KR20090114321A - Pharmaceutical formulation for treating cardiovascular disease - Google Patents

Abstract

PURPOSE: A pharmaceutical formulation containing simvastatin and valsartan as pharmacologically active ingredient is provided to enhance drug efficiency with reduced side effects. CONSTITUTION: A pharmaceutical formulation contains an immediate release compartment containing simvastatin as a pharmacologically active ingredient, its isomer or its pharmaceutically acceptable salt and a sustained release compartment containing valsartan as a pharmacologically active ingredient, its isomer or its pharmaceutically acceptable salt. The valsartan is released two hour after releasing of simvastatin. The pharmaceutical formulation is used in the form of particle, granule, pellet, tablet of sustained release compartment and capsule containing particle, granule, pellet, or tablet of immediate release compartment.

Description

Pharmaceutical formulation for treating cardiovascular disease

The present invention relates to a pharmaceutical formulation for treating cardiovascular diseases containing simvastatin and valsartan.

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 sequence 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 the drug combination. It is a well known fact.

More specifically, if the drug passes through the barrier in the first stage, enters the liver in the second stage, metabolizes and activates in the liver cells in the tertiary stage, and the biliary tract in the fourth stage Efflux transporters, influx transporters, and metabolic enzymes that absorb, metabolize, and excrete drugs everywhere, such as when exiting cells, exist 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 the aim 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.

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)

On the other hand, statin-based lipid lowering drugs are the first choice for the prevention and treatment of heart disease and hyperlipidemia due to coronary atherosclerosis, such as angina pectoris and myocardial infarction [Lancet1995; 346: 750-753, Am J Cardiol 1998; 82: 57T-59T, Am J Cardiol 1995; 76: 107C-112C, Hypertens Res 2003; 26: 699-704, Hypertens Res 2003; 26: 273-280, BrMed Bull 2001; 59: 3-16, Am J Med 1998; 104 (Suppl1): 6S-8S, Clin Pharmacokinet 2002; 41: 343-370.] Simvastatin, a representative drug thereof, strongly inhibits the conversion of HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA), to mevalonate, thereby inhibiting the production of cholesterol in the liver. It has the effect of lowering the production of low density lipoprotein cholesterol (LDL-C). In addition, simvastatin decreases the production of NO in the blood vessel wall and increases the NO production in the blood vessel wall of atherosclerosis patients or diabetic patients with increased blood pressure to a normal level, and shows an anti-pressure effect when combined with an anti-pressure agent. Physiol Renal Physiol Vol 281 Issue 5: F802-F809, 2001].

Valsartan, along with blood pressure lowering, prevents and treats heart failure, arrhythmia after myocardial infarction, diabetic complications, renal failure, stroke, antiplatelet action, prevents atherosclerosis, inhibits aldosterone harmful effects, relieves metabolic syndrome, and circulatory disease It has a wide range of actions, including prevention of chain deterioration. Clin, Exp. Hypertens., Vol. 20 (1998), p. 205-221, J. Hypertens., Vol. 13 (8) (1995), p. 891-899, Kidney Int., Vol. 57 (2) (2000), p. 601-606, Am. J. Hypertens., Vol. 10 (12PT2) Suppl. (1997), p. 325-331, Circulation, vol. 101 (14) (2000), p. 1653-1659, J. Hypertension., Vol 17 (7) (1999), p.907-716, Circulation, vol. 101 (2000), p.2349]

On the other hand, hypertension is the most frequent disease among chronic circulatory diseases, and it is divided into essential hypertension (primary hypertension), the cause of which is not obvious, and secondary hypertension (secondary hypertension), in which the causative disease is obvious. Primary hypertension accounts for more than 85% to 90% of patients with hypertension. The genetic predisposition is strong, but the detailed cause is not clear. Secondary hypertension is associated with kidney disease, renal vascular disease, endocrine disease, and hormone secretion. It is caused by various causes.

Hypercholesterolemia and hyperlipidemia are involved in the early development of atherosclerosis, with an uneven distribution of lipid deposits in arteries including coronary, carotid and peripheral arteries. See Wilson et al., Am. J. Cardiol., Vol. 59 (14) (1987), p. 91G-94G.

In addition, hypertension often coexists with coronary artery disease. In other words, atherosclerosis 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.

Therefore, a combination therapy containing HMG-CoA reductase inhibitor and angiotensin-II-receptor blocker has been proposed as a combination therapy for improving the condition of hypertension with coronary artery disease.

For example, WO 95/26188 discloses a method for treating atherosclerosis and lowering cholesterol using angiotensin-II-receptor blockers, including HMG-CoA reductase inhibitors and valsartan. Publication WO 97/37688 discloses the use of HMG-CoA reductase inhibitors and angiotensin-II-receptor blockers for the treatment of numerous symptoms including hypertension and atherosclerosis.

In addition, WO 99/11260 discloses a combination of atorvastatin with valsartan, valsartan, ibesartan and losartan for lowering blood pressure and lipid levels and for treating angina and atherosclerosis in mammals. WO 00/45818 describes the use of a combination of HMG-CoA reductase inhibitors and angiotensin-II-receptor blockers to alleviate diabetic neuropathy and to improve the rate of nerve delivery and blood flow to nerves, especially in patients with diabetes. It is starting.

