KR101207618B1 - Pharmaceutical formulation for treating cardiovascular disease - Google Patents

Abstract

The present invention relates to a pre-release compartment comprising Rosuvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, and amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. It provides a pharmaceutical formulation comprising a delayed-release compartment comprising a. The formulation of the present invention is configured to vary the dissolution rate of roschvastatin and amlodipine to prevent antagonism and side effects between drugs, and to facilitate the patient's taking by single administration of two drugs.

Hypertension, hyperlipidemia, amlodipine, roschvastatin, pharmaceutical preparations

Description

Pharmaceutical formulation for treating cardiovascular disease

The present invention relates to pharmaceutical preparations containing roschvastatin and amlodipine.

Atherosclerosis is a type of deformation caused by the loss of elasticity of the arterial wall and the thickening of the wall. The main causes of the disease are hypercholesterolemia, a type of hypertension and hyperlipidemia. diabetes association, Diabetic care, 23 (supple.), p. 57-65, 2000].

Therefore, lipid lowering therapies that delay the progression of atherosclerosis or induce regression of atherosclerosis have been studied to reduce the risk of cardiovascular disease, particularly coronary artery disease, in individuals diagnosed with hyperlipidemia or hypercholesterolemia. .

Statin-based lipid lowering drugs, on the other hand, are the first choice in the prevention and treatment of cardiac diseases caused by coronary atherosclerosis, such as angina pectoris and myocardial infarction [Lancet, 346, p. 750-753, 1995; Am J Cardiol, 82, p. 57-59 1998; Am J Cardiol, 76, p. 107-112, 1995; Hypertens Res, 26, p. 699-704, 2003; Hypertens Res, 26, p. 273-280, 2003; Br Med Bull, 59, p. 3-16, 2001; Am J Med, 104 (Suppl1), p. 6-8, 1998; Clin Pharmacokinet, 41, p. 343-370, 2002.

Among them, Rochevastatin is a drug that inhibits HMG-CoA reductase by regulating cholesterol synthesis pathway [US Pat. No. 6,858,618] and is elevated to primary hypercholesterolemia, and mixed dyslipidemia. Dietary supplements are known to reduce levels of total cholesterol, LDL-cholesterol, LDL-cholesterol-B apophore, and triglycerides and increase levels of high density lipoprotein (HDL) -cholesterol.

Calcium antagonists are one of the most prescribed anti-pressure drugs in combination with statin-based lipid-lowering drugs to relax arterial smooth muscle, reduce blood pressure, expand coronary arteries, and reduce coronary blood resistance [Cardiology, 80 (Suppl1), p. 31-36, 1992; J Cardiovasc Pharmacol, 12 (Suppl7), p. 110-113, 1988; Lancet, 356, p. 359-365, 2000; Hypertens Res, 25, p. 717-725, 2002; Hypertens Res, 25, p. 329-333, 2002.

In this regard, atherosclerosis can be obtained by administering a calcium channel blocker such as amlodipine, which is a therapeutic agent for hypertension, with lipid lowering agents [Kramsch et.al., Journal of Human Hypertension, (Suppl. 1), p.53. -59, 1995], especially in humans, calcium channel blockers are known to have beneficial effects in the treatment of early atherosclerotic lesions [Lancet, 335, p. 1109-1139, 1990; And Circulation, 82, p. 194-1953, 1990]. In addition, the expression of Orekkov et al. (Int J Cardiol, 62, p67-77, 1997) discloses the use of amlodipine in combination with a lipid lowering agent (lovastatin) for the treatment of atherosclerosis.

However, when roschvastatin and amlodipine move to the liver at the same time, amlodipine inhibits cytochrome P450 in the liver, and roschvastatin is not metabolized by cytochrome P450 and moves to the blood, reducing pharmacological effects and causing side effects such as muscle lysis. Cause. In addition, amlodipine may not be converted into amlodipine carboxylic acid, which is an active metabolite, due to competitive inhibition of the two drugs, and thus the original effect of amlodipine may be halved.

Therefore, simple co-administration of rochevastatin and amlodipine is not possible in effective drug delivery in consideration of pharmacological mechanisms such as metabolism of absorption distribution of drugs, resulting in side effects such as deterioration of therapeutic effect, induction of drug interactions and increase of side effects. .

Thus, the present inventors have completed the present invention as a result of research to develop a more effective pharmaceutical agent for the treatment of cardiovascular diseases that can prevent the mutual antagonism of the drug due to simultaneous or co-administration of a single agent.

The problem to be solved by the present invention is very effective in the treatment of hypertension and hyperlipidemia and the prevention of complications of people with metabolic syndrome, rosvastatin showing the effect of improving patient compliance, optimization of drug delivery time, avoiding drug interactions and reducing side effects And pharmaceutical preparations containing amlodipine.

The present invention provides a prior-release compartment comprising Rosuvastatin, an isomer thereof, or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and amlodipine (amlodipin), an isomer thereof, or a pharmacologically active ingredient thereof. A pharmaceutical formulation comprising a delayed-release compartment comprising an acceptable salt is provided.

Hereinafter, "Roschvastatin" is meant to include both isomers thereof and pharmaceutically acceptable salts thereof unless otherwise noted, and "amlodipine" is also its isomer and its pharmaceutically acceptable unless otherwise specified. It means to include all possible salts.

The formulation according to the present invention provides a more effective therapeutic effect by providing a physical compartment controlling the release between two active ingredients, thereby improving the problem of co-administration or co-administration of existing single agents.

The present invention provides a pharmaceutical formulation in which at least 80% of the total amount of roschvastatin is released within 30 minutes, preferably 15 minutes after the start of release.

The present invention also provides a pharmaceutical formulation in which amlodipine is released 2 hours after the start of roschvastatin release upon oral administration.

In addition, the present invention provides a pharmaceutical formulation in which roschvastatin is first released when released orally, and 80% or more is released within 30 minutes, and amlodipine is sufficiently delayed to release less than 40% within 4 hours after oral administration. do. Preferably, Rochevastatin is released at least 80% within 15 minutes, and amlodipine is sufficiently delayed to release at 30% or less within a total of 4 hours after oral administration.

The present invention also provides a pharmaceutical formulation in which amlodipine is all eluted within 8 hours.

The present invention provides a pharmaceutical formulation that is absorbed in the liver 2 to 4 hours later than amlodipine roschvastatin.

Pharmaceutical formulations of the present invention for implementing such drug delivery systems consist of amlodipine or its pharmaceutically acceptable salts, and desired excipients, so that they can be physically separated or partitioned to obtain different release times and rates of the two drugs. Delayed-release compartment and rochevastatin or a pharmaceutically acceptable salt thereof, and a prior-release compartment consisting of the desired excipient. In addition, the presently disclosed and delayed-release compartments can be implemented in various formulations.

Such pharmaceutical preparations of the present invention have an effective effect when taken once daily, between 5 and 11 pm.

Each component of the pharmaceutical formulation of the present invention will be described in more detail as follows.

1.Preventive compartment

Pre-release compartment refers to the compartment that is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention, includes roschvastatin as a pharmacologically active ingredient, and further includes a pharmaceutically acceptable additive as necessary. can do.

In the present invention, the prior release compartment is in the form of a mixture, granules, pellets, or tablets through conventional procedures for preparing oral administration agents such as mixing, coalescing, drying and granulation together with pharmaceutically acceptable additives in addition to roschvastatin. It can manufacture. In addition, in the case where the fluidity is not good and tableting is not possible directly, it may be compressed, granulated, and granulated to granulate.

(1) pharmaceutical active ingredients

The pharmacologically active component of the prior release compartment comprises roschvastatin, its isomers or pharmaceutically acceptable salts wherein the isomers of roschvastatin are the (R, R) isomers, (R, S) isomers, (S, R) Means an isomer or an optical isomer such as the (S, S) isomer.

In the formulation of the present invention, roschvastatin, which is an active ingredient in the prior-release compartment, is 1 to 160 mg of the formulation (200 mg to 1,200 mg total), preferably 5 to 80 mg, on a daily basis for an adult (65 to 75 kg adult male). It includes.

Roschvastatin in the prior-release compartment releases at least about 80% of the total amount of roschvastatin in the unit formulation within 1 hour, preferably within 30 minutes, more preferably within 15 minutes after initiation of release, resulting in rapid drug efficacy. Can be.

