KR20090114323A - Pharmaceutical Formulation - Google Patents

Abstract

PURPOSE: A pharmaceutical formulation containing rosuvastatin and candesartan is provided to treat hypertension and hyperlipidemia and prevent complication. CONSTITUTION: A pharmaceutical formulation comprises immediate release compartment containing a rosuvastatin as a pharmacologically active ingredient, its isomer, or its pharmaceutically acceptable salt, and a sustained release compartment containing candesartan as a pharmacologically active ingredient, its pharmaceutically acceptable salt or its prodrug.

Description

Pharmaceutical Formulation

The present invention relates to a pharmaceutical formulation containing roschvastatin and candesartan.

The present invention relates to a technology for formulating a functional combination that can suppress the decrease in drug efficacy due to drug interactions and prevent side effects from occurring when two drugs are simultaneously administered.

All drugs should be carefully reviewed for the characteristics of drug transporters, metabolic enzymes, and genes involved in the absorption, metabolism, distribution, drug expression and excretion of individual drugs when two or more components are taken. By determining the dissolution order and time difference of the ingredients and maintaining the time difference of absorption, it is possible to minimize the mutual antagonism between the drugs in the body. As a result, it is possible to reduce side effects and enhance the efficacy of drug combination. Is true.

More specifically, when drugs cross the barrier in the first stage, enter the liver in the secondary stage, metabolize and activate in the liver cells in the tertiary stage, and biliary tract in the fourth stage, Efflux transporters, influx transporters, and metabolic enzymes that absorb, metabolize, and excrete drugs everywhere, such as when exiting the liver cells, are present everywhere.

However, depending on the type of drug, it may also inhibit the action of these transporters, enzymes and genes.

 Therefore, when two drugs pass through each step at the same time, one component may interfere with the absorption, distribution, and metabolism of the other, thereby reducing the efficacy or increasing the side effects. Therefore, one component must be passed first, and the other component must be passed at a time difference to eliminate drug interaction.

There are currently 300 such transporters, 500 metabolic enzymes, and 57 genes. Soon, gene genome analysis will find transporters and enzymes for all drugs.

Therefore, it is impossible to claim that there is no interaction between two or more drugs because it is a private example that any drug whose metabolic enzyme or transporter is currently unknown will be discovered soon. Therefore, even if a drug of two components for which metabolic enzymes or transporters are not known, it is reasonable to absorb it with a dissolution time difference between the two components.

Background of the Invention The purpose of the present invention is to determine the dissolution order and maintain the time difference between the two components with a certain antagonistic interaction between the two components for the purpose of realizing the ideal combination method when all the drugs are heterogeneously administered. It is absorbed to enable functional combinations that maximize the efficacy and minimize side effects.

Illustrative examples of transporters and drug metabolizing enzymes that have been tested or reviewed for the preparation of the functional combination of the present invention are as follows.

1) Efflux Transporter: P-glycoprotein (P-gp), Multidrug resistance (MDR), Multidrug resistance associated protein (MRP)

2) Influx Transporter: Organic anion transport protein (OATP), Sodium taurocholate cotransporting polypeptide (NTCP), Organic cation transporter (OCT)

Drug metabolism: Cytochrome P450 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4 / 5

Other metabolic enzymes: Uridine-5-phophate-glucuronosyltransferase (UDP-gt), Sulfatase, Sulfotransferase (1a1, 2a1, 1e1)

Nucleic Receptor: Pregnane-X-Receptor (PXR), Constitutive Androstane Receptor (CAR)

Hypertension often coexists with coronary artery disease, all of which is a major cause of heart disease. The expression of these risk factors is potentially due to the joint mechanism. Arteriosclerosis caused by hypertension and hyperlipidemia is a vicious cycle that worsens in parallel. As blood pressure rises, arteriosclerosis worsens, and when arteriosclerosis worsens, blood pressure rises and worsens each other. These symptoms are also considered as a serious risk factor for developing cardiovascular disease. For example, hypercholesterolemia and hyperlipidemia are involved in the early development of atherosclerosis, a symptom characterized by the uneven distribution of lipid deposits in arteries including coronary, carotid and peripheral arteries. Irregular lipid distribution is also a hallmark of coronary heart injury, cardiovascular disease and its risk and predominance are also affected by left ventricular hypertrophy, which occurs as a side effect of diabetes, human gender, smoking and hypertension. [Wilson et al., Am J. Cardiol., Vol. 59 (14) (1987), p. 91-94].

Accordingly, the inventors have surprisingly found that, while studying a combination formulation of Rochevastatin and candesartan, a combination formulation of two drugs simply as one formulation, as in the conventional formulation, may cause various problems.

For example, cholesterol synthesis is active at night, so HMG-CoA reductase inhibitors are most effective in the evening. Therefore, Rochevastatin, an HMG-CoA reductase inhibitor, should be taken in the evening to maximize the natural effects of drugs that lower cholesterol synthesis.

The risk of hypertension is largely high in the morning, which is caused by a sharp rise in blood pressure when waking up in the morning after sleep [William et al., The American Journal of Cardiology. vol.100 (3) (2007) ps10-s16] Therefore, when the angiotensin-2-receptor blocker candesartan has the highest blood pressure lowering effect in the morning, the risk of hypertension can be reduced and the blood peak of candesartan can be reduced. Given that the drug concentration time (Tmax) is 3 to 4 hours, it is most preferable to administer at night.

However, while taking single doses of rosvastatin in the evening and candesartan in the morning is best suited for therapeutic effects, knowledge of these dosages is not easily communicated to the patient. In many cases and because of this poor patient compliance is not taken properly.

In other words, due to the development of a simple combination of Rochevastatin and candesartan, improvement of patient compliance can be expected due to the medication convenience, but effective drug delivery using biorhythm cannot be achieved with the simple combination, and the absorption distribution metabolism of drugs, etc. The pharmacological mechanism of pharmacology will not be considered. As a result, there is a side problem of decreasing the therapeutic effect, inducing drug interactions and increasing side effects.

Therefore, the present inventors have recognized the problem of the simple drug complex of Rochevastatin and candesartan and studied to solve the problem. As a result, the optimization of cholesterol lowering effect of Rochevastatin and blood pressure control effect of candesartan, that is, drug delivery time Through the optimization of the present invention has been completed to solve this problem.

The problem to be solved by the present invention is to provide a formulation that is very effective in the treatment of hypertension and hyperlipidemia and prevention of complications of those with metabolic syndrome, and improves patient compliance, optimize drug delivery time, avoid drug interactions and reduce side effects. It is.

The present invention relates to a prior-release compartment comprising Rochevastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and candesartan, a pharmaceutically acceptable salt thereof, or a pro pharmaceutically active ingredient thereof. A pharmaceutical formulation comprising a delayed-release compartment comprising a drug is provided.

In the present invention, the term "roschvastatin" means roschvastatin, an isomer thereof, or a pharmaceutically acceptable salt thereof, unless otherwise specified. "Candesartan" means candesartan, or a pharmaceutically acceptable salt thereof, or a prodrug thereof unless otherwise specified.

The pharmaceutical formulation of the present invention releases the candesartan of the delayed-release compartment after a certain time after the release of the rochevastatin of the prior-release compartment and has a release suitable for the characteristics of each drug.

