KR20090091083A - Controlled release pharmaceutical formulation for treating cardiovascular disease - Google Patents

Abstract

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

Description

Controlled release pharmaceutical formulation for treating cardiovascular disease

 The present invention is designed to control and release each drug at a specific rate by applying the so-called Chronotherapy principle and Xenobiotics, which are administered at a time difference at the time of expression of pharmacological action of each of the complex components. A pharmaceutical formulation comprising active release of amlodipine and its pharmaceutically acceptable salts, isomers (hereafter amlodipine) and simvastatin and its pharmaceutically acceptable salts (simovastatin) as active ingredients.

Arteriosclerosis and hypertension are symptoms of a vicious cycle of mutual exacerbation, so both hyperlipidemic patients and hypertensive patients should treat arteriosclerosis and hypertension at the same time and prevent exacerbations [HypertensRes 2001; 24: 3-11, HypertensRes2003; 26: 1-36, Hypertens Res 2003; 26: 979-990.

Therefore, many studies have been published on the combination of calcium channel blocker that lowers blood pressure and statin-based lipid lowering agent that inhibits cholesterol synthesis. According to Kramsch et al., Journal of Human Hypertension (1995) (Suppl. 1), 53-59, the combination of amlodipine and lipid-lowering agents for the prophylaxis of atherosclerosis has shown a better therapeutic effect. . Jukema et al. (Arteriosclerosis, Thrombosis and Vascular Biology, vol. 16 No. 3, 1996, 425-430) also demonstrate that a synergistic effect can be obtained by combining calcium channel blockers with lipid lowering agents.

On the other hand, for the above purpose, simovastatin of amlodipine and statin-based lipid lowering agent as a dihydropyridine calcium channel blocker is a typical combination prescription case.

It is well known that amlodipine is not only an antihypertensive agent but also an angina agent, and simvastatin is not only a lipid lowering agent but also an anti-inflammatory agent for various conditions. As much as possible, the drug is recognized for stability.

Cardiology 1992; 80 (Suppl1): S31-S36, JCardiovasc Pharmacol1988; 12 (Suppl7): S110-S113, Lancet2000; 356: 359-365, HypertensRes2002; 25: 717-725, HypertensRes2002; 25: 329-333.: Am J Manag Care. 2004 Oct; 10 (11 Suppl): S332-8 .: Curr Control Trials Cardiovasc Med 2000, 1: 161165.

When combined with these two drugs, amlodipine acts to enhance the lipid-lowering effect of simvastatin through synergism with lipid-lowering agents, as well as its own anti-hypertensive action, and simvastatin also synergizes with amlodipine as well as its intrinsic lipid-lowering action. Through the drug-specific blood pressure lowering effect will increase the function.

Statin-based lipid lowering agents have the following general information:

It is well known that statin-based lipid-lowering agents, HMG-CoA reductase inhibitors, are the first choice for the prevention and treatment of coronary heart disease such as angina and myocardial infarction. [Lancet1995; 346: 750-753, AmJCardiol1998; 82: 57T -59T, Am J Cardiol 1995; 76: 107 C-112 C, 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.

In addition, simvastatin is one of the most prescribed statin-based hypolipidemic drugs, and it is well known that the effects of reducing the incidence of coronary heart disease and reducing mortality have been demonstrated in large-scale clinical trials [Lancet1994; 344: 1383-1389.

This is because simvastatin strongly inhibits HMG-CoA reductase, which plays a key role in the synthesis of cholesterol in the liver, and at the same time inhibits inflammation-inducing factors ["Scandinavian Simvastatin Survival Study" published in the Lancet, 1994, 344, 1383-89.

Atherosclerotic or diabetic patients have abnormal NO production in their walls. This reduces NO production and increases blood pressure. Statin-based lipid lowering agents, including simvastatin, raise the normal levels of eNOS in these vessel walls. This is also one of the complex prescription effects in which hypolipidemic activity helps with anti-pressure activity [Am J Physiol Renal Physiol Vol 281 Issue 5: F802-F809, 2001].

Simvastatin itself is an inactive lactone-based compound and active metabolite, such as β-hydroxy acid of simvastatin, which is an active form that enters the liver and has a lipid-lowering effect by esterase. Changes to. Simvastatin is metabolized in several stages by cytochrome P450 3A4 in the liver, and activated metabolites exert a potent lipid lowering action.