(2) pharmaceutically acceptable additives

The pre-release compartment of the present invention may use additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusting agents, stabilizers, dissolution aids and the like within the scope of not impairing the effects of the present invention.

In the prerelease compartment of the present invention, the additive comprises 0.01-100 parts by weight with respect to 1 part by weight of roschvastatin.

The diluent in the pre-release compartment of the present invention may use starch, microcrystalline cellulose, lactose monohydrate, glucose, di-mannitol, alginate, alkaline earth metal salts, clays, polyethylene glycols, anhydrous calcium hydrogen phosphate, or mixtures thereof. have.

In the pre-release compartment of the present invention, the binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, natural gum, Synthetic gum, copovidone, gelatin, mixtures thereof, and the like. The disintegrating agent in the prior-release compartment of the present invention may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.

In the prior release compartment of the present invention, the lubricant is talc, stearic acid, magnesium stearate, calcium stearate, sodium laurylsulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monolate , Glyceryl monostearate, glyceryl palmitostearate, or a mixture thereof can be used.

In the pre-release compartment of the present invention, the pH adjusting agent may use acidifying agents such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and basicizing agents such as precipitated calcium carbonate, aqueous ammonia, meglumine, and the like. have.

In the pre-release compartment of the present invention, stabilizers may be used alkalizing agents which are salts of alkali metals, salts of alkaline earth metals, or mixtures thereof. As the salt of the alkali metal and the salt of the alkaline earth metal, calcium carbonate, sodium carbonate, sodium hydrogen carbonate, magnesium oxide, magnesium carbonate, sodium citrate, tribasic calcium phosphate, and the like can be used.

In the pre-release compartment of the present invention, the dissolution aid may be polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, sodium docusate and the like.

In addition, a pharmaceutically acceptable additive may be selected and used in the preparation of the present invention as various additives selected from colorants and fragrances.

The range of additives usable in the pre-release compartments of the present invention is not limited to the use of such additives, and the additives described above may be formulated containing a range of doses in a usual range by selection.

2. Delayed release block

In the present invention, the delayed-release compartment refers to a compartment in which the active ingredient is released after a certain time of release of the prior-release compartment active ingredient. The delayed-release compartment comprises (1) the pharmacologically active ingredient amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof, and (2-1) a release controlling substance or (2-2) an osmotic pressure regulator and a semipermeable membrane coating base. If necessary, (3) may further include a pharmaceutically acceptable additive.

(1) pharmacologically active ingredients

The pharmacologically active ingredient of the delayed-release compartment includes amlodipine and a pharmaceutically acceptable salt, wherein the active ingredient in the delayed-release compartment may comprise about 1-100 mg of amlodipine in the unit formulation, with 1-20 mg being preferred.

In the formulations of the present invention, amlodipine is released at no more than 30% of the total amount of amlodipine in the unit formulation up to 3 hours after initiation of release of roschvastatin, and preferably at no more than 20%, leaving the liver at a time difference from roschvastatin. Metabolized in

(2-1) Release control substance

The delayed-release compartment in the pharmaceutical formulation of the present invention comprises at least one release controlling substance selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers. And at least one release controlling material selected from water-insoluble polymers and hydrophilic polymers.

In the delayed-release compartment of the present invention, the release control material may be used in an amount of 0.05 to 100 parts by weight based on 1 part by weight of amlodipine, and when the amount is less than the above range, sufficient delayed release property cannot be obtained. This delay results in no significant clinical effect.

The enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or higher. The enteric polymer usable in the present invention is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative, and the enteric cellulose derivative is hydroxypropylmethylcellulose acetate succinate. Nate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl At least one selected from cellulose, ethyl hydroxyethyl cellulose phthalate and methyl hydroxyethyl cellulose; The enteric acrylic acid copolymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylates (e.g., acrylics), butyl-styrene acrylate-acrylic acid copolymers, methacrylic acid-methacrylates Methyl acid copolymer (e.g. Eudragit L 100, Eudragit S, Evonik, Germany), methacrylic acid-ethyl acrylate copolymer (e.g. Eudragit L 100-55, Evonik, Germany), and At least one selected from methyl acrylate-methacrylic acid and octyl acrylate copolymer; The enteric maleic acid-based copolymer may be a vinyl acetate-maleic anhydride copolymer, a styrene-maleic anhydride copolymer, a styrene-maleic acid monoester copolymer, a vinyl methyl ether-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, or a vinyl butyl ether At least one selected from maleic anhydride copolymer, acrylonitrile-methyl methacrylate-maleic anhydride copolymer, and butyl styrene-maleic-maleic anhydride copolymer; The enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetacetal phthalate. In the formulation of the present invention, the enteric polymer is preferably one or more selected from methyl methacrylate acrylic acid copolymer and hydroxypropyl methylcellulose source phthalate.

The enteric polymer according to the present invention may be included in an amount of 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight, and less than 0.1 parts by weight compared to amlodipine. There is a problem that the total weight of the formulation is unnecessarily large or excessively delayed dissolution.

The water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug. The water insoluble polymers usable in the present invention include polyvinyl acetate, polymethacrylate copolymers, poly (ethylacrylate-methyl methacrylate) copolymers, poly (ethylacrylate-methyl methacrylate-trimethylaminoethylmethacrylate Copolymers (e.g. Eudragit RS30D), ethylcellulose, cellulose esters, cellulose ethers, cellulose acylates, cellulose dicylates, cellulose triacylates, cellulose acetates, cellulose diacetates and cellulose triacetates It is one or more selected. In the formulation of the present invention, the water-insoluble polymer is selected from polyvinyl acetate (colicoat SR30D), poly (ethylacrylate-methyl methacrylate-trimethylaminoethylmethacrylate) copolymer (eudragit RS30D) and cellulose acetate. It is preferable that it is a species or more.

The water-insoluble polymer according to the present invention may be included in an amount of 0.1 to 30 parts by weight, preferably 0.5 to 20 parts by weight, and less than 0.1 parts by weight, and the release of the drug is not controlled. In this case, excessive dissolution is delayed.

The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug. The hydrophobic compounds usable in the present invention are selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof, and the fatty acids and fatty acid esters are glyceryl palmitostearate, glycerol. At least one selected from aryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl mono oleate, and threaric acid; The fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol; The wax is at least one selected from carnauba wax, beeswax, and microcrystalline wax; The inorganic substance is at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum.

The hydrophobic compound according to the present invention may be included in an amount of 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight, and less than 0.1 parts by weight of the amlodipine. There is a problem that elution is excessively delayed.

The hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug. The hydrophilic polymer usable in the present invention is selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. At least one selected from dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin ; The cellulose derivative is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, and hydroxyethyl methyl cellulose. One or more; The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, and xanthan gum; The protein is at least one selected from gelatin, casein, and zein; The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate; The polymethacrylate copolymer is poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer, poly (methacrylate-methylmethacrylate) copolymer, and poly One or more selected from (methacrylic acid-ethylacrylate) copolymers; The polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide; And the carboxyvinyl polymer is carbomer. Preferably hydroxypropyl cellulose and polymethacrylate copolymer are used, more preferably poly (methacrylic acid-methyl methacrylate).

The hydrophilic polymer according to the present invention may be included in 0.05 to 30 parts by weight, preferably 0.5 to 20 parts by weight with respect to 1 part by weight of amlodipine, when the release rate is less than 0.05 parts by weight, there is a problem that the release rate is not controlled, 30 parts by weight If it exceeds, there is a problem that the release rate is not controlled, if more than 30 parts by weight excessive dissolution is delayed.

Preferred release controlling substances of the present invention are hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate, polyvinylacetate, polymethacrylate copolymer, ethyl cellulose, poly (methacrylate, methyl Methacrylate) copolymer, and at least one selected from the group consisting of methyl methacrylate copolymer, or hydroxypropyl cellulose, cellulose acetate, ethyl cellulose, poly (methacrylate, methyl methacrylate) copolymer At least one selected from the group consisting of:

(2-2) Osmotic pressure regulator and semipermeable membrane coating base

The delayed-release compartment of the present invention includes an osmotic pressure control agent and may be a compartment coated with a semipermeable membrane coating base.

