of the present invention comprise ramipril in combination with at least one other active agent, wherein the rate of ramipril decomposition to ramipril-DKP, is less than about 0.75% or less than 0.75% of the total weight of the ramipril during about the first 6 months after the compositions are formed.

[0111] In yet another preferred embodiment, the compositions of the present invention comprise ramipril in combination with at least one other active agent, wherein the rate of ramipril decomposition to ramipril-DKP, is less than about 3.0% or less than 3.0% of the total weight of the ramipril during about the first 36 months after the compositions are formed.

[0112] In all of the above embodiments, the active agent formulated in combination with ramipril is preferably a diuretic. In such embodiments, the bioavailability and/or potency and stability of the diuretic is the same or improved when compared to single agent formulations. For example in certain embodiments, the active agent formulated in combination with ramipril is hydrochlorothiazide. Preferably the ramipril/ hydrochlorothiazide combination is formulated in the form of a tablet. The ramipril/ hydrochlorothiazide tablet can be formulated for once-a-day dosing. In certain instances once-a-day dosing is preferred due to the fact that a once-a-day dosing regimen is easier for a patient to take as compared with dosage forms that must be administered more than once daily, which leads to increased patient compliance. An example of a once-a-day tablet comprising ramipril and hydrochlorothiazide is a tablet that comprises 20 mg of ramipril and 12.5 mg or 25 mg of hydrochlorothiazide.

[0113] In other embodiments, the ramipril/ hydrochlorothiazide tablet can be formulated for twice-a-day dosing. In certain instances twice-a-day dosing is preferred should the twice-a-day dosing regimen lead to increase bioavailability of the combination therapy. An example of a twice-a-day tablet comprising ramipril and hydrochlorothiazide is a tablet that comprises 10 mg of ramipril and 12.5 mg or 25 mg of hydrochlorothiazide. [0114] In a preferred embodiment the tablet for once-a-day dosing comprising 10 mg of ramipril and 12.5 mg or 25 mg of HCTZ is bioequivalent to one 10 mg tablet or capsule of ramipril co-administered with one tablet or capsule of 12.5 mg or 25 mg of HCTZ once a day.

[0115] In another preferred embodiment the tablet for twice-a-day dosing comprising

10 mg of ramipril and 12.5 mg or 25 mg of HCTZ is bioequivalent to one 10 mg tablet or capsule of ramipril co-administered with one tablet or capsule of 12.5 mg or 25 mg of HCTZ twice a day.

6.3 Methods of Treatment

[0116] The dosage forms of the present invention can be administered to a patient for the treatment of cardiovascular disorders. Cardiovascular disorders can include, but are not limited to, hypertension, heart failure, congestive heart failure, myocardial infarction, atherosclerotic cardiovascular disease, asymptomatic left ventricular dysfunction, chronic renal insufficiency, and diabetic or hypertensive nephropathy. In certain embodiments the dosage forms of the present invention can be administered to a patient for the treatment of hypertension. [01171 In certain embodiments, the present invention is directed to methods of treating hypertension comprising administering to a patient in need thereof a tablet comprising ramipril and hydrochlorothiazide. In certain embodiments, the tablet includes 2.5 mg to 20 mg of ramipril and 12.5 mg or 25 mg of hydrochlorothiazide and is administered once-a-day. In certain embodiments, the tablet includes 2.5 mg to 10 mg of ramipril and 12.5 mg of hydrochlorothiazide and is administered twice-a-day. In certain embodiments, the tablet includes 10 mg of ramipril and 12.5 mg of hydrochlorothiazide and is administered twice-a-day. In other embodiments, the tablet includes 20 mg of ramipril and 25 mg of hydrochlorothiazide and is administered once-a-day. The present invention also includes, methods of treating hypertension comprising orally administering to a patient in need thereof a once daily tablet comprising a therapeutically effective amount of ramipril and a therapeutically effective amount hydrochlorothiazide, wherein the once daily tablet is at least as effective in lowering diastolic blood pressure when compared to a twice a day dosage form having equivalent amounts of ramipril and hydrochlorothiazide. [0118] In other embodiments the present invention includes methods of treating hypertension in a patient in need thereof comprising administering to a patient diagnosed with hypertension or diagnosed to be at risk for hypertension a daily oral dose of no more than 20 mg of ramipril and no more than 25 mg of hydrochlorothiazide, wherein the dosage form contains both ramipril and hydrochlorothiazide. The 20 mg of ramipril can be administered in one dose or, alternatively, in more than one dose, so that no more than 20 mg of ramipril is administered to the patient. Also, the 25 mg of hydrochlorothiazide can be administered in one dose or, alternatively, in more than one dose, so that no more than 25 mg of hydrochlorothiazide is administered to the patient. For example, the daily dose of 20 mg of ramipril and the daily dose of 25 mg of hydrochlorothiazide can be administered to the patient in one dose over a period of 24 hours or the daily dose of 20 mg of ramipril and the daily dose of 25 mg of hydrochlorothiazide can be administered to the patient in two doses over a period of 24 hours.

[0119] In certain embodiments, the total daily dose of 20 mg of ramipril and the total daily dose of 25 mg of hydrochlorothiazide is administered to the patient in multiple doses over a period of 24 hours. The daily dose of 20 mg of ramipril and the daily dose of 25 mg of hydrochlorothiazide can be administered in two, three, four, five, six, seven or eight times a day. Alternatively, a dose of ramipril and hydrochlorothiazide can be administered hourly, every 2, 4, 6, 8 or 12 hours until the daily dose of 20 mg of ramipril and the daily dose of 25 mg of hydrochlorothiazide has been administered.

[0120] Such tablets can contain 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide, 5 mg of ramipril and 12.5 mg of hydrochlorothiazide, 5 mg of ramipril and 25 mg of hydrochlorothiazide, 10 mg of ramipril and 12.5 or 25 mg of hydrochlorothiazide or 20 mg of ramipril and 12.5 or 25 mg of hydrochlorothiazide. [0121] The present invention is also directed to treatment of hypertension in certain patient populations. In other embodiments, the present invention is directed to methods of treating hypertension in a patient requiring a reduction in systolic blood pressure of > 20 mm Hg or a reduction in diastolic blood pressure of > 10 mm Hg comprising orally administering to the patient a tablet comprising an effective amount of ramipril and an effective amount of hydrochlorothiazide.

[0122] Also the present invention includes methods of treating hypertension in a patient in need thereof comprising orally administering to a patient an effective amount of ramipril and an effective amount of hydrochlorothiazide, wherein response to the administration of ramipril and hydrochlorothiazide was the same or similar in an individual of African descent and an individual of non- African descent.

[0123] The present invention is also directed to methods of reducing blood pressure in a patient. In certain embodiments, the present invention includes methods of reducing blood pressure comprising administering to a patient in need thereof a tablet comprising a therapeutically effective amount of ramipril and a therapeutically effective amount hydrochlorothiazide, wherein the reduction in blood pressure of the patient is greater than the reduction of blood pressure in the patient if the patient is administered an equivalent of ramipril or hydrochlorothiazide alone.

[0124] In other embodiments, the present invention is directed to methods of treating hypertension comprising administering to a patient in need thereof a dosage form comprising ramipril alone. The inventors have shown that administration of 20 mg of ramipril in either a once-a-day dosage form or a twice-a-day dosage from lowers the blood pressure of an individual with Stage 2 essential hypertension.

[0125] In certain embodiments, the present invention is directed to methods of treating hypertension comprising administering to a patient in need thereof a dosage form comprising ramipril alone, wherein the dosage form is administered at least twice daily and is at least as effective and in some cases more effective than the administration of an equivalent amount of ramipril once daily. In certain embodiments, the dosage form includes 10 mg of ramipril in the form of a tablet and is administered twice-a-day. The present invention also includes, methods of treating hypertension comprising orally administering to a patient in need thereof a twice daily dosage form comprising ramipril, wherein the twice daily dosage form of ramipril is at least as effective in lowering the sitting systolic or diastolic or both the sitting systolic and diastolic blood pressure when compared to a once-a-day dosage forms having an equivalent amount of ramipril.

[0126] In still other embodiments the present invention includes methods of treating hypertension in a patient in need thereof comprising administering to a patient diagnosed with hypertension or diagnosed to be at risk for hypertension a daily oral dose of no more than 20 mg of ramipril. The 20 mg of ramipril can be administered in one dose or, alternatively, in more than one dose, so that no more than 20 mg of ramipril is administered to the patient. For example, the daily dose of 20 mg of ramipril can be administered to the patient in two doses over a period of 24 hours.

[0127] In certain embodiments, the total daily dose of 20 mg of ramipril is administered to the patient in multiple doses over a period of 24 hours. The daily dose of 20 mg of ramipril can be administered in one, two, three, four, five, six, seven or eight times a day. Alternatively, a dose of ramipril can be administered hourly or every 2, 4, 6, 8 or 12 hours until the daily dose of 20 mg of ramipril has been administered. [0128] The dosage form of ramipril can be administered as a tablet, capsule or caplet and such dosage forms can contain 1.25 mg, 2.5 mg, 5 mg, 10 mg or 20 mg of ramipril. For example, if the dosage form is a tablet such tablets can contain 1.25 mg, 2.5 mg, 5 mg, 10 mg or 20 mg of ramipril.

[0129] In other embodiments, the present invention is directed to methods of treating hypertension comprising administering to a patient in need thereof a tablet comprising ramipril. In certain embodiments, the tablet includes 10 mg of ramipril and is administered twice-a-day. In other embodiments, the tablet includes 20 mg of ramipril and is administered once-a-day. The present invention also includes, methods of treating hypertension comprising orally administering to a patient in need thereof a twice daily tablet comprising ramipril, wherein the twice daily tablet of ramipril is at least as effective in lowering the systolic or diastolic or both the systolic and diastolic blood pressure when compared to a once-a-day dosage form having an equivalent amount of ramipril.

[0130) In certain embodiments the present invention includes methods of reducing blood pressure in a patient. Such methods include orally administering to a patient in need thereof at least twice daily a tablet comprising ramipril or a pharmaceutically acceptable salt, wherein the reduction in blood pressure of the patient is greater than the reduction of blood pressure in the patient if the patient is administered a once daily dosage form with the equivalent amount of ramipril. For example, the present invention includes methods of reducing the sitting systolic blood pressure of an individual who has a sitting systolic blood pressure between about 140 and 180 mm Hg by orally administering to the individual at least 10 mg of ramipril at least twice daily and methods of reducing the sitting diastolic blood pressure of an individual who has a sitting diastolic blood pressure between about 100 and 115 mm Hg by orally administering to the individual at least 10 mg of ramipril at least twice a day.

[0131] In certain embodiments the present invention is directed to methods of treating hypertension in a patient in need thereof comprising administering to a patient diagnosed with hypertension or diagnosed to be at risk for hypertension a daily oral dose of 20 mg of ramipril, wherein the oral dose is administered in the from of at least two tablets, each tablet comprising 10 mg of ramipril. For example, the present invention includes methods of treating hypertension in a female in need thereof by administering to the female at least 10 mg of ramipril at least twice a day and methods of treating hypertension in a patient in need thereof, wherein the patient is 65 years or older by orally administering to the patient at least 10 mg of ramipril at least twice a day.

[0132] In still other embodiments the present invention includes methods of treating hypertension comprising orally administering to a patient in need thereof at least twice daily a tablet comprising ramipril or a pharmaceutically acceptable salt, wherein the at least twice daily administration of the tablet is more effective in lowering blood pressure as a once daily dosage form having an equivalent amount of ramipril. The present invention also includes methods for the treatment of hypertension comprising administering twice daily to a patient in need thereof a tablet comprising ramipril, wherein the increase in ambulatory trough blood pressure is less than the increase in ambulatory trough blood pressure when the patient is administered a once daily dosage form with the equivalent amount of ramipril. [0133] In still other embodiments of the present includes methods of improving the efficacy and/or bioavailability of ramipril in certain patient populations. Patient populations include individuals who have been diagnosed with hypertension or who have been diagnosed with the risk of developing hypertension, females, individuals 65 years of age or older, individuals of non- African descent, naive individuals and non-naϊve individuals. In certain embodiments, the present invention is directed to methods of improving the efficacy and/or bioavailability of ramipril in females, individuals 65 years of age or older, individuals of non- African descent, naive individuals and non-naϊve individuals by administering to such individuals at least 10 mg of ramipril at least twice a day. Additionally, such females, individuals 65 years of age or older, individuals of non- African descent, naϊve individuals and non-naϊve individuals can be diagnosed with hypertension or be diagnosed to be at risk of developing hypertension.

[0134] In still other embodiments, the present invention includes methods of lowering the 24-hour mean systolic and diastolic of an individual who has been diagnosed with hypertension or who is at risk of being diagnosed with hypertension by administering to the individual a once-a-day dose of 20 mg of ramipril. The once-a-day dose of 20 mg of ramipril can be in the form of a tablet. It should be noted that the 24-hour mean systolic and diastolic blood pressure can be measured using a 24-hour ambulatory blood pressure monitor.

6.4 Excipients

[0135] The pharmaceutical compositions described herein can also include at least one pharmaceutically acceptable excipient. Suitable are described in the paragraphs below. [0136] The blending agent in each of the compositions of the invention can be any substance suitable for pre-blending and co-milling, which stabilizes the drug and significantly reduces the degradation of the drug. The phrase "blending agent" is interchangeable with "blending compound". Preferably, the blending agent can coat the ramipril and reduce the degradation rate.

[0137] Blending agents contemplated by the present invention include polymers, starches, stearates, silicas, waxes (atomized glyceryl palmitostearate, dioctyl sodium sulphosuccinate), surfactants, and fatty acids (preferably having a chain length of eight carbons or greater which may contain one or more double bonds). For example, blending agents suitable for the present invention include, but are not limited to, include long chain fatty acid-containing glycerol esters. Blending agents include, but are not limited to, glyceryl behenate, glyceryl stearate, stearyl alcohol, magnesium stearate, macrogol stearate ether, palmitosearate, ethylene glycol, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumerate, leucine, stearic acid, cetyl alcohol, lauryl alcohol, amylopectin, poloxymer or combinations thereof. Most preferably, the blending agent is glyceryl behenate.

[0138] The blending agent can be present from at least about 0.1 wt% or from at least about 0.1 wt% and above by weight of the total composition. In a specific embodiment, the blending agent is present at about 0.5 wt. % and above or 0.5 wt. % and above. In another specific embodiment, the blending agent is present at about 1.0 wt. % and above or 1.0 wt. % and above. In another specific embodiment, the blending agent is present at about 2.0 wt. % and above or 2.0 wt. % and above. In a specific and preferred embodiment, the blending agent is present at about 3.0 wt. % and above or 3.0 wt. % and above. In another specific embodiment, the blending agent is present at about 4 wt. % and above (e.g., 5 and 10 wt.%). [0139] Additionally, the blending agent can be present in a ratio of about 1 : 10 to about 10:1 or in a ratio of 1 : 10 to 10: 1 of the drug. The blending agent can be present in a ratio of about 1 :5 to about 5:1 or in a ratio of 1 :5 to 5: 1 or about 1 :2 or 2:1 or in a ratio of 1 :2 to 2:1 of the drug.

[0140] In yet another embodiment, the pharmaceutical compositions of the present invention comprise ramipril and a blending agent in combination with at least one other active agent, wherein ramipril is coated by the blending agent. In certain embodiments ramipril can be substantially coated by the blending agent. The ramipril is substantially coated when the blending agent coats ramipril wherein ramipril has a low or no rate of degradation. For example, the ramipril can be between about 50% to 100% or between 50% to 100% coated by the blending agent. Preferably, the ramipril is between about 75% to 100% or between 75% to 100% coated by the blending agent or more preferably between about 85% to 100% or between 85% to 100% coated by the blending agent. Most preferably, the ramipril is between about 95% to 100% or between 95% to 100% coated by the blending agent.