The pharmaceutical formulation of the present invention has a release delay time for the release of candesartan in the form of delayed release of candesartan after a predetermined time after the release of roschvastatin.

The pharmaceutical formulation of the present invention provides that the release of candesartan, the active ingredient of the delayed-release compartment, is between about 1 hour and 8 hours after initiation of the release of roschvastatin, the active ingredient of the prior-release compartment, preferably from about 2 hours to Provided is a pharmaceutical formulation that is initiated between four hours.

The present invention also provides about 0 to about the total amount of candesartan in the unit formulation until the candesartan of the delayed-release compartment is about 2 hours after initiation of the release of roschvastatin in the prior release compartment, preferably about 3 hours. A pharmaceutical formulation is provided in which 40% is released.

Hereinafter, the components of the preparations according to the present invention will be described in detail.

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.

(1) pharmacologically active ingredients

The pharmacologically active ingredient of the prior release compartment comprises roschvastatin, isomers thereof, or a pharmaceutically acceptable salt thereof, and preferably roschvastatin or a pharmaceutically acceptable salt thereof, more preferably Roche It may contain a vastatin calcium salt. Roschvastatin has a Tmax of about 3 to 5 hours.

Roschvastatin is one of the drugs that regulate HMG-CoA reductase, which regulates the cholesterol synthesis pathway and inhibits cholesterol production in the liver. Roschvastatin has the effect of reducing total cholesterol, low density lipoprotein-cholesterol (LDL-C), and triglycerides and increasing high density lipoprotein-cholesterol (HDL-C). Judy et al., Clinical Therapeutics. vol. 26 (9) (2004), p1368-1387. Due to this lipid control effect, Rochevastatin is used for the treatment of primary hyperlipidemia, mixed dyslipidemia and familial hypercholesterolemia.

The pharmacologically active ingredient of the prior release compartment comprises about 0.1 to 500 mg, preferably about 0.2 to 100 mg, more preferably about 5 to 40 mg, as Roschvastatin in the unit formulation.

(2) pharmaceutically acceptable additives

The formulations of the present invention may also be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, etc. without departing from the effects of the present invention.

Pharmaceutically acceptable diluents may include starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, mixtures thereof, and the like.

Pharmaceutically acceptable binders include starch, microcrystalline cellulose, highly disperse silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, natural gums, synthetic gums , Copovidone, gelatin, or a mixture thereof can be used.

Pharmaceutically acceptable disintegrants include starch or modified starch, such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, clay microcrystalline cellulose such as bentonite, montmorillonite, or veegum, hydroxypropyl Cellulose such as cellulose or carboxymethyl cellulose Crosslinked cellulose such as sodium alginate or alginate such as alginic acid Croscarmellose Crosslinked polymer such as guar gum, gum gum and xanthan gum Crosslinked polymer such as crospovidone Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.

Pharmaceutically acceptable lubricants include talc, stearic acid, magnesium stearate, calcium stearate and the like, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl Monostearate, glyceryl palmitostearate, polyethylene glycol 4000, and the like. Pharmaceutically acceptable stabilizers may include ascorbic acid, citric acid, butylhydroxy anisole, butylhydroxy toluene, tocopherol derivatives 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 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.

The content of the additive in the pre-release compartment is preferably about 0.1 to 100 parts by weight based on 1 part by weight of roschvastatin.

2. Delayed release block

Delayed-release compartment refers to the compartment in which the active ingredient is released after a certain time after the release of the prior-release compartment active ingredient in the pharmaceutical formulation according to the present invention. The delayed-release compartment comprises (1) the pharmacologically active candesartan, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and (2-1) a release controlling substance or (2-2) an osmotic pressure regulator and a semipermeable membrane coater. Agent, and may further include (3) a pharmaceutically acceptable additive as necessary.

(1) pharmacologically active ingredients

The pharmacologically active ingredient of the delayed-release compartment comprises candesartan, a pharmaceutically acceptable salt thereof, or a prodrug thereof. "Prodrugs of candesartan" are derivatives of certain active compounds which, when administered in vivo, can be converted into their active ingredient candesartan by enzymatic action, metabolism, etc., for example candesartan cilexetil Etc. Candesartan Tmax is about 3-4 hours.

Candesartan is one of the non-peptide angiotensin-2-receptor blockers and has the effect of relaxing blood vessels by selectively inhibiting angiotensin-2 binding to receptors in tissues such as vascular smooth muscle cells and adrenal glands [M burnier, The Lancet. vol. 355 (2000), p637-645]. Candesartan is used for the treatment of hypertension and heart failure due to this vasorelaxation.

The active ingredient in the delayed-release compartment comprises about 1-1000 mg, preferably about 2-500 mg, more preferably about 4-32 mg, as candesartan cilexetil in the unit formulation.

(2-1) Release Control Substances

The delayed-release compartment in the formulation of the present invention refers to a pharmaceutically acceptable substance for controlling the release of the active ingredient, selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof. Contains emission control materials. Preferred examples include an enteric polymer, a water insoluble polymer, a hydrophilic polymer, and a mixture of a hydrophobic compound and a hydrophilic polymer.

The release controlling substance comprises about 0.05 to 100 parts by weight, preferably about 0.1 to 50 parts by weight, based on 1 part by weight of candesartan. If the release control material is less than 0.05 parts by weight it may be difficult to have a sufficient delay time, there is a problem that the release of the drug does not occur or more than 10 hours of the delay time is too long when more than 100 parts by weight.

In the present invention, 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 conditions of pH 5 or higher, and includes, for example, an enteric cellulose derivative, an enteric acrylic acid copolymer, and an enteric polymethacrylate. It may be selected from the group consisting of copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and mixtures thereof. The enteric polymer is selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, and a mixture thereof, and the enteric cellulose derivative is hydroxypropylmethylcellulose acetate succinate, Hydroxypropylmethyl cellulose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl cellulose, ethyl hydrate At least one selected from oxyethyl 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-acrylic acid acrylates, and methyl methacrylates (methacrylates). At least one selected from an acid-octyl copolymer; The enteric polymethacrylate copolymer is a poly (methyl methacrylate) copolymer (e.g. Eudragit L, Eudragit S, Evonik, Germany), poly (methacrylate acrylate) air At least one selected from coalescing (eg, Eudragit L100-55); The enteric maleic acid copolymer is vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinylmethyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether- At least one selected from maleic anhydride copolymer, acrylonitrile-methyl acrylate maleic anhydride copolymer, and butyl styrene-maleic-maleic anhydride copolymer; Or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate, polyvinyl butyrate phthalate and polyvinylacetacetal phthalate. Preferably, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, methacrylic acid acrylate copolymer, methacrylic acid and ethyl acrylate copolymer, styrene-maleic acid monoester copolymer, polyvinylacetate It may be at least one selected from phthalates, and more preferably at least one selected from hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, methacrylic acid acrylate copolymer, methacrylic acid and ethyl acrylate copolymer. Can be.

Enteric polymer according to the present invention may be included in about 5 to 80% by weight, preferably about 10 to 30% by weight based on the total weight of the formulation, when less than 5% by weight has a problem that is not dissolved or stable under acidic conditions, If it is more than 80% by weight there is a problem that does not dissolve even under basic conditions.