In the delayed-release compartment of the present invention, the osmotic pressure regulator is at least one selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate, and mixtures thereof. Preferably sodium chloride and sodium sulfate are used.

Here, the osmotic pressure regulator may be included in 0.05 parts by weight to 30 parts by weight, preferably 0.1 to 20 parts by weight in 1 part by weight of amlodipine, when less than 0.1 parts by weight, the osmotic pressure generating effect is weak, and more than 30 parts by weight In this case, there is a problem in that it is impossible to unnecessarily increase the total weight of the formulation or to realize a suitable drug release rate.

In the delayed-release compartment of the present invention, the semi-permeable membrane coating base is a pharmaceutically usable coating base, which is formulated into the coating layer of the pharmaceutical formulation to be used to form a film which allows some components to pass but not others. It is also possible to use the above-mentioned water insoluble polymer. The semipermeable membrane coating base in the present invention is, for example, polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate 1) selected from the group consisting of copolymers, ethyl cellulose, cellulose esters, cellulose ethers, cellulose acylates, cellulose diacetates, cellulose triacylates, cellulose acetates, cellulose diacetates, cellulose triacetates, and mixtures thereof Or more species.

Here, the semi-permeable membrane coating base may be included in an amount of 0.05 parts by weight to 30 parts by weight, preferably 0.1 parts by weight to 20 parts by weight, and less than 0.05 parts by weight with respect to 1 part by weight of amlodipine. In the case of more than 30 parts by weight, there is a problem in that the release of the drug does not occur or the delay time is over 9 hours or longer.

(3) pharmaceutically acceptable additives

The formulations of the present invention are diluents, binders, and borates other than those mentioned as pharmaceutically acceptable (2-1) release controlling substances and (2-2) osmotic pressure regulators and semipermeable membrane coating agents within the scope of not impairing the effects of the present invention. Commonly used additives such as releases, lubricants, pH adjusters, antifoams, dissolution aids and the like can be formulated further using within a range not departing from the nature of delayed release.

For example, as a diluent, starch, microcrystalline cellulose, lactose monohydrate, glucose, mannitol, di-mannitol, alginate, alkaline earth metal salts, clays, polyethylene glycols, anhydrous calcium hydrogen phosphate, or mixtures thereof may be used. ; Starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, povidone, gelatin Or mixtures thereof.

As a disintegrant, starch or modified starches, such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch (starch gelatinized starch); Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.

Talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, colloidal silicon dioxide, sodium stearyl fumarate, glyceryl behenate, glyceryl monolate, glyceryl monostearate , Glyceryl palmitostearate, polyethylene glycol and the like can be used.

As a pharmaceutically acceptable additive of the present invention, the pH adjusting agent may include acidifying agents such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and basicizing agents such as precipitated calcium carbonate, aqueous ammonia, and meglumine. Can be used.

As the pharmaceutically acceptable additive of the present invention, the antifoaming agent may use dimethicone, oleyl alcohol, propylene glycol alginate, simethicone such as simethicone emulsion and the like.

In the pharmaceutically acceptable additives of the present invention, the dissolution aid may be polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium and the like. It is also possible to add a plasticizer such as triethyl citrate.

In addition, a pharmaceutically acceptable additive may be selected and used in the preparation of the present invention as various additives selected from colorants and fragrances. The range of additives usable in the present invention is not limited to the use of such additives, and the above additives may be formulated to contain a range of dosages, usually by selection.

In addition, in the delayed-release agent of the present invention, purified water, ethanol, methylene chloride, and the like may be used as a solvent of the binding solvent and the delayed-release additive, and more preferably purified water and ethanol.

In the pharmaceutically acceptable additives of the present invention, the range of usable additives is not limited to the use of such additives, and the above-mentioned additives may be formulated to contain a range of dosages by selection.

The formulations of the present invention can be prepared in a variety of formulations, for example, can be formulated in tablets, powders, granules, capsules and the like, such as uncoated tablets, coated tablets, multi-layered tablets, or nucleated tablets.

The preparations of the present invention are tablets prepared by selectively mixing additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like. This may be in the form of uncoated tablets will be eluted separately to show the respective effects.

The formulation of the present invention may be in the form of a biphasic matrix tablet consisting of the delayed-release compartment and the pre-release compartment surrounding it.

In addition, the formulation of the present invention may be in the form of a film coated tablet consisting of a tablet consisting of a delayed-release compartment and a film-coating layer composed of a pre-release compartment surrounding the outside of the tablet, the film coating layer as the Roche bar of the film coating layer dissolved Statins are eluted first.

In addition, the formulation of the present invention is obtained by mixing the pharmaceutical additives in the granules constituting the delayed-release compartment and the prior-release compartment, and tableting into double or triple wells using a multiple tableting machine, delayed-release compartment and pre-release The compartments may be in the form of multi-layered tablets forming a multi-layered structure. Each layer constituting the multilayer tablet may be in a parallel state. This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.

In addition, the formulation of the present invention may be in the form of a nucleated tablet consisting of an inner core consisting of a delayed-release compartment and an outer layer composed of a prior-release compartment surrounding the outer surface of the inner core. The nucleated tablet may be an osmotic nucleated tablet, and the osmotic nucleated tablet contains an osmotic agent inside the tablet for tableting for delayed release, followed by tableting, followed by coating the surface of the tablet with an osmotic semipermeable membrane coating agent to make it an inner core. In addition, the granules constituting the pre-release compartment are mixed with pharmaceutical additives and compressed into an outer layer to have a delayed-release inner core, and the surface of the inner core is surrounded by a pre-release layer.

The formulations of the present invention may be in the form of particles, granules, pellets, or capsules comprising tablets and particles, granules, pellets, or tablets, which consist of delayed-release compartments.

The tablet consisting of the delayed-release compartment of the capsule may include an osmotic pressure-controlling agent within the tablet and an osmotic coated tablet having a semipermeable membrane coating base on the surface of the tablet.

The material of the capsule may be one selected from gelatin, succinate gelatin, or hydroxypropyl methyl cellulose, or a mixture thereof.

The formulations of the present invention may further form a coating layer on the outside of the delayed release compartment and / or the prior release compartment. That is, the surface of particles, granules, pellets, or tablets, etc., which are composed of delayed-release compartments and / or pre-release compartments, may be coated for the purpose of delayed release or stabilization of the formulation.

The formulation according to the present invention may be provided in a state such as uncoated tablet without additional coating, but may be in the form of a coated tablet further comprising a coating layer by forming a coating layer on the outside of the formulation, if necessary. By forming the coating layer, it is possible to provide a formulation that can further ensure the stability of the active ingredient.

The method of forming the coating layer may be appropriately selected by a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer, a method such as a fluidized bed coating method, a fan coating method may be applied, and preferably Fan coating can be applied.

The coating layer may be formed by using a coating agent, a coating aid, or a mixture thereof. For example, the coating agent may be a cellulose derivative such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, or fatty acids. Gelatin, mixtures thereof, and the like; Coating aids may include polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, or mixtures thereof.

The coating layer may include 0.5 to 15% by weight based on the total weight of the tablet.

By taking the formulation of the present invention once a day, especially in the evening (17-23 hours), the effects of each active ingredient can be maximized and side effects can be minimized. In general, an important factor to consider in the treatment of hypertension and hyperlipidemia is biorhythm. For example, the lipid synthesis in the liver becomes vigorous after early dinner, and the blood pressure of the general public, including people with high blood pressure, drops between night and dawn, and the blood pressure starts to rise in the morning after waking up, peaking during the day (active). This leads to. Considering this fact, when the preparation of the present invention is taken in the evening, the pre-release roschvastatin is administered at the time when the liver enzyme is activated, which shows a greater lipid lowering effect and delayed-release blood pressure after dawn by amlodipine. This effectively lowers blood pressure evenly from dawn to morning, avoiding the drug's competitive antagonism and maximizing the effectiveness of each active ingredient.

The pharmaceutical preparations of the present invention may be formulated using a time-dose dosing principle disclosed in Chrontherpeutics (2003, Peter Redfern, PhP) by any suitable method in the art, and specifically, in a method comprising the following steps: Can be prepared by

The first step is to mix, associate, dry, granulate, or coat amlodipine by administering one or two of the release controlling substances selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, and a hydrophilic polymer with a conventional additive used in pharmaceuticals, And obtaining delayed-release granules or tablets through tableting, or mixing, association, drying, sizing, or tableting amlodipine with an osmotic pressure-controlling agent and a conventional additive used in pharmaceuticals, and then coating with a semi-permeable membrane coating base to delay-release Obtaining granules or tablets.