[0141] Pharmaceutical compositions of the present invention may also include pharmaceutically acceptable additives into any suitable type of unit dosage form. Suitable additives include, but are not limited to, diluents, binders, vehicles, carriers, excipients, binders, disintegrating agents, lubricants, swelling agents, solubilizing agents, wicking agents, cooling agents, preservatives, stabilizers, sweeteners, flavors, polymers etc. While any pharmaceutically acceptable additive is contemplated by the present invention, it should be understood that the additive(s) selected for compounding with coated ramipril particles should not defeat the stability objectives of the present invention. Even though some pharmaceutically acceptable additives may cause ramipril to degrade, such additives may be suitable for the present invention so long as such additives do not cause ramipril, as it is combined with a blending agent, to degrade. Moreover, in certain preferred embodiments, such additives also will not affect the bioavailability of the other active agent formulated in combination with ramipril.

[0142] Examples of excipients include, but are not limited to, acacia, alginic acid, croscarmellose, gelatin, gelatin hydrosylate, mannitol, plasdone, sodium starch glycolate, sorbitol, sucrose, and xylitol. For molded or compressed tablet formulations, suitable excipients that may be used include amorphous lactose, beta lactose, microcrystalline cellulose, croscarmellose sodium, dicalcium phosphate, carboxymethyl cellulose, hydroxypropyl cellulose, polyethylene gylcols, sodium lauryl sulfate, and the like. [0143] Examples of additional stabilizers or preservatives include, but are not limited to, parahydroxybenzoic acid alkyl esters, antioxidants, antifungal agents, and other stabilizers/preservatives known in the art.

[0144] Examples of coloring agents include, but are not limited to, water soluble dyes, Aluminum Lake, ion oxide, natural colors, titanium oxide, red ferric oxide, yellow ferric oxide and the like.

[0145] Examples of diluents or fillers include, but are not limited to, water-soluble and/or water-insoluble tabletting fillers. The water-soluble diluent agent may be constituted from a polyol of less than 13 carbon atoms, in the form of directly compressible material (the mean particle size being between about 100 and about 500 microns or between 100 and 500 microns), in the form of a powder (the mean particle size being less than about 100 microns or less than 100 microns) or a mixture thereof. The polyol is preferably chosen from the group comprising of mannitol, xylitol, sorbitol and maltitol. The water-insoluble diluent agent may be a cellulosic derivative, such as, microcrystalline cellulose or a starch, such as, pregelatinized starch. Especially preferred diluents are those with minimal moisture content, such as lactose monohydrate and magnesium oxide. [0146] Examples of disintegrating agents include, but are not limited to, cross-linked sodium carboxymethylcellulose, crospovidone and their mixtures. A part of the disintegrating agent may be used for the preparation of PPI, cholinergic agonist, parietal activator and/or antacid granules.

[0147] Examples of lubricating agents include, but are not limited to, magnesium stearate, stearic acid and its pharmaceutically acceptable alkali metal salts, sodium stearyl fumarate, Macrogol 6000, glyceryl behenate, talc, colloidal silicon dioxide, calcium stearate, sodium stearate, Cab-O-Sil, Syloid, sodium lauryl sulfate, sodium chloride, magnesium lauryl sulfate, talc and their mixtures. A portion of the lubricant may be used as an internal solid lubricant which is blended and granulated with other components of the granulation. Another portion of the lubricant may be added into the final blended material just before compression or encapsulation that coats the outside of the granules in the final blend. Lubricating agents and blending agents can comprise of the same material, e.g. glycerol behenate, however, as a lubricating agent the material does not act to stabilize the active agent. [0148] Examples of swelling agents include, but are not limited to, starches; polymers; cellulosic materials, such as, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose and ethyl cellulose; waxes such as bees wax; natural materials, such as, gums and gelatins; or mixtures of any of the above. [0149] Examples of polymers include, but are not limited to, polysaccharides, celluloses, and organic moieties such as polyvinyl pyrrolidines and plastics. [0150] Examples of celluloses include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxylpropyl-methylcellulose, hydroxyethylcellulose, ethylcellulose, cellulose acetate phthalate, cellulose acetate, polyvinyl acetate phthalate, polyvinylpyrrolidone, gelatin, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxylpropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimelllitate succinate, cellulose propionate trimellitate, cellulose butryrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid, cellulose acetate, ethyl picolinic acid cellulose acetate. [0151] Other polymers that may be suitable for use with the present invention include, but are not limited to, acrylate and methacrylate copolymers. Exemplary commercial grades of such copolymers include the EUDRAGIT® series, which are copolymers of methacrylates, acrylates, carboxylic acid-functionalized vinyl polymers, such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates, amine-functionalized polyacrylates and polymethacrylates; proteins such as gelatin and albumin, and carboxylic acid functionalized starches such as starch glycolate, carboxylic acid functionalized polymethyacrylates, carboxylic acid functionalized polyacrylate, amine-functionalized polyacrylates, amine-functionalized polymethacrylates, proteins, carboxylic acid functionalized starches, vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; polyethylene polyvinyl alcohol copolymers, polyoxyethylene- polyoxypropylene copolymers, alkylacyloxy-containing repeat units, or cyclicamido- containing repeat units; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed form; polyvinyl alcohol polyvinyl acetate copolymers; polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinyl pyrrolidone polyethylene polyvinyl alcohol copolymers, and polyoxyethylene-polyoxypropylene block copolymers. [0152] The flavoring maybe advantageously chosen to give a combination of fast onset and long-lasting sweet taste and get a "round feeling" in the mouth with different textures or additives. Cooling agents can also be added in order to improve the mouth feeling and provide a synergy with flavors and sweetness. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both.

[0153] Additional illustrations of adjuvants which may be incorporated in the tablets include, but are not limited to, a binder such as gum tragacanth (arabic), acacia, corn starch, potato starch, alginic acid, povidone, acacia, alginic acid, ethylcellulose, methylcellulose, microcrystalline cellulose, a derivatized cellulose, such as carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, dextrin, gelatin, glucose, guar gum, hydrogenated vegetable oil, type I, polyethylene glycol, lactose, lactose monohydrate, compressible sugars, sorbitol, mannitol, dicalcium phosphate dihydrate, tricalcium phosphate, calcium sulfate dihydrate, maltodextrins, lactitol, magnesium carbonate, xylitol, magnesium aluminum silicate, maltodextrin, methylcellulose, hydroxypropylcellulose, polyethylene, polyethylene oxide, polymethacrylates, plasdone, sodium alginate, starch, pregelatinized starch, zein or the like; a sweetening agent such as sucrose, potassium acesulfame, aspartame, lactose, dihydrochalcone neohesperidine, saccharin, sucralose, polyols such as xylitol, mannitol, and maltitol, sodium saccharide, Asulfame-K, Neotame®, glycyrrhizin, malt syrup and combinations thereof; a flavoring such as berry, orange, peppermint, oil of wintergreen, cherry, citric acid, tartaric acid, menthol, lemon oil, citrus flavor, common salt, and other flavors known in the art.

[0154] In certain embodiments of the present invention, the dosage forms of the present invention can include ramipril; hydrochlorothiazide; fillers such as hypromellose, calcium sulfate dehydrate, pregelatinized starch, microcrystalline cellulose or a combination thereof; blending agents or lubricating agents such as, sodium stearyl fumarate, sodium hydrogen carbonate; and coloring agents such as red ferric oxide and yellow ferric oxide or a combination thereof. It is apparent to one of ordinary skill in the art that any of the previously mentioned excipients can be replaced with another excipient. [0155] In certain embodiments, the tablets of the present invention can contain about

1.4-2.5% of ramipril, about 8.5-10.5% of hydrochlorothiazide, about 65-75% of calcium sulfate dehydrate, about 1.0-2.5% of sodium hydrogen carbonate, about 12-18% of pregelatinized starch and about 0.5-1.5% sodium stearyl fumarate by weight. For example, a tablet in accordance with the present invention can include ramipril (1.9% w/w), hydrochlorothiazide (9.6% w/w), pregelatinized starch (15.0% w/w), sodium stearyl fumarate (1.0% w/w), calcium sulfate dehydrate (Compactrol)(70.5% w/w) and sodium hydrogen carbonate (1.9% w/w).

6.5 Administration

[0156] Pharmaceutical compositions of the present invention can be administered orally or internally to subjects. This can be accomplished, for example, by administering to the subject a solid or liquid oral dosage form by mouth or via a gastric feeding tube, a duodenal feeding tube, a nasogastric (ng) tube, a gastrostomy, or other indwelling tubes placed in the GI tract. Other forms of the drug may be in suppositories, suspensions, liquids, powders, creams, transdermal patches, and depots.

[0157] Oral pharmaceutical compositions of the present invention are generally in the form of individualized or multi unit doses, such as tablets, caplets, powders, suspension tablets, chewable tablets, rapid melt tablets, capsules, e.g., a single or double shell gelatin capsule, tablet-filled capsules, effervescent powders, effervescent tablets, pellets, granules, liquids, solutions, or suspensions, respectively. Suitable tablets include, but are not limited to coated tablets, uncoated tablets, sustained release tablets, delayed release tablets, modified release tablets or immediate release tablets. In certain embodiments the tablets are designed to disintegrate in the stomach or intestine. In alternative embodiments the tablets are orally disintegrating tablets (ODT).

[0158] While the present invention contemplates any solid dosage form suitable for oral administration, ramipril tablets, capsules, tablet-filled capsules and caplets are especially preferred. When the pharmaceutical compositions of the present invention are formed into tablets or caplets, it is to be understood that the tablets or caplets may be scored, and that they may be of any suitable shape and size, such as round, square, rectangular, oval, diamond, pentagon, hexagon or triangular, so long as the objectives of the present invention are not defeated. It is to be further understood that when tablet-filled capsules are selected, the tablets utilized therewith may be formed into shapes that either (a) correspond to the capsules to permit over-coating or encapsulation via the capsules or (b) readily fit inside the capsules. [0159] The oral pharmaceutical compositions may contain a drug in any therapeutically effective amount, such as from about 0.001 mg or from 0.001 mg or less to about 200 mg or less than 200 mg or more, or preferably from about 0.01 mg to about 100 mg or from 0.01 mg to 100 mg or preferably from about 0.1 mg to about 50 mg or from 0.1 mg to 50 mg. Preferably, the dosage range will be between about 1.25 mg to about 25 mg per patient per day or 1.25 mg to 25 mg per patient per day; more preferably about 10 mg to about 20 mg per patient per day or 10 mg to 20 mg per patient per day, and most preferably about 10 mg or 20 mg per day or 10 mg or 20 mg per day.

[0160] By way of example, a particularly preferred stabilized oral unit dose or composition of the present invention may contain ramipril in a dosage amount of about 1.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, 12.5 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg or 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, or 100 mg. Of course, it should be appreciated that a particular unit dosage form and amount can be selected to accommodate the desired frequency of administration used to achieve a specified daily dosage and therapeutic effect.

[0161] Of particular interest are oral dosage forms that comprise stabilized ramipril having 1.25, 2.5, 5, 10, 15 and 20 mg ramipril per unit dosage form. Such dosage forms can be tablets, caplets, capsules or tablet-filled capsules.

[0162] Of particular interest are oral dosage forms that comprise stabilized ramipril and chlorthalidone having 6.5, 12.5, and 25 mg chlorthalidone per unit dosage form. [0163] Of particular interest are oral dosage forms that comprise stabilized ramipril and hydrochlorothiazide having 6.5, 12.5 and 25 mg hydrochlorothiazide per unit dosage form.

[0164] In certain embodiments the dosage forms of the present invention, such as a tablet can include 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide, 5 mg of ramipril and 12.5 mg of hydrochlorothiazide, 5 mg of ramipril and 25 mg of hydrochlorothiazide, 10 mg of ramipril and 12.5 mg of hydrochlorothiazide, 10 mg of ramipril and 25 mg of hydrochlorothiazide and 20 mg of ramipril and 25 mg of hydrochlorothiazide. [0165] Consistent with the present invention, the dosage forms of the instant invention may be administered to individuals on a regimen of one, two or more doses per day, at any time of the day. For example the present invention also includes dosing regimens wherein a total daily dose of a therapeutically effective amount of ramipril is administered to a patient in multiple daily doses such that the administration of multiple daily dosages of ramipril is more effective than a single daily dose containing an equivalent amount of ramipril. Ramipril can be administered a twice a day, or more than twice a day in any of the dosage forms discussed above.

[0166] For example, a dosage form with 10 mg of ramipril can be administered to an individual twice daily for a total daily dose of 20 mg of ramipril. Alternatively, a dosage form with 5 mg of ramipril can be administered to an individual four times a day for a total daily dose of 20 mg of ramipril, or a dosage form with 2.5 mg of ramipril can be administered to an individual eight times a for a total daily dose of 20 mg of ramipril. In other embodiments, the total daily dose of ramipril can be higher or lower than 20 mg and the multiple daily doses of ramipril can be administered to accommodate the desired total daily dose of ramipril.

[0167] The dosage of active ingredient, such as ramipril or ramipril in combination with another active agent, in the compositions of the invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets being followed by a patient, concurrent medication, and other factors, recognized by those skilled in the art. Based upon the foregoing, precise dosages depend on the condition of the patient and are determined by discretion of a skilled clinician. Generally, ramipril daily dosage levels of between about 0.010 to about 1.5 mg/kg or 0.010 to 1.5 mg/kg of body weight are administered daily to mammalian patients, e.g., humans having a body weight of about 70 kg. The ramipril dosage range will generally be about 1.25 mg to 50 mg or 1.25 mg to 50 mg per patient per day, administered in single or multiple doses.

[0168] Nonetheless, it should be understood that safe and effective amounts of ramipril and the other active agents utilized in accordance with the present invention will vary with the particular cardiovascular disorder, conditions and/or symptoms being treated, the age, weight and physical conditions of the subjects being treated, the severity of the cardiovascular disorder, conditions and/or symptoms, the duration of treatments, the nature of concurrent therapies, the specific dosage form employed, the particular pharmaceutically acceptable carriers utilized, and like factors within the knowledge and expertise of the attending physicians. Exemplary safe and effective amounts of ramipril include those amounts mentioned herein, administered one or more times per day, as will be more fully describe herein below. Exemplary safe and effective amounts of other active agents such as chlorthalidone or hydrochlorothiazide and other diuretics, or of calcium channel blockers and beta blockers are readily apparent to those skilled in the art and can be found in sources such as the Physician's Desk Reference, 59^th Edition (2005). 6.6 Methods of Making

[0169] The present invention is also generally directed towards methods of making pharmaceutical compositions with improved stability, bioavailability and shelf-life. The following methods of making pharmaceutical compositions in accordance with the present can be used with any drug. Specifically, the methods of the present invention are directed to making pharmaceutical compositions comprising any drug that is susceptible to degradation when exposed to the environment or exposed to physical stresses during the manufacturing process.

[0170] The pharmaceutical compositions of the present invention can be made by first combining a drug with a blending agent so that the drug is coated with a blending agent before being processed into tablets. Combining the drug with the blending agent can be accomplished by blending, mixing, milling or co-milling, compressing, granulating, suspending, dissolving or precipitating the drug and the blending agent together. [0171] Preferably, the combined drug and blending agent is suitable for use in preparing dosage forms by processes including, but not limited to, dry blend, direct compression formulations and hot melt extrusion processes.

[0172] Preferably, the methods of the present invention comprise an ACE inhibitor and more preferably, ramipril.

[0173] Methods of the present invention comprise combining ramipril with a blending agent. Such methods can also further comprise adding an additive such as, but not limited to, a polymer, diluent, disintegrant or a combination thereof, before or after the ramipril is combined with the blending agent. Combining ramipril with the blending agent can be accomplished by blending, mixing, milling or co-milling, compressing, granulating, suspending, dissolving or precipitating the drug and the blending agent together. [0174] In various embodiments, the invention contemplates methods comprising combining a blending agent and ramipril before the ramipril is further processed with at least one other active agent and other excipients into a dosage form. Preferably, the blending agent and ramipril are pre-blended or co-milled before the ramipril is further processed into the formulations of the instant invention. The invention also contemplates methods that further comprise adding additives including, but not limited to, diluents, binders, vehicles, carriers, excipients, binders, disintegrating agents, lubricants, swelling agents, solubilizing agents, wicking agents, cooling agents, preservatives, stabilizers, sweeteners, flavors, polymers, to the pre-blended or co-milled ramipril and blending agent. [0175] In preferred embodiments methods of the present invention comprise first pre- blending and or co-milling ramipril with a blending agent. Such methods can also further include additional steps comprising combining the pre-blended ramipril and blending agent along with a polymer, diluent, disintegrant or a combination thereof. Further, the methods will comprise the additional step of adding at least one other active agent to the co-milled or pre-blended ramipril. In alternate embodiments, the methods comprise co-milling and/or pre- blending ramipril and at least one other active agent with the blending agent prior to further formulation of ramipril and the other active agent into a dosage form.