However, the above prior art relates to a simple combination of a statin-based hyperlipidemia treatment agent and ARB for the treatment and prevention of hyperlipidemia and hypertension conditions, which is different from the pharmaceutical formulation of the present invention based on the time-dose principle of the two active ingredients. .

An object of the present invention is very effective in the treatment of hypertension and hyperlipidemia and prevention of complications, and selectively released controlled simvastatin and valsartan which can improve patient compliance, optimize drug delivery time, avoid drug interactions and reduce side effects. It is to provide a pharmaceutical formulation containing a.

The present invention provides a prior-release compartment comprising simvastatin, an isomer thereof, or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and Valsartan, an isomer thereof, or a pharmaceutically acceptable salt thereof, as a pharmacologically active ingredient. A pharmaceutical formulation is provided that is a timed release formulation comprising a delayed release compartment comprising a salt.

In the following, “simvastatin” means including its isomers and pharmaceutically acceptable salts thereof unless otherwise noted, and “balsartan” includes both its isomers and pharmaceutically acceptable salts unless otherwise specified. It means to include.

In the present invention, pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic ionic salts made of calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, Inorganic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid prepared with iodic acid, perchloric acid, tartaric acid and sulfuric acid , Benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanic acid, Organic acid salts prepared with hydroiodic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and nathalenesulfonic acid, sulfonic acid salts, glycine, arginine, Although the amine salt produced in the amino acid salt and trimethylamine, triethylamine, ammonia, pyridine, picoline, etc. prepared in the like who is and is not a salt type, which means in the present invention by the enumeration of these salts is not limited.

The pharmacological action of the pharmacologically active ingredients used in the pharmaceutical preparations of the present invention is shown in Table 1 below.

[Table 1] Pharmacological Actions of Simvastatin and Valsartan

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% and preferably at least 90% of the total amount of simvastatin is released within 30 minutes after initiation of simvastatin dissolution.

The present invention also provides a pharmaceutical formulation in which valsartan is eluted 2 hours after the start of simvastatin elution upon oral administration.

The present invention provides a pharmaceutical formulation wherein valsartan is absorbed in the liver 2 to 4 hours later than simvastatin.

Pharmaceutical formulations of the present invention for implementing such drug delivery systems consist of valsartan or a pharmaceutically acceptable salt thereof, and the desired excipients, so that they can be physically separated or partitioned to obtain different release times and rates of the two drugs. A delayed-release compartment and simvastatin 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.

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

One. Prerelease  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, and may include a pharmacologically active ingredient simvastatin and may further include a pharmaceutically acceptable additive as necessary. have.

In the present invention, the prior-release compartment may be prepared in the form of a mixture, granules, pellets, or tablets through a conventional procedure for preparing oral administration agents such as mixing, coalescing, drying and granulation together with pharmaceutically acceptable additives besides simvastatin. Can be. 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

Pre-release compartments include simvastatin, its isomers or pharmaceutically acceptable salts as pharmacologically active ingredients.

Simvastatin, the active ingredient in the prior-release compartment in the formulation of the present invention comprises 1 to 160 mg of the formulation (200 mg to 1,200 mg total) on an adult (65-75 kg adult male) daily basis, preferably 5 to 80 mg.

 (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, antioxidants, 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 simvastatin.

Diluents in the pre-release compartment of the present invention may contain starch, microcrystalline cellulose, lactose (lactose monohydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clays, polyethylene glycols, anhydrous calcium hydrogen phosphate, or mixtures thereof. Can be used.

In the pre-release compartment of the present invention, the binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), hypromellose, hydroxypropyl cellulose , Natural gums, synthetic gums, copovidone, gelatin, or mixtures thereof.

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, colloidal silicon dioxide or mixtures thereof and the like can be used.

In the prior-release compartment of the present invention, the pH adjusting agent is acidified with precipitated calcium carbonate and acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid) And basic agents such as aqueous ammonia, meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, calcium tribasic phosphate, and the like.

Antioxidants in the pre-release compartment of the present invention may use dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium bisulfite, sodium pyrosulfite and the like.

In the pre-release compartment of the present invention, the dissolution aid can be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium, poloxamer 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 valsartan, 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 comprises the isomer of valsartan and a pharmaceutically acceptable salt, wherein the active ingredient in the delayed-release compartment may comprise 1 to 800 mg of valsartan in the unit formulation, preferably 20 to 640 mg.