The second step is a pre-release granule obtained through a conventional procedure for producing oral solids by mixing, coalescing, drying, granulating or coating, and tableting by administering roschvastatin and a pharmaceutically acceptable conventional additive, or Obtaining tablets.

In the third step, the granules or tablets obtained in the first step and the second step are mixed with pharmaceutical excipients, tableted or filled to obtain a preparation for oral administration.

The first step and the second step may be reversed or executed simultaneously.

The composite formulation of the present invention may be prepared by the above process, and the formulation method is described in more detail as follows, but is not limited thereto.

[A] Preparation of two-phase matrix tablet

The particles or granules obtained in the first step are further coated as they are or with a release controlling material, and then mixed with the granules prepared in the second step and compressed into a certain amount of weight to prepare a tablet. The obtained tablet can be film coated as necessary for the purpose of improving stability or property.

[B] Preparation of Film-Coated Tablets Containing Active Ingredients

The coated tablets or granules obtained in the first step are further coated as they are or with a release control material, dried, and then compressed into a predetermined amount to prepare tablets as they are or further coated, and then separately dissolve Rochevastatin in an aqueous film coating solution. By dispersing the coating on the tablet outer layer obtained in the first step it can be prepared orally administered film coating tablet containing the active ingredient in the film coating.

Preparation of multi-layered tablets

The granules obtained in the first step as they are or are additionally coated and dried with a release controlling substance and the granules obtained in the second step can be prepared in double tablets using a tablet press. Coated multi-layered tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release aid layer as needed, or by formulation.

[D] Preparation of Nucleated Tablets

The coated tablet or granules obtained in the first step are additionally coated as it is or with a release control material, dried, and then compressed into a predetermined amount to be coated as it is or additionally to the inner core, followed by a nucleated tableting machine together with the granules obtained in the second step. The coated nucleated tablet may be prepared by preparing or coating a nucleated tablet in a form surrounded by a pre-release layer on the surface of the first-stage tablet.

[E] Preparation of Capsules (Granules or Tablets)

The granules obtained in the first step are additionally coated as is or with a release controlling substance, and the dried granules or tablets and the granules or tablets obtained in the second step are placed in a capsule charger and filled into capsules of a predetermined size by an effective amount of each active ingredient in an appropriate amount. Can be prepared.

[Bar] Preparation of capsules (pellets)

(1) Dissolve or suspend amlodipine and the release control material and, if necessary, pharmaceutically acceptable additives in water, an organic solvent, or a mixed solvent and coat the spherical granules with sugar, and release the release control material alone or as necessary. Capsules may be prepared by dissolving in water, an organic solvent or a mixed solvent using more than one species, coating, drying, granulating obtained in the second step or tablets obtained in the third step, and then mixing the capsules and filling the capsule with a capsule filler. have.

(2) After dissolving or suspending the Cheloschvastatin and pharmaceutically acceptable additives in water, an organic solvent or a mixed solvent, coating the spherical granules with sugar and drying them, followed by mixing with the release control pellet containing amlodipine as described in (1). A capsule may be prepared by filling the capsule with a capsule filling machine.

[Product] Kit Preparation

The amlodipine-containing preparation obtained in the first step and the rochevastatin-containing preparation obtained in the second step can be prepared together with a foil, blister, bottle, or the like to be used as a kit.

The combination drug system of the present invention as described above is formulated with a combination of amlodipine and roschvastatin as active ingredients to be administered only once in the evening hours, so that each medication is formulated separately and compared to take it at the same time Easy and also do not occur antagonism between the drugs can reduce the side effects due to the antagonism, blood pressure control and lipid control effect of each drug appears to be improved than their own effect alone.

In the present invention, in order to prevent the amlodipine from interfering with the hepatic action of Rochevastatin, Rochevastatin is first composed of a prior-release compartment to be absorbed first in the small intestine, and amlodipine is 2 hours to 4 hours later than Rochevastatin. It is composed of delayed-release compartments that can be absorbed by the liver.

The preparation of the present invention prevents antagonism and side effects between drugs by varying the elution time of the active active ingredients of amlodipine and roschvastatin, which affect or receive the same enzyme, the cytochrome P450 enzyme. Pharmacological and clinical studies in the prevention or treatment of cardiovascular, cardiopulmonary, pulmonary or renal disease in patients with metabolic syndrome and insulin resistance and patients suspected of diabetes or prediabetes, compared to the combination regimen in which the drug components are taken simultaneously simultaneously. It has the effect of making it scientifically, scientifically and economically more useful.

In addition, according to the present invention, since the composite composition can be taken at a time, the medication guide and the medication for the patient are easy.

Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various different forms, only the embodiments are to make the disclosure of the present invention complete and have ordinary skill in the art to which the present invention belongs. It is provided to fully inform the scope of the invention, and the invention is defined only by the scope of the claims.

Example 1 Preparation of Nucleated Tablets

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

(1) Preparation of prior-release compartments (Rochevastatin prior-release granules)

Rochevastatin calcium (MSN, INDIA), tribasic calcium phosphate, microcrystalline cellulose (AvicelPH101, FMC Biopolymer, USA), lactose hydrate (DMV, Germany), pregelatinized starch (Starch 1500G, Colorcon, USA) Then, a mixture was prepared by mixing at room temperature for 5 minutes using a double cone mixer (Dasan Pharmatech, Korea). Separately, hydroxypropyl cellulose (HPC-L, Nippon Soda, Japan) was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer (H-W-C, Samgong, Japan). Crospovidone was mixed with the sieved material, and magnesium stearate (Nitika Chemical, India) was added thereto, followed by final mixing in a double cone mixer to prepare the title-releasing compartment.

(2) Production of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, pregelatinized starch (Starch 1500G, Colorcon, USA) were apples with No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer (H-W-C, Samgong, Japan). Separately, a solution obtained by dissolving cellulose acetate 320S (acetal group 32%) and cellulose acetate 398-10NF (acetal group 39.8%) in a mixture of ethanol and methylene chloride was prepared to prepare a fluidized bed granulation coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Pharmatech, Korea) equipped with a 5 mm diameter punch to prepare a core tablet having a titled delayed-release compartment.

(3) tableting and coating

A nucleocrystal tableting machine (RUD-1: Kilian, Germany) equipped with an 11 mm punch was used as the outer layer of the Roschvastatin calcium pre-release granules of (1), and the amlodipine besylate delayed-release tablet of (2) was used. It was compressed into a nuclear tablet. Separately, hydroxypropylmethylcellulose 2910 (Shin-etsu, Japan), polyethylene glycol 6,000 (BASF, Germany), talc (Luzenac, France) and titanium oxide (Tioside Americas, USA) were dissolved and dispersed in ethanol and purified water. To prepare the tablet in the form of a nucleated tablet by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example 2 Preparation of Nucleated Tablets

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

(1) Preparation of prior-release compartments (Rochevastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, pregelatinized starch and apples in No. 35 were mixed and mixed for 5 minutes at room temperature in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 18 sieve, and dried at 60 ° C. using a hot water dryer, and then established in No. 20 sieve. Crospovidone was mixed with the sieved material, and magnesium stearate was added thereto, followed by final mixing in a double cone mixer to prepare the title-releasing compartment.

(2) Production of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch were appled in a No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water and combined and granulated as a binding liquid, which was dried at 60 ° C. using a hot water dryer, and then sieved to No. 20 sieve. Separately, a solution of Eudragit RS30D (Evonik Degussa, Germany) and triethyl citrate (Vertellus, England) was prepared in methylene chloride, and the above formulation was placed in a fluid bed granulator coater and coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Pharmatech, Korea) equipped with a 5 mm diameter punch to prepare a core tablet having a titled delayed-release compartment.

(3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example (3).

Example 3 Preparation of Nucleated Tablets

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

(1) Preparation of prior-release compartments (Rochevastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate and pregelatinized starch were appled in a No. 35 sieve and mixed for 5 minutes at room temperature in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, the mixture was established as a No. 20 sieve, and then the crospovidone was mixed with the sieved material. Magnesium stearate was added and finally mixed with a double cone mixer to prepare the title-release compartment.

