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WO1993009778A2 - Use of brl 38227 for the treatment and prophylaxis of hyperlipidemia - Google Patents

Use of brl 38227 for the treatment and prophylaxis of hyperlipidemia Download PDF

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Publication number
WO1993009778A2
WO1993009778A2 PCT/GB1992/002141 GB9202141W WO9309778A2 WO 1993009778 A2 WO1993009778 A2 WO 1993009778A2 GB 9202141 W GB9202141 W GB 9202141W WO 9309778 A2 WO9309778 A2 WO 9309778A2
Authority
WO
WIPO (PCT)
Prior art keywords
hyperlipidemia
treatment
prophylaxis
brl
pharmaceutically acceptable
Prior art date
Application number
PCT/GB1992/002141
Other languages
French (fr)
Other versions
WO1993009778A3 (en
Inventor
Thomas Conway Hamilton
Timothy Charles Gadsden Tasker
David Robert Howlett
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1993009778A2 publication Critical patent/WO1993009778A2/en
Publication of WO1993009778A3 publication Critical patent/WO1993009778A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • the present invention relates to a method for the treatment and/or prophylaxis of hyperlipidemia.
  • EP-A-120428 (Beecham Group p.l.c.) describes the potassium channel activator, BRL 38227 and its use as an antihypertensive agent.
  • BRL 38227 lowers the level of plasma lipids such as triglycerides and cholesterol. As such, this compound is of value in the treatment of hyperlipidemia, and is especially useful in the lowering of lipid levels in hypertensive patients. It is also known that certain classes of compound tend to be associated with increasing lipid levels in patients, such as ⁇ -blockers or diuretics, thus, BRL 38227 in combination with ⁇ -blockers and/or diuretics has the potential of counteracting the lipid raising effects of these agents.
  • the present invention provides a method for the treatment and/or prophylaxis of hyperlipidemia especially that associated with ⁇ - blockers or diuretic therapy in mammals, such as humans, especially those also suffering from hypertension (which is concomitantly treated), which method comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic amount of BRL 38227, or a pharmaceutically acceptable salt thereof.
  • BRL 38227 is suitable for specifically reducing the percentage of low density lipoproteins (LDL) in patients as well as the percentage of triglycerides and cholesterol which are the lipids associated with artery hardening. The reduction of such lipids is believed to be of benefit to the patient.
  • LDL low density lipoproteins
  • HDL high density lipoproteins
  • BRL 38227 is the (-)-enantiomer of the compound of Example 1 of EP-A- 76075 and United States Patent No. 4446113, ( ⁇ )-6-cyano-3,4-dihydro-2,2- dimethyl-trans-4-(2-oxo- 1- pyrrolidinyl)-2H-benzo[b]pyran-3-ol.
  • Examples of pharmaceutically acceptable salts are as described in the aforementioned European Patent references, the subject matter of which are incorporated herein by reference.
  • references to BRL 38227 include solvates such as hydrates.
  • BRL 38227 may be prepared as described in the aforementioned Patent Publications/References, or as described in EP-A-385584 (Beecham Group p.l. ⁇ ).
  • BRL 38227 is in substantially pure pharmaceutically acceptable form.
  • the administration of the compound may be by way of oral, sublingual, transdermal or parenteral administration.
  • a unit dose will normally contain 0.1 to 50 mgfor example 0.5 to 10 mg, of BRL 38227.
  • Unit doses will normally be administered once or more than once a day, for example 2, 3, or 4 times a day, more usually 1 to 3 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 50 mg, for example 0.5 to 10 mg, that is in the range of approximately 0.001 to 1 mg/kg/day, more usually 0.005 to 0.2 mg/kg/day.
  • BRL 38227 is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral aoministration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, d luents, tabletting agents, lubricants, disintegrants, colourants, 5 flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, 10 polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional
  • additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated
  • coconut oil oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the potassium channel activator and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform, distribution of the compound.
  • formulations suitable for topical use may be employed, optionally containing penetration enhancers.
  • compositions will usually be accompanied by written or printed directions for use in the treatment concerned.
  • the present invention also provides the use of BRL 38227, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of hyperlipidemia especially that associated with ⁇ -blockers or diuretic therapy .
  • Such treatment and/or prophylaxis may be carried out as hereinbefore described.
  • the above use of BRL 38227 is especially beneficial to patients also suffering from hypertension, (which is concomitantly treated).
  • the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of hyperlipidemia especially that associated with ⁇ -blockers or diuretic therapy which comprises BRL 38227 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for use in the treatment and/or prophylaxis of hyperlipidemia especially that associated with ⁇ -blockers or diuretic therapy which comprises BRL 38227 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the above pharmaceutical composition is especially beneficial to patients also suffering from hypertension, (which is concomitantly treated).
  • compositions may be prepared in the manner as hereinbefore described.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