(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 enteric 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 valsartan. If 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 that can be used 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 polymethacrylate copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative, and the enteric cellulose derivative Hypromellose acetate succinate, hypromellose phthalate (hypromellose phthalate), hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose prolate At least one selected from cationate phthalate, methyl cellulose phthalate, carboxymethyl ethyl 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-acrylic acid acrylates, and methyl methacrylates (methacrylates). At least one selected from octyl acrylate copolymers; The enteric polymethacrylate copolymer is a poly (methacrylate-methyl methacrylate) copolymer (e.g. Eudragit L 100, Eudragit S, Evonik, Germany), poly (methacrylate, ethyl Acrylate) copolymers (eg Eudragit L 100-55, Evonik, Germany); The enteric maleic acid copolymers include vinyl acetate-maleic anhydride copolymers, styrene-maleic anhydride copolymers, styrene-maleic acid monoester copolymers, vinylmethyl ether-maleic anhydride copolymers, ethylene-maleic anhydride copolymers, and vinyl butyl ether- At least one selected from a maleic anhydride copolymer, an acrylonitrile-methyl acrylate maleic anhydride copolymer, and a 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 acetal phthalate. In the formulation of the present invention, the enteric polymer is preferably hypromellose 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, compared to 1 part by weight of valsartan. If exceeded, there is a problem in 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 polyvinylacetate (eg, colicoat SR30D), water-insoluble polymethacrylate copolymers [eg, poly (ethylacrylate-methyl methacrylate) copolymers (eg, Eudragit) NE30D), poly (ethylacrylate-methyl methacrylate-trimethylaminoethylmethacrylate chloride) copolymer (e.g. Eudragit RSPO, RL, RS), etc.], ethyl cellulose, cellulose ester, cellulose ether, cellulose acyl At least one member selected from the group consisting of latex, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate. The water insoluble polymer in the formulation of the present invention is preferably polyvinylacetate or poly (ethylacrylate-methyl methacrylate-trimethylaminoethylmethacrylate chloride) copolymer.

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 with respect to 1 part by weight of valsartan. In the case of minor excess, the dissolution is excessively delayed.

The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water (eg, purified 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. In the formulation of the present invention, the hydrophobic compound is preferably carnauba wax.

Hydrophobic compound according to the present invention may be included 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight relative to 1 part by weight of valsartan, when less than 0.1 parts by weight has a problem that the release of the drug is not controlled, 20 parts by weight If it exceeds, there is a problem that excessive dissolution is 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, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. The sugar is one selected from dextrin, polydextrin, dextran, pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin Above; The cellulose derivative is at least one selected from hypromellose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium; 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 is a poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (eg Eudragit E100, Evonik, Germany); The polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide; And the carboxyvinyl polymer is carbomer. In the formulation of the present invention, the hydrophilic polymer is preferably one or more selected from hydroxypropyl cellulose.

The hydrophilic polymer according to the present invention may be included in an amount of 0.05 to 30 parts by weight, preferably 0.5 to 20 parts by weight with respect to 1 part by weight of valsartan. 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.

(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 regulating agent 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 At least one selected from the group consisting of 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, and less than 0.1 parts by weight of valsartan. There is a problem that unnecessarily increase the total weight of the formulation or implement 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. Say. The semipermeable membrane coating base in the present invention is, for example, polyvinyl acetate, water insoluble polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, And at least one selected from the group consisting of cellulose diacetate, cellulose triacetate and mixtures thereof. In the preparation of the present invention, the semipermeable membrane coating base is preferably ethyl cellulose.

Here, the semi-permeable coating agent 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 valsartan. In 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 becomes 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, starch, microcrystalline cellulose, lactose monohydrate, glucose, mannitol, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, or a mixture thereof may be used as a diluent; As binders starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone, hypromellose, 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.

As lubricant, talc, stearic acid, magnesium stearate, calcium stearate, etc., sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, colloidal silicon dioxide, sodium stearyl fumarate, glyceryl behenate, glyceryl monolate, glyceryl monostea Latex, glyceryl palmitostearate, polyethylene glycol, magnesium aluminate silicate, 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, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and precipitated calcium carbonate, Basic agents such as ammonia water, meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, calcium tribasic phosphate and the like 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 additive of the present invention, the dissolution aid may be used 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 and polyethylene glycol.

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, or the like may be used as a solvent of the binding solvent and the delayed-release additive, and more preferably, purified water and ethanol are preferable.

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 preparation of the present invention is a tabletting by selectively mixing additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like to have a pre-release compartment and a delayed-release compartment in a single tablet, and thus the active ingredient of each compartment. 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 film consisting of a tablet consisting of a delayed-release compartment and a pre-release compartment surrounding the outside of the tablet, simbastatin of the film coating layer as the film coating layer is dissolved It will elute 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 pressure control agent inside the tablet for delayed release, followed by tableting, followed by coating the surface of the tablet with an osmotic semipermeable membrane 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 hypromellose, 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 using a coating agent, a coating aid, or a mixture thereof. For example, the coating agent may be a cellulose derivative such as hypromellose, hydroxypropyl cellulose, sugar derivatives, polyvinyl derivatives, waxes, fats, Gelatin, mixtures thereof, and the like; Coating aids may be 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.

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

In the first step, valsartan is mixed, combined, dried, granulated or coated by administering one or two release controlling substances selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, and a hydrophilic polymer with conventional additives used in pharmaceuticals, And obtaining delayed-release granules or tablets through tableting, or mixing, associating, drying, sizing or tableting valsartan with an osmotic pressure-controlling agent and a conventional additive used in pharmaceuticals, and then coating the semipermeable membrane coating base to delay-release Obtaining granules or tablets.