(2) Production of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, microcrystalline cellulose, di-mannitol (Roquette, USA) were apples in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, polyvinylpyrrolidone (Kollidon 30, BASF, Germany) was dissolved in purified water, combined and granulated as a binder, and dried at 60 ° C. using a hot water dryer. Separately, a solution obtained by dissolving ethyl cellulose (HERCULES, USA) and poly (methacrylate, methyl methacrylate) copolymer (Evonik degussa, USA) in a mixture of ethanol and methylene chloride was prepared, and the above formulation was placed in a fluidized bed granulator coater. Coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press equipped with a 5 mm diameter punch to prepare a titled delayed-release compartment.

(3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example (3).

Example 4 Preparation of Nucleated Tablets

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate and pregelatinized starch were appled in a No. 35 sieve, and mixed in a double cone mixer at room temperature for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture at room temperature. After the association, granulation was carried out using an oscillator in No. 18 sieve, and dried at 60 ° C. using a hot water dryer, and then established in No. 20 sieve. Sodium starch glycolate (DMV, Germany) and magnesium stearate were added to the sieved material, followed by final mixing at room temperature with a double cone mixer to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release tablet)

Amlodipine maleate (Daehee Chemical, Korea) A microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and di-mannitol were appled with a No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, and then it was associated and granulated with a mixture of the main components, which was dried at 60 ° C. using a hot water dryer, and then formed into No. 20 sieve. Magnesium stearate sieved through No. 35 sieve was added to the sieved material, followed by mixing for 4 minutes to prepare HMG-CoA reductase inhibitor delayed-elution layer granules. HMG-CoA reductase inhibitor delayed rapid dissolution granules were compressed into tablets with a rotary tablet press equipped with a 5 mm diameter punch to prepare nuclear tablets. Separately, a coating solution obtained by dissolving and dispersing acryl- (methacrylic acid copolymer type C, talc, PEG, colloidal silicon dioxide, sodium bicarbonate, SLS, Colorcon, USA) in purified water was prepared to prepare the above amlodipine tablet as a high coater. A coating layer was formed to prepare the amlodipine tablet, the title delayed-release compartment.

(3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example (3).

Example 5 Preparation of Nucleated Tablets

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

(1) Preparation of prior-release compartments (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, corn starch (Colorcon, USA), weighed in apple No. 35, and mixed in a double cone mixer at room temperature for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After coalescence, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. Crospovidone was mixed with the sieved material, and magnesium stearate was added thereto, followed by final mixing in a double cone mixer to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release tablet)

Amlodipine maleate and microcrystalline cellulose were appled into a No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. The mixture was added to a double cone mixer, colicoat SR30D (BASF, Germany) was added, the mixture was granulated using an oscillator with a No. 18 sieve, it was dried at 60 ° C. using a hot water dryer, and then No. 20 was established. Magnesium stearate sieved through No. 35 sieve was added to the sieved material, mixed for 4 minutes, and tableted with a rotary tablet press equipped with a 5 mm diameter punch to prepare a nuclear tablet. Separately, hydroxypropylmethylcellulose phthalate (Shin-etsu, Japan) was dissolved and dispersed in a mixture of ethanol and methylene chloride to prepare a coating solution. This coating solution was used to form a coating layer on amlodipine core tablets with a high coater to prepare amlodipine tablets, which are the titled delayed-release compartments.

(3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example (3).

<Example 6>: Nucleic acid tablet manufacturing

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, corn starch, apples in No. 35 sieve, and mixed for 5 minutes at room temperature using a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was combined with the main ingredient mixture, and then granulated using No. 18 sieve using an oscillator and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glycolate (DMV, Germany) and magnesium stearate were added to the formulation and finally mixed in a double cone mixer to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release tablet)

Amlodipine besylate, pregelatinized starch, corn starch were apples in No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl methyl cellulose was dissolved in purified water to prepare a binding solution, and the main ingredient mixture was added thereto, followed by association and granulation. The mixture was dried at 60 ° C. using a hot water dryer, and then sieved to No. 20. Separately, hydroxypropylmethylcellulose phthalate was dissolved in a mixture of ethanol and methylene chloride to prepare a coating solution, which was then placed in a fluidized bed granulation coater (GPCG-1; Glatt, Germany) and coated with the coating solution. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press equipped with a 5 mm diameter punch to prepare a core tablet having a titled delayed-release compartment.

(3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example (3).

Example 7 Preparation of Two-Phase Matrix Tablets

With the components and contents shown in Table 1, two-phase matrix tablets were prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, lactose monohydrate, pregelatinized starch and apples with No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granules were prepared using a No. 20 oscillator, and dried at 60 ° C. using a hot water dryer, and then re-established into No. 18 to prepare a title discharge compartment.

(2) Preparation of delayed-release compartments (amlodipine delayed-release granules)

Amlodipine besylate, microcrystalline cellulose, calcium hydrogen phosphate anhydrous were apples in No. 35, and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution, and then combined and granulated with the main ingredient mixture. Separately, cellulose acetate 320S (acetal group 32%) and cellulose acetate 398-10NF (acetal group 39.8%) were dissolved in a mixture of ethanol and methylene chloride to prepare a coating solution, and then the above formulation was flow-bed granulated coating machine (GPCG-1: Glatt, Geramny) and coated to prepare the delayed-release compartment of the title.

(3) post-mixing, tableting and coating

The products of (1) and (2) were placed in a double cone mixer and mixed at room temperature. Sodium starch glycolate and magnesium stearate were added to the mixture, followed by final mixing in a double cone mixer. The final mixture was compressed using a rotary tablet press equipped with a 10 mm diameter punch. Separately, hydroxypropylmethylcellulose 2910, polyethylene glycol 6,000, talc, and titanium oxide were dissolved and dispersed in ethanol and purified water to prepare a coating solution, and a high coater (SFC-30N: Sejong Machinery, Korea) was used for the above purification. To form a film coating layer to prepare a two-phase matrix tablet.

Example 8 Preparation of a 2-Phase Matrix Tablet

With the components and contents shown in Table 1, two-phase matrix tablets were prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate and microcrystalline cellulose were appled in a No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After association, granules were prepared using a No. 20 oscillator, and dried at 60 ° C. using a hot water dryer, and then reconstituted as No. 18 to prepare a title-release compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine maleate, microcrystalline cellulose, and pregelatinized starch were appled in a No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, polyvinylpyrrolidone was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. The dried material was placed in a fluidized bed coater and separately prepared by dissolving Eudragit RS30D and triethylcitrate in methylene chloride, and the above granules were placed in a fluidized bed granulator coater and coated to prepare the titled delayed-release compartment.

(3) post-mixing, tableting and coating

In the same manner as in Example (3), after mixing, tableting and coating to prepare a tablet in the form of a two-phase matrix.

Example 9 Preparation of # 2 Phase Matrix Tablet

With the components and contents shown in Table 2, two-phase matrix tablets were prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose hydrate were appled with No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After association, granules were prepared using a No. 20 oscillator, and dried at 60 ° C. using a hot water dryer, and then reconstituted as No. 18 to prepare a title-release compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

S-amlodipine besylate (Glochem, INDIA), microcrystalline cellulose, di-mannitol were apples with No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. The mixture was added to a high-speed mixer, and colicoat SR30D was added to assemble and granulated using No. 20 sieve using an oscillator, which was dried at 60 ° C. using a hot water dryer, and then re-assembled into No. 18 to prepare a delayed-release compartment of the title. It was.

(3) post-mixing, tableting and coating

In the same manner as in Example (3), after mixing, tableting and coating to prepare a tablet in the form of a two-phase matrix.