In the present invention, a water-insoluble polymer refers to a polymer that does not dissolve in pharmaceutically acceptable water that controls the release of the drug, such as polyvinylacetate (eg, collicoat SR30D), water-insoluble polymethacrylate copolymer [eg , Poly (ethylacrylate-methyl methacrylate) copolymer (e.g. Eudragit NE30D, poly (ethyl acrylate-methyl methacrylate-trimethylaminoethylmethacrylate chloride) copolymer (e.g. Eudragit RSPO) etc.], ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof. Polyvinyl acetate , Poly (ethylacrylate-methyl methacrylate) copolymer, poly (ethylacrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride) copolymer, ethyl cellulose, cellulose acetate, More preferably, it may be at least one selected from polyvinyl acetate, poly (ethyl acrylate-methyl methacrylate) copolymer, ethyl cellulose, and cellulose acetate.

Water-insoluble polymer according to the present invention may be included in about 5 to 80% by weight, preferably about 10 to 30% by weight based on the total weight of the formulation, when less than 5% by weight is difficult to have a sufficient delay time, 80 If it is more than the weight%, there is a problem that the release of the drug does not occur or becomes too long to be 9 hours or more of the delay time.

In the present invention, the hydrophobic compound refers to a substance which does not dissolve in pharmaceutically acceptable water that controls the release of the drug, and includes, for example, fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof. It may be selected from the group. The fatty acids and fatty acid esters are at least one selected from glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and stearic acid; The fatty acid alcohol is at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol; At least one selected from carnauba wax, beeswax, and microcrystalline wax as waxes; Or one or more selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and non-gum as inorganic materials. Preferably may be at least one selected from glyceryl palmitostearate, glyceryl behenate, stearic acid, cetyl alcohol, carnauba wax, more preferably 1 selected from glyceryl behenate, stearic acid, carnauba wax It can be more than one species.

Hydrophobic compound according to the present invention may be included in about 5 to 80% by weight, preferably about 10 to 30% by weight relative to the total weight of the formulation, if less than 5% by weight has a problem that does not affect the release of the drug at all In the case of more than 80% by weight, there is a problem that the release of the drug does not occur or is difficult to formulate.

In the present invention, the hydrophilic polymer refers to a polymer material which is dissolved in pharmaceutically acceptable water for controlling the release of the drug, such as sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, It may be selected from the group consisting of polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. The saccharide is one selected from dextrin, polydextrin, dextran, pectin, pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, and amylopectin More than; 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 hydrophilic polymethacrylate copolymers include poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymers (eg Eudragit E100, Evonik, Germany); The polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide; Or the carboxyvinyl polymer may be a carbomer, preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, guar gum, xanthan gum, gelatin, polyvinyl pyrrolidone, poly (butyl methacrylate- (2-dimethyl Aminoethyl) methacrylate-methyl methacrylate) copolymer, poly (methacrylate-methyl methacrylate) copolymer may be one or more selected, more preferably hydroxypropyl methyl cellulose, hydroxypropyl cellulose It may be at least one selected from xanthan gum and polyvinyl pyrrolidone.

Hydrophilic polymer according to the present invention may be included in about 5 to 80% by weight, preferably about 10 to 30% by weight based on the total weight of the formulation, when less than 5% by weight does not affect the disintegration of the tablet at all And, if it is more than 80% by weight, there is a problem that it is difficult to control disintegration and release.

In the present invention, preferred release control materials are hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methyl methacrylate copolymer, polyvinylacetate, ethylcellulose, cellulose acetate, carnauba wax, hydrate Hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, and mixtures thereof; More preferred release control materials are hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methyl methacrylate acrylic acid, polyvinylacetate, ethylcellulose, carnauba wax, hydroxypropylmethylcellulose, hydroxy Propylcellulose, and mixtures thereof; More preferred release controlling substances are selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropyl cellulose, polyvinylacetate, and mixtures thereof.

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

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

In the present invention, the semi-permeable membrane coating base is a pharmaceutically usable coating base, and refers to a material used in forming a membrane which is blended into the coating layer of the pharmaceutical formulation and passes some components but does not pass other components. Acetates, water-insoluble polymethacrylate copolymers, ethylcellulose, cellulose esters, cellulose ethers, cellulose acylates, cellulose dicylates, cellulose triacylates, cellulose acetates, cellulose diacetates, cellulose triacetates, and their It may be selected from the group consisting of a mixture, preferably at least one selected from polyvinyl acetate, water-insoluble polymethacrylate copolymer, ethyl cellulose, cellulose triacetate, more preferably Polyvinyl acetate may be, water-insoluble polymethacrylate copolymer, at least one selected from ethyl cellulose.

Semi-permeable membrane coating base according to the present invention may be included in about 5 to 80% by weight, preferably about 10 to 30% by weight based on the total weight of the formulation, when less than 5% by weight has a problem that it is difficult to form the desired semi-permeable membrane If it is more than 80% by weight, there is a problem that all components may not pass.

Osmotic pressure control agent in the present invention refers to a component used to control the release rate of the drug using the principle of osmotic pressure, for example magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate, and their It may be selected from the group consisting of a mixture, preferably using sodium chloride.

Osmotic pressure control agent according to the present invention may be included in about 1 to 80% by weight, preferably about 2 to 50% by weight based on the total weight of the formulation, there is a problem that the osmotic pressure is not formed when less than 1% by weight.

(3) pharmaceutically acceptable additives

The formulations of the present invention may also be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, etc., within the scope of not impairing the effects of the present invention, preferably 1 to 95% by weight of the total weight of the formulation, preferably Preferably it may be included in 5 to 90% by weight, if less than 1% by weight has a problem of formulating, in the case of more than 95% by weight there is a problem that is difficult to oral administration.

The diluent may be starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof.

The binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, gelatin Or mixtures thereof.

The disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or 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 a mixture thereof can be used.

The lubricant is talc, stearic acid, magnesium stearate, calcium stearate and the like, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostea Elate and polyethylene glycol, etc. can be used.

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.

The pharmaceutical preparations of the present invention may be prepared in various formulations, and may be formulated, for example, in tablets, powders, granules, capsules, and the like, such as uncoated tablets, coated tablets, multi-layered tablets, or nucleated tablets. It can be formulated into capsules containing delayed-release compartments in the form of bilayer tablets, nucleated tablets, pellets and the like.

The pharmaceutical formulation of the present invention may be in the form of a two-phase matrix tablet obtained by tableting after the delayed-release compartment and the prior-release compartment are uniformly mixed.

In addition, the pharmaceutical 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 of the film coating layer as it is dissolved Angiotensin-2 receptor antagonist will elute first.

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

In addition, the pharmaceutical 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 pressure regulator within the tablet for delayed release, followed by tableting. Then, the surface of the tablet is coated with a semipermeable membrane coating base to make it an inner nuclear tablet. In addition, the granules constituting the prior-release compartment are mixed with pharmaceutical additives and compressed into an outer layer to have a delayed-release inner-core tablet, and a dosage form in which the front-release layer surrounds the surface of the inner core tablet.

Pharmaceutical formulations of the invention may be in the form of particles, granules, pellets, or tablets comprising delayed-release compartments, or capsules comprising particles, granules, pellets, or tablets, consisting of pre-release compartments. That is, for example, the capsule may be filled with a pre-release tablet-delayed-release tablet, a pre-release tablet-delayed-release tablet, a pre-release tablet-delayed-release granule, a pre-release granule-delayed-release granule and the like.