Metabolic enzymes that primarily activate simvastatin in the body are cytochrome P450 3A4 and 2C9, and metabolites are excreted through the biliary tract from the liver while acting in the liver [DrugMetabDispos1990; 18: 138-145, Drug Metab Dispos 1990; 18: 476-483, DrugMetabDispos 1997; 25: 1191-1199.: Drugs 1997; 53: 828-847, ClinPharmacokinet 1996; 5: 348-371, ArchBiochemBiophys1991; 290: 355-361, DrugMetabDispos1997; 25: 321-331: DrugMetabDispos 1999 Mar; 27 (3): 410-6.

Therefore, when a drug used in combination with simvastatin inhibits the cytochrome P450 enzyme activating it, the intrahepatic metabolism of simvastatin is inhibited, and simvastatin and intermediate metabolites are leaked into the blood, thereby increasing blood concentration. Simvastatin body substances and active metabolites released into the blood can cause fatal side effects such as myolysis. [Clin Pharmacol Ther 1998; 63: 332-341, Clin Pharmacol Ther 1998; 64: 177-182, Physicians Desk Reference 2006 (Zocor), J Pharmacol Exp Ther 1997; -300, Pharmacol Exp Ther 1999; 290: 1116-1125, LifeSci 2004; 76: 281-292.: Drug Metab Dispos 1991; 19: 740-748: Eur J Clin Pharmacol 1996; 50: 209-215. In other words, when amlodipine and simvastatin are simultaneously administered, amlodipine first reaches the liver and inhibits the induction of cytochrome P450 enzymes. Therefore, a large amount of blood leaked into the blood, delayed excretion, or accumulate action, and β-hydroxy acid of simvastatin or simvastatin, which is not metabolized by the cytochrome P450 enzyme, migrates into the blood and the blood concentration becomes higher than necessary, resulting in muscle solubility. May cause muscle disorders such as.

On the other hand, lipid synthesis in the liver becomes vigorous after the early dinner, so simvastatin has been recommended to be taken in the early evening. Arterioscler Thromb 11: 816-826, Clinic Oharmacol Ther 40: 338-343 .: Am J Cardiol. 2006 Jan 1; 97 (1): 44-7. Epub 2005 Nov 8].

However, as described above, simvastatin requires special administration in combination with drugs such as amlodipine, which inhibit the production of cytochrome P450 enzymes that activate it.

Calcium channel blockers are one of the most prescribed anti-pressure agents used in combination with statin-based lipid lowering agents. Among these calcium channel blockers, amlodipine is the most prescribed worldwide as an anti-pressure agent and angina drug.

Cardiology 1992; 80 (Suppl1): S31-S36, JCardiovasc Pharmacol 1988; 12 (Suppl7): S110-S113, Lancet 2000; 356: 359-365, Hypertens Res 2002; 25: 717-725, Hypertens Res 2002; 25: 329-333.

Amlodipine is an antihypertensive drug that lowers blood pressure by inducing peripheral artery expansion by blocking calcium influx in vascular smooth muscle, and is effective in angina due to convulsive vasoconstriction.

Amlodipine has the chemical name 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedica It is a very useful calcium channel blocker with a half-life of 30 to 50 hours and showing activity over a long period of time as a carboxylate (European Patent Publication No. 89,167 and U.S. Patent No. 4,572,909).

In addition, amlodipine is absorbed by the small intestine upon oral administration, and is degraded by 40% or more in the liver. The amlodipine is a 24 hour daily lasting drug and is therefore prescribed for administration to people with common diseases at any time.

However, from a pathophysiological point of view, the increase in blood pressure during the day, especially in the morning after waking up, is due to the increase in blood pressure caused by vascular wall spasm caused by stress stimulation. This main pharmacological action, the blood pressure lowering action of amlodipine is most urgently required during the time period, ie morning after morning weather. Therefore, in order to obtain the maximum effect at the same dose, the pharmacokinetics of ammodipine which are rapidly released and absorbed in the body should be administered in the evening, so that amlodipine reaches the highest blood concentration before waking up. It may be the most potent hypotensive in the after-work [Clin Invest 72: 864-869].

On the other hand, due to the inherent pharmacological characteristics, when a cytochrome P450 enzyme is already present, amlodipine, which may be partially inhibited by this enzyme, will soon act to inhibit the production of cytochrome P 450 3A4 enzyme, Amlodipine is mostly metabolized by cytochrome P450 3A4 enzyme and is also metabolized by enzymes other than cytochrome P450 3A4 such as cytochrome P450 2C9 [ArchInternMed. 2002 Feb 25; 162 (4): 405-12., DrugMetabDispos. 2000 Feb; 28 (2): 125-30.]