Example 10 Preparation of Two-Phase Matrix Tablets

With the components and contents shown in Table 2, two-phase matrix tablets were prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, corn starch, pregelatinized starch was appled in a No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After association, granules were prepared using a No. 20 oscillator, and dried at 60 ° C. using a hot water dryer, and then reconstituted as No. 18 to prepare a title-release compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch were appled in a No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, polyvinylpyrrolidone was dissolved in purified water to prepare a binding solution, which was combined and granulated with the main ingredient mixture, which was dried at 60 ° C. using a hot water dryer, and then sieved to No. 20. The formulation is placed in a fluidized bed coater, and a coating solution obtained by separately dissolving ethyl cellulose (HERCULES, USA) and poly (methacrylate, methyl methacrylate) copolymer in ethanol and methylene chloride mixture is used as a coating solution. The granules were coated with a fluid bed granule coater (GPCG-1; Glatt, Germany) to produce the title slow release compartment.

(3) post-mixing, tableting and coating

In the same manner as in Example (3), after mixing, tableting and coating to prepare a tablet in the form of a two-phase matrix.

Example 11 Preparation of Multi-Layered Tablets

By the component and content shown in Table 2, the multilayer tablet was produced with the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose hydrate was weighed and appled with No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. Thereafter, the sieved material and sodium starch glyconate were mixed, and magnesium stearate was added thereto, followed by final mixing in a double cone mixer to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine besylate, microcrystalline cellulose, pregelatinized starch, corn starch were apples in No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, polyvinylpyrrolidone was dissolved in purified water to prepare a binding solution, coalescing and granulating the same, and drying it at 60 ° C. using a hot water dryer, followed by formulation as No. 20. Put the sieved material in a fluidized bed coater, and separately dissolved ethyl cellulose, poly (methacrylate, methyl methacrylate) copolymer in a mixture of ethanol and methylene chloride to prepare a coating solution, and using the coating solution to prepare the above granulated fluid bed granules Coating with a coater. After the coating was completed, magnesium stearate was added and mixed for 4 minutes to prepare a titled delayed-release compartment.

(3) post-mixing, tableting and coating

The final product of (1) was put into the primary powder feeder of a multi-layer tablet press (MRC-37T: Sejong), and the final product of (2) was put into the secondary powder feeder to minimize the mixing between the layers. Tableting. Separately, hydroxypropylmethylcellulose 2910, polyethylene glycol 6,000, talc, and titanium oxide were dissolved and dispersed in ethanol and purified water to prepare a coating solution, and using the above tablets to form a film coating layer with a high coater to form a multi-layered tablet. Tablets in the form were prepared.

<Example 12>: Multilayer tablet manufacture

By the component and content shown in Table 2, the multilayer tablet was produced with the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, corn starch were apples in No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. The starch sodium starch glycolate was mixed with magnesium stearate and finally mixed with a double cone mixer to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine maleate, microcrystalline cellulose, pregelatinized starch, di-mannitol were apples in No. 35 and mixed in a double cone mixer at room temperature for 5 minutes to prepare a mixture. Separately, polyvinylpyrrolidone was dissolved in purified water to prepare a binding solution, and then the main ingredient mixtures were combined and granulated, which was dried at 60 ° C. using a hot water dryer, and then formed into No. 20 sieve. The granulated product was placed in a fluidized bed coater, and separately prepared by dissolving cellulose acetate 320S (acetal group 32%) and cellulose acetate 398-10NF (acetal group 39.8%) in a mixture of ethanol and methylene chloride 1: 1 mixture. It was placed in a fluid bed granulator coater and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes to prepare a titled delayed-release compartment.

(3) post-mixing, tableting and coating

In the same manner as in Example 11 (3), after the mixing, tableting and coating to prepare a tablet in the form of a multi-layered tablet.

Example 13 Preparation of Multi-Layered Tablets

By the component and content shown in Table 2, the multilayer tablet was produced with the following method.

(1) Preparation of prior-release compartment (roschvastatin immediate release granule)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, corn starch, apples in No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, and dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. Crospovidone was mixed with the sieved material, and magnesium stearate was added thereto, followed by final mixing in a double cone mixer to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

A mixture of S-amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch with apple 35 was mixed with a double cone mixer for 5 minutes at room temperature. The mixture was added to a high speed mixer, fed with Colicoat SR30D, and then granulated using No. 20 sieve using an oscillator, which was dried at 60 ° C. using a hot water dryer, and then re-formed into No. 18 sieve. Magnesium stearate was added to the sieved material, followed by mixing for 4 minutes, thereby preparing the titled delayed-release compartment.

(3) post-mixing, mixing and coating

In the same manner as in Example 11 (3), post-mixing, tableting, and coating were carried out to form a tablet in a multilayer tablet form.

<Example 14>: Multilayer tablet manufacture

By the component and content shown in Table 2, the multilayer tablet was produced with the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, pregelatinized starch were apples in No. 35 sieve, and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. Thereafter, granules were prepared by using an oscillator in No. 20 sieve, which was heated at 60 ° C. using a hot water dryer, and then No. 18 was established. Crospovidone was mixed with the sieved material, and magnesium stearate was added and finally mixed with a double cone mixer to prepare the title-releasing compartment of the title.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine besylate, anhydrous calcium hydrogen phosphate, and di-mannitol were appled in a No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it was established as No. 18 body again. The sieved material was placed in a fluidized bed coater, and a solution obtained by dissolving Eudragit RS30D and triethyl citrate in methylene chloride was separately prepared, and the above granules were put in a fluidized bed granulator coater and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes to prepare a titled delayed-release compartment.

(3) post-mixing, tableting and coating

In the same manner as in Example 11 (3), after the mixing, tableting and coating to prepare a tablet in the form of a multi-layered tablet.

Example 15 Preparation of Capsules (Pellets-Granules)

With the components and contents shown in Table 2, a capsule was prepared by the following method.

(1) Preparation of Sun-Release Compartment (Rochevastatin Pellets)

Sugar seeds (NP Pharmaceutical, France) were added to a fluidized bed granulator (GPCG, Glatt, Germany), and then pellets were sprayed separately by spraying a binder solution of hydroxypropylcellulose and rosuvastatin calcium in purified water. Form and dry to give the titled prior release compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine besylate, microcrystalline cellulose and anhydrous calcium hydrogen phosphate were appled in a No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Collicoat SR30D was added and associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, and dried using a hot water dryer, and then reconstituted in No. 18 sieve to prepare a delayed-release compartment of the title.

(3) post-mixing, tableting and coating

The final product of (1) and (2) was mixed at room temperature with a double cone mixer, and magnesium stearate was added to the mixture for final mixing. The final mixed mixture was put into a powder feeder and filled into capsules (Seoheung capsule, Korea) using a capsule charger (SF 40N, Sejong Machinery, Korea) to prepare the title capsule.

Example 16 Preparation of Capsules (Pellets-Pellets)

With the components and contents shown in Table 2, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release pellet)

Sugar seeds were introduced into a fluidized bed granulator and sprayed separately with hydroxypropyl cellulose and roschvastatin calcium in water to form a sprayed and dried product to form the titled release-releasing compartment, Roschvastatin-containing pellets. (2) Preparation of delayed-release compartments (amlodipine delayed-release pellets)

Sugar seed was introduced into a fluidized bed granulator, and then a binder solution in which hydroxypropyl cellulose and amlodipine besylate was dissolved in purified water was sprayed to form amlodipine-containing pellets and dried. Again, a solution of hydroxypropylmethylcellulose phthalate (Shin-etsu, Japan) dissolved in a mixture of ethanol and methylene chloride was sprayed on the pellet to prepare an amlodipine delayed-release pellet as a titled delayed-release compartment.

(3) post-mixing, tableting and coating

The final product of the process (1) and (2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the pharmaceutical preparation in capsule form.

Example 17 Preparation of Capsules (Pellets-Osmotic Tablets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release pellet)

Sugar seed was introduced into a fluidized bed granulator and sprayed and dried by separately dissolving a hydroxypropyl cellulose and roschvastatin calcium in purified water to prepare a roschvastatin-containing pellet, the title-releasing compartment.

(2) Preparation of delayed-release compartment (amlodipine osmotic tablets)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and corn starch were appled in a No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. Sodium chloride and magnesium stearate were added to the formulation and mixed for 4 minutes. The mixture was tableted with a rotary tableting machine equipped with a 5 mm diameter punch to prepare tablets. Separately, cellulose acetate 320S (acetal group 32%) and cellulose acetate 398-10NF (acetal group 39.8%) were dissolved in a mixture of ethanol and methylene chloride to prepare a coating solution. Using this to form a film coating layer with a high coat on the tablet to prepare an osmotic tablet of amlodipine, the delayed-release compartment of the title.