[0176] In other preferred embodiments the methods of the present invention comprise pre-blending ramipril with a blending agent and then co-milling the ramipril and the blending agent. Such methods can also further include additional steps comprising combining the co- milled ramipril and blending agent along with a polymer, diluent, disintegrant or a combination thereof. Further, the methods will comprise the additional step of adding at least one other active agent to the co-milled or pre-blended ramipril. In alternate embodiments, the methods comprise co-milling or pre-blending ramipril and at least one other active agent with the blending agent prior to further formulation of ramipril and the other active agent into a dosage form.

[0177] In other embodiments the methods of the present invention comprises blending ramipril with a blending agent; co-milling the ramipril and the blending agent and then re-blending the ramipril with the blending agent. Such methods can also further include additional steps comprising combining the ramipril and blending agent along with a polymer, diluent, disintegrant or a combination thereof. Further, the methods will comprise the additional step of adding at least one other active agent to the co-milled or pre-blended ramipril. In alternate embodiments, the methods comprise co-milling or pre-blending ramipril and at least one other active agent with the blending agent prior to further formulation of ramipril and the other active agent into a dosage form. [0178] In yet other embodiments, the method of the present invention comprises blending ramipril with a polymer and co-milling the ramipril and polymer with a blending agent. Such methods can also further include additional steps comprising combining the ramipril with a second polymer, diluent, disintegrant or a combination thereof, before or after being co-milled with the blending agent. Further, the methods will comprise the additional step of adding at least one other active agent to the co-milled or pre-blended ramipril. In alternate embodiments, the methods comprise co-milling or pre-blending ramipril and at least one other active agent with the blending agent prior to further formulation of ramipril and the other active agent into a dosage form.

[0179] In one embodiment the method of making solid oral ramipril pharmaceutical compositions comprises blending coated ramipril with a blending agent; co-milling the coated ramipril and the blending agent; and re-blending the coated ramipril with a blending agent. Additionally, a polymer, a diluent, a lubricant or a disintegrant can be combined with the ramipril before or after being milled. Further, the methods will comprise the additional step of adding at least one other active agent to the co-milled or pre-blended ramipril. In alternate embodiments, the methods comprise co-milling or pre-blending ramipril and at least one other active agent with the blending agent prior to further formulation of ramipril and the other active agent into a dosage form.

[0180] In the above methods, one purpose of the pre-blending and co-milling the blending agent and ramipril before the ramipril is further processed into tablets is to facilitate coating the ramipril with the blending agent. In all of the above methods the blending agent coats the ramipril. Preferably the blending agent coats between about 50% to 100% of the ramipril, or between about 75% to 100% or 50% to 100% of the ramipril, or between about 85% to about 100% or 85% to 100% and most preferably between about 95% to 100% or 95% to 100% . Also in all of the above methods the preferred blending agent is glyceryl behenate

[0181] In a particularly preferred embodiment, ramipril and glyceryl behenate are first co-milled, then followed by additional steps wherein, sodium stearyl fumarate and croscarmellose sodium are added to the ramipril and glyceryl behenate blend. Further, the methods will comprise the additional step of adding at least one other active agent to the co- milled or pre-blended ramipril. In alternate embodiments, the methods comprise co-milling or pre-blending ramipril and at least one other active agent with the blending agent prior to further formulation of ramipril and the other active agent into a dosage form.

[0182] Figure 1 shows one method of making pharmaceuticals of the present invention comprising GECoated ramipril. GEcoated ramipril is pre-milled though a 60-mesh screen. The milled ramipril is then pre-blended with glyceryl behenate for 15 minutes in a blender that has been grounded to reduce electrostatic charges. Croscarmellose sodium, sodium stearyl fumerate and silicified microcrystalline cellulose are added to the mixture and mixed for another 20 minutes. The co-milled mixture is then passed through a 20-mesh sieve. The sieved mixture is then placed into blender and mixed for an additional 8 minutes.

The mixture is then compressed with a tablet press. The tablets finished tablets then can be packaged.

[0183] This process can be scaled, for example, to about 6 kg, in a 16-quart V-shell

PK blender, and larger as needed. Tablets can be produced with a Fette P 1200 24-station press, or similar equipment.

[0184] In the alternative, pharmaceutical compositions made by the above process can be formulated with uncoated ramipril as well. Also, microcrystalline cellulose can be replaced with diluents and fillers including but not limited to Ceolus®, lactose, anhydrous lactose, lactose monohydrate, starch, spray-dried mannitol (Pearlitol 200 SD), Prosolv®

SMCC 90, or a combination thereof. Also, glyceryl behenate can be replaced with magnesium stearate.

[0185] The method, as shown in Figure 1, can be used with any type of ramipril.

Also, the mixing times and other parameters of the process can be varied to achieve the pharmaceutical compositions of the present invention comprising ramipril, wherein the ramipril has a low rate of degradation compared to current formulations.

[0186] An article of manufacture, as contemplated by the present invention, comprises a container holding a pharmaceutical composition suitable for oral administration of stabilized ramipril in combination with at least one other active agent along with printed labeling instructions providing a discussion of when a particular dosage form should be administered.

[0187] The composition will be contained in any suitable container capable of holding and dispensing the dosage form and which will not significantly interact with the composition and will further be in physical relation with the appropriate labeling advising that a dosage form is more stable and/or bioavailable with extended shelf life.

[0188] The labeling instructions will be consistent with the methods of treatment as described hereinbefore. The labeling may be associated with the container by any means that maintain a physical proximity of the two, by way of non-limiting example, they may both be contained in a packaging material such as a box or plastic shrink wrap or may be associated with the instructions being bonded to the container such as with glue that does not obscure the labeling instructions or other bonding or holding means.

[0189] The compositions, of the present invention, comprising ramipril in combination with at least one other active agent, can be administered to a subject for the treatment of cardiovascular disorders. Cardiovascular disorders include but are not limited to, hypertension, heart failure, congestive heart failure, myocardial infarction, atherosclerotic cardiovascular disease, asymptomatic left ventricular dysfunction, chronic renal insufficiency, and diabetic or hypertensive nephropathy.

[0190] An embodiment of the subject invention is a pharmaceutical composition comprising ramipril, another active agent, and a blending agent, wherein the ramipril is coated by the blending agent, and wherein the blending agent is selected from glyceryl behenate, glyceryl stearate, stearyl alcohol, macrogol stearate ether, palmitostearate, ethylene glycol, polyethylene glycol, stearic acid, cetyl alcohol, lauryl alcohol, amylopectin, poloxymer or combinations thereof.

[0191] In another embodiment of the subject invention, the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

[0192] In another embodiment of the subject invention, the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

[0193] In another embodiment of the subject invention, the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

[0194] Another embodiment of the subject invention is a pharmaceutical composition comprising ramipril, another active agent, and a blending agent, wherein the ramipril is coated by a blending agent and wherein the rate of decomposition of the ramipril to ramipril- diketopiperazine is less than about 0.4% of the total weight of ramipril during the first 3 months when the pharmaceutical composition is at room temperature.

[0195] In another embodiment of the subject invention, the rate of decomposition is about 0.4%.

[0196] Another embodiment of the subject invention is a pharmaceutical composition comprising ramipril, another active agent, and a blending agent, wherein the ramipril is coated by a blending agent and wherein the rate of decomposition of the ramipril to ramipril- diketopiperazine is less than about 1.0 % of the total weight of ramipril during the first 6 months when the pharmaceutical composition is at room temperature and 60% relative humidity.

[0197] In another embodiment of the subject invention, the rate of decomposition is about 0.75%.

[0198] Another embodiment of the subject invention is a pharmaceutical composition comprising ramipril, another active agent, and a blending agent, wherein the ramipril is coated by a blending agent and wherein the rate of decomposition of the ramipril to ramipril- diketopiperazine is less than about 3.0% of the total weight of ramipril during the first 36 months when the pharmaceutical composition is at room temperature.

[0199] In another embodiment of the subject invention, the rate of decomposition is about 2.0%.

[0200] In another embodiment of the subject invention, the rate of decomposition is about 1.5%.

[0201] Another embodiment of the subject invention is a pharmaceutical composition comprising ramipril, another active agent, and a blending agent, wherein the ramipril is coated by a blending agent and wherein the rate of decomposition of the ramipril to ramipril- diketopiperazine is less than about 0.15%, on average, of the total weight of ramipril per month when the pharmaceutical compositions are at room temperature.

[0202] In another embodiment of the subject invention, the rate of decomposition is about 0.09% or less.

[0203] In another embodiment of the subject invention, the blending agent is glyceryl behenate.

[0204] In another embodiment of the subject invention, about 50 to 100% of the ramipril is coated by the blending agent. [0205] In another embodiment of the subject invention, about 75 to 100% of the ramipril is coated by the blending agent.

[0206] In another embodiment of the subject invention, about 95 to 100% of the ramipril is coated by the blending agent.

[0207] In another embodiment of the subject invention, the blending agent is at least

0.1 % by weight.

[0208] In another embodiment of the subject invention, the blending agent is at least 1

% by weight.

[0209] In another embodiment of the subject invention, the blending agent is at least 4

% by weight.

[0210] In another embodiment of the subject invention, the ramipril is substantially stable against decomposition into a degradant product.

[0211] In another embodiment of the subject invention, the degradant product is ramipril-diacid or ramipril-diketopiperazine.

[0212] In another embodiment of the subject invention, the ramipril is coated ramipril.

[0213] In another embodiment of the subject invention, the composition is a solid dosage form.

[0214] In another embodiment of the subject invention, the composition is an oral dosage form.

[0215] In another embodiment of the subject invention, the composition is a tablet, caplet or capsule.

[0216] In another embodiment of the subject invention, the composition is a tablet.

[0217] In another embodiment of the subject invention, the composition further comprises an excipient.

[0218] In another embodiment of the subject invention, the ramipril is in the amount of about 0.1 mg to 50 mg.

[0219] In another embodiment of the subject invention, the ramipril is in the amount of about 1 mg to 30 mg.

[0220] In another embodiment of the subject invention, the ramipril is in the amount of about 2.5 mg. [0221] In another embodiment of the subject invention, the ramipril is in the amount of about 5 mg.

[0222] In another embodiment of the subject invention, the ramipril is in the amount of about 10 mg.

[0223] In another embodiment of the subject invention, the ramipril is in the amount of about 15 mg.

[0224] In another embodiment of the subject invention, the ramipril is in the amount of about 20 mg.

[0225] In another embodiment of the subject invention, the active agent is a diuretic, an angiotensin receptor blocker, an ACE inhibitor, a cholesterol lowering drug, a calcium channel blocker, a beta blocker, a glucose lowering agent, or oral hypoglycemics.

[0226] In another embodiment of the subject invention, the active agent is a diuretic.

[0227] In another embodiment of the subject invention, the diuretic is chlorthalidone.

[0228] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 0.1 mg to 50 mg.

[0229] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 1 mg to 30 mg.

[0230] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 6.5 mg.

[0231] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 12.5 mg.

[0232] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 25 mg.

[0233] In another embodiment of the subject invention, the diuretic is hydrochlorothiazide .

[0234] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 0.1 mg to 50 mg.

[0235] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 1 mg to 30 mg.

[0236] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 6.5 mg. [0237] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 12.5 mg.

[0238] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 25 mg.

[0239] Another embodiment of the subject invention is a method of making a pharmaceutical composition comprising coating ramipril with a blending agent, wherein the pharmaceutical composition further comprises another active agent.

[0240] Another embodiment of the subject invention is a method of making a pharmaceutical composition comprising: a) pre-blending milled ramipril with a blending agent; and b) combining the product of step a) with another active agent, wherein the blending agent is glyceryl behenate, glyceryl stearate, stearyl alcohol, macrogol stearate ether, palmitostearate, ethylene glycol, polyethylene glycol, stearic acid, cetyl alcohol, lauryl alcohol, amylopectin, poloxymer or combinations thereof.

[0241] Another embodiment of the subject invention is a method of making a pharmaceutical composition comprising: a) pre-blending and co-milling ramipril with a blending agent; and b) combining the product of step a) with another active agent, wherein the blending agent is glyceryl behenate, glyceryl stearate, stearyl alcohol, macrogol stearate ether, palmitostearate, ethylene glycol, polyethylene glycol, stearic acid, cetyl alcohol, lauryl alcohol, amylopectin, poloxymer or combinations thereof.

[0242] In another embodiment of the subject invention, the method of making a pharmaceutical composition further comprising blending the ramipril with the blending agent before the ramipril and blending agent are co-milled.

[0243] In another embodiment of the subject invention, the method of making a pharmaceutical composition further comprising blending the ramipril with the blending agent after the ramipril and blending agent are co-milled.

[0244] In another embodiment of the subject invention, the method of making a pharmaceutical composition further comprising adding a diluent, lubricant, disintegrant or a combination thereof. [0245] In another embodiment of the subject invention, the method of making a pharmaceutical composition further comprising compressing the product of step b) into tablets.

[0246] In another embodiment of the subject invention, the blending agent is glyceryl behenate.

[0247] In another embodiment of the subject invention, the blending agent is at least

0.1 % by weight.

[0248] In another embodiment of the subject invention, the blending agent is at least 1

% by weight.

[0249] In another embodiment of the subject invention, the blending agent is at least 4

% by weight.

[0250] In another embodiment of the subject invention, the ramipril is coated ramipril.

[0251] In another embodiment of the subject invention, the composition is a solid dosage form.

[0252] In another embodiment of the subject invention, the composition is an oral dosage form.

[0253] In another embodiment of the subject invention, the composition is a tablet, caplet or capsule.

[0254] In another embodiment of the subject invention, the composition is a tablet.

[0255] In another embodiment of the subject invention, the ramipril is in the amount of about 0. 1 mg to 50 mg.

[0256] In another embodiment of the subject invention, the ramipril is in the amount of about 1 mg to 30 mg.

[0257] In another embodiment of the subject invention, the ramipril is in the amount of about 2.5 mg.

[0258] In another embodiment of the subject invention, the ramipril is in the amount of about 5 mg.

[0259] In another embodiment of the subject invention, the ramipril is in the amount of about 10 mg.

[0260] In another embodiment of the subject invention, the ramipril is in the amount of about 15 mg. [0261] In another embodiment of the subject invention, the ramipril is in the amount of about 20 mg.

[0262] In another embodiment of the subject invention, the active agent is a diuretic, an angiotensin receptor blocker, an ACE inhibitor, a cholesterol lowering drug, a calcium channel blocker, a beta blocker, a glucose lowering agent, or oral hypoglycemics.

[0263] In another embodiment of the subject invention, the active agent is a diuretic.

[0264] In another embodiment of the subject invention, the diuretic is chlorthalidone.

[0265] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 0.1 mg to 50 mg.

[0266] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 1 mg to 30 mg.

[0267] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 6.25 mg.

[0268] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 12.5 mg.

[0269] In another embodiment of the subject invention, the chlorthalidone is in the amount of about 25 mg.

[0270] In another embodiment of the subject invention, the diuretic is hydrochlorothiazide.

[0271] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 0.1 mg to 50 mg.

[0272] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 1 mg to 30 mg.

[0273] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 6.5 mg.

[0274] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 12.5 mg.

[0275] In another embodiment of the subject invention, the hydrochlorothiazide is in the amount of about 25 mg.

[0276] In another embodiment of the subject invention, the method of making a pharmaceutical composition further comprising combining the produce of step b) with microcrystalline cellulose and croscarmellose sodium. [0277] In still another embodiment, the present invention includes methods of making a pharmaceutical dosage form such as a tablet that includes ramipril and hydrochlorothiazide, wherein glycerol behenate is used not as a blending agent to coat and stabilize ramipril but as a lubricating agent. In addition to glycerol behenate being used as a lubricating agent, other exicipients such as those discussed above can be used in the tablet. Such tablets can contain 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide, 5 mg of ramipril and 12.5 mg of hydrochlorothiazide, 5 mg of ramipril and 25 mg of hydrochlorothiazide, 10 mg of ramipril and 25 mg of hydrochlorothiazide or 20 mg of ramipril and 25 mg of hydrochlorothiazide. [0278] Another embodiment of the subject invention is a product made by the above methods.