In addition, the pharmaceutical formulation of the present invention may be in the form of a kit comprising a delayed-release compartment, and a prior-release compartment, specifically the present invention to prepare particles, granules, pellets, or tablets constituting the prior-release compartment, The granules, pellets or tablets constituting the delayed-release compartment may be separately prepared, and may be in the form of a kit prepared in a form that can be simultaneously taken by filling together with a foil, a blister, a bottle, and the like.

The kit may be composed of a unit dosage form of the delayed-release compartment, a unit dosage form of the pre-release compartment, and a packaging container for packaging the unit dosage form of the delayed-release compartment and the pre-release compartment, wherein the packaging container may be formed of a delayed-release compartment. Each of the unit dosage form and the pre-release compartment may be packed separately or together.

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 the particles, granules, pellets, or tablets composed of delayed-release compartments and / or pre-release compartments may be coated for the purpose of release control or formulation stability.

The formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but if necessary, a coating layer is formed on the outside of the formulation to form a coating tablet or coating capsule further comprising a coating layer. Can be. 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 can be appropriately selected by the choice of those 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 fluidized bed coating method, fan coating method, dry coating method can be applied. Preferably, a pan coating method can be applied.

The coating layer may be formed using a coating agent, a coating aid, or a mixture thereof. Specifically, the coating agent may be a cellulose derivative such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, or the like. Or a mixture thereof, and the like, and a coating aid may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, a mixture thereof, or the like. In the present invention, the coating layer may further include a release controlling material, which may be, for example, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methyl methacrylate copolymer, polyvinyl acrylate. Acetate, ethylcellulose, cellulose acetate, carnauba wax, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, or mixtures thereof.

The present invention provides a pharmaceutical formulation for evening administration.

The present invention also provides pharmaceutical preparations for the treatment and prevention of cardiovascular diseases.

The present invention provides a method for treating cardiovascular disease comprising administering the pharmaceutical formulation of the present invention to a mammal.

The cardiovascular disease refers to all other vascular diseases including cardiovascular and cerebrovascular diseases. The cardiac disease is representative of ischemic heart disease (myocardial infarction, angina pectoris, etc.) caused by arteriosclerosis, and hypertension, heart failure, arrhythmia, Cardiomyopathy, endocarditis, hyperlipidemia, hypercholesterolemia, and the like, and vascular diseases include stroke (palsy) and peripheral vascular disease. In addition, hypertension, diabetes mellitus, obesity, hyperlipidemia, coronary artery disease, including a combination of hypertension or hyperlipidemia of people with so-called metabolic syndrome.

The pharmaceutical formulation of the present invention may be suitably formulated according to each disease by using a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, as an appropriate method in the art, specifically the following steps It can be by.

In the first step, candesartan is administered with one or two release controlling substances selected from an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, a semipermeable membrane coating base, and an osmotic pressure control agent, and a conventional additive used in pharmaceuticals. It is a step of obtaining delayed-release granules or tablets through mixing, granulation, film coating or dry coating.

The second step is to obtain the pre-release granules, tablets obtained through a conventional procedure for producing oral solids such as mixing, associating, drying and granulating Rochevastatin with conventional pharmaceutically acceptable additives.

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 additionally coated as they are or with a release control material, dried and then compressed into a predetermined amount to produce tablets as they are or additionally coated, and then the drugs of the prior release compartment are separately dissolved or dissolved in a film coating solution. After dispersing, by coating the outer layer of the tablet 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 may be further coated as they are or with a release control material, and the dried granules and the granules obtained in the second step may be added to produce double tablets using a multi-layer 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 in which a pre-release layer surrounds 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) Candesartan and release control substances or pharmaceutically acceptable additives are dissolved or suspended in water, organic solvents or mixed solvents, coated on spherical granules of sugar, dried and only one or two release control substances as necessary. Using the above, it is possible to prepare a capsule by dissolving in water, an organic solvent, or a mixed solvent, coating, drying, and filling the capsule after mixing with the granule obtained in the second step or the tablet obtained in the third step.

(2) After dissolving or suspending cheloschvastatin and a pharmaceutically acceptable additive in water, an organic solvent or a mixed solvent, coating the spherical granules with sugar, drying and mixing them with a release control pellet containing a beta adrenergic blocker in the defroster. Capsules may be prepared by filling the capsules.

Preparation of Capsules Containing Capsules

(1) The granules obtained in the first step are additionally coated as is or with a release controlling substance and the dried granules or tablets are filled into capsules.

(2) The granules or tablets obtained in the second step may be put in a capsule charger, and capsules may be prepared by inserting a corresponding amount of the active ingredient into the capsule of a predetermined size and the capsule prepared in (1) above.

[H] Preparation of Capsules Containing Delayed-Release Capsules

(1) Controlled release materials selected from enteric polymers, water-insoluble polymers, hydrophobic compounds, hydrophilic polymers, semipermeable membrane coating bases, and osmotic pressure regulators of the first stage after filling into capsules, such as candesartan and pharmaceutically acceptable additives 1 It can be prepared by the coating method using a conventional additive used in pharmaceuticals with the species or two species.

(2) 과립 Capsules can be prepared by putting the granules or tablets obtained in step 2 into the capsule charger and putting the capsules prepared in (1) above with the effective amount of each main ingredient in a capsule of a certain size.

Manufacture of kits

The candesartan-containing preparation obtained in the first step and the rochevastatin-containing preparation obtained in the second step may be filled together in a foil, blister, bottle, or the like to prepare a kit that can be taken at the same time.

The human dosage of the preparation of the present invention is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, but generally in adults about 5 to 40 as roschvastatin per day. It can be administered mg, and candesartan can be administered about 4 ~ 32 mg per day to exhibit anti-pressure, hypolipidemic and prevent complications.

The pharmaceutical preparations of the present invention are very effective in treating hypertension and hyperlipidemia and preventing complications of those with metabolic syndrome, and provide preparations that exhibit improved patient compliance, optimization of drug delivery time, avoidance of drug interactions and reduction of side effects. .

When the pharmaceutical preparation according to the present invention is taken in the evening, cholesterol release is effectively lowered by optimizing the drug expression time by releasing roschvastatin, and after a certain release delay time, that is, 1 to 10 hours after drug administration. Candesartan is released from the point of view to maximize the effect of lowering blood pressure at dawn and in the morning.

The pharmaceutical formulation of the present invention applies the so-called Chronotheraphy principle, which is administered at a time difference in the time of expression of pharmacological action in the body, thereby releasing each drug at a specific rate, thereby optimizing drug delivery time as well as easily once. By taking this drug, the patient's compliance with the increased convenience of taking it is also high.

The pharmaceutical formulation of the present invention exhibits the effect of avoiding drug interactions and reducing side effects.

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 forms, and only the embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the technical field to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

Example 1 Preparation of Cheloschvastatin Calcium-Released Granules

A mixture was prepared by mixing Rochevastatin calcium, microcrystalline cellulose, lactose monohydrate, tribasic calcium phosphate, and crospovidone with the ingredients and contents shown in Table 1. Separately, hydroxypropyl cellulose was dissolved in purified water, and then combined using a mixture of the above and a speed mixer (Lab. Pharma Mixer, Diosna, below), and dried. After granulating the dried granules, magnesium stearate was added thereto, followed by mixing to prepare roschvastatin calcium pre-release granules.