Because of this property, the combination of simvastatin and amlodipine, a drug that requires the cytochrome P450 enzyme, should be administered at a timed interval to prevent drug interaction. [MedChem1991; 34: 1838-1844, EurJClin Pharmacol 2000; 55: 843-852. ].

However, to date, no preparations that allow amlodipine and simvastatin to act in time have not been invented and have not been approved. In addition, prescribers are not able to co-prescribe the two drugs, but can't give the patient proper medication guidance such as taking the two drugs in time.

As described above, the two drugs may cause side effects due to an increase in blood concentration of simvastatin due to simultaneous administration, and it is difficult to obtain a more effective blood pressure lowering action and an effective lipid lowering action that can be obtained by using the two drugs together.

In this study, Shinichiro Nishio et al. [Hypertens Res, 2005, Vol. 28, No. 3] studied whether hyperlipidemic patients with hypertension were given a single drug of amlodipine and simvastatin and only simvastatin monotherapy. A comparative experiment is published.

According to the experimental results of Table 1 below, simultaneous administration of simvastatin and amlodipine inhibited cytochrome P450 3A4 enzyme due to amlodipine, which resulted in an increase of 30% or more in blood concentrations of simvastatin and active metabolites when measured by activity titer. And the potential for side effects from this [Hypertension Research Vol. 28 (2005), No. 3 March 223-227.

Table 1

As shown in Table 1, the blood concentration of the lipid-lowering component was 30% higher in the concentration of the activity when measured by the activity titer than the single administration of simvastatin alone. Nevertheless, no lipid lowering action was raised. If the blood levels of simvastatin-activated metabolites, which must act in the liver, are higher than necessary, the inhibitory effect of cholesterol biosynthesis is reduced, and the likelihood of serious side effects such as muscle lysis is increased.

Korean Registered Patent No. 582347 discloses a combination agent that releases amlodipine immediately and elutes first, while simvavastatin is slowly eluted over 24 hours, thereby preventing simvastatin from eluting and absorbing at one time. This is a combination of a concept that is completely different from the concept of first eluting simvastatin in the present invention to be metabolized first in the liver, and is considered to be an irrational agent that logically and pharmacologically reduces the efficacy of statins. Because amlodipine first enters the liver, the production of cytochrome P450 3A4 is inhibited in the liver. Soon, a small amount of simvastatin, which enters the liver, is not metabolized by the liver and is released into the blood. The patent only increases the side effects of simvastatin, which should act in the liver, into the blood, resulting in muscle lysis.

In addition, Korean Patent No. 742432 discloses a patent for a combination formulation including amlodipine camsylate and simvastatin and a method for preparing the same, but cytochrome P450 3A4, which is required by simvastatin, is incorporated into amlodipine because both components are eluted and absorbed into the liver. Because it is inhibited by simvastatin, it is released in the blood with intermediate activator, which is not sufficiently activated in the liver, resulting in decreased lipid lowering and increased side effects (proven in clinical trials of the present invention). ). Thus, the invention is a simple combination concept and this simple combination is rejected due to lack of progress. In other words, according to the above results, it is possible to prevent the mutual antagonism of the drug, which is a problem that is easy to appear from simply prescribing a single agent or taking a dihydropyridine calcium channel blocker before the statin lipid lowering agent. There is a greater need for the development of dosage or pharmaceutical formulations.

Thus, in the present invention, by introducing a pharmaceutical concept eluted at intervals of time to develop a special pharmaceutical formulation that can overcome the side effects caused by the mutual antagonistic action of the drug.

Accordingly, the inventors of the present invention have tried to solve the above problems and to find a method that can reduce the side effects while increasing the therapeutic effect clinically in combination prescription.

In the present invention, a liver clinical trial comparing the time-lag group and the co-administration group of simvastatin and amlodipine was conducted. As a result, it was confirmed that the expression and safety of the drug-time group were significantly improved than the co-administration group.

In other words, if the difference between simvastatin and amlodipine dissolution and absorption time in the gastrointestinal tract, respectively, it is judged that it is possible to prevent the increase of blood concentration of simvastatin and prevent the accumulation effect, thereby preventing the increase of blood concentration and preventing the side effects. The present invention was completed by developing a pharmaceutical formulation containing them by confirming that they could be prevented.