[0279] Another embodiment of the subject invention is a method of treating cardiovascular disorders in a human comprising administering to the human an effective amount of any of the above compositions.

[0280] In another embodiment of the subject invention, the cardiovascular disorder is hypertension, heart failure, congestive heart failure, myocardial infarction, atherosclerotic cardiovascular disease, asymptomatic left ventricular dysfunction, chronic renal insufficiency, and diabetic or hypertensive nephropathy.

[0281] As shown in the examples below, the introduction of another active agent into the ramipril formulation of the present invention did not result in a significant change in the long term stability of ramipril in the formulation. This result was unexpected given the known stability problems associated with prior ramipril formulations. Moreover, it was also surprising that the diuretics formulated in combination with ramipril demonstrate the same stability or bioavailability as the current single agent formulations. [0282] The examples throughout herein and that follow are provided solely to illustrate representative embodiments of the invention. Accordingly, it should be understood, that the invention is not to be limited to the specific conditions or details described in these or any other example discussed herein, and that such examples are not to be construed as limiting the scope of the invention in any way. Throughout the specification, any and all references are specifically incorporated herein by reference in their entireties. 7.0 EXAMPLES

Example 1 - Methods of making combinations

[0283) The ramipril/chlorthalidone combination tablets were made by pre-blending the coated ramipril with glyceryl behenate, sodium stearyl fumarate and croscarmellose sodium in a 16-quart V-shell blender and blending for a suitable mount of time, then mill- blending the mixture through a Quadro Co-mil. Chlorthalidone was then added to the mixture with microcrystalline cellulose, sodium stearyl fumarate and croscarmellose sodium in a 16-quart container and mixed, then compressed on a Stokes B2 tablet press, tooled with 16 stations with ¹A" standard concave (about 100 mg tablet weight) or 5/16" standard concave (about 200 mg tablet weight) double-sided debossed tooling at about 48 rpm. [0284] Ramipril/hydrochlorthiazide combination tablets were made by pre-milling coated ramipril (ramipril coated with hydroxypropyl methylcellulose) through a 40 or 60 mesh screens and then pre-blended with a blending agent such as, glyceryl behenate. Hydrochlorthiazide, silicified microcrystalline cellulose and croscarmellose sodium were added and mixed for an additional period of time. The mixture was co-milled through a 20 mesh screen and blended. The mixture was compressed into tablets.

Example 2 - Combination of ramipril and chlorthalidone

[0285] This study was conducted as a single-dose, randomized, open-label, three-way crossover design in healthy male and female volunteers. Forty-five subjects (40% - 60% female) were enrolled in the study. Following a 14-day screening period, subjects underwent a two-stage randomization process for treatment group and sequence. Table 1 shows the treatments that were utilized.

Table 1. Summary of Treatment Groups

Treatment

Ramipril- Chlorthalidone Commercial Chlorthalidone

Treatment Chlorthalidone Tablet Tablet

Group N Tablet (chlorthalidone, USP)

I 15 4 x 2.5 mg/6.25 1 x 25 mg (B) 4 x 6.25 mg mg (A) (C)

II 15 2 x 10 mg/12.5 1 x 25 mg (E) 2 x 12.5 mg mg (D) (F)

III 15 1 x 20 mg/25 1 x 25 mg (H) 1 x 25 mg (I) mg (G) [0286] Subjects were randomized to Treatment Group I, II, or III and received three treatments (ramipril-chlorthalidone tablet, chlorthalidone commercial tablet, and chlorthalidone tablet) in random order. Treatments were separated by a 3 -week washout period.

[0287] During each period, on the evening before dosing, subjects were admitted to the clinical research unit (CRU) and underwent a supervised overnight fast for at least 10 hours before dosing. Study drug was administered with 240 mL (8 fluid ounces) of water. [0288] Serial blood sampling was performed at specified times pre- and post dose for quantitation of chlorthalidone in whole blood. Vital signs, 12-lead electrocardiogram (ECGs), clinical laboratory determinations, and adverse event (AE) assessments were done at specified times (Table 2). A final safety assessment was performed at the end of the last period. During each period, subjects were confined to the CRU for approximately 60 hours (3 nights and 2 days). The estimated time of participation in the study including Screening was 9 weeks.

Table 2. Overall Schedule of Time and Events

¹ Defined as 120 hours postdose during Period III.

² Vital signs (seated blood pressure and pulse rate) were determined at predose (time 0, within 1 hour of dosing) and at 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, and 120 hours postdose. Oral temperature was taken at check-in only.

³ Pharmacokinetic blood sampling was performed at predose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose. Serious adverse events were reported from the time written informed consent was obtained until completion of the end-of-study visit. Adverse events were reported for the time of administration of study drug through the end-of-study visit.

⁵ Serum chemistry: blood urea nitrogen (BUN), creatinine, total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, potassium, sodium, calcium, chloride, carbon dioxide, gamma glutamyl transferase, triglycerides, total cholesterol, and glucose. ⁶ Hematology: white blood cell (WBC) count with differential (%), red blood cell (RBC) count with indices, hemoglobin, hematocrit, and platelet count.

⁷ Urinalysis: dipstick for protein, glucose, ketones, bilirubin, and blood; if urine was positive for blood then a microscopic examination was performed.

⁸ Pregnancy test (females only): serum test at screening, check-in for Periods I, II, and III, and end-of-study.

[0289] The single-dose treatments administered in this study are listed in Table 3.

Table 3. Treatments Administered

Treatment Dose (mg)

Group Treatment Ramipril Chlorthalidone

I A: 4 x 2.5 mg/6.25 mg ramipril- 10 25 chlorthalidone tablets

B: 1 x 25 mg chlorthalidone 0 25 commercial tablet

C: 4 x 6.25 mg chlorthalidone tablets 0 25

II D: 2 x 10 mg/12.5 mg ramipril- 20 25 chlorthalidone tablets

E: 1 x 25 mg chlorthalidone 0 25 commercial tablet

F: 2 x 12.5 mg chlorthalidone tablets 0 25

III G: 1 x 20 mg/25 mg ramipril- 20 25 chlorthalidone tablet

H: 1 x 25 mg chlorthalidone 0 25 commercial tablet

I: 1 x 25 mg chlorthalidone tablet 0 25

[0290] Subjects were instructed to swallow the treatment whole and not to chew or crush it. The test products were administered as a single oral dose taken with 240 mL water. [0291] There were 3 kinds of test products used in this study:

Ramipril/chlorthalidone combination tablets manufactured by King Pharmaceuticals, Inc.: 2.5 mg/6.25 mg, 10 mg/12.5 mg, and 20 mg/25 mg.

Chlorthalidone commercial 25 mg tablets (chlorthalidone, USP,) manufactured by Mylan Pharmaceuticals, Inc.

Chlorthalidone tablets manufactured by King Pharmaceuticals, Inc.: 6.25 mg, 12.5 mg, and 25 mg.

[0292] The following noncompartmental pharmacokinetic parameters for chlorthalidone were calculated from the whole blood concentrations using WinNonlin Pro Version 4. Actual sample times were used in the calculations. Whole blood concentrations below the limit of quantitation (BLQ) prior to the first quantifiable concentrations were replaced with zero for the calculation of the pharmacokinetic parameters. Concentrations BLQ after the first quantifiable concentration were treated as missing. In this study, there were no BLQ values after the first quantifiable concentration; therefore, any values listed as missing in the concentration tables are true missing values.

AUCo._t The area under the whole blood concentration versus time curve, from time 0 to time t, where C_t is the last quantifiable concentration, as calculated by the linear trapezoidal method.

AUCo.j_nf The area under the whole blood concentration versus time curve, from time 0 to infinity, calculated as AUCo-_t + Q/K_ei, where K_eι is the terminal elimination rate constant.

Cm_ax Maximum (peak) observed whole blood concentration.

T_max Time of the maximum (peak) observed whole blood concentration.

K_ei Apparent terminal elimination rate constant, calculated from the linear regression of the terminal linear portion of the ln(concentration) versus time curve, where K is the absolute value of the slope.

Ti/₂ Apparent terminal elimination half-life, calculated as ln(2)/K_ei.

[0293] Linear regressions were performed using at least three data points. KeI was assigned if the terminal phase was apparent, if T_max was not one of the 3 last data points, and if the R² value (correlation of linear regression) was greater than 0.8.

[0294] Venous blood samples (5 mL) for the Pharmacokinetic studies were obtained from an indwelling catheter (heparin flush as needed) or by direct venipuncture. Blood samples were collected at predose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36,

48, 72, 96, and 120 hours postdose.

[0295] Whole blood concentrations of chlorthalidone were determined using a specific liquid chromatography/mass spectrometry/ mass spectrometry (LC/MS/MS) method.

The assay was validated with respect to accuracy, precision, linearity, sensitivity, and specificity.

[0296] Data from all subjects with an evaluable profile were included in the pharmacokinetic analysis. Of the 45 subjects enrolled in the study, only 2 subjects did not complete all 3 periods. Data from these 2 subjects were included in the pharmacokinetic summary statistics and in the statistical analysis of the treatment comparisons.

[0297] Of the 45 subjects enrolled in this study, 23 were female and 22 were male.

Regarding race, 37 subjects were Caucasian, 4 subjects were Hispanic, and 1 subject each was Asian, Black, European/Middle Eastern, and of "other" race. The mean age for all subjects was 25.8 years (range 19 - 48 years), the mean weight was 71.4 kilograms (range 55.8 - 94.3 kilograms), and the mean height was 174.3 centimeters (range 160.0 - 193.0 centimeters). Regarding body frame size, 5 subjects had a small frame, 33 subjects had a medium frame, and 7 subjects had a large frame.

[0298] Descriptive statistics including arithmetic mean, standard deviation (SD), coefficient of variation (C V%), standard error of the mean (SEM), number (N), minimum, maximum, and median were presented for whole blood chlorthalidone concentrations at each time point, and for all PK parameters by treatment. Additionally, geometric mean was presented for C_max, AUCo-t, and AUC_0- j_nf; and harmonic mean was presented for Ti/₂. [0299] To evaluate the chlorthalidone bioavailability, analyses of variance (ANOVA) were performed on the In-transformed C_max, AUCo-t, and AUCo-inf- The ANOVA model included terms for treatment, period, sequence, and subject within sequence. A separate ANOVA model was applied to the data from each of the three treatment groups. The bioavailability of chlorthalidone from the ramipril-chlorthalidone tablets was compared to that of the chlorthalidone commercial tablet, and to that of the chlorthalidone tablets. In addition, the bioavailability of chlorthalidone from the chlorthalidone tablets was compared to that of the chlorthalidone commercial tablet. For each comparison, the ratios of least- squares means (LSM) and the 90% confidence intervals (CI) were expressed as a percentage relative to the commercial chlorthalidone tablet, or chlorthalidone tablet. A conclusion of equivalent bioavailability was based on the mean ratios and whether the 90% CI for the In-transformed C_max, AUC_0-t, and AUC₀.j_nf were within the 80-125% range where the rate and extent of exposure to chlorthalidone are considered equivalent between the treatments. [0300] The Group I statistical comparisons (% mean ratios and 90% CI) of the chlorthalidone In-transformed C_max, AUC₀-_t, and AUCo-inf for the 4 x 2.5 mg/6.25 mg ramipril-chlorthalidone tablets (Treatment A), the 1 x 25 mg commercial chlorthalidone tablet (Treatment B), and the 4 x 6.25 mg chlorthalidone tablets (Treatment C) are presented in the following table. Table 4. Relative Bioavailability Results for Whole Blood Chlorthalidone for

Group I (Treatments A, B, and C)

[0301] The Group II statistical comparisons (% mean ratios and 90% CI) of the chlorthalidone In-transformed C_max, AUC_0-t, and AUC₀.i_nf for the 2 x 10 mg/12.5 mg ramipril- chlorthalidone tablets (Treatment D), the 1 x 25 mg commercial chlorthalidone tablet (Treatment E), and the 2 x 12.5 mg chlorthalidone tablets (Treatment F) are presented in the following table.

Table 5. Relative Bioavailability Results for Whole Blood Chlorthalidone for

Group II (Treatments D, E, and F)

[0302] The Group III statistical comparisons (% mean ratios and 90% CI) of the chlorthalidone In-transformed C_max, AUCo-t, and AUC₀.j_nf for the 1 x 20 mg/25 mg ramipril- chlorthalidone tablets (Treatment G), the 1 x 25 mg commercial chlorthalidone tablet (Treatment H), and the 1 x 25 mg chlorthalidone tablet (Treatment I) are presented in the following table. Table 6. Relative Bioavailability Results for Whole Blood Chlorthalidone for

Group HI (Treatments G, H, and I)

[0303] Mean (SD) Plasma Ramipril Concentrations Versus Time for Groups I - III of

Example 2 are presented in Figures 2-4.

Results

[0304] The PK and statistical analyses of the data resulting from this study indicate equivalent chlorthalidone bioavailability between the 2.5 mg/6.25 mg, 10 mg/12.5 mg, and 20 mg/25 mg ramipril-chlorthalidone tablets, and the commercial 25 mg chlorthalidone tablet, as well as the 6.25 mg, 12.5 mg, and 25 mg chlothalidone tablets. The comparison of the chlothalidone tablets and the 25 mg commercial chlorthalidone tablet also indicate equivalent chlorthalidone bioavailability.

Example 3 - Randomized, Single-Dose, Three-Way Crossover Study to Determine the Bioavailability of Ramipril and Ramiprilat From Ramipril- Chlorthalidone Tablets, Ramipril Tablets, and ALT ACE® Capsules in Healthy Volunteers

[0305] The study followed a single-dose, open-label, three-period, three-treatment, crossover design and utilized a 2-stage randomization process for treatment group and sequence.

[0306] The following treatments were utilized.

[0307] Treatment ( 12 treatments, A - L)

[0308] Subjects were enrolled in Treatment Group I, II, III, or IV and received a total of 3 treatments (ramipril-chlorthalidone tablet, ramipril commercial capsule, and ramipril tablet), which were randomized with respect to sequence. All study drugs were administered as a single dose with 240 mL (8 fluid ounces) of water following an overnight fast. Each treatment was separated by a 3 -week washout period.

[0309] Sixty (60) subjects were enrolled and 56 subjects completed the study. 56 subjects were included in the pharmacokinetic (PK) analyses.

[0310] There were 3 test products examined in this study:

[0311] Ramipril/Chlorthalidone combination tablets manufactured by King

Pharmaceuticals, Inc.: 2.5 mg/6.25 mg (lot no. 040050, Treatment A), 5 mg/12.5 mg (lot no.

040024, Treatment D), 10 mg/12.5 mg (lot no. 040025, Treatment G), and 20 mg/25 mg (lot no. 040027, Treatment J).

[0312] Ramipril commercial capsules (ALTACE®) manufactured by Aventis

Pharmaceuticals, Inc. (2.5 mg) or King Pharmaceuticals, Inc. (5 mg and 10 mg): 2.5 mg (lot no. 1063626, Treatment B), 5 mg (lot no. 14888, Treatment E), and 10 mg (lot no. 13053, 1 capsule for Treatment H, and 2 for Treatment K).

[0313] Ramipril tablets manufactured by King Pharmaceuticals, Inc.: 2.5 mg (lot no.

040049, Treatment C), 5 mg (lot no. 040019, Treatment F), 10 mg (lot no. 040020, Treatment

I), and 20 mg (lot no. 040021, Treatment L).

[0314] A single dose of these study drugs was administered with 240 mL of water following an overnight fast. The duration of the treatment was nine (9) weeks including screening.