Example 2 Preparation of Cheloschvastatin Calcium-Released Granules

It was prepared in the same manner as in Example 1 with the ingredients and contents shown in Table 1.

Example 3 Preparation of Pheroschvastatin Calcium-Released Granules

It was prepared in the same manner as in Example 1 with the ingredients and contents shown in Table 1.

TABLE 1 Rochevastatin Prior-Release Granule Composition

Example 4 Preparation of Releasing Pellets of Rochevastatin Calcium

The fluidized bed granules were prepared by dispersing and dissolving Rochevastatin calcium, tribasic calcium phosphate, hydroxypropyl cellulose, and crospovidone in purified water to 10% (v / v) in purified water in the ingredients and contents shown in Table 2. Rochevastatin calcium pre-release pellets were prepared by spraying, coating, and drying using a group (GPCG 1, Glatt, hereinafter, the same type).

TABLE 2 Rochevastatin Prerelease Pellets Composition

Example 5 Preparation of Candesartan Silexetil Delayed-Release Granules Containing Enteric Polymers

A mixture was prepared by mixing lactose, corn starch, and carboxymethylcellulose calcium with the ingredients and contents shown in Table 3. Separately, polyethylene glycol 6000 was dissolved in purified water, and candesartan cilexetil was dispersed in the solution, and the dispersion was sprayed onto the lactose monohydrate, corn starch, and carboxymethylcellulose calcium mixture by using a fluidized bed granulator. The obtained material was further sprayed with an aqueous hydroxypropylcellulose solution (5% (v / v)) to form granules. Separately, hypromellose acetate succinate was dissolved in 80% ethanol to 8% (w / w) and then sprayed on the granules formed above to coat the granules and then dry. Magnesium stearate was added to the granules, followed by mixing to prepare candesartan cilexetil delayed-release granules.

Example 6 Preparation of Candesartan Silexetil Delayed-Release Tablet Comprising Enteric Polymers with Film Coating

A mixture was prepared by mixing candesartan cilexetil, lactose monohydrate, corn starch, and carboxymethyl cellulose calcium in the ingredients and amounts shown in Table 3. Separately, polyethylene glycol 6000 and hydroxypropyl cellulose were dissolved in purified water, and then combined with the above mixture and dried. After the granules were dried, magnesium stearate was added, mixed, and compressed into tablets in a rotary tablet press equipped with a 6.0 mm diameter punch (MRC-33, Sejong, below). A tablet prepared by dissolving hypromellose acetate succinate in 80% ethanol to 8% (w / w) in a tablet that has been tableted and coated using a coating machine (SFC-30F, Sejong, hereinafter) Candesartan cilexetil delayed-release tablets were prepared.

<Example 7> Candesartan cilexetil delayed-release nucleated tablet preparation containing an enteric polymer by dry coating

A mixture was prepared by mixing candesartan cilexetil, lactose monohydrate, corn starch, and carboxymethyl cellulose calcium in the ingredients and amounts shown in Table 3. Separately, polyethylene glycol 6000 and hydroxypropyl cellulose were dissolved in purified water, and then combined with the above mixture and dried. After the granules were dried, magnesium stearate was added, mixed, and compressed into tablets using a rotary tablet press equipped with a 6.0 mm diameter punch. Tablets that have been tableted as an inner core and pulverized in a nucleated tableting machine (RUD-1, Killian, below) using a 11 mm punch with a mixture of hypromellose acetate succinate, microcrystalline cellulose, and magnesium stearate A dry-coated candesartan cilexetil delayed-release nucleated tablet was prepared.

TABLE 3 Candesartan delayed-release granules and tablets composition containing enteric polymer

Example 8 Preparation of Candesartan Silexetil Delayed-Release Granules Including Water Insoluble Polymer

A mixture was prepared by mixing lactose, corn starch, and carboxymethylcellulose calcium with the ingredients and contents shown in Table 4. Separately, polyethylene glycol 6000 was dissolved in purified water, and candesartan cilexetil was dispersed in the solution, and the dispersion was sprayed onto the milk monohydrate, corn starch, and carboxymethylcellulose calcium mixture using a fluid bed granulator. The obtained material was further sprayed with an aqueous hydroxypropylcellulose solution (5% (v / v)) to form granules. Separately, the granules were coated by spraying Colicoat SR 30D (Kollicoat SR 30D, polyvinylacetate 27%, povidone 2.7%, sodium laurylsulfate 0.3%, and purified water 70%, Basf) onto the granules formed above and dried. It was. Magnesium stearate was added to the granules, followed by mixing to prepare candesartan cilexetil delayed-release granules.

Example 9 Preparation of Candesartan Silexetil Delayed-Release Tablet Including Water-Insoluble Polymer

A mixture was prepared by mixing candesartan cilexetil, lactose monohydrate, corn starch, and carboxymethylcellulose calcium with the ingredients and contents shown in Table 4. Separately, polyethylene glycol 6000 and hydroxypropyl cellulose were dissolved in purified water, and then combined with the above mixture and dried. After the granules were dried, magnesium stearate was added and mixed, followed by compression in a rotary tablet press equipped with a 6.0 mm diameter punch. Candesartan cilexetil delayed-release tablets were prepared by coating with tablets coated with Colicoat SR30D.

TABLE 4 Candesartan delayed-release granules and tablets composition comprising a water insoluble polymer

Example 10 Preparation of Candesartan Silexetil Delayed-Release Granules Containing Hydrophobic Compounds and Hydrophilic Polymers

A mixture was prepared by mixing lactose, corn starch, and carboxymethylcellulose calcium with the ingredients and contents shown in Table 5. Separately, polyethylene glycol 6000 was dissolved in purified water, and candesartan cilexetil was dispersed in the solution, and the dispersion was sprayed onto the lactose monohydrate, corn starch, and carboxymethylcellulose calcium mixture by using a fluidized bed granulator. The obtained material was further sprayed with an aqueous hydroxypropylcellulose solution (5% (v / v)) to form granules. Separately, carnauba wax, hypromellose, and polyethylene glycol 6000 were dispersed in purified water to 10% (v / v) and then sprayed on the granules formed above to coat the granules and then dry. Magnesium stearate was added to the granules, followed by mixing to prepare candesartan cilexetil delayed-release granules.

Example 11 Preparation of Candesartan Silexetil Delayed-Release Tablet Containing Hydrophobic Compound and Hydrophilic Polymer

A mixture was prepared by mixing candesartan cilexetil, lactose monohydrate, corn starch, and carboxymethylcellulose calcium with the ingredients and contents shown in Table 5. Separately, polyethylene glycol 6000 and hydroxypropyl cellulose were dissolved in purified water, and then combined with the above mixture and dried. After the granules were dried, magnesium stearate was added and mixed, followed by compression in a rotary tablet press equipped with a 6.0 mm diameter punch. Carnauba wax, hypromellose, and polyethylene glycol 6000 were dispersed in purified water to 10% (v / v) in the tableted tablets and coated with a coating solution to prepare candesartan cilexetil delayed-release tablets. It was.