The second step consists in administering simvastatin and pharmaceutically acceptable conventional additives to produce the prior-release granules or tablets obtained through conventional procedures for producing oral solids by mixing, coalescing, drying, granulating or coating, and tableting. It is a step to get.

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 additionally coated, and then separately dissolved simvastatin in an aqueous film coating solution and dispersed By coating on the tablet outer layer obtained in the first step it can be prepared orally administered film coating tablets 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 design.

[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) Dissolve or suspend valsartan, a release control substance, and a pharmaceutically acceptable additive, if necessary, in water, an organic solvent, or a mixed solvent, coating the spherical granules (sugar seed), drying, and controlling the release as necessary. After dissolving in water, organic solvent, or mixed solvent using the substance alone or two or more, coating, drying, granulation obtained in the second step or tablets obtained in the third step, mixed with the capsule filling machine to fill the capsule Can be prepared.

(2) simvastatin and pharmaceutically acceptable additives are dissolved or suspended in water, organic solvents or mixed solvents, coated on sugar spherical granules (sugar seeds), dried, and the release control pellets containing valsartan of the above (1). After mixing with the capsule filling the capsule can be prepared by the capsule.

[Product] Kit Preparation

The valsartan-containing preparation obtained in the first step and the simvastatin-containing preparation obtained in the second step can be prepared together with a foil, a blister, a bottle, or the like to be taken at the same time.

The human dosage of the formulation 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, the total amount of valsartan and simvastatin, 2.0 per day ~ 960 mg, preferably 22 ~ 700mg per day to be able to exert anti-pressure action and prevent complications.

The present invention also provides a method for treating a cardiovascular disease comprising administering a pharmaceutical agent of the present invention to a mammal. Preferably, the present invention provides a method for treating hypertension and hyperlipidemia or consequent cardiovascular disease or metabolic syndrome, comprising administering a pharmaceutical preparation of the present invention to a mammal at 5 pm to 11 pm once a day.

The cardiovascular disease is a very broad disease that refers to both cardiovascular and other vascular diseases including cerebrovascular disease. Types of heart diseases include hypertension, heart failure, arrhythmia, cardiomyopathy, and endocarditis, representing ischemic heart disease (myocardial infarction, angina pectoris, etc.) due to the progression of arteriosclerosis. Vascular diseases include stroke (stroke) and peripheral vascular disease. . In addition, it includes hypertension and complications of those with metabolic syndrome, in which hypertension, diabetes, obesity, hyperlipidemia, and coronary artery disease are combined.

The pharmaceutical preparations of the present invention are very effective in treating hypertension and hyperlipidemia and preventing complications, and have an effect of improving patient compliance, optimizing drug delivery time, avoiding drug interactions and reducing side effects.

Hereinafter, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

Example 1 Preparation of Simvastatin-Valsartan Nucleated Tablets

1) Preparation of simvastatin prior-release compartment

Following the ingredients and contents shown in Table 2, simvastatin (Simvastatin, Biocon, India), microcrystalline cellulose (Vivapur 12, JRS, Germany), di-mannitol (Pearlitol, Roquette, France) as apple No. 35 and mixed in a high-speed mixer It was. Separately, hydroxypropyl cellulose (Klucel LF, Hercules, USA) and citric acid (Citric acid monohydrate, Merck, USA) were dissolved in purified water to prepare a binding solution, and the mixture was added to a high-speed mixer with the main ingredient mixture and fed together. It was granulated using and dried at 60 ° C. using a hot water dryer, and then sieved to No. 20 sieve again. Butylated hydroxyanisole (BHA, Merck, USA), sodium starch glycolate (Explotab, JRS, Germany) and colloidal silicon dioxide (Aerosil pharma 200, Degussa, USA) were mixed and magnesium stearate The final mixture was put into a double cone mixer.

2) Preparation of Chamvalsartan Delayed-Release Compartment

The valsartan (Dr. Reddy's, India) was appled into a No. 35 sieve and added to a high speed mixer as shown in Table 2 below. Separately, the binding solution of hydroxypropyl cellulose dissolved in purified water was added to a high-speed mixer, coalesced, and granulated using an oscillator with No. 20 sieve, and dried by a fluid bed dryer.

GPCG-1 (Glatt, Germany) was used for the fluid bed granule dryer, and the granulation was carried out under the following conditions. The air flow was 120 m ³ / hour, the inlet air temperature was 65 ° C, and the filter shaking (delta P filter <4000 pa) was performed in asynchronous mode for 5 seconds in 30 seconds. When the product temperature reaches 40 ℃, the sample was taken and completed if it meets the criteria of 2.5% or less of drying loss, and if it exceeds, it proceeds further and re-measures to complete drying.

When the drying is completed, the dried product is established using an F-type sizer equipped with a No. 20 body, and put into a double cone mixer, microcrystalline cellulose, cross-linked polyvinylpyrrolidone (Crospovidone, BASF, Germany), colloidal silicon dioxide , Sodium lauryl sulfate (Jeelate, Jeen, USA) was added and mixed with a double cone mixer, and then magnesium stearate was added to the mixture and finally mixed. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and used as a nuclear tablet.