[0315] Pharmacokinetic analyses were performed using plasma concentrations of ramipril and ramiprilat. Pharmacokinetic parameters included the maximum observed plasma concentration (C_max),time of the maximum observed plasma concentration (T_max), and area under the plasma concentration-time curves from time zero to time "t" hours postdose (AUC_0-t), where t is the last time point with a measurable drug concentration, AUCo_-I2, AUCo-24, and AUC_0-4S, where t = 12 and 24 for ramipril and t = 24 and 48 for ramiprilat. [0316] To evaluate the relative bioavailability, analyses of variance (ANOVA) were performed on the In-transformed AUCo-t, AUC_0-I2, AUC_0-24, and C_max for ramipril and the In- transformed AUCo-t, AUC_0-24, and AUC_0-48, and C_max for ramiprilat. The ANOVA model included terms for treatment, period, sequence, and subject within sequence. A separate ANOVA model was applied to the data from each of the treatment groups. The relative bioavailability of ramipril and ramiprilat from the ramipril-chlorthalidone tablets were compared to that of the ramipril commercial capsules, and to that of the ramipril tablets. In addition, the relative bioavailability of ramipril and ramiprilat from the ramipril tablets were compared to that of the ramipril commercial capsules. For each comparison, the ratios of least-squares means (LSM) and the 90% confidence intervals (CI) were expressed as a percentage relative to the ramipril commercial capsules, or ramipril tablets. A conclusion of equivalent bioavailability was based on the mean ratios and whether the 90% CI for the In- transformed C_max, AUCo-t, AUCo-12, AUC_0-24, and AUC_0-48 (for ramipril and ramiprilat as appropriate) were within the 80 - 125% range where the rate and extent of exposure to ramipril and ramiprilat are considered equivalent between the treatments. [0317] A linear relationship between the In-transformed PK parameters (Cmax and

AUC) and the In-transformed dose was fitted using the model In(Y) = β₀ + β lnDose + ε. The 95% CI for the slope between the lntransformed PK parameters and the In-transformed dose was calculated for each parameter using the above model. If the 95% CI included 1, then dose proportionality was concluded for the given parameter.

[0318] The ratios of the LSM with the 90% CI derived from the analysis of the In- transformed Cmax, AUCo-t, AUCo-12, and AUCo-24 for ramipril and In-transformed C_max, AUCo-_t, AUCo_-24, and AUC0-4S for ramiprilat are presented in the following tables.

Table 7. Ramipril Relative Bioavailability Results in Plasma for Equivalent Doses of 2.5, 5, 10, and 20 mg from Ramipril-Chlorthalidone Combination Tablets Compared to Ramipril Commercial Capsules (ALT ACE®) Ratios of LSM (90% CI)

Table 8. Ramiprilat Relative Bioavailability Results in Plasma for Equivalent Doses of 2.5, 5, 10, and 20 mg from Ramipril-Chlorthalidone Combination Tablets Compared to Ramipril Commercial Capsules (ALT ACE®) Ratios of LSM (90% CI)

Table 9. Ramipril Relative Bioavailability Results in Plasma for Equivalent Doses of 2.5, 5, 10, and 20 mg from Ramipril-Chlorthalidone Tablets Compared to Ramipril Tablets Ratios of LSM (90% CI)

Table 10. Ramiprilat Relative Bioavailability Results in Plasma for Equivalent Doses of 2.5, 5, 10, and 20 mg from Ramipril-Chlorthalidone Tablets Compared to Ramipril Tablets Ratios of LSM (90% CI)

Table 11. Ramipril Relative Bioavailability Results in Plasma for Equivalent Doses of 2.5, 5, 10, and 20 from Ramipril Tablets Compared to Ramipril Commercial Capsules (ALTACE®) Ratios of LSM (90% CI)

- 57 -

NYI-4082986vl

Table 12. Ramiprilat Relative Bioavailability Results in Plasma for Equivalent

Doses of 2.5, 5, 10, and 20 from Ramipril Tablets Compared to Ramipril Commercial Capsules (ALT ACE®) Ratios of LSM (90% CI)

[0319] The PK and statistical analyses of the data resulting from this study indicate comparable bioavailability for both ramipril and ramiprilat (in terms of the C_max and AUC₀._t LSM) between the 10 mg/12.5 mg ramipril-chlorthalidine tablets and the 10 mg ramipril commercial capsules, between the 5 mg/12.5 mg ramipril-chlorthalidone tablets and the 5 mg ramipril tablets, and between the 20 mg/25 mg ramipril-chlorthalidone tablets and the 20 mg ramipril tablets.

[0320] Ramipril and ramiprilat exposure (AUCo-O was comparable between the ramipril-chlorthalidine tablets and both the ramipril commercial capsules and the ramipril tablets at all dose levels, as well as between the ramipril tablets and the ramipril commercial capsules.

[0321] In general, the ramipril maximum peak concentrations (C_max) for both the ramipril-chlorthalidone tablets and ramipril tablets tended to be higher than the ramipril commercial capsules following the low dose levels (2.5 mg and 5 mg), but lower following the highest dose level (20 mg). Ramiprilat C_max following ramipril-chlorthalidone tablets and ramipril tablets compared to the ramipril commercial capsules was comparable at the lower dose levels (2.5 mg and 5 mg, and 10 mg), but lower following the high dose level (20 mg). [0322] The ramipril tablets were dose proportional with respect to ramipril AUCo-_I2 and AUCo-₂4. For all formulations, ramipril AUC_0-t and C_max showed a greater than proportional increase at the 20 mg dose level. All formulations were dose proportional with respect to ramiprilat AUCo_-24. However, ramiprilat AUC_0-t and AUCo^₈ showed a lower than proportional increase with dose level while C_max showed a greater than proportional increase. [0323] Mean (SD) Plasma Ramipril Concentrations Versus Time for Groups I - IV of

Example 3 are presented in Figures 5-9.

Results

[0324] The pharmacokinetic and statistical analyses of the data resulting from this study also indicate equivalent ramipril bioavailability between the 2.5 mg/6.25 mg, 10 mg/12.5 mg, and 20 mg/25 mg ramipril-chlorthalidone tablets, and the commercial 2.5 mg, 5 mg, and 10 mg ramipril tablets, as well as the 2.5 mg, 5 mg, and 10 mg ramipril tablets.

Example 4 - Combination of ramipril and hydrochlorothiazide

[0325] Exemplary tablets of ramipril/hydrochlorthiazide combination tablets were made and evaluated for their stability. Batch A was 2.5 mg of GECoated ramipril (ramipril coated with hydroxypropyl methylcellulose) combined with 6.25 mg of hydrochlorothiazde (HCTZ). Batch B was 5 mg of GECoated ramipril (ramipril coated with hydroxypropyl methylcellulose) combined with 25 mg of hydrochlorothiazde.

[0326] Samples of batches A and B were exposed to temperature/relative humidity conditions of either 25°C/60% R.H. or 40°C/75% R.H. for up to 6 months. Chemical, physical and dissolution data were collected at one, two, three and six month time periods. [0327] The data from these batches was compared to the data from tablets in batch C which are ramipril only tablets.

ND = not detected

Table 14. Batch A Stability Study - Physical Data

RSD = relative standard deviation DT = disintegration time NP = not performed

Table 15. Batch A Stability Study Dissolution Data

RSD = relative standard deviation DT = disintegration time NP = not performed Table 18. Batch B Stability Study Dissolution Data

Example 5 - Combination of ramipril and hydrochlorothiazide

[0328] Stability assays were conducted to determine the stability of both the ramipril and hydrochlorothiazide components in ramipril/HCTZ combination tablets at the various strengths, described Tables 20-22.

Table 20. Unit Formula Comparison by Site: Ramipril-Hydrochlorothiazide Tablets from Blend A

* Used to coat the Ramipril granules to form GE-coated ramipril.

Table 21. Unit Formula Comparison by Site: Ramipril-Hydrochlorothiazide Tablets from Blend B

* Used to coat the Ramipril granules to form GE-coated ramipril.

Table 22. Unit Formula Comparison by Site: Ramipril-Hydrochlorothiazide Tablets from Blend C

* Used to coat the Ramipril granules to form GE-coated ramipril

[0329] Stability Studies of Blends A-C [0330] Stability studies on Ramipril/HCTZ combination tablets comprised of blends

A-C above, were conducted over up to a 12 month period at 25⁰C and 60% relative humidity. [0331] Ramipril Assay

[0332] Results of the statistical analyses for the ramipril assay for exemplary ramipril/HCTZ combination tablets are provided in Table 23. The y-intercept represents the starting assay value of ramipril, while the slope reflects the rate of change in this assay value per month.

Table 23. Ramipril Assay Statistical Data (Two Sided 95% CI, Proposed Specification Limits: 90.0 - 110.0%LC)

[0333] Hydrochlorothiazide Assay

[0334] Results of the statistical analyses for the hydrochlorothiazide assay for exemplary ramipril/hydrochlorothiazide combination tablets are provided in Table 24. The y- intercept represents the starting assay value of hydrochlorothiazide, while the slope reflects the rate of change in this assay value per month.

Table 24. Hydrochlorothiazide Assay Statistical Data (Two Sided 95% CI, Proposed Specifications Limits: 90.0 - 105.0%LC)

Sum of Ramipril Degradation Products

[0335] Results of the statistical analyses for the sum of ramipril degradation products for exemplary ramipril/hydrochlorothiazide combination tablets are provided in Table 25. The y-intercept represents the starting assay value of the combined ramipril degradation products, while the slope reflects the rate of change in this assay value per month.

Table 25. Sum of Ramipril Degradation Products Statistical Data (One Sided 95% CI, Proposed Specification Limits: Not more than 6.0%)

[0336] Ramipril-Diketopiperazine Content

[0337] Results of the statistical analyses for the ramipril-diketopiperazine content in ramipril/hydrochlorothiazide combination tablets are provided in Table 26. The y-intercept represents the starting assay value of ramipril-diketopiperazine, while the slope reflects the rate of change in this assay value per month.

Table 26. Ramipril-diketopiperazine Content Statistical Data (One Sided 95% CI, Proposed Specification Limits: Not more than 5.0%)

Dissolution of Ramipril/HCTZ Combination Tablets

[0338] Dissolution analyses were also conducted for ramipril/HCTZ combination tablets. For ramipril dissolution, statistical analyses were conducted for both the mean dissolution result and the minimum dissolution result observed at each stability time-point. The two analyses were conducted to evaluate the ability of the product to meet the USP staged acceptance criteria. For the statistical analyses, both the mean and minimum dissolution results are compared to the USP Stage 1 acceptance criteria (Q + 5%). [0339] Results of the statistical analyses for the ramipril mean dissolution for ramipril/HCTZ combination tablets are provided in Table 27. The rate of change in the results (slope) was not consistently increasing or decreasing, and, in all cases, the absolute value of the change was less than 0.2% per month.

Table 27. Ramipril Mean Dissolution Statistical Data (One Sided 95% CI, Proposed Specification Limits: NLT Q = 75%LC)

[0340] Results of the statistical analyses for the ramipril minimum dissolution for ramipril/HCTZ combination tablets are provided in Table 28. The rate of change in the results (slope) was not consistently increasing or decreasing, and, in all cases, the absolute value of the change was less than 0.4% per month.

Table 28. Ramipril Minimum Dissolution Statistical Data, (One Sided 95% CI, Proposed Specification Limits: NLT Q = 75%LC)

Hydrochlorothiazide Dissolution

[0341] For hydrochlorothiazide dissolution, statistical analyses were conducted for both the mean dissolution result and the minimum dissolution result observed at each stability time-point. The two analyses are conducted to evaluate the ability of the product to meet the USP staged acceptance criteria. For the statistical analyses, both the mean and minimum dissolution results are compared to the USP Stage 1 acceptance criteria (Q + 5%). [0342] There were eight packaged groups of exemplary tablets that required Stage 2 testing at one or more stability time-points to conform to the proposed specification, but all of these tablets met the proposed Stage 1 criteria at the 12-month time-point. A summary of the Stage 2 results is provided in Table 29.

RT = 25°C/60%R.H.

[0343] In addition, there were two packaged groups of exemplary tablets (both from the same bulk tablets) that did not conform to Stage 1 testing at the time the tablets were set on stability (approximately 2 months after manufacture); however, the bulk tablets that were packaged conformed to Stage 1 testing at the time of manufacture and at all of the other stability time-points tested thus far. The non-conforming results are summarized in Table 30.

Table 30. Hydrochlorothiazide Dissolution Results Not Conforming to Stage 1 at Time of Stability Set

[0344] Results of the statistical analyses for the hydrochlorothiazide mean dissolution for ramipril/HCTZ combination tablets are provided in Table 31. Table 31. Hydrochlorothiazide Mean Dissolution Statistical Data (One Sided 95% CI, Proposed Specification Limits: NLT Q = 75%LC)

[0345] Dissolution data for ramipril/hydrochlorothiazide tablets, A7 (Figure 11.1) and B4 (Figure 11.2) exhibit a fairly high degree of curvature in the 95% CI prediction, most likely due to results at 6 months and 9 months respectively. This degree of curvature in the 95% CI prediction may result in underestimation of the predicted stability. The predicted linear regression line is significantly above the proposed specification limit at the 24 month time-point. Therefore, it is expected that results will ultimately support a 24 month expiration date for this product.

[0346] Results of the statistical analyses for the hydrochlorothiazide minimum dissolution for ramipril/HCTZ combination tablets are provided in Table 32.

Table 32. Hydrochlorothiazide Minimum Dissolution Statistical Data (One Sided 95% CI, Proposed Specification Limits: NLT Q = 75%LC)

Strength Package | Pooling | Intercept | Slope | Expiration

[0347] Review of the results for the hydrochlorothiazide minimum dissolution for exemplary ramipril/HCTZ combination tablets, Al, reveal that these tablets required Stage 2 testing at the 12 month time-point. In addition, review of the graph for the hydrochlorothiazide minimum dissolution for these tablets (Figure 11.3) exhibits a fairly high degree of curvature in the 95% CI prediction, which may result in underestimation of the predicted stability. The predicted linear regression line also predicts that the results will be outside of the Stage 1 dissolution criteria before the 24 month time-point. However, the high variability of the minimum results for these tablets, including the 12 month results requiring Stage 2 testing, have resulted in a much higher rate of decrease in results for these tablets (slope of -0.87%/month) as compared to all others. Also, the Stage 1 criteria for the minimum which is being used to assess the stability is more stringent than the actual overall acceptability criteria. Thus, it is expected that results will ultimately support a 24 month expiry date for this product. [0348] Predicted linear regressions for the graphs of hydrochlorothiazide minimum dissolution in for the tablets described in Figures 11.4-11.13, indicate that these exemplary ramipril/HCTZ combination tablets will ultimately support a 24 month expiration date.

Summary of Results for Ramipril/HCTZ Tablet Stability Studies [0349] Both stability assays and dissolution data indicates that ramipril/hydrochlorothiazide (HCTZ) combination tablets are stable with little decomposition of either ramipril or hydrochlorothiazide. Moreover, the decomposition of ramipril in the combination tablets was similar to the decomposition of ramipril only formulations.

Example 6-Bioequivalence of Ramipril/Hydrochlorothiazide Combination Tablets to Ramipril and Hydrochlorothiazide Co-Administration [0350] Studies were conducted to determine the relative bioavailability, and therefore the bioequivalence, of various strengths of ramipril-HCTZ tablets compared with equivalent strengths of ramipril or HCTZ alone, and to the equivalent strengths of ramipril and HCTZ co-administered.

Study 1: Relative Bioavailability Results Following 10 mg/25 mg Ramipril/HCTZ Tablets Compared to Ramipril 10 mg Capsules (Altace^®) and HCTZ 25 mg Tablets Under Fasted Conditions

[0351] This study determined the relative bioavailability, and therefore the bioequivalence, of ramipril-HCTZ 10/25 mg tablets compared with ramipril 10 mg capsules (Altace^®) and HCTZ 25 mg tablets, administered concomitantly under fasted conditions, in healthy volunteers. The study followed a randomized, open-label, single-dose, 3-way crossover design. Forty-eight (48) healthy adult volunteers (40% - 60% female) were enrolled and randomly assigned to 1 of 6 treatment sequences. Subjects completed a Screening Phase, a Treatment Phase consisting of 3 dosing periods, and an End-of-Study Phase. Each treatment was separated by a 21 -day washout period. Subjects entered the Treatment Phase of the study on Day 1 and received one of the following treatments following an overnight fast:

[0352] Treatment A: 1 x 10 mg/25 mg ramipril-HCTZ tablet with 240 mL of water under fasted conditions. [0353] Treatment B: 1 * 10 mg ramipril capsule (Altace^®) plus 1 * 25 mg HCTZ tablet taken concomitantly with 240 mL of water under fasted conditions.