(3) post-mixing, tableting and coating

The final product of (1) and (2) was filled in a capsule (Seoheung capsule, South Korea) using a capsule charger (EXC 40F, Seoheung capsule, Korea) to prepare a delayed eluent in the form of the title capsule.

Example 18 Preparation of Capsules (Pellets-Tablets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release pellet)

Sugar seed was introduced into a fluidized bed granulator and sprayed and dried separately with a combined solution of hydroxypropyl cellulose and roschvastatin calcium in water to prepare a title-releasing roschvastatin-containing pellet.

(2) Preparation of delayed-release compartment (amlodipine delayed-release tablet)

Amlodipine besylate, microcrystalline cellulose, pregelatinized starch were apples in No. 35 sieve, and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was then combined with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. Magnesium stearate sieved through No. 35 sieve was added to the sieved material, mixed for 4 minutes, and the mixture was compressed into tablets using a rotary tablet press equipped with a 5 mm diameter punch. Separately, a coating solution obtained by dissolving and dispersing acryl-ides in purified water was prepared, and the tablet was formed by using a coater with a coater using the same to prepare a delayed-release amlodipine tablet of the title.

 (3) post-mixing, tableting and coating

The final product of (1) and (2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to prepare the title capsule.

Example 19 Preparation of Capsules (Tablet-Pellets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release tablet)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, corn starch were apples in No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. Starch sodium glyconate and magnesium stearate were added to the sieved material, mixed for 4 minutes, and compressed into a rotary tableting machine equipped with a 5 mm diameter punch to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartments (delayed-release pellets of amlodipine)

Sugar seed (Sugarsphere) was added to the fluidized bed granulator and sprayed separately with a binder solution in which polyvinylpyrrolidone and S-amlodipine besylate were dissolved in purified water to form amlodipine-containing pellets and dried. Again, the pellet was sprayed with a solution of Eudragit RS30D (Evonik Degussa, Germany) and triethyl citrate (Vertellus, England) in methylene chloride to prepare the titled delayed-release compartment.

(3) post-mixing, tableting and coating

The final product of (1) and (2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to prepare the title capsule.

Example 20 Preparation of Capsules (Tablets-Tablets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release tablet)

Rochevastatin calcium, tribasic calcium phosphate and corn starch were apples in No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. Sodium starch glycolate and magnesium stearate sieved through No. 35 sieve were added to the sieved material, mixed for 4 minutes, and compressed into a rotary tableting machine equipped with a 5 mm diameter punch to prepare the title-release compartment.

(2) Preparation of delayed-release compartments (amlodipine delayed-release tablets)

S-amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate were appled in a No. 35 sieve, and mixed in a double cone mixer at room temperature for 5 minutes to prepare a mixture. Separately, it was associated with the main ingredient mixture using Colicoat SR30D as the binding solution. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. Magnesium stearate sieved through No. 35 sieve was added to the sieved material, mixed for 4 minutes, and tableted with a rotary tablet press equipped with a 5 mm diameter punch to prepare tablets. Separately, a coating solution obtained by dissolving and dispersing a poly (methacrylate and methyl methacrylate) copolymer (Colorcon, USA) in purified water was prepared to form a coating layer using the above amlodipine tablet as a high coater to prepare a delayed-release compartment of the title. It was.

 (3) post-mixing, tableting and coating

The final product of (1) and (2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to prepare the title capsule.

Example 21 Preparation of Capsule (Granule-Granule)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin immediate release layer granule)

Rochevastatin calcium, tribasic calcium phosphate and lactose hydrate were weighed and appled with No. 35 sieve, and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, dried at 60 ° C. using a hot water dryer, and then erected in No. 18 to prepare the title-release compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed granules)

Amlodipine besylate, microcrystalline cellulose, and di-mannitol were appled in a No. 35 sieve and mixed for 5 minutes at room temperature with a double cone mixer to prepare a mixture. Collicoat SR30D was put together with the main ingredient mixture and granulated using No. 20 sieve using an oscillator and dried at 60 ° C. using a water dryer. It was established as No. 18 sieve after drying.

(3) post-mixing, tableting and coating

The final product of (1) and (2) was mixed in a double cone mixer. Sodium starch glycolate was added to the mixture and mixed with a double cone mixer. Magnesium stearate was added to the mixture, followed by final mixing. The final mixed mixture was put into a powder feeder and filled into capsules (Seoheung capsule, Korea) using a capsule charger to prepare the title capsule.

Example 22 Preparation of Capsules (Granules-Pellets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, pregelatinized starch were apples in No. 35 and mixed in a double cone mixer at room temperature for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulate with No. 20 sieve using an oscillator and dry it at 60 ℃ using a hot water dryer. After completion of drying, it was reestablished as No. 18 to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartments (amlodipine delayed-release pellets)

Sugar seed was introduced into a fluidized bed granulator, and then a binder solution in which polyvinylpyrrolidone and amlodipine besylate was dissolved in purified water was sprayed to form amlodipine-containing pellets and dried. Again, the pellet was sprayed with a solution of Eudragit RS30D and triethyl citrate in methylene chloride to prepare the titled delayed-release compartment.

(3) post-mixing, tableting and coating

The final product of (1) and (2) was mixed in a double cone mixer. Sodium starch glycolate was added to the mixture and mixed with a double cone mixer. Magnesium stearate was added to the mixture, followed by final mixing. The final mixed mixture was put into a powder feeder and filled into capsules (Seoheung capsule, Korea) using a capsule charger to prepare the title capsule.

Example 23 Preparation of Capsules (Granules-Tablets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin fast-release granules)

Rochevastatin calcium, tribasic calcium phosphate, lactose monohydrate and corn starch were weighed and appled in a No. 35 sieve, and mixed with a double cone mixer at room temperature for 5 minutes to prepare a mixture. Purified water was added to the mixture, followed by granulation using No. 18 sieve using an oscillator, which was dried at 60 ° C. using a hot water dryer. Thereafter, sieved to No. 20 sieve and sodium starch glycolate was added to the sieved material and mixed with a double cone mixer. Magnesium stearate was added to the mixture, followed by final mixing to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release tablet)

Amlodipine besylate, anhydrous calcium hydrogen phosphate, and pregelatinized starch were appled in a No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it is established as No. 18 again. Magnesium stearate sieved through No. 35 sieve was added to the sieved material, mixed for 4 minutes, and the mixture was compressed into tablets using a rotary tablet press equipped with a 5 mm diameter punch. Separately, a coating solution obtained by dissolving and dispersing acrylic-isolated in purified water was prepared, and the above-described amlodipine tablets were coated with a high coater to form a coating layer.

(3) post-mixing, tableting and coating

The product of (1) and (2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to prepare the title capsule.

Example 24 Preparation of Capsules (Tablets-Granules)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (Rochevastatin immediate release tablet)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, pregelatinized starch was appled in a No. 35 sieve and mixed at room temperature for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After coalescence, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then formed in No. 18 sieve. Crospovidone and magnesium stearate, which were sieved through No. 35 sieve, were added to the sieved material, mixed for 4 minutes, and the mixture was compressed into a rotary tablet press equipped with a 5 mm diameter punch to prepare the title-release compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and hydroxypropyl methyl cellulose were appled in a No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Purified water was added and combined with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then established in No. 18 sieve. Magnesium stearate was added to the sieved material and finally mixed to prepare a titled delayed-release compartment.

 (3) post-mixing, tableting and coating

The final product of (1) and (2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to prepare the title capsule.

Example 25 Preparation of Rochevastatin-Amlodipine Besylate Blister Packaging Kit

Byloxvastatin-amlodipine besylate blister packaging kit was prepared by the following method.

Each of the Roschvastatin calcium pre-eluting granules prepared in Example 7 (1) and the amlodipine besylate delayed-dissolution granules prepared in Example 7 (2) were compressed using a rotary tableting machine equipped with a 7 mm punch. After the tablets are manufactured, the blister packaging kit is packaged by using blister packaging machine (Minister A, Heunga Engineering) to simultaneously pack each tablet in the blister packaging container (silver foil, Dongyang, PVDC, Jeonmin industry). Manufactured

Table 1

[Table 2]

Table 3

Experimental Example 1 Comparative Dissolution Profile Test of Amlodipine-Roschvastatin Nucleated Tablets

Comparative dissolution tests of Rochevastatin / Amlodipine besylate nucleated tablets prepared according to Example 4 and a control drug (Cresto: Roschvastatin monotherapy, AstraZeneca, Gennosac: Amlodipine monotherapy, Pfizer) were performed. In the case of the amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid from 2 hours. The dissolution test method for each component is as follows.