In the above purification, a solution of hypromellose phthalate (HPMC-P, Shin-Etsu, Japan) dissolved in a 1: 1 (w / w) mixture of ethanol and methylene chloride was used as a high coater (SFC-30N, Sejong Machinery, Korea) to form a film coating layer to prepare a nuclear tablet.

3) tableting and coating

Tableting using a nucleated tablet tablet machine (RUD-1: Kilian) as the inner core of the valsartan nuclear tablet and the composition containing simvastatin as an outer layer, followed by hypromellose 2910 (Pharmacoat 603, Shin-Etsu, Japan), hydroxypropyl A coating solution made by dissolving cellulose, titanium oxide (Fanglian, JHP, China), and talc (Talc, Nippon soda, Japan) in a mixture of ethanol and purified water (8: 2 (v / v)). Machine, Korea) to form a film coating layer to produce a nucleated tablet.

Example  2: Simvastatin  - Valsartan Nuclear Justice  Produce

1) Preparation of simvastatin prior-release compartment

It was prepared according to the ingredients and contents shown in Table 2 below and the preparation method of 1) simvastatin pre-release compartment of Example 1.

2) Preparation of Chamvalsartan delayed-release compartment (inner core)

As shown in Table 2, the ingredients and contents of the valsartan apples No. 35 and put into a high speed mixer. Separately, the binder solution dissolved in hydroxypropyl cellulose purified water was added to a high speed mixer, coalesced, granulated using an oscillator with No. 20 sieve, and dried in a fluid bed dryer.

When the drying was completed, the dried product was sized using an F type sizer equipped with a No. 20 sieve, and put into a fluidized bed granulator (GPCG 1: Glatt). The granules were sprayed onto the granules by spraying a hypromellose phthalate solution dissolved in a 1: 1 (w / w) mixture of ethanol and methylene chloride. The granules were put in a double cone mixer, microcrystalline cellulose, crosslinked polyvinyl pyrrolidone, colloidal silicon dioxide, sodium lauryl sulfate were added and mixed.

Magnesium stearate was added thereto, mixed with a final double cone mixer, and the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong), which was used as an inner core tablet.

3) tableting and coating

Simvastatin-valsartan nucleated tablets were prepared in the same manner as in Example 1, 3) Tableting and Coating.

Example  3: Simvastatin  - Valsartan  Multilayer Tablet Preparation

1) Preparation of simvastatin prior-release compartment

It was prepared according to the ingredients and contents shown in Table 2 below and the preparation method of 1) simvastatin pre-release compartment of Example 1.

2) Preparation of Chamvalsartan Delayed-Release Compartment

Next, as shown in Table 2, valsartan, microcrystalline cellulose, and poloxamer 188 (Lutrol, BASF, USA) were mixed with a No. 35 sieve and mixed with a double cone mixer, and separately a hypromellose was dissolved in purified water. Was sprayed to form granules and dried. Again, the granules were sprayed onto the granules by spraying a hypromellose phthalate solution dissolved in a 1: 1 (w / w) mixture of ethanol and methylene chloride. Magnesium stearate was added and mixed in a final double cone mixer.

3) tableting and coating

In this process, it was compressed using a multi-layer tablet press (MRC-37T: Sejong). That is, the composition containing simvastatin is placed in a primary powder feeder, the composition containing valsartan is placed in a secondary powder feeder, and tableted under conditions that can minimize the incorporation between layers, hypromellose 2910 and hydroxypropyl. A coating solution prepared by dissolving cellulose, titanium oxide, and talc in a mixture of ethanol and purified water (8: 2 (v / v)) to form a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea). Release tablets were prepared.

Example  4: Simvastatin  - Valsartan  Multilayer Tablet Preparation

1) Preparation of simvastatin prior-release compartment

It was prepared according to the ingredients and contents shown in Table 2 below and the preparation method of 1) simvastatin pre-release compartment of Example 1.

2) Preparation of Chamvalsartan Delayed-Release Compartment

Next, valsartan, microcrystalline cellulose and poloxamer 188 were apples in No. 35 and mixed in a double cone mixer as shown in the following Table 2, and the granules were formed by spraying a binding solution prepared by dissolving hypromellose in water. Dried. Again, the granules were coated by spraying a Eudragit RS PO (Evonik, USA) solution dissolved in a 1: 1 (w / w) mixture of ethanol and methylene chloride. Magnesium stearate was added thereto and mixed in a final double cone mixer.

3) tableting and coating

Simvastatin-valsartan multi-layered tablets were prepared in the same manner as in Example 3, 3) Tableting and Coating.

Example  5: Simvastatin  - Valsartan  Preparation of Biphasic Matrix Tablets

1) Preparation of simvastatin prior-release compartment

Following the ingredients and contents shown in Table 2, simvastatin, microcrystalline cellulose, di-mannitol were apples into No. 35 sieve and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid are dissolved in purified water to prepare a binding solution, and the mixture is added to a high speed mixer together with the mixture of the main ingredients, and then granulated using an oscillator with No. 20 sieve and dried at 60 ° C. using a hot water dryer. Next, the mixture was stipulated as No. 20, and butylated hydroxyanisole was added thereto and mixed.