[0354] The ratios of the least-squares means (LSM) with the 90% CI derived from the analysis of the In-transformed AUCs and C_max for ramipril, ramiprilat, and HCTZ under fasted conditions for the comparable bioavailability assessment are presented in Table 33.

Table 33. Relative Bioavailability Results Following 10 mg/25 mg Ramipril/HCTZ Tablets (Treatment A) Compared to Ramipril 10 mg Capsules (Altace^®) and HCTZ 25 mg Tablets (Treatment B) Under Fasted Conditions

% Mean Ratio (90% CI)

NA: Not applicable

[0355] The PK and statistical analyses of the data in Table 33 as well as the overlay of mean plasma concentration profiles indicate that the rate and extent of absorption of ramipril/ramiprilat and HCTZ from the ramipril-HCTZ tablet taken under fasted conditions were comparable to that of the single-entity drugs (Altace^® capsules and HCTZ tablets) taken together under fasted conditions. On the basis of the In-transformed values for C_max and AUC for ramiprilat (the active form of ramipril) and HCTZ, the ramipril-HCTZ tablet met the conditions of bioequivalence as compared with the reference drugs (Altace^® capsules and HCTZ tablets) taken together.

Study 2: Relative Bioavailability Results Following 2 x 10 mg/12.5 mg Ramipril-HCTZ Tablets Compared to 2 x 10 mg Ramipril Capsules (Altace^®) plus 1 x 25 mg HCTZ Tablet

[0356] A second study was conducted to determine the relative bioavailability, and therefore the bioequivalence, of ramipril-HCTZ combination tablets (2 * 10 mg/12.5 mg) compared with ramipril (2 x 10 mg Altace^® capsules) and HCTZ (1 x 25 mg tablet)^' administered concomitantly under fasted conditions in healthy volunteers, and to determine the drug-drug interaction potential under conditions in which the maximum dose of ramipril- HCTZ tablets (20 mg of ramipril + 25 mg of HCTZ) is administered. This study was an open-label, single-dose, randomized, 4-way crossover study in healthy young (age 19 - 45 years) adult male and female volunteers. Forty-eight (48) subjects (50% female) were enrolled and randomly assigned to 1 of 8 treatment sequences; a minimum of 40 subjects were to complete the study. Subjects completed a Screening Phase, a Treatment Phase consisting of 4 dosing periods, and an End-of-Study Phase. The 4 treatments were separated by a 21 -day washout period. Subjects entered the Treatment Phase of the study on Day 1 and received one of the following treatments following an overnight fast: Treatment A: 2 * 10 mg/12.5 mg ramipril-HCTZ tablets with 240 mL of water. Treatment B: 2 x 10 mg ramipril capsules (Altace^®) plus 1 x 25 mg HCTZ tablet administered concomitantly with 240 mL of water.

Treatment C: 2 x 10 mg ramipril capsules (Altace^®) with 240 mL of water. Treatment D: 1 x 25 mg HCTZ tablet with 240 mL of water.

[0357] Pharmacokinetic analyses were performed using plasma concentrations of ramipril, ramiprilat, and HCTZ. Pharmacokinetic parameters included the maximum observed concentration (C_max), time-to-maximum observed concentration (T_maχ), and area under the plasma concentration-time curve over various time points (AUC_0-t for all compounds, AUCo_-I2 for ramipril, AUC_0-24 for ramiprilat and HCTZ, and AUC_O-48 for ramiprilat).

[0358] Descriptive statistics were provided for ramipril, ramiprilat, and HCTZ plasma concentrations and PK parameters. Analyses of variance (ANOVA) were performed on the In-transformed parameters (C_max and AUCs). A general linear model (GLM) procedure in SAS^® was used, with treatment, sequence, and period as fixed effects; and subject within sequence as a random effect was used to test for the sequence effect. The geometric mean ratios (A/B and AJC for ramipril and ramiprilat, and A/B and A/D for HCTZ) and 90% confidence intervals (CIs) were calculated as evidence of comparable bioavailability. Comparable relative bioavailability and lack of drug-drug interaction were to be concluded based on the mean ratios and whether the 90% CIs for the In-transformed parameters were within 80% to 125%. [0359] The ratios of the least-squares means (LSM) with the 90% CI derived from the analysis of the In-transformed AUCs and C_max for ramipril, ramiprilat, and HCTZ for the comparable bioavailability assessment are presented in Table 34.

Table 34. Relative Bioavailability Results Following 2 x 10 mg/12.5 mg Ramipril- HCTZ Tablets (Treatment A) Compared to 2 x 10 mg Ramipril Capsules (Altace^®) plus 1 x 25 mg HCTZ Tablet (Treatment B)

% Mean Ratio (90% CI)

NA: Not applicable

[0360] The ratios of the LSM with the 90% CI derived from the analysis of the In- transformed AUCs and C_max for ramipril, ramiprilat, and HCTZ for the potential drug-drug interaction assessment are presented in Table 35.

Table 35. Drug-Drug Interaction Assessment Following 2 x 10 mg/12.5 mg

Ramipril-HCTZ Tablets (Treatment A) Compared to 2 x 10 mg Ramipril Capsules (Altace^®) (Treatment C) and Compared to 1 x 25 mg HCTZ Tablet (Treatment D)

% Mean Ratio 90% CI

NA: Not applicable [0361) The PK and statistical analyses of data as well as the overlay of mean plasma concentration profiles indicate that the rate and extent of absorption of ramipril/ramiprilat and

HCTZ from the ramipril-HCTZ tablet were comparable to that of the single-entity drugs

(Altace^® capsules and HCTZ tablets) taken together.

[0362] On the basis of the In-transformed values for C_max and AUC for ramiprilat (the active form of ramipril) and HCTZ, the ramipril-HCTZ tablet met the conditions of bioequivalence as compared with the reference drugs (Altace^® capsules and HCTZ tablets) taken together.

[0363] On the basis of the In-transformed values for C_max and AUC for ramiprilat (the active form of ramipril) and HCTZ, the ramipril-HCTZ tablet met the conditions of bioequivalence as compared with the reference drugs (Altace^® capsules and HCTZ tablets) taken together.

[0364] Administration of the combination ramipril-HCTZ tablet resulted in similar rates and extents of ramiprilat and HCTZ absorption compared with administration of the reference products alone.

[0365] On the basis of the In-transformed values for C_max and AUC for ramiprilat (the active form of ramipril) and HCTZ, the ramipril-HCTZ tablet met the conditions of no apparent drug-drug interaction compared to the reference products alone.

Study 3: Relative Bioavailability Results Following 2.5 mg/12.5 mg Ramipril-HCTZ

Tablet (Treatment A) Compared to Ramipril 2.5 mg Capsule (Altace^®) and HCTZ 12.5 mg

Capsule (Treatment B).

Study 3: Relative Bioavailability Results Following 2.5 mg/12.5 mg Ramipril-HCTZ Tablet Compared to Ramipril 2.5 mg Capsule (Altace^®) and HCTZ 12.5 mg Capsule

[0366] A third study was conducted to determine the relative bioavailability, and therefore the bioequivalence, of the ramipril-HCTZ 2.5 mg/12.5 mg combination tablet compared with the ramipril 2.5 mg capsule (Altace^®) and HCTZ 12.5 mg capsule, administered concomitantly under fasted conditions in healthy volunteers. [0367] This was an open-label, single-dose, randomized, 2-way crossover study in healthy young (age 19 - 45 years) adult male and female volunteers. Forty-eight (48) subjects (50% female) were enrolled and randomly assigned to 1 of 2 treatment sequence groups; a minimum of 40 subjects were to complete the study. Subjects completed a Screening Phase, a Treatment Phase consisting of 2 dosing periods, and an End-of-Study Phase. The 2 treatments were separated by a 21 -day washout period. Subjects entered the Treatment Phase of the study on Day 1 and received one of the following treatments following an overnight fast:

Treatment A: 1 x 2.5 mg/12.5 mg ramipril-HCTZ tablet with 240 mL of water.

Treatment B: 1 x 2.5 mg ramipril capsule (Altace^®) plus 1 x 12.5 mg HCTZ capsule (Microzide^®), administered concomitantly with 240 mL of water.

[0368] Pharmacokinetic analyses were performed using plasma concentrations of ramipril, ramiprilat, and HCTZ. Pharmacokinetic parameters included the maximum observed concentration (C_max), time-to-maximum observed concentration (T_max), and area under the plasma concentration-time curve over various time points (AUC_0-t for all compounds, AUC₀-_I2 for ramipril, AUC_0-24 for ramiprilat and HCTZ, and AUC_0-48 for ramiprilat).

[0369] Descriptive statistics were provided for ramipril, ramiprilat, and HCTZ plasma concentrations and PK parameters. Analyses of variance (ANOVA) were performed on the In-transformed parameters (C_max and AUCs). A general linear model (GLM) procedure in SAS^® was used, with treatment, sequence, and period as fixed effects and subject within sequence as a random effect (used to test for the sequence effect). The geometric mean ratios (A/B) and 90% confidence intervals (CIs) were calculated as evidence of comparable bioavailability. Comparable relative bioavailability was concluded based on the mean ratios and whether the 90% CIs for the In-transformed parameters were within 80% to 125%. [0370] The ratios of the least-squares means (LSM) with the 90% CI derived from the analysis of the In-transformed AUCs and C_maχ for ramipril, ramiprilat, and HCTZ for the comparable bioavailability assessment are presented in Table 36.

Table 36. Relative Bioavailability Results Following 2.5 mg/12.5 mg Ramipril- HCTZ Tablet (Treatment A) Compared to Ramipril 2.5 mg Capsule (Altace^®) and HCTZ 12.5 mg Capsule (Treatment B)

% Mean Ratio 90% CI

NA: Not applicable

[0371] The PK and statistical analyses of the data, as well as the overlay of mean plasma concentration profiles, indicated that the rate and extent of absorption of ramipril/ramiprilat and HCTZ from the ramipril-HCTZ tablet taken under fasted conditions were comparable to that of the single-entity drugs (Altace® capsule and HCTZ capsule) taken together under fasted conditions.

[0372] On the basis of the In-transformed values for C_max and AUC for ramiprilat (the active form of ramipril) and HCTZ, the ramipril-HCTZ tablet met the conditions of bioequivalence as compared with the reference drugs (Altace^® capsule and HCTZ capsule) taken together.

Study 4: Relative Bioavailability Results Following 10 mg/25 mg Ramipril-HCTZ Tablet Compared to HCTZ 25 mg Capsule [0373] The purpose of study 4 was to determine the relative bioavailability, and therefore the bioequivalence, of ramipril-HCTZ (10 mg/25 mg) tablets compared with HCTZ 25 mg capsules in healthy volunteers. This was a randomized, open-label, single-dose, 2-way crossover study in healthy young (age 19 - 45 years) adult male and female volunteers. Thirty (30) subjects (50% female) were enrolled and randomly assigned to 1 of 2 treatment sequences; a minimum of 24 subjects was to complete the study. Subjects completed a Screening Phase, a Treatment Phase consisting of 2 dosing periods, and an End-of-Study Phase. The 2 treatments were separated by a 21 -day washout period. Subjects entered the Treatment Phase of the study on Day 1 and received one of the following treatments following an overnight fast: Treatment A: 1 * 10 mg/25 mg ramipril-HCTZ tablet with 240 mL of water.

Treatment B: 1 x 25 mg HCTZ capsule with 240 mL of water.

[0374] Pharmacokinetic analyses were performed using plasma concentrations of

HCTZ. Pharmacokinetic parameters included the maximum observed concentration (C_maχ), time-to-maximum observed concentration (T_max), apparent terminal elimination rate constant (K_ci), terminal elimination half-life (t/,), and area under the plasma concentration-time curve over various time points (AUC₀._t, AUC₀-₂4, and AUC_0-i_nf).

[0375] Descriptive statistics were provided for HCTZ plasma concentrations and PK parameters. Analyses of variance (ANOVA) were performed on the HCTZ In-transformed parameters (C_max and AUCs). A general linear model (GLM) procedure in SAS^® was used, with treatment, sequence, and period as fixed effects; and subject within sequence as a random effect was used to test for the sequence effect. The geometric mean ratios (Treatment A/Treatment B) and 90% confidence intervals (CIs) were calculated as evidence of comparable bioavailability. Comparable relative bioavailability was concluded based on the mean ratios and whether the 90% CIs for the In-transformed parameters were within 80% to 125%.

[0376] The ratios of the least-squares means (LSM) with the 90% CI derived from the analysis of the HCTZ In-transformed AUCs and C_max for the comparable bioavailability assessment are presented in Table 37.

Table 37. Relative Bioavailability Results Following 10 mg/25 mg Ramipril-HCTZ Tablet (Treatment A) Compared to HCTZ 25 mg Capsule (Treatment B)

[0377] The PK and statistical analyses of the data, as well as the overlay of mean plasma concentration profiles, indicated that the rate and extent of absorption of HCTZ from the ramipril-HCTZ tablet taken under fasted conditions were comparable to that of the single- entity drug (HCTZ capsule) taken under fasted conditions.

[0378] On the basis of the In-transformed values for C_max and AUC for HCTZ, the ramipril-HCTZ tablet met the conditions of bioequivalence as compared with the reference HCTZ capsule. Example 7 - A Randomized, Double-Blind, Multicenter, Parallel Study Evaluating the Efficacy and Safety of a Combination of Ramipril Plus Hydrochlorothiazide versus the Component Monotherapies in Subjects with Essential Hypertension

[0379] An 8 week randomized, double-blind, double-dummy, parallel-arm study evaluating the effects of a dose combination of ramipril 20 mg and HCTZ 25 mg (co-administered once daily) versus ramipril 20 mg once daily, ramipril 10 mg twice daily, and HCTZ 25 mg once daily in subjects with essential hypertension was conducted. Approximately 360 subjects (actual number of subjects was 341) were randomized across 4 treatment groups to achieve 306 completed subjects.

[0380] The objects of the study were to compare the effect (change from baseline) on the diastolic blood pressure of the combination of ramipril and HCTZ after 8 weeks of treatment in patients with Stage 2 essential hypertension and to compare the change from baseline of the systolic blood pressure of the combination of ramipril with HCTZ dosed once daily to ramipril and HCTZ dosed once daily. Further objectives were to compare clinical blood pressure among different patient groups, compare changes from baseline in ambulatory blood pressure in different patient groups and assess safety and tolerance of ramipril plus HCTZ compared to the three monotherapy treatments.

[0381] Subjects were randomized in a 2:2: 1 : 1 allocation to the combination treatment,

HCTZ 25 mg, ramipril 20 mg once daily, and ramipril 10 mg twice daily. Up to 60 United States study centers participated in the trial.

[0382] Each subject completed a 2- to 4-week Screening/Washout/Placebo-Lead-In

Period, an 8-week Treatment Period, and a 1-week Follow-Up Period. All subjects were required to washout from their current antihypertensive medications (if applicable). Subjects where randomized to double-blind study drug after 2 weeks, if the subject met the inclusion criteria at that time (including blood pressure readings between Visits 2 and 3). Subjects who do not met the blood pressure inclusion criteria at Visit 3 may continue in the Screening/Washout/Placebo-Lead-In Period for up to 2 more weeks (Visits 2a and 2b). [0383] The 2- to 4-week Screening/Washout/Placebo-Lead-In Period allowed for up to a cumulative 4-week washout period for subjects on medications with long elimination half-lives, or who had extenuating clinical issues in the judgment of the Investigator. At the end of this period, all subjects were required to meet the following criteria prior to entry into the Treatment Period: • a mean clinic sitting systolic blood pressure between 140 and 180 mm Hg (inclusive) at each of Visits 2 and 3,

• a mean clinic sitting diastolic blood pressure between 100 and 115 mm Hg (inclusive) at each of Visits 2 and 3, and

• a difference in clinic sitting systolic blood pressure of <10 mm Hg between the mean sitting systolic blood pressure at Visit 2 and the mean sitting systolic blood pressure at Visit 3.