[Amlodipine Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.01M hydrochloric acid solution, 750mL (0 ~ 2 hours)

pH 6.8 artificial intestine, 1,000 mL (after 2 hours)

Analytical Method: Ultraviolet-visible Spectrophotometry (Detect Wavelength = 240nm Max)

[Rochevastatin Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.01M hydrochloric acid solution, 750mL (0 ~ 2 hours)

pH 6.8 artificial intestine, 1,000 mL (after 2 hours)

Analytical Method: Ultraviolet-visible Spectrophotometry (Detect Wavelength = 220nm)

The result is shown as shown in FIG.

According to Figure 1, the Rochevastatin component of the nucleated tablet of the present invention was confirmed to exhibit almost the same elution characteristics compared to the control formulation Cresto, the amlodipine component can confirm the very slow dissolution rate compared to the control formulation Novasque. . Specifically, in the nucleophilic tablet of amlodipine / roschvastatin of the present invention, the amlodipine component hardly eluted up to 1 hour after the start of the dissolution test, and thus it was confirmed that it was much slower than the 1 hour dissolution rate (about 99%) of the control formulation. .

As described above, the harmful tablets of amlodipine / roschvastatin of the present invention, unlike the amlodipine single drug, the initial dissolution of amlodipine is much slower than roschvastatin, so the probability of metabolism in the liver is lower than that of roschvastatin.

Experimental Example 2 Comparative Dissolution Profile Test of Rochevastatin-Amlodipine Capsule

The dissolution test was carried out in the same manner as in Experimental Example 1 for the Examples 17 and 18 formulations, and the dissolution rate of amlodipine in each formulation was measured and shown in FIG. 2.

According to Figure 2, in Example 17 (when the semi-permeable membrane coating after tablet tableting) and Example 18 (when the enteric coating after tablet tableting), amlodipine was suddenly only 1 hour and 30 minutes after the start of elution of roschvastatin. Elution was confirmed. In addition, the dissolution rate of the amlodipine component was eluted at least 90% within a total of 480 minutes.

As described above, the Rochevastatin / Amlodipine capsule of the present invention rapidly elutes amlodipine besylate after having a delay time to the intended time by semipermeable membrane coating and enteric coating.

In addition, unlike the dissolution of the Roschvastatin calcium / amlodipine besylate capsules of the present invention at the same time when the Rochevastatin calcium mono- and amlodipine besylate single-agent is administered, the initial dissolution of amlodipine besylate is Since it is much slower than statins, Rochevastatin calcium is first metabolized in the liver, and thus sufficient time for regeneration of metabolic enzyme cytochrome P450 can be reduced, thereby reducing the possibility of side effects.

FIG. 1 is a graph showing the comparative elution curves of Rochevastatin / Amlodipine nucleated tablets prepared according to Example 4 and a control agent (Cresto: Roschvastatin monoclonal, Novask: Amlodipine monoclonal).

2 is a graph showing the dissolution profiles of roschvastatin / amlodipine in the formulations prepared according to Examples 17 and 18. FIG.

Claims (46)

Roche fluvastatin (Rosuvastatin) a pharmacologically active ingredient, an isomer thereof, or a pharmaceutically acceptable salt thereof and amlodipine in the prior-release compartment, and a pharmacologically active ingredient, including additives, salts of pharmaceutically acceptable isomer thereof, or a pharmaceutical for the A delayed-release compartment comprising at least one release control material selected from the group consisting of enteric polymers, water insoluble polymers, and hydrophilic polymers, Rochevastatin of the prior release compartment releases 80% or more of the total amount of Rochevastatin within 1 hour after oral administration, and amlodipine of the delayed-release compartment releases all within 8 hours after oral administration. Additives include microcrystalline cellulose, lactose monohydrate, calcium hydrogen phosphate anhydrous, sodium starch glycolate, crospovidone, sodium stearyl fumarate, corn starch, magnesium stearate, tribasic calcium phosphate, croscarmellose sodium, potato starch, pregelatinized starch At least one selected from the group consisting of bentonite, dagum, montmorillonite, guar gum, sodium alginate, alginic acid and sodium bicarbonate, The enteric polymer is a group consisting of hydroxypropyl methyl cellulose phthalate (HPMCP), methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) At least one selected from polyvinylacetate and ethylcellulose, and the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol and polyvinyl alcohol In one, the enteric polymer is included in 0.1 parts by weight to 20 parts by weight based on 1 part by weight of the amlodipine, the water-insoluble polymer is included in 0.1 parts by weight to 30 parts by weight based on 1 part by weight of amlodipine, the hydrophilic polymer is Amro 0.05 part by weight to 30 parts by weight with respect to 1 part by weight of dipine, Rochevastatin is included in the dosage form of 5 to 80mg, the amlodipine is included in the unit dosage form of 1 to 20mg Pharmaceutical formulation. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in the form of a biphasic matrix tablet consisting of the delayed-release compartment and a pre-release compartment surrounding it. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in the form of a film-coated tablet consisting of a tablet consisting of a delayed-release compartment and a film-coating layer composed of a prior-release compartment surrounding the outside of the tablet. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in the form of a multi-layered tablet in which the delayed-release compartment and the prior-release compartment are layered. The pharmaceutical formulation according to claim 1, wherein the formulation is in the form of a nucleus tablet consisting of an inner core consisting of a delayed-release compartment and an outer layer consisting of a prior-release compartment surrounding an outer surface of the inner core. delete The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in the form of a capsule comprising particles, granules, pellets, or tablets consisting of delayed-release compartments, and particles, granules, pellets, or tablets consisting of prior-release compartments. . The pharmaceutical formulation of claim 1, further comprising a coating layer on the exterior of at least one of the delayed-release compartment or the prior-release compartment. The pharmaceutical formulation according to claim 1, which is in the form of a coated tablet further comprising a coating layer on the outside. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a kit comprising a delayed release compartment and a prior release compartment. The pharmaceutical formulation of claim 1, wherein the formulation is for evening administration. delete delete delete delete The pharmaceutical formulation of claim 1, wherein the enteric polymer is 0.5 part by weight to 10 parts by weight based on 1 part by weight of amlodipine. The pharmaceutical formulation of claim 1, wherein the water-insoluble polymer is 0.5 to 20 parts by weight based on 1 part by weight of amlodipine. The pharmaceutical formulation according to claim 1, wherein the hydrophilic polymer is 0.5 to 20 parts by weight based on 1 part by weight of amlodipine. A releasing compartment comprising Rosuvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof and an additive thereof as a pharmacologically active ingredient, and an amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as an pharmacologically active ingredient A delayed-release compartment comprising at least one release controlling material selected from the group consisting of enteric polymers, water insoluble polymers and hydrophilic polymers, The additives in the prerelease compartments are microcrystalline cellulose, lactose monohydrate, calcium hydrogen phosphate anhydrous, sodium starch glycolate, crospovidone, sodium stearyl fumarate, corn starch, magnesium stearate, calcium tribasic phosphate, croscarmellose sodium, At least one selected from the group consisting of potato starch, pregelatinized starch, bentonite, bum, montmorillonite, guar gum, sodium alginate, alginic acid and sodium bicarbonate, The enteric polymer is a group consisting of hydroxypropyl methyl cellulose phthalate (HPMCP), methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) At least one selected from polyvinylacetate and ethylcellulose, and the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol and polyvinyl alcohol One, The release controlling material is 0.5 to 20 parts by weight based on 1 part by weight of the amlodipine, The Rochevastatin comprises 5 to 80 mg of the unit dosage form, and the amlodipine is included 1 to 20 mg of the unit dosage form. 45. The pharmaceutical formulation of claim 44, wherein at least 80% of the roschvastatin of the prior release compartment is released within 1 hour after oral administration. 45. The pharmaceutical formulation of claim 44, wherein the amlodipine in the delayed-release compartment is released within 8 hours after oral administration.

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