2) Preparation of Chamvalsartan Delayed-Release Compartment

Next, valsartan, microcrystalline cellulose and poloxamer 188 were appled in a No. 35 sieve and mixed in a double cone mixer as shown in Table 2 below.

The mixture was poured into a fluidized bed granulator (GPCG 1: Glatt) and sprayed with a bonding liquid prepared by dissolving hypromellose in purified water, to form granules and dried. Again, the granules were sprayed onto the granules by spraying a Eudragit RS PO solution dissolved in a 1: 1 (w / w) mixture of ethanol and methylene chloride.

3) After mixing, tableting and coating

Each final composition prepared above was mixed with a double cone mixer, sodium starch glyconate and colloidal silicon dioxide were mixed, and magnesium stearate was added thereto, followed by final mixing with a double cone mixer.

The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong), and then a high coater (SFC-30N) was prepared by dissolving hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc in ethanol and purified water. , Sejong Machine, Korea) to form a film coating layer to prepare a two-phase matrix tablet.

Example 6: Preparation of simvastatin-valsartan two phase matrix tablets

1) Preparation of simvastatin prior-release compartment

To the ingredients and contents shown in Table 2 and 1) simvastatin pre-release compartment of Example 5 was prepared according to

2) Preparation of Chamvalsartan Delayed-Release Compartment

Next, valsartan, microcrystalline cellulose and poloxamer 188 were appled in a No. 35 sieve and mixed in a double cone mixer as shown in Table 2 below. The mixture was poured into a fluidized bed granulator (GPCG 1: Glatt) and sprayed with a bonding liquid prepared by dissolving hypromellose in purified water, to form granules and dried. Again, the granules were sprayed onto the granules by spraying a solution of hypromellose phthalate dissolved in a (1: 1 (w / w)) mixture of ethanol and methylene chloride.

3) tableting and coating

Simvastatin-valsartan biphasic matrix tablets were prepared in the same manner as in Example 5, 3) post-mixing, tableting and coating.

Example  7: Simvastatin  - Valsartan  2-phase capsule formulation

1) Preparation of simvastatin prior-release compartment (granule)

It was prepared according to the ingredients and contents shown in Table 2 below and the preparation method of simvastatin pre-release compartment of Example 5.

2) Preparation of Valsartan Delayed-Release Compartment (Granule)

It was prepared according to the ingredients and contents shown in Table 2 below and the preparation method of 2) valsartan delayed-release compartment of Example 6.

3) Mixing and capsule filling

The final compositions of steps 1) and 2) were mixed with a double cone mixer, sodium starch glycolate was added thereto, mixed with a double cone mixer, colloidal silicon dioxide was mixed, and magnesium stearate was added to the final mixture. . The final mixed mixture was put into a powder feeder and filled into No. 1 gelatin hard capsules using a capsule charger.

Example  8: Simvastatin  - Valsartan  Containing tablets Capsule

1) Preparation of simvastatin pre-release compartment (tablet)

Following the ingredients and contents shown in Table 2, simvastatin, microcrystalline cellulose, di-mannitol were apples into No. 35 sieve and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid are dissolved in water to prepare a binding solution, which is combined with a main ingredient mixture in a high-speed mixer, fed together, granulated using No. 20 sieve using an oscillator, and dried at 60 ° C. using a hot water dryer, and then again. It was established as No. 20. Butylated hydroxyanisole, sodium starch glycolate, and colloidal silicon dioxide were mixed, and magnesium stearate was added and finally mixed in a double cone mixer, and the final mixture was subjected to a rotary tablet press (MRC-33: Sejong). It was tableted using. The tablet is a high coater (SFC-30N) using a coating solution prepared by dissolving and dispersing hypromellose 2910, polyethylene glycol 6000 (PEG6000, Duksan, Korea), titanium oxide and talc in 80 (w / w)% ethanol , Sejong Machinery, Korea).

2) Preparation of Chamvalsartan Delayed-Release Compartment (Tablet)

It was prepared according to the ingredients and contents shown in Table 2 below and the preparation method of 2) valsartan delayed-release compartment of Example 1.

3) Filling capsule

The simvastatin tablet of step 1) and the valsartan tablet of step 2) were filled into No. 1 hard gelatin capsules using a capsule charger.

Example  9: Simvastatin - Valsartan Capsule

1) Preparation of simvastatin prior-release compartment (granule)

Following the ingredients and contents shown in Table 2, apples with simvastatin, microcrystalline cellulose, di-mannitol No. 35 sieve and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid are dissolved in purified water to prepare a binding solution, which is combined with a main ingredient mixture in a high-speed mixer, and then combined, and granulated using No. 20 sieve using an oscillator and dried at 60 ° C. using a hot water dryer, and then again. It was established as No. 20. Butylated hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed, and magnesium stearate was added thereto, followed by final mixing in a double cone mixer.

2) Preparation of Chamvalsartan Delayed-Release Compartment (Tablet)

It was prepared according to the ingredients and contents shown in Table 2 below and the preparation method of 2) valsartan delayed-release compartment of Example 1.