TABLE 5 Candesartan cilexetil delayed-release granules and tablet compositions comprising hydrophobic compounds and hydrophilic polymers

Example 12 Preparation of Candesartan Silexetil Delayed-Release Granules Containing Hydrophilic Polymer

A mixture was prepared by mixing lactose, corn starch, and carboxymethylcellulose calcium with the ingredients and contents shown in Table 6. Separately, polyethylene glycol 6000 was dissolved in purified water, and candesartan cilexetil was dispersed in the solution, and the dispersion was sprayed onto the lactose monohydrate, corn starch, and carboxymethylcellulose calcium mixture by using a fluidized bed granulator. The obtained material was further sprayed with an aqueous hydroxypropylcellulose solution (5% (v / v)) to form granules. Separately, hydroxypropyl cellulose and polyethylene glycol 6000 were dissolved in purified water to 10% (v / v) and then sprayed on the granules formed above to coat the granules and then dry. Magnesium stearate was added to the granules, followed by mixing to prepare candesartan cilexetil delayed-release granules.

Example 13 Preparation of Candesartan Silexetil Delayed-Release Tablet Containing Hydrophilic Polymer

A mixture was prepared by mixing candesartan cilexetil, lactose monohydrate, corn starch, and carboxymethylcellulose calcium with the ingredients and contents shown in Table 6. Separately, polyethylene glycol 6000 and hydroxypropyl cellulose were dissolved in purified water, and then combined with the above mixture and dried. After the granules were dried, magnesium stearate was added and mixed, followed by compression in a rotary tablet press equipped with a 6.0 mm diameter punch. Hydroxypropyl cellulose and polyethylene glycol 6000 were dissolved in purified water so as to be 10% (v / v) in tablets, and then coated with a coating solution to prepare candesartan cilexetil delayed-release tablets.

TABLE 6 Candesartan cilexetil delayed-release granules and tablet composition comprising hydrophilic polymer

<Example 14> candesartan cilexetil delayed-release granules preparation comprising a semi-permeable membrane coating base and an osmotic pressure regulator

A mixture was prepared by mixing lactose, corn starch, calcium carboxymethyl cellulose, and sodium chloride with the ingredients and contents shown in Table 7. Separately, polyethylene glycol 6000 was dissolved in purified water, and candesartan cilexetil was dispersed in the solution, and the dispersion was sprayed onto the lactose monohydrate, corn starch, and carboxymethylcellulose calcium mixture by using a fluidized bed granulator. The obtained material was further sprayed with an aqueous hydroxypropylcellulose solution (5% (v / v)) to form granules. Separately, ethyl cellulose was dissolved in a 1: 1 mixture of methylene chloride and ethanol to 8% (w / w) and then sprayed on the granules formed above to coat the granules and then dry. Magnesium stearate was added to the granules and mixed to prepare candesartan cilexetil delayed-release granules.

<Example 15> candesartan cilexetil delayed-release tablet preparation containing a semi-permeable membrane coating base and an osmotic pressure regulator

A mixture was prepared by mixing candesartan cilexetil, lactose monohydrate, corn starch, calcium carboxymethyl cellulose, and sodium chloride with the ingredients and contents shown in Table 7. Separately, polyethylene glycol 6000, and hydroxypropyl cellulose were dissolved in purified water, and then combined with the above mixture, followed by drying. After the granules were dried, magnesium stearate was added and mixed, followed by compression in a rotary tablet press equipped with a 6.0 mm diameter punch. Candesartan cilexetil delayed-release tablets were prepared by coating ethyl cellulose with a coating solution prepared by dissolving ethyl cellulose in a 1: 1 mixture of methylene chloride and ethanol (w / w).

TABLE 7 Candesartan delayed-release granules and tablets composition comprising semipermeable membrane coating base and osmotic pressure regulator

Example 16 Preparation of delayed-release pellets of candesartan cilexetil containing enteric polymer

In the sugar bead with the components and contents shown in Table 8, candesartan cilexetil, polyethylene glycol 6000, hydroxypropyl cellulose, and carboxymethyl cellulose calcium dispersed and dissolved in purified water were sprayed and coated using a fluidized bed granulator. Separately, a solution prepared by dissolving hypromellose acetate succinate to 8% (w / w) in 80% ethanol was sprayed onto the upper bead again, coated, and dried to prepare a delayed-release pellet of candesartan cilexetil. Prepared.

TABLE 8 Delayed-Release Pellets Composition of Candesartan Silecetyl Containing Enteric Polymers

Example 17 Preparation of Matrix Tablets for Rochevastatin Calcium-Candesartan Silecetyl Two-Phase

Candesartan cilexetil delayed-release granules (16 mg as candesartan cilexetil) comprising the roschvastatin calcium pre-release granules of Example 2 (10.4 mg equivalent as Roschvastatin) and the enteric polymer of Example 5 Equivalent weight) was mixed and tableted with a rotary tablet press equipped with a 10 mm diameter punch. The two-phase matrix tablet having the tableting completed was coated with a coating solution dissolved in purified water to 10% (v / v) in the ingredients and contents shown in Table 9.

[Table 9] Composition of film coating layer

Example 18 Preparation of a Candesartan Silecetyl Film-Coated Tablet Containing Rochevastatin Calcium in a Coating Layer

Rochevastatin coated with a coating solution dispersed and dissolved to 10% (v / v) in purified water in the candesartan cilexetil delayed-release tablet containing the water-insoluble polymer of Example 9 to the ingredients and contents shown in Table 10 Film-coated tablets containing calcium were prepared in the coating layer.

TABLE 10 Composition of Film Coating Layer Containing Rochevastatin Calcium

Example 19 Preparation of Candesartan Silecetyl Nucleated Film Coated Tablet Containing Rochevastatin Calcium in Coating Layer

Candesartan cilexetil delayed-release nucleated tablet containing the enteric polymer of Example 7 as a dry coating was coated with a coating solution dissolved in purified water to 10% (v / v) with the ingredients and contents shown in Table 10. A nucleated film coated tablet containing statin calcium in the coating layer was prepared.

Example 20 Preparation of Rochevastatin Calcium-Candesartan Silexetil Two-Layered Tablet

Candesartan cilexetil delayed-release granules (16, as candesartan cilexetil) comprising the roschvastatin calcium pre-release granules of Example 2 (10.4 mg equivalent as Roschvastatin) and the water-insoluble polymer of Example 8 mg equivalent amount) was put into each other granule inlet of a rotary triple tablet press (model name, manufacturer name, using the same model below) equipped with a 10 mm diameter punch and tableted to prepare two-layer tablets. Tablets that have been compressed are coated with a coating solution dissolved in purified water to 10% (v / v) in the ingredients and contents shown in Table 9.

Example 21 Rochevastatin Calcium-Candesartan Silexetil Multilayer Tablet Preparation

Candesar containing the hydrophobic compound and hydrophilic polymer of Example 10 by dividing the Roschvastatin calcium linear-release granules (10.4 mg equivalent amount as Roschvastatin) of Example 2 into 1 layer and 3 layers, respectively. The tansilexetil delayed-release granules (16 mg equivalent of candesartan cilexetil) as intermediate layers (second layer) were put into different granule inlets of a rotary triple tablet tablet press equipped with a 10 mm diameter puncher, and compressed into a multi-layer tablet. Was prepared. Tablets that have been compressed are coated with a coating solution dissolved in purified water to 10% (v / v) in the ingredients and contents shown in Table 9.