[0384] Subjects satisfying the blood pressure requirements and all other screening criteria entered the Treatment Period and were randomized to 1 of the 4 parallel treatment groups: ramipril (20 mg)/ HCTZ (25 mg) administered once daily, ramipril (20 mg) administered once daily, HCTZ (25 mg) administered once daily, ramipril (10 mg) administered twice a day Tables 38 and 39 show the overall schedule of visits and events.

Table 38.

The mean clinic sitting systolic blood pressure from each of Visit 2 and Visit 3 must be between 140 and 180 mm Hg (inclusive); and the mean clinic SiDBP must be between 100 and 1 15 mm Hg (inclusive) from each of Visit 2 and Visit 3. In addition, the difference in clinic SiDBP between Visit 2 and Visit 3 must be <10 mm Hg. Subjects who require a longer washout period (which may be required depending on the antihypertensive therapy of the subject prior to the study, or for other clinical reasons) may continue the placebo lead-in for 2 additional weeks prior to randomization (Visits 2a and 2b). One week will separate Visit 2 from Visit 2a, and one week will separate Visit 2a from Visit 2b. Blood pressure criteria must be met as noted above for Visit 2 (or 2a or 2b, as applicable) and

Visit 3. 2 If the subject's Visit 3a blood pressure values indicate that the Visit 2 (or 2a or 2b, as applicable) and Visit 3 blood pressure criterion will not be met, the subject should be considered a screen failure, and the ABPM session should not be initiated.

Additional ECG monitoring may be done if clinically indicated, at the discretion of the

Investigator. 4 All females.

Table 39.

¹ The mean clinic sitting systolic blood pressure from each of Visit 2 and Visit 3 must be between 140 and 180 mm Hg (inclusive); and the mean clinic SiDBP must be between 100 and 115 mm Hg (inclusive) from each of Visit 2 and Visit 3. In addition, the difference in clinic SiDBP between Visit 2 and Visit 3 must be <10 mm Hg. Subjects who require a longer washout period (which may be required depending on the antihypertensive therapy of the subject prior to the study, or for other clinical reasons) may continue the placebo lead-in for 2 additional weeks prior to randomization (Visits 2a and 2b). One week will separate Visit 2 from Visit 2a, and one week will separate Visit 2a from Visit 2b. Blood pressure criteria must be met as noted above for Visit 2 (or 2a or 2b, as applicable) and Visit 3.

² If the subject's Visit 3a blood pressure values indicate that the Visit 2 (or 2a or 2b, as applicable) and Visit 3 blood pressure criterion will not be met, the subject should be considered a screen failure, and the ABPM session should not be initiated.

[0385] Subjects were titrated to their final dose of study drug over the first 2 weeks of the Treatment Period as noted in Table 39. At Visit 3, subjects received ramipril 10 mg with or without HCTZ 12.5 mg, or HCTZ 12.5 mg, according to the randomization schedule. At Visit 4, subjects had their dose increased to ramipril 20 mg (administered once daily, or in equally divided doses twice daily), with or without HCTZ 25 mg (administered once daily), or HCTZ 25 mg as noted in Table 39. The subject remained on this dose for the duration of the Treatment Period. At the end-of-treatment 24-hour ambulatory blood pressure monitoring period began one day prior to Visit 7 (i.e., Visit 7a), and concluded the morning of Visit 7. Exclusion Criteria

[0386] A subject was eligible for enrollment if all of the following criteria apply:

1. Subject is able to understand the information in the informed consent form (ICF) and is willing and able to sign the written ICF prior to enrollment into the study.

2. Subject has either a previous diagnosis of essential hypertension, or has newly diagnosed hypertension according to the JNC 7 guidelines. To qualify for study entry, the subject must have a mean clinic sitting systolic blood pressure between 140 and 180 mm Hg (inclusive) at each of Visits 2 and 3, and a mean clinic SiDBP between 100 and 115 mm Hg (inclusive) at each of Visit 2 (or 2a or 2b, as applicable) and Visit 3.

3. Subject can be safely withdrawn from antihypertensive medications during the Screening/Washout/Placebo Lead-in Period.

4. Subject is male or female between 18 and 80 years of age (inclusive).

5. If female, subject must be:

• Of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal; post-menopausal is defined as permanent cessation of menses that has been documented for at least 1 year); or

• Surgically sterilized via hysterectomy, oophorectomy, or bilateral tubal ligation; or

• Of childbearing potential and using an acceptable method of contraception defined as systemic hormonal contraception (oral, implant, injection, patch, ring), diaphragm with intravaginal spermicide, cervical cap with spermicide, intrauterine device, or condom with spermicide. (NOTE: the subject must have used the chosen method of birth control for at least one month/cycle prior to enrollment into the study), and

• Not pregnant and/or not lactating.

[0387] A subject who met any of the following exclusion criteria was not enrolled.

Medical History/Current Medical Conditions

1. Known hypersensitivity to ramipril, HCTZ, sulfonamides, or other ACE inhibitors. 2. A mean clinic sitting blood pressure measurement above either 180 mm Hg systolic or 1 15 mm Hg diastolic during the Screening Period.

3. Subject has a >10 mm Hg difference between the mean SiDBP at Visit 2 (or 2a/2b, as applicable), and the mean SiDBP at Visit 3.

4. Secondary causes of hypertension such as pheochromocytoma, primary aldosteronism, chronic kidney disease, renal artery stenosis, or obstructive sleep apnea (according to the Investigator's judgment).

5. History of angioedema.

6. History of stroke within the past 3 years.

7. History of myocardial infarction or symptomatic angina pectoris within the past 3 years.

8. History of congestive heart failure (New York Heart Association [NYHA] Class 2-4). Note: subjects classified as NYHA Class 1 who do not require treatment with beta- blockers or diuretics may be enrolled.

9. Hypertensive retinopathy grade 3 or 4.

10. Second or third degree heart block, QT_C interval greater than 450 milliseconds in male subjects or greater than 500 milliseconds in female subjects, or other arrhythmias considered clinically relevant by the Investigator (or which requires anti-arrhythmic therapy).

1 1. Clinically significant renal disease (e.g., serum creatinine >2.5 mg/dL, and/or calculated glomerular filtration rate [GFR] <40 mL/minute, based on body surface area, and calculated by the Cockcroft-Gault method). NOTE: The Investigator should use clinical judgment in assessing renal disease status (e.g., assessing GFR in a small, elderly subject with a serum creatinine of 1.8 mg/dL).

12. Clinically significant hepatic disease (e.g., 2 times the upper limit of normal for alanine aminotransferase [ALT] or aspartate aminotransferase [AST]).

13. Active collagen vascular disease with sequelae.

14. History of thiazide-induced gout.

15. History of any disease state, or surgery, known to affect the gastrointestinal absorption of drugs.

16. Mental or psychiatric condition rendering the subject unable to understand the nature, scope, and possible consequences of the study. Medications/Therapies

17. Current use of concomitant antihypertensive medications including alpha-adrenergic blockers (e.g., tamsulosin) for the treatment of benign prostatic hyperplasia.

18. Use of 3 or more antihypertensive medications to control blood pressure prior to study entry.

19. A need for, or use of, any drug or nutraceutical known to increase or decrease blood pressure, or alter serum potassium concentrations.

20. Use of high-dose aspirin (i.e., >325 mg/day), nonsteroidal anti-inflammatory agents, or cyclooxygenase-2 (COX-2) inhibitors more than 3 times per week. Any dose of such medication is not allowed within 24 hours of a study visit. Also, such medications should not be started or stopped during the study. Note: Subjects on a stable dose of such medications (which include as needed doses up to 3 times per week) for >3 months prior to study entry, and who satisfy this criterion are eligible for entry. In addition, celecoxib doses of <200 mg daily are allowed in the study.

21. Use of lithium.

22. Inability to refrain from the use of the cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE₅) inhibitors Viagra^® (sildenafil) or Levitra^® (vardenafϊl) within 2 days of any study visit or ABPM session. Use of Cialis^® (tadalafil) is NOT permitted at any time during the study. The subject must be on a stable dose of the PDE₅ inhibitor for at least 30 days prior to signing the ICF.

23. Use of investigational medications or invasive devices within 30 days prior to study entry.

24. Use of systemic steroids (acute or chronic administration) during the study. NOTE: Inhaled, nasal, or topical steroids are permitted.

Social/Compliance

25. Subject has a history of chronic alcohol consumption and/or drug addiction within the past 2 years (DSM-IV TR).

26. Not willing, or unable, to follow procedures specified by the protocol and/or instructions of clinical study center personnel. Unable to comply with the outpatient visit schedule required by the protocol. Results

[0388] The randomized, double-blind, controlled trial with 3 monotherapy dose schedules (ramipril 20 mg QD, ramipril 10 mg BID, and HCTZ 25 mg QD) as comparators was carried out in 341 patients with Stage 2 hypertension. The clinic BP was assessed using a semi-automatic digital device and 24-hour BP was measured using ambulatory BP recordings at baseline and after 8 weeks of therapy. At baseline, the demographics and baseline BP values were similar in the 4 treatment groups (mean age = 51-53 years, 52-58% male, 64-68% non-black, mean clinic BP = 155-157/103-104 mm Hg). Ramipril-HCTZ induced greater reductions in both clinic and ambulatory BP than HCTZ alone and ramipril 20 mg once-a-day. The following data also shows that clinically meaningful blood pressure reduction can be achieved by administering to patients 20 mg of ramipril alone, either as a once-a-day dose of 20 mg of ramipril or, alternatively, a twice-a-day dose of 10 mg of ramipril. Reductions from baseline were typically greater for the clinic BP derived from device measurements compared to daytime BPs derived from ambulatory BP measurements. In conclusion, data supports the continued use of ambulatory BP monitoring even when automated BP devices are used for the assessment of clinical BP in trials that attempt to differentiate BP responses among active comparator groups. [0389] Figures 10.1 - 10.2 show a boxplot of change from baseline to end of treatment (Visit 7) in mean sitting diastolic and systolic blood pressure mm Hg) of 341 subjects. The box plot shows the smallest observed change in blood pressure, the upper quartile, the median, the lower quartile and the largest observed change in blood pressure. As shown in Figures 10.1 and 10.2 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering sitting diastolic and systolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. Additionally, the twice-a-day monotherapy of ramipril was more effective in lowering blood pressure than the once-a-day monotherapy of ramipril.

[0390] Figures 10.3 - 10.4 show a boxplot of change from baseline to end of treatment (Visit 7) in mean standing diastolic and systolic blood pressure (mm Hg) of 341 subjects. As shown in Figures 10.3 and 10.4 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering standing diastolic and systolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. Additionally, the twice-a-day monotherapy of ramipril was more effective in lowering blood pressure than the once-a-day monotherapy of ramipril.

[0391] Figures 10.5 - 10.6 show a boxplot of change from baseline to the first visit after baseline measurements were taken (Visit 4) in mean sitting diastolic and systolic blood pressure (mm Hg) of 330 subjects. As shown in Figures 10.5 and 10.6 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering sitting diastolic and systolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. [0392] Figures 10.7 - 10.8 show a boxplot of change from baseline to the first visit after baseline measurements were taken (Visit 4) in mean standing diastolic and systolic blood pressure (mm Hg) of 330 subjects. As shown in Figures 10.7 and 10.8 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering standing diastolic and systolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. [0393] Figures 10.9 - 10.10 show a boxplot of change from baseline to end of treatment (Visit 7) in mean 24-hour ambulatory diastolic and systolic blood pressure (mm Hg) of 232 subjects. Changes from baseline in the clinic sitting systolic and diastolic blood pressure were confirmed by the 24 hour ambulatory measurements. As shown in Figures 10.9 and 10.10 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering 24-hour ambulatory diastolic and systolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. Additionally, the twice-a-day monotherapy of ramipril was more effective in lowering blood pressure than the once-a-day monotherapy of ramipril.

[0394] Figure 10.1 1.1 shows a plot of mean sitting diastolic blood pressure over time by treatment group. As shown in Figure 10.1 1.1 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering the mean sitting diastolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. Figure 10.1 1.2 shows a plot of change from baseline (Visit 3) in mean sitting diastolic blood pressure over time by treatment group. As shown in Figures 10.11.2 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering the mean sitting diastolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril.

[0395] Figure 10.12.1 shows a plot of mean sitting systolic blood pressure over time by treatment group. As shown in Figures 10.12.1 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering the mean sitting systolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. Also, as shown in Figure 10.12.1 the twice daily monotherapy of ramipril was more effective in lowering the mean sitting systolic blood pressure than the once daily monotherapy of ramipril. Figure 10.12.2 shows a plot of change from baseline (Visit 3) in mean sitting systolic blood pressure over time by treatment group. As shown in Figures 10.11.2 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering the mean sitting systolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. Also, as shown in Figure 10.12.2 the twice daily monotherapy of ramipril was more effective in lowering the mean sitting systolic blood pressure than the once daily monotherapy of ramipril.

[0396] Figures 10.13 and 10.14 show plots of the mean ambulatory diastolic and systolic blood pressure (mm Hg) at baseline (Visit 3) by hour and treatment group. Figures 10.15 and 10.16 show plots of the mean ambulatory diastolic and systolic blood pressure (mm Hg) at the end of treatment (Visit 7) by hour and treatment group. [0397] Figures 10.17 - 10.18 show plots of change from baseline (Visit 3) to the end of treatment (Visit 7) in mean ambulatory diastolic and systolic blood pressure (mm Hg) by hour and treatment group. As shown in Figures 10.17 - 10.18 the once daily combination treatment of 20 mg of ramipril and 25 mg of HCTZ (R-20 mg QD + HCTZ - 25 mg QD) was more effective in lowering the mean ambulatory diastolic and systolic blood pressure than the monotherapies of 20 mg once daily treatment of ramipril (R-20 mg QD), 25 mg once daily treatment of HCTZ (HCTZ - 25 mg QD) and 10 mg twice daily treatment of ramipril. [0398] Tables 40 and 41 contain a summary of the mean hourly ambulatory diastolic and systolic pressure at hours 22, 23 and 24 at baseline (Visit 3) and end of treatment (Visit 7). Tables 40 and 41 show that the combination therapy of ramipril and HCTZ was more effective in lowering the ambulatory SBP and DBP at hours 22, 23, and 24 than ramipril and HCTZ monotherapies. Additionally, as shown in Tables 40 and 41 the combination therapy of ramipril and HCTZ showed a reduction in the increase in ambulatory trough blood pressure. Trough blood pressure is defined as blood pressure at 22-24 hours following the morning dose of the study drug, and 10-12 hours following the evening dose of the study drug.

Table 40.

R-20 mg QD +

HCTZ-25 mg OD (N= 78) R-2C I mg QD (N= 36) HCTZ-25 mg QD ( ^"N= 81) R-10 mg BID (N= : 55) 0

Hour Visit 3 Visit 7 ( Change ^ ^isit 3 Visit 7 Change Visit 3 Visit 7 Change Visit 3 Change

Hour 22 n 78 78 78 35 35 35 79 79 79 35 35 35

Mean 87.2 78.6 -8.6 85.8 80.2 -5.6 88.8 83.2 -5.6 87.1 81.8 -5.3

SD 13.48 12.26 13.90 13.12 12.39 10.87 11.70 12.33 12.29 10.08 12.99 10.68

Minimum 55.0 53.0 -39.0 65.0 56.0 -28.0 67.3 46.7 -32.0 68.3 57.5 -33.3

Median 85.4 77.8 -7.0 83.7 81.3 -4.8 88.5 82.8 -8.1 89.0 80.0 -7.3

Maximum 118.0 111.0 21.0 110.3 113.0 14.7 116.5 108.0 34.3 110.0 111.5 14.5

Hour 23 n 77 77 77 36 36 36 80 80 80 35 35 35

Mean 92.6 82.5 -10.1 93.2 89.3 -4.0 93.4 87.9 -5.5 94.5 88.2 -6.2

SD 12.17 13.48 13.02 11.86 12.22 13.65 12.54 12.69 11.82 9.59 12.84 11.05

Minimum 62.0 57.0 -56.8 65.0 59.0 -56.4 62.0 56.5 -29.9 74.7 65.0 -33.0

Median 93.0 81.7 -10.3 94.5 89.3 -3.2 92.9 86.3 -6.0 94.5 89.0 -5.5

Maximum 120.3 112.7 29.8 115.4 113.5 18.0 123.8 121.8 24.3 111.0 119.3 21.3

Hour 24 n 78 78 78 36 36 36 80 80 80 35 35 35

Mean 97.3 86.2 -11.2 98.6 92.7 -6.0 97.5 93.1 -4.4 98.2 91.5 -6.6

SD 12.37 11.45 10.53 10.27 10.22 11.09 9.70 11.09 11.69 8.17 10.99 10.18

Minimum 63.8 55.0 -40.3 67.8 73.0 -25.4 72.3 67.5 -30.3 74.6 68.7 -29.0

Median 96.9 86.9 -10.6 102.5 91.0 -5.7 98.6 93.5 -5.2 98.5 92.7 -4.2

Maximum 120.6 110.0 12.0 111.0 114.3 21.3 116.8 126.8 25.3 113.2 109.0 17.3

The ABPM start time at Visit 7 will define Hour 0 for hourly calculations at both Visits : 3 and 7. i n = number of subjects with data for the specified hour at Visit 3 and 1 Visit 7, . SD = standard deviation.