3) Filling capsule

Simvastatin tablets of step 1) and valsartan tablets of step 2) were filled into 1st hypromellose hard capsules using a capsule charger.

Example  10: Simvastatin - Valsartan Coated tablet

1) Preparation of simvastatin pre-release coating solution

Following the ingredients and contents shown in Table 2, simvastatin, butylated hydroxyanisole, colloidal silicon oxide, hypromellose 2910, polyethylene glycol 6000, titanium oxide, talc, ethanol and methylene chloride (1: 1 ( w / w)) dissolved and dispersed in a mixed solution to prepare a pre-release simvastatin coating solution.

2) Preparation of Chamvalsartan Delayed-Release Compartment (Tablet)

It was prepared according to the ingredients and contents shown in Table 2 below and the preparation method of 2) valsartan delayed-release compartment of Example 1.

3) first coating

Valsartan tablets prepared above were administered to a high coater (SFC-30N, Sejong Machinery, Korea) and then first coated with simvastatin coating solution.

4) 2nd coating

Hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc described in the coating layer of Table 2 were dissolved in ethanol and purified water mixture ((8: 2 (v / v)). Second coating was performed to prepare a film coated tablet.

Example  11: Simvastatin Discharge - Valsartan Osmotic Nuclear Justice  Produce

1) Preparation of simvastatin prior-release compartment

To the ingredients and contents shown in Table 2 and 1) simvastatin pre-release compartment of Example 1 was prepared according to

2) Preparation of Valsartan Delayed-Release Compartment (Tablet)

As shown in Table 2, the ingredients and contents of the valsartan apples No. 35 and put into a high speed mixer. Separately, the binding solution in which hydroxypropyl cellulose was dissolved in purified water was added to a high-speed mixer, coalesced, granulated using an oscillator, and dried in a fluid bed dryer.

When the drying was completed, the F-type sizer equipped with a No. 20 body was used as a dry matter. The granules were placed in a double cone mixer, microcrystalline cellulose, crosslinked polyvinylpyrrolidone, colloidal silicon dioxide, sodium lauryl sulfate, sodium chloride were added and mixed.

Magnesium stearate was added thereto, mixed with a final double cone mixer, and the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong).

After tableting, Colicord SR 30D (polyvinyl acetate 30% suspension, BASF) and triethyl citrate (Citroflex 2, Morimura BROS, USA) are dispersed in purified water as osmotic base, and then high coater (SFC-30N, Sejong Machinery , Korea) was coated on the inner core to prepare an osmotic core tablet.

3) tableting and coating

Simvastatin pre-release-valsartan osmotic nucleated tablets were prepared in the same manner as in Example 1, 3) Tableting and Coating.

Example  12: Simvastatin - Valsartan Blister  Packing Kit

Prepared as shown in Table 2 and the ingredients, except that the valsartan tablets and simvastatin tablets of Example 8 instead of the simultaneous filling in capsules were prepared as in Example 8 to be packaged for simultaneous use in a blister packaging container It was.

TABLE 2

Experimental Example 1 Dissolution Profile Test

Comparative dissolution tests were carried out using the tablets of the various formulations of Examples 1, 3, 5, and 8 and a control drug (Zoko: simvastatin single agent, Diovan: valsartan single agent). In the case of simvastatin dissolution test, the dissolution test was carried out based on the US Pharmacopeia (USP 30), and in the valsartan dissolution test, the eluate was buffered at pH 6.8 (phosphate solution) in 0.1 N hydrochloric acid solution (acidic environment). The dissolution test was carried out by changing to (12 test populations).

[Simvastatin test method]

Dissolution test basis: Simvastatin tablet in USP30

Test method: Paddle method, 50 revolutions / minute

Test drug: pH = 7.0 buffer (composition = 0.01 M sodium dihydrogen phosphate solution containing 0.5% weight / weight of sodium lauryl sulfate as surfactant), 900 mL

Analytical Method: Ultraviolet-visible Spectrophotometry (Detect Wavelength = Max 247, Min 257 nm)

[Valsartan Test Method]

Dissolution test basis: 'Valsartan and Hydrochlorothiazide tablet' in USP 31

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.01 N hydrochloric acid solution, 1000ml (0 ~ 2 hours)

pH = 6.8 buffer (phosphate solution), 1000 mL (after 2 hours)

Analytical Method: Ultraviolet-visible Spectrophotometry (Detect Wavelength = Max 270, Min 250 nm)

According to FIGS. 1, 2, 3, and 4, the tablets of Examples 1, 3, 5, and 8 were found to have almost the same elution characteristics as the simvastatin component compared to the control preparation, Zoko, in the dissolution test under the following conditions. On the other hand, while the dissolution rate of the control agent Dioban up to 120 minutes was about 30%, the dissolution rate of the valsartan component in the simvastatin / valsartan formulation of the present invention was less than about 5% up to 120 minutes, which is an artificial gastric juice section, and delayed release over about 2 hours. It was found to be effective.

Figure 1 is a graph showing the dissolution rate of simvastatin / valsartan nucleated tablets prepared according to Example 1 and the valsartan of simvastatin and diovan of each single agent Koza.