Example 22 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Nucleated Tablets

An 11 mm punch with the Rochevastatin calcium pre-release granules (10.4 mg equivalent amount as Roschvastatin) of Example 3 was prepared using the candesartan cilexetil delayed-release tablet containing the enteric polymer of Example 6 as an inner core. Nucleating tablets were prepared by tableting in a nucleating tablet press. Tablets that have been compressed are coated with a coating solution dissolved in purified water to 10% (v / v) in the ingredients and contents shown in Table 9.

Example 23 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Nucleic Acid 2 Tablets

When injection of the candesartan cilexetil delayed-release nucleated tablet containing the enteric polymer of Example 7 as a dry coating, the injection of the Roschvastatin pre-release granules (10.4 mg equivalent amount as Roschvastatin) of Example 1 The nucleus double well was prepared by compressing one layer of the double well to be a nucleated well. Tablets that have been compressed are coated with a coating solution dissolved in purified water to 10% (v / v) in the ingredients and contents shown in Table 9.

<Example 24> Rochevastatin calcium-candesartan cilexetil capsules (tablets + tablets) preparation

The tablets of the Rochevastatin calcium linear-release granules (10.4 mg equivalent as Roschvastatin) of Example 1 were compressed into tablets with a 6 mm punch, and then the tablets were prepared.The candesar containing the hydrophilic polymer of Example 13 Capsules were prepared by filling into No. 0 capsules with tanlexetyl delayed-release tablets.

Example 25 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Capsule (Granule + Tablet)

The Rochevastatin calcium linear release granules (10.4 mg equivalent as Roschvastatin) of Example 1 were added to capsule No. 0 together with the candesartan cilexetil delayed-release tablet containing the hydrophobic compound and the hydrophilic polymer of Example 11. The capsule was prepared by filling.

Example 26 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Capsule (Tablet + Granule)

The Rochevastatin calcium linear release granules (10.4 mg equivalent as Roschvastatin) of Example 1 were compressed into tablets after a tablet press equipped with a 6 mm punch, and then the tablet was subjected to candesar containing the hydrophilic polymer of Example 12. Capsules were prepared by filling into No. 0 capsules with tansilexetil delayed-release granules (16 mg equivalent as candesartan cilexetil).

Example 27 Rochevastatin Calcium-Candesartan Silecetyl Capsule (Granule + Granule) Preparation

Candesartan cilexetil delayed-release granules (candesartanyl) comprising the roschvastatin calcium pre-release granules of Example 1 (10.4 mg equivalent as Roschvastatin) and the semipermeable membrane coating base of Example 14 and an osmotic pressure regulator. Capsules were prepared by filling No. 0 capsules with 16 mg equivalents as Lexetyl).

<Example 28> Rochevastatin calcium-candesartan cilexetil capsules (pellets + tablets) preparation

Rochevastatin calcium pre-release pellet of Example 4 (10.4 mg equivalent as Roschvastatin) and candesartan cilexetil delayed-release tablet containing the semi-permeable membrane coating base and the osmotic pressure regulator of Example 15 No. 0 Capsules were prepared by filling the capsules.

Example 29 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Capsule (Pellets + Granules)

Candesartan cilexetil delayed-release granules (16 mg as candesartan cilexetil) comprising the roschvastatin calcium pre-release pellet of Example 4 (10.4 mg equivalent as Roschvastatin) and the enteric polymer of Example 5 Capsules were prepared by filling into capsule 0 together with the corresponding amount).

Example 30 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Capsule (Tablet + Pellets)

The Rochevastatin calcium pre-release granules (10.4 mg equivalent as Roschvastatin) of Example 1 were tableted in a rotary tablet press equipped with a 6 mm punch, and then the tablets were purified.The candesar containing the enteric polymer of Example 16 Capsules were prepared by filling into No. 0 capsules with tansilexetil delayed-release pellets (16 mg equivalent as candesartan cilexetil).

Example 31 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Capsule (Granule + Pellets)

Candesartan cilexetil delayed-release pellet (16 mg as candesartan cilexetil) comprising the roschvastatin calcium pre-release granules of Example 1 (10.4 mg equivalent as Roschvastatin) and the enteric polymer of Example 16 Capsules were prepared by filling into capsule 0 together with the corresponding amount).

<Example 32> Rochevastatin calcium-candesartan cilexetil capsules (granules + capsules) preparation

Candesartan cilexetil delayed-release granules (16 mg equivalent as candesartan cilexetil) containing the enteric polymer of Example 5 were filled into No. 2 capsules, and the capsules of Rochevastatin calcium of Example 1 Capsules were prepared by filling into No. 0 capsules with pre-release granules (equivalent to 10.4 mg as Roschvastatin).

Example 33 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Capsule (Granule + Delayed-Release Capsule)

Filled No. 2 capsules with candesartan cilexetil, lactose monohydrate, polyethylene glycol 6000, carboxymethylcellulose calcium, and magnesium stearate to the ingredients and contents shown in Table 11, and then the capsules were filled with hypromellose acetate succinate. It was coated using a coating solution prepared by dissolving to 8% (w / w) in% ethanol. A capsule coated with an enteric polymer was filled into No. 0 capsule together with the roschvastatin calcium pre-release granules (10.4 mg equivalent as Roschvastatin) of Example 1 to prepare a capsule.

TABLE 11 Delayed-Release Capsule Composition Containing Candesartan Silecetyl

Example 34 Preparation of Rochevastatin Calcium-Candesartan Silecetyl Blister Packaging Kit

The Rochevastatin calcium pre-release granules (10.4 mg equivalent as Roschvastatin) of Example 1 were compressed into tablets after tableting with a rotary tablet press equipped with a 6 mm punch, and then the candesar containing the enteric polymer of Example 6 A package kit capable of simultaneous use was prepared by packaging in a single PTP (Press Through Pack) packaging container (Minister A, Heung-A Engineering) together with delayed release of tansilexetil.

Experimental Example 1 Dissolution profile test 1 (dissolution profile test)

The tablets obtained in Example 18 and Example 20 and the capsules obtained in Example 24 were used as the control agent using crest tablets (Astrazeneca: Roschvastatin mono) and atacane tablets (Astrazeneca: candesartan mono). A comparative dissolution test was performed accordingly.

Similar to the absorption path of the drug of the living body, the acidic conditions above are pH 1.2 solution (1st solution of 9 Pharmacopoeia Dissolution Test Method) and intestinal conditions are pH 6.8 (2nd solution of 9 Pharmacology Dissolution Test Method). The test was conducted by setting the dissolution time in consideration of the above residence time and proceeding with elution for 2 hours in pH 1.2 solution and then proceeding the test at pH 6.8.

Dissolution test conditions are as follows. Since candesartan is a poorly soluble material, it was tested by adding polysorbate 80, a surfactant, to the eluate at a concentration of 1%.

Dissolution test condition

Test method: Paddle method

Number of specimens: 12 each

RPM: 회전 50 rev / min

Test solution: pH 1.2 solution containing 1% polysorbate 80, and pH 6.8 solution

Liquid volume: 900 mL

The sample solution obtained in the dissolution test was quantified by liquid chromatography according to the following conditions to determine the dissolution rate of each formulation.