Table 41.

R-20 mg OD + HCTZ-25 mg QD (N= 78) R-20 mg QD (N= 36) HCTZ-25 mg QD (N= 81) R-IO mg BID (N= 35)

Hour Visit 3 Visit 7 Change Visit 3 Visit 7 Change Visit 3 Visit 7 Change Visit 3 Visit 7 Change

Hour 22 n 78 78 78 35 35 35 79 79 79 35 35 35

Mean 141.6 126.5 -15.2 141.3 131.0 -10.3 144.2 134.6 -9.6 140.0 130.3 -9.7

SD 18.15 15.59 18.29 18.54 16.65 16.13 17.65 17.11 15.96 14.91 19.55 16.76

Minimum 107.3 94.8 -63.7 112.0 103.0 -47.5 114.7 92.0 -45.0 110.0 97.7 -42.5

Median 139.0 124.9 -10.2 141.0 132.8 -7.7 141.7 130.3 -10.3 138.0 131.5 -11.0

Maximum 189.3 173.3 21.3 201.0 173.8 20.3 192.8 166.5 34.9 164.8 187.5 40.5

Hour 23 n 77 77 77 36 36 36 80 80 80 35 35 35

Mean 146.5 129.8 -16.7 149.9 141.8 -8.2 148.9 139.2 -9.6 148.2 139.2 -9.0

SD 17.29 16.88 17.27 17.67 16.52 19.64 17.78 17.44 15.98 16.01 18.70 16.89

Minimum 105.0 98.0 -69.3 114.3 108.8 -71.3 104.8 106.3 -53.7 112.3 104.3 -44.8

Median 149.0 129.0 -15.0 148.4 143.9 -4.9 149.6 138.6 -10.0 149.3 135.3 -8.0

Maximum 188.0 170.7 23.5 201.5 175.0 25.7 197.0 192.8 30.2 174.3 187.7 35.3

Hour 24 n 78 78 78 36 36 36 80 80 80 35 35 35

Mean 153.2 134.7 -18.5 155.2 145.6 -9.6 154.0 145.2 -8.8 154.6 143.5 -11.1

SD 17.65 15.51 15.7 14.71 13.66 14.94 14.57 14.89 16.29 12.81 15.22 14.22

Minimum 109.3 98.3 -61.5 118.5 115.5 -39.3 119.7 117.7 -54.8 119.0 109.0 -41.0

Median 154.0 135.3 -15.8 154.0 146.0 -11.0 152.6 143.3 -9.2 156.0 143.0 -10.3

Maximum 193.3 175.7 18.0 193.5 175.0 27.0 185.0 192.3 29.7 177.8 177.8 20.5

The ABPM start time at Visit 7 will define Hour 0 for hourly calculations at both Visits 3 and 7. n = number of subjects with data for the specified hour at Visit 3 and visit 7. SD = standard deviation.

[0399] Table 42 shows the average baseline sitting systolic (SiSBP) and sitting diastolic blood pressure (SiSBP) and the average baseline awake ambulatory blood pressure of the treatment group. Table 42 also shows the mean reduction in sitting systolic and diastolic blood pressure and ambulatory blood pressure from baseline at the end of treatment of the combination therapy group administered ramipril and HCTZ versus the monotherapy groups. Table 42 also shows the change in sitting systolic and diastolic blood pressure and ambulatory blood pressure at the end of treatment between the combination therapy group and the three monotherapy groups.

Table 42.

[0400] Table 42 shows that the combination therapy of ramipril and HCTZ was more effective in reducing sitting systolic blood pressure and the sitting diastolic blood pressure than the ramipril or HCTZ monotherapies. Also, as shown in Table 42, the combination therapy of ramipril and HCTZ was more effective in reducing mean 24-hour systolic blood pressure and the mean 24-hour diastolic blood pressure, measured as the awake ambulatory blood pressure, than the ramipril or HCTZ monotherapies. Achieving better 24-hour hypertension control with a once daily fixed dose of this combination will help reduce the risks associated with the increase in blood pressure that sometimes occurs at the end of dosing interval with monotherapy treatment.

[0401] Additionally, the twice daily administration of ramipril was more effective in reducing the sitting systolic blood pressure and the sitting diastolic blood pressure than the once-a-day administration of ramipril.

[0402] However, 20 mg of ramipril administered once-a-day was more effective in lowering the mean 24-hour blood pressure, measured as the awake ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DPB), than the twice daily administration of 10 mg of ramipril. Reductions in mean 24-hour blood pressure, as DBP and SBP were reduced from baseline by 6.7 mm Hg and 13.3 mm Hg, respectively, in patients taking 20 mg of ramipril once a day. Ambulatory blood pressure measurements have been shown to correlate better than office measurements for predicting adverse effects of high blood pressure on end organs such as the kidney, heart or brain.

[0403] The Tables 43-46 show the reduction from baseline at the end of treatment in mean sitting systolic blood pressure and the sitting diastolic blood pressure by subgroup. Table 43 shows the reduction from baseline at the end of treatment in mean sitting systolic blood pressure and the sitting diastolic blood pressure in individuals of African descent and individuals of non- African descent.

Table 43.

[0404] Table 43 shows that the combination therapy of ramipril and HCTZ was more effective than the other monotherapies in lowering the blood pressure of individuals of African and non-African descent. Additionally, Table 43 shows that the combination therapy of ramipril and HCTZ was as effective in individuals of African descent as individuals of non African descent. This, however, was not the case for the HCTZ and ramipril monotherapies. The once daily and twice daily monotherapies of ramipril was shown to be more effective in individuals of non- African descent than individuals of African descent. The HCTZ monotherapy was shown to be more effective in individuals of African descent than individuals of non African descent. Also, the twice-a-day monotherapy of ramipril was more effective in lowering the blood pressure in individuals of non- African descent than the once- a-day monotherapy of ramipril.

[0405] Table 44 shows the reduction from baseline at the end of treatment in mean systolic blood pressure and diastolic blood pressure in males and females.

Table 44.

[0406] Table 44 shows that the combination therapy of ramipril and HCTZ was more effective than the other monotherapies in lowering the blood pressure in males and females. Table 44 also shows that the combination therapy of ramipril and HCTZ was more effective in females than in males. The once daily monotherapy of ramipril was shown to be more effective in males than females. The once daily HCTZ monotherapy was shown to be more effective in females than males. Additionally, the twice daily administration of ramipril monotherapy was more effective in reducing the systolic blood pressure and diastolic blood pressure in females and the systolic blood pressure in males than the once daily monotherapy administration of ramipril. [0407] Table 45 shows the reduction from baseline to the end of treatment in mean systolic blood pressure and diastolic blood pressure in individuals younger than 65 years old and individuals 65 years and older.

Table 45.

[0408] Table 45 shows that the combination therapy of ramipril and HCTZ was more effective in reducing the systolic blood pressure and diastolic blood pressure than ramipril or HCTZ monotherapies in individuals less than 65 years old and more effective in reducing the diastolic blood pressure in individuals 65 years of age or more. Additionally, the once daily and twice daily ramipril monotherapies were shown to be more effective in individuals 65 years of age or older than individuals less than 65 years of age. Also, the twice daily ramipril therapy was more effective in lowering the systolic blood pressure in individuals 65 years or older than the single daily dose of ramipril. The HCTZ monotherapy was shown to be more effective in individuals 65 years of age or older than individuals less than 65 years of age. [0409] Table 45 shows the reduction from baseline at the end of treatment in mean sitting systolic blood pressure and the sitting diastolic blood pressure in naive individuals and individuals who were not naive. Naϊve individuals are individuals who had not previously received any medication for the treatment of hypertension until they were enrolled in the study. Non-naϊve individuals are individuals who have previously received medication for the treatment of hypertension before being enrolled in the study.

Table 46.

[0410] Table 46 shows that the combination therapy of ramipril and HCTZ was more effective in reducing the systolic blood pressure and the diastolic blood pressure than ramipril or HCTZ monotherapies in both naive and non-naϊve individuals. Table 46 also shows that the combination therapy of ramipril and HCTZ was more effective in naϊve individuals than non-naϊve individuals. This, however, was not the case for the HCTZ and the ramipril once daily monotherapies. The once daily and twice daily monotherapies of ramipril was shown to be more effective in lowering the diastolic blood pressure in naϊve individuals than non-naϊve individuals but more effective in lowering the systolic blood pressure in non-naϊve individuals than naϊve individuals. The HCTZ monotherapy was shown to be more effective in non-naϊve individuals than naϊve individuals.

[0411] Additionally, the twice daily administration of the ramipril monotherapy was more effective in reducing the systolic blood pressure and diastolic blood pressure than the once daily administration of ramipril monotherapy in naϊve and non-naϊve individuals. [0412] Table 47 shows the proportion of patients who met blood pressure goals at the end of treatment.

Table 47.

[0413] As shown in Table 47, a higher percent of the patient population treated with the combination of ramipril and HCTZ met the blood pressure goals at the end of treatment compared to the three monotherapies. [0414] Table 48 shows the adverse events according to the various treatment groups.

Table 48.

[0415] As shown in Table 48 the superior efficacy of the combination of ramipril and

HCTZ as compared to the ramipril and HCTZ monotherapies in patients with Stage 2 hypertension was not associated with an increase in adverse events or worsened tolerability compared to either monotherapy. [0416] The description and examples contained herein is for purposes of illustration and not for purposes of limitation. Changes and modifications may be made to the embodiments of the description and still be within the scope of the invention. Furthermore, obvious changes, modifications or variations will occur to those skilled in the art. Also, all references cited above are incorporated herein, in their entirety, for all purposes related to this disclosure.

Claims

WHAT IS CLAIMED:

1. A method for the treatment of hypertension comprising administering a tablet comprising from 2.5 mg to 10 mg of ramipril or a pharmaceutically acceptable salt at least twice a day.

2. The method of claim 1, wherein the ramipril is substantially stable against decomposition into a degradant product.

3. The method of claim 2, wherein the degradant product is ramipril-diacid or ramipril-diketopiperazine .

4. The method of claim 3, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

5. The method of claim 3, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

6. The method of claim 3, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

7. A method of reducing the sitting systolic blood pressure of an individual who has a sitting systolic blood pressure between about 140 and 180 mm Hg by orally administering to the individual a tablet comprising from at least 2.5 mg to 10 mg of ramipril at least twice daily.

8. The method of claim 7, wherein the ramipril is substantially stable against decomposition into a degradant product.

9. The method of claim 8, wherein the degradant product is ramipril-diacid or ramipril-diketopiperazine.

10. The method of claim 9, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

11. The method of claim 9, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

12. The method of claim 9, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

13. A method of reducing the sitting diastolic blood pressure of an individual who has a sitting diastolic blood pressure between about 100 and 115 mm Hg by administering to the individual a tablet comprising from at least 2.5 mg to 10 mg of ramipril at least twice a day.

14. The method of claim 13, wherein the ramipril is substantially stable against decomposition into a degradant product.

15. The method of claim 14, wherein the degradant product is ramipril-diacid or ramipril-diketopiperazine .

16. The method of claim 15, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

17. The method of claim 15, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

18. The method of claim 15, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

19. A method of improving therapeutic efficacy of ramipril in a female by administering to the female a tablet comprising at least 10 mg of ramipril at least twice a day.

20. The method of claim 19, wherein the female has been diagnosed with hypertension or diagnosed to be at risk for hypertension.

21. The method of claim 19, wherein the ramipril is substantially stable against decomposition into a degradant product.

22. The method of claim 21, wherein the degradant product is ramipril-diacid or ramipril-diketopiperazine.

23. The method of claim 22, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

24. The method of claim 22, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

25. The method of claim 22, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

26. A method of improving therapeutic efficacy of ramipril in an individual who is 65 years of age or older by administering to the individual a tablet comprising at least 10 mg of ramipril at least twice a day.

27. The method of claim 26, wherein the individual has been diagnosed with hypertension or diagnosed to be at risk for hypertension.

28. The method of claim 26, wherein the ramipril is substantially stable against decomposition into a degradant product.

29. The method of claim 26, wherein the degradant product is ramipril-diacid or ramipril-diketopiperazine .

30. The method of claim 29, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

31. The method of claim 29, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

32. The method of claim 29, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

33. A method of improving therapeutic efficacy of ramipril in an individual of non- African decent by administering to the individual a tablet comprising at least 10 mg of ramipril at least twice a day.

34. The method of claim 33, wherein the individual has been diagnosed with hypertension or diagnosed to be at risk for hypertension.

35. The method of claim 33, wherein the ramipril is substantially stable against decomposition into a degradant product.

36. The method of claim 35, wherein the degradant product is ramipril-diacid or ramipril-diketopiperazine .

37. The method of claim 36, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

38. The method of claim 36, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

39. The method of claim 36, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

40. A method of improving therapeutic efficacy of ramipril in a naive individual by administering to the individual a tablet comprising at least 10 mg of ramipril at least twice a day.

41. The method of claim 40, wherein the individual has been diagnosed with hypertension or diagnosed to be at risk for hypertension.

42. The method of claim 40, wherein the ramipril is substantially stable against decomposition into a degradant product.

43. The method of claim 42, wherein the degradant product is ramipril-diacid or ramipril-diketopiperazine .

44. The method of claim 43, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

45. The method of claim 43, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

46. The method of claim 43, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

47. A method of improving therapeutic efficacy of ramipril in a non-naϊve individual by administering to the individual a tablet comprising at least 10 mg of ramipril at least twice a day.

48. The method of claim 47, wherein the individual has been diagnosed with hypertension or diagnosed to be at risk for hypertension.

49. The method of claim 47, wherein the ramipril is substantially stable against decomposition into a degradant product.

50. The method of claim 49, wherein the degradant product is ramipril-diacid or ramipril-diketopiperazine .

51. The method of claim 50, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.4% by weight during about the first three months.

52. The method of claim 50, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 3.0% by weight during about the first thirty-six months.

53. The method of claim 50, wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less than about 0.12% by weight, on average, per month.

54. A method of treating hypertension comprising orally administering to a patient in need thereof at least twice daily a tablet comprising ramipril or a pharmaceutically acceptable salt, wherein the at least twice daily administration of the tablet is more effective in lowering blood pressure as a once daily dosage form having an equivalent amount of ramipril.

55. A method of reducing blood pressure in a patient comprising orally administering to a patient in need thereof at least twice daily a tablet comprising ramipril or a pharmaceutically acceptable salt, wherein the reduction in blood pressure of the patient is greater than the reduction of blood pressure in the patient if the patient is administered a once daily dosage form with the equivalent amount of ramipril.

56. A method for the treatment of hypertension comprising administering twice daily to a patient in need thereof a tablet comprising ramipril, wherein the increase in ambulatory trough blood pressure is less than the increase in ambulatory blood pressure when the patient is administered a once daily dosage form with the equivalent amount of ramipril.

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