A method for the treatment and/or prophylaxis of hyperlipidemia in mammals, which method comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic amount of BRL 38227.

Description

USE OF BRL 38227 FOR THE TREATMENT AND PROPHYLAXIS OF HYPERLIPIDEMIA
The present invention relates to a method for the treatment and/or prophylaxis of hyperlipidemia.
EP-A-120428 (Beecham Group p.l.c.) describes the potassium channel activator, BRL 38227 and its use as an antihypertensive agent.
It has now been discovered that in hypertensive patients, BRL 38227 lowers the level of plasma lipids such as triglycerides and cholesterol. As such, this compound is of value in the treatment of hyperlipidemia, and is especially useful in the lowering of lipid levels in hypertensive patients. It is also known that certain classes of compound tend to be associated with increasing lipid levels in patients, such as β-blockers or diuretics, thus, BRL 38227 in combination with β-blockers and/or diuretics has the potential of counteracting the lipid raising effects of these agents.
Accordingly, the present invention provides a method for the treatment and/or prophylaxis of hyperlipidemia especially that associated with β- blockers or diuretic therapy in mammals, such as humans, especially those also suffering from hypertension (which is concomitantly treated), which method comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic amount of BRL 38227, or a pharmaceutically acceptable salt thereof.
It should be appreciated that the term hyperlipidemia refers to high lipid levels in general, however, BRL 38227 is suitable for specifically reducing the percentage of low density lipoproteins (LDL) in patients as well as the percentage of triglycerides and cholesterol which are the lipids associated with artery hardening. The reduction of such lipids is believed to be of benefit to the patient. On aolrninistration of BRL 38227 to a patient the percentage of high density lipoproteins (HDL) tends to increase, as does the ratio of HDL to total cholesterol. These increases are believed to have an overall beneficial effect on the patient.
BRL 38227 is the (-)-enantiomer of the compound of Example 1 of EP-A- 76075 and United States Patent No. 4446113, (±)-6-cyano-3,4-dihydro-2,2- dimethyl-trans-4-(2-oxo- 1- pyrrolidinyl)-2H-benzo[b]pyran-3-ol. Examples of pharmaceutically acceptable salts are as described in the aforementioned European Patent references, the subject matter of which are incorporated herein by reference.
References to BRL 38227 include solvates such as hydrates.
BRL 38227 may be prepared as described in the aforementioned Patent Publications/References, or as described in EP-A-385584 (Beecham Group p.l.α).
Preferably, BRL 38227 is in substantially pure pharmaceutically acceptable form.
The administration of the compound may be by way of oral, sublingual, transdermal or parenteral administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the severity of the disorder being treated and the weight of the mammal. However, a unit dose will normally contain 0.1 to 50 mgfor example 0.5 to 10 mg, of BRL 38227. Unit doses will normally be administered once or more than once a day, for example 2, 3, or 4 times a day, more usually 1 to 3 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 50 mg, for example 0.5 to 10 mg, that is in the range of approximately 0.001 to 1 mg/kg/day, more usually 0.005 to 0.2 mg/kg/day.
For oral or parenteral administration, it is greatly preferred that BRL 38227 is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral aoministration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use. Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, d luents, tabletting agents, lubricants, disintegrants, colourants, 5 flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, 10 polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
15 These solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
20
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional
25 additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated
30 coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
•*
35 Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the potassium channel activator and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform, distribution of the compound.
For transdermal administration, formulations suitable for topical use may be employed, optionally containing penetration enhancers.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the treatment concerned.
The present invention also provides the use of BRL 38227, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of hyperlipidemia especially that associated with β-blockers or diuretic therapy . Such treatment and/or prophylaxis may be carried out as hereinbefore described. The above use of BRL 38227 is especially beneficial to patients also suffering from hypertension, (which is concomitantly treated).
The present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of hyperlipidemia especially that associated with β-blockers or diuretic therapy which comprises BRL 38227 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The above pharmaceutical composition is especially beneficial to patients also suffering from hypertension, (which is concomitantly treated).
Such compositions may be prepared in the manner as hereinbefore described.
The clinical test results of BRL 38227 (3S,4R-6-cyano-3,4-dihydro-2,2- dimethyl-4-(2-oxopyrrolidin-l-yl)-2H-l-benzopyran-3-ol) are shown in the table.
BRL 38227 - LIPID PROFILE
% Change from Baseline following 8 weeks treatment
Figure imgf000007_0001