Analysis condition

Method: Liquid Chromatograph

Flow rate: 1 mL / min

Column: C18, 150 mm × 4.5 mm (5 μm)

Injection amount: 10 μL

Detector: UV absorbance photometer (wavelength 257 nm)

Mobile phase: 45:55 mixture of acetate buffer and acetonitrile

Acetic acid buffer solution: 1.54 g of ammonium acetate is dissolved in purified water to make 1,000 mL, and the pH is adjusted to 4.5 using acetic acid.

As a result of the dissolution test, the results as shown in FIG. 1 were obtained, and the Rochevastatin components of Examples 18, 20, and 24 exhibited the same dissolution characteristics as compared to the control formulation cresto tablet. However, it can be seen that the candesartan component has a release delay time of 120 minutes to 180 minutes compared to the control agent atacane tablet.

In addition, it can be seen that the release delay time can be controlled according to the type and dosage form of the delayed-release substance, and through this, it can be confirmed that the pharmaceutical formulation of the present invention can be developed in all formulations of the examples.

Experimental Example 2 Dissolution profile test 2 (dissolution profile test)

The dissolution test of the tablets obtained in Example 22 and the capsules obtained in Example 31 and Example 33 was carried out, and dissolution test conditions and analysis conditions were performed in the same manner as in Experiment 1.

As a result of the dissolution test, the results as shown in FIG. 2 were obtained, and the Rochevastatin components of Examples 22, 31, and 33 exhibited the same dissolution characteristics as compared to the control formulation cresto tablet. However, it can be seen that the candesartan component has a release delay time of 120 minutes to 150 minutes compared to the control agent atacane tablet.

In addition, it can be seen that the release delay time can be controlled according to the formulation, and through this, it can be seen that the pharmaceutical formulation of the present invention can be developed with all formulations of the examples.

1 is a graph showing the dissolution rate of roschvastatin and candesartan in the pharmaceutical preparations and the control formulations of Examples 18, 20, and 24, Cresto tablet and Atakan tablet.

Figure 2 is a graph showing the dissolution rate of roschvastatin, candesartan in the pharmaceutical formulations and control agents of the Examples 22, 31, 33, Cresto tablets, Atakan tablets.

Claims (34)

A releasing compartment comprising Roschvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and candesartan, a pharmaceutically acceptable salt thereof, or a prodrug thereof as a pharmacologically active ingredient A pharmaceutical formulation comprising a delayed-release compartment. The pharmaceutical formulation of claim 1, wherein the release of candesartan is initiated between 1 hour and 8 hours after initiation of the rochevastatin release. The pharmaceutical formulation of claim 1, wherein the release of candesartan is initiated between 2 and 4 hours after initiation of the rochevastatin release. The pharmaceutical formulation of claim 1, wherein the candesartan is released from 0 to 40% of the total amount of candesartan in the unit formulation until 2 hours after the start of the release of roschvastatin. The pharmaceutical formulation of claim 1, wherein the candesartan is released between 0 and 40% of the total amount of candesartan in a unit until 3 hours after the start of the release of roschvastatin. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises a release controlling substance selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof. The pharmaceutical formulation of claim 6, wherein the release controlling substance is included in an amount of 0.05-100 parts by weight based on 1 part by weight of candesartan. The enteric polymer according to claim 6, wherein the enteric polymer is selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, and a mixture thereof. Pharmaceutical preparations. The method of claim 8, wherein the enteric cellulose derivative is hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzo At least one selected from eight phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose and ethyl hydroxyethyl cellulose phthalate; The enteric acrylic acid copolymer is selected from the group consisting of styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylate, butyl styrene-acrylic acid acrylate, and methyl methacrylate-octyl acrylate copolymer. One or more selected; The enteric polymethacrylate copolymer is at least one selected from poly (methyl methacrylate) copolymer and poly (methacrylate ethylacrylate) copolymer; The enteric maleic acid copolymer is vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl At least one selected from an ether-maleic anhydride copolymer, an acrylonitrile-methyl methacrylate-maleic anhydride copolymer, and a butyl styrene-maleic-maleic anhydride copolymer; Or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate, polyvinyl butyrate phthalate, and polyvinylacetacetal phthalate. The method of claim 6, wherein the water-insoluble polymer is polyvinylacetate, water-insoluble polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, A pharmaceutical formulation selected from the group consisting of cellulose diacetate, cellulose triacetate, and mixtures thereof. The pharmaceutical formulation of claim 6, wherein the hydrophobic compound is selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof. 12. The method of claim 11, wherein the fatty acid and fatty acid esters are at least one selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and sleanic acid; The fatty acid alcohol is at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol; The waxes are at least one selected from carnauba wax, beeswax, and microcrystalline wax; Or the inorganic substance is at least one selected from talc, precipitated calcium carbonate, calcium monohydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. The method of claim 6, wherein the hydrophilic polymer is selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. Pharmaceutical preparations. The method of claim 13, wherein the saccharide is dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose At least one selected from amylopectin, 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 hydrophilic polymethacrylate copolymer may be a poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer; The polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide; Or the carboxyvinyl polymer is a carbomer. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises an osmotic pressure regulator and is coated with a semipermeable membrane coating base. The method of claim 15, wherein the semipermeable membrane coating base is polyvinyl acetate, water-insoluble polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate , Cellulose diacetate, cellulose triacetate, and mixtures thereof. The pharmaceutical formulation of claim 15, wherein the osmotic pressure regulator is 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. The pharmaceutical formulation of claim 1, wherein the roschvastatin comprises 5-40 mg of the formulation. The pharmaceutical formulation of claim 1, wherein the candesartan comprises 4 to 32 mg of the formulation with candesartan cilexetil. The pharmaceutical formulation according to claim 1, wherein the formulation is in the form of a biphasic matrix tablet obtained by tableting after the delayed-release compartment and the prior-release compartment are uniformly mixed. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a film consisting of a tablet consisting of a delayed-release compartment and a pre-release compartment surrounding the exterior of the tablet. The pharmaceutical formulation of claim 1, wherein the 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 preparation according to claim 1, wherein the preparation is in the form of a nucleated 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 tablet. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a capsule, granules, pellets, tablets, or capsules consisting of delayed-release compartments and capsules comprising particles, granules, pellets, or tablets 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 of claim 1, wherein the formulation is in the form of a coated tablet or coated capsule further comprising a coating layer on the outside. The pharmaceutical formulation of claim 25, wherein the coating layer comprises a release controlling substance. 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. 30. The pharmaceutical formulation of any one of claims 1 to 29, wherein the formulation is for the treatment and prevention of cardiovascular diseases. The method of claim 6, wherein the release control material is hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl methacrylate copolymer, polyvinylacetate, ethyl cellulose, cellulose acetate, carnauba wax, Pharmaceutical formulations selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, and mixtures thereof. The method of claim 6, wherein the release control material is hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl methacrylate copolymer, polyvinylacetate, ethyl cellulose, carnauba wax, hydroxypropyl Pharmaceutical formulations selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, and mixtures thereof. 33. The pharmaceutical formulation of claim 31 or 32, wherein the formulation is a capsule comprising a delayed-release compartment in the form of a bilayer tablet, nucleated tablet, or pellets. The method of claim 27, wherein the release control material is hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl methacrylate copolymer, polyvinylacetate, ethyl cellulose, cellulose acetate, carnauba A pharmaceutical formulation selected from the group consisting of waxes, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, and mixtures thereof.

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