Figure 2 is a graph showing the dissolution rate of simvastatin / valsartan multi-layered tablet prepared according to Example 3 and the valsartan of simvastatin and dioban of each single agent Koza simovastatin.

Figure 3 is a graph showing the dissolution rate of simvastatin / valsartan matrix tablets prepared according to Example 5 and valsartan of simovastatin and diovan of each single agent Koza.

Figure 4 is a graph showing the dissolution rate of the capsule containing simvastatin valsartan tablets prepared according to Example 8 and the valsartan of simovastatin and diovan of each single agent Koza.

Claims (35)

Pharmacologically active ingredients include simvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof, and a releasing compartment comprising the pharmacologically active ingredient Valsartan, an isomer thereof or a pharmaceutically acceptable salt thereof A pharmaceutical formulation comprising a delayed-release compartment. The pharmaceutical formulation of claim 1, wherein the simvastatin releases at least 80% of the total amount of simvastatin within 30 minutes after initiation of dissolution. The pharmaceutical formulation of claim 1, wherein the valsartan is released after oral administration two hours after the start of simvastatin elution. The pharmaceutical formulation according to claim 1, wherein the simvastatin is 1 to 160 mg in the formulation. The pharmaceutical formulation of claim 1, wherein the valsartan is 1 to 800 mg in the formulation. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises one or more release agent fish substances selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers. The pharmaceutical formulation of claim 6, wherein the release controlling substance is at least one selected from an enteric polymer and a water insoluble polymer. The pharmaceutical preparation according to claim 6, wherein the release controlling substance is included in an amount of 0.05 parts by weight to 100 parts by weight with respect to 1 part by weight of valsartan. The pharmaceutical preparation according to claim 6, wherein the enteric polymer is at least one selected from an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative. 10. The method of claim 9, wherein the enteric cellulose derivative is hypromellose acetate succinate, hypomellose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, At least one selected from cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl 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 acrylic acid copolymers, butyl styrene-acrylate-acrylic acid copolymers, and methyl acrylate-methacrylic acid-octyl acrylate. At least one selected from coalescing; The enteric polymethacrylate copolymer is at least one selected from a poly (methacrylate-methyl methacrylate) copolymer and a poly (methacrylate-ethylacrylate) copolymer; The enteric maleic acid copolymers include vinyl acetate-maleic anhydride copolymers, styrene-maleic anhydride copolymers, styrene-maleic acid monoester copolymers, vinylmethyl ether-maleic anhydride copolymers, ethylene-maleic anhydride copolymers, and vinyl butyl ether- At least one selected from maleic anhydride copolymer, acrylonitrile-methyl methacrylate-maleic anhydride copolymer, and butyl styrene-maleic-maleic anhydride copolymer; Or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, and polyvinyl acetacetal phthalate. The pharmaceutical formulation of claim 10 wherein the enteric polymer is hypromellose phthalate. The pharmaceutical formulation of claim 9, wherein the enteric polymer is 0.1 part by weight to 20 parts by weight based on 1 part by weight of valsartan. 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 which is at least one selected from cellulose diacetate, and cellulose triacetate. The pharmaceutical formulation of claim 13, wherein the water insoluble polymer is a poly (ethylacrylate-methyl methacrylate-trimethylaminoethylmethacrylate chloride) copolymer which is polyvinylacetate or water-insoluble polymethacrylate. The pharmaceutical formulation of claim 13, wherein the water-insoluble polymer is 0.1 parts by weight to 30 parts by weight with respect to 1 part by weight of valsartan. The pharmaceutical formulation of claim 6, wherein the hydrophobic compound is at least one selected from fatty acids and fatty acid esters, fatty alcohols, waxes and inorganic substances. 17. The method of claim 16, wherein the fatty acids and fatty acid esters are at least one selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and stearic acid; The fatty acid alcohol is at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol, and 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 pharmaceutical formulation according to claim 16, wherein the hydrophobic compound is 0.1 to 20 parts by weight based on 1 part by weight of valsartan. The pharmaceutical formulation of claim 6, wherein the hydrophilic polymer is at least one selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, and carboxyvinyl polymers. 20. The method of claim 19, wherein the saccharide is dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose And amylopectin; The cellulose derivative is at least one selected from hypromellose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium; 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 is a poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer; The polyethylene derivative is at least one selected from polyethylene glycol and polyethylene oxide; The carboxyvinyl polymer is a carbomer. 20. The pharmaceutical formulation of claim 19, wherein the hydrophilic polymer is 0.05 to 30 parts by weight based on 1 part by weight of valsartan. 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 pharmaceutical formulation of claim 22, wherein 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. 23. The method of claim 22, 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 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. The pharmaceutical formulation of claim 28, wherein the nucleated tablet is an osmotic nucleated tablet. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in the form of a capsule comprising granules, granules, pellets, or tablets consisting of delayed-release compartments and granules, granules, pellets, or tablets of prior release compartments. Formulation. 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 administration between 5 pm and 11 pm. 35. A method of treating cardiovascular disease, comprising administering the pharmaceutical formulation of any one of claims 1 to 34 to a mammal.

Images