Claims

Claims
1. A method for the treatment and/or prophylaxis of hyperlipidemia in mammals, which method comprises administering to the mammal in need of such treatment and or prophylaxis an effective and/or prophylactic amount of BRL 38227, or a pharmaceutically acceptable salt thereof..
2. A method according to claim 1 in which the hyperlipidemia is associated with β-blocker or diuretic-agent therapy.
3. A method according to claim 1 in which the sufferer in need of treatment and/or prophylaxis of hyperKpidemia also has hypertension which is concomitantly treated.
4. A method according to claim 1 in which the lipid whose level is lowered is low density lipoprotein and/or triglycerides and/or cholesterol.
5. The use of BRL 38227, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of hyperlipidemia.
6. A use according to claim 5 in which the hyperlipidemia is associated with β-blocker or diuretic-agent therapy.
7. A use according to claim 5 in which the sufferer in need of treatment and/or prophylaxis of hyperlipidemia also has hypertension which is concomitantly treated.
8. A use according to anyone of claims 5 to 7 in which the lipid whose level is lowered is low density lipoprotein and/or triglycerides and/or cholesterol.
9. A pharmaceutical composition for use in the treatment and/or prophylaxis of hyperlipidemia which comprises BRL 38227, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition according to claim 9 in which the hyperlipidemia is associated with β-blocker or diuretic-agent therapy.
11. A pharmaceutical composition according to claim 9 for use in the treatment and/or prophylaxis of hyperlipidemia, concomitant treatment of hyperlipidemia.
12. A pharmaceutical composition in the treatment and/or prophylaxis of hyperlipidemia according to any one of claims 9 to 11 in which the lipid whose level is lowered is low density lipoprotein and/or triglycerides and/or cholesterol.
PCT/GB1992/002141 1991-11-21 1992-11-19 Use of brl 38227 for the treatment and prophylaxis of hyperlipidemia WO1993009778A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9124754.4 1991-11-21
GB919124754A GB9124754D0 (en) 1991-11-21 1991-11-21 Pharmaceuticals

Publications (2)

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WO1993009778A2 true WO1993009778A2 (en) 1993-05-27
WO1993009778A3 WO1993009778A3 (en) 1993-07-22

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GB (1) GB9124754D0 (en)
WO (1) WO1993009778A2 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8800199D0 (en) * 1988-01-06 1988-02-10 Beecham Group Plc Pharmaceutical preparation
GB8927980D0 (en) * 1989-12-11 1990-02-14 Beecham Group Plc Pharmaceuticals

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AU2949592A (en) 1993-06-15
GB9124754D0 (en) 1992-01-15
WO1993009778A3 (en) 1993-07-22

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