The combination system provided by the present invention allows simvastatin to be first absorbed and converted to the active form in the liver upon administration of the formulation, and the inactive metabolites are thoroughly metabolized and excreted by cytochrome P450, and simvastatin acts on the cytochrome P450. Amlodipine was absorbed from the gastrointestinal tract after sufficient absorption time after receiving the dragon, so that the inhibitory effect of amlodipine on cytochrome P450 had no effect on simvastatin.

The present invention invented a time lag release system that allows the lipid-synthesizing inhibitory activity of simvastatin, the first-pass metabolic drug that is absorbed in the small intestine and enters the liver, is performed in the liver, so that it stays in the liver and does not leak out into the blood more than necessary. .

That is, the present invention constitutes a delayed-release compartment comprising amlodipine as an active ingredient and a prior-release agent having simvastatin as an active ingredient so that elution or small intestine absorption of amlodipine is achieved at a difference of 2 to 4 hours from simvastatin. An invention in which the release controlling component is adjusted to form a compartment.

The pharmacokinetics of simvastatin (Pharmcokinetics & Pharmacodynamics) are more preferably clinically administered when the pharmaceutical preparations of amlodipine and simvastatin according to the present invention are administered simultaneously with each of the single formulations of amlodipine and simvastatin. do.

The present invention provides a synergistic effect of the combined administration of amlodipine and simvastatin by taking a single oral formulation, and the competitive interaction of drugs with the mechanisms of absorption, metabolism and action of individual drugs over time through controlled release. To avoid antagonism, the effect of each active ingredient is maximized and the side effects are minimized, and in addition to the convenience by taking one tablet once a day in the evening, preferably between 5 to 10 pm, It can increase the compliance even more.

It is an object of the present invention to provide a functional time-division pharmaceutical formulation of amlodipine and simvastatin with controlled release.

The present invention comprises a prior-release compartment comprising simvastatin, an isomer thereof, or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and an amlodipine, an isomer thereof, or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. Provided is a pharmaceutical formulation comprising a delayed release compartment.

Hereinafter, 'simvastatin' is meant to include all of its racemates, isomers thereof and pharmaceutically acceptable salts thereof unless otherwise noted, and 'amlodipine' also refers to its racemates, isomers unless otherwise noted. And pharmaceutically acceptable salts thereof.

In the present invention, simvastatin in the pre-release compartment releases at least about 80% of the total amount of simvastatin in the unit formulation within about 1 hour, preferably within about 30 minutes, more preferably within about 15 minutes, of release. Provided is a pharmaceutical formulation in which at least about 90% is released.

The present invention also provides a pharmaceutical formulation wherein the release of amlodipine in the formulation is initiated about 1 hour after simvastatin release and is completed before about 8 hours, preferably about 2 hours after simvastatin release and is completed about 6 hours before. To provide.

The pharmaceutical formulation of the present invention provides a formulation in which release of about 40% or less of the total amount of amlodipine is maintained within about 2 hours, preferably within about 3 hours, more preferably within about 4 hours after initiation of the release of simvastatin. By providing a drug, the effect of amlodipine can effectively occur after a certain delay time has elapsed.

In a preferred formulation of the invention, simvastatin elutes at least about 80%, preferably at least about 90%, within about 1 hour; Amlodipine begins to dissolve after about 2 hours and is adjusted to release up to about 4 hours at a dissolution rate of about 40%, preferably no more than about 30%.

In addition, the above-mentioned prior release compartment and controlled release compartment may be embodied in various formulations.

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

1.Preventive compartment

Pre-release compartment refers to a compartment that is physically separated from the delayed-release compartment in the pharmaceutical formulation of the present invention and is released prior to the delayed-release compartment.

(1) pharmacologically active ingredients

The pharmacologically active ingredient of the prior release compartment comprises simvastatin or a pharmaceutically acceptable salt thereof, and may further comprise a pharmaceutically acceptable additive as necessary.

Simvastatin of the present invention includes all isomers, racemates, and the like, including the optical isomers of the filaments. The active ingredient in the prior release compartment may contain about 1 to about 160 mg, preferably about 2 to about 80 mg, simvastatin in the unit formulation.

Simvastatin in the prior release compartment may release at least about 80%, preferably at least about 90%, of the total amount of simvastatin in the unit formulation within about 1 hour after initiation of release, thereby providing rapid drug efficacy.

(2) pharmaceutically acceptable additives

The formulations of the present invention may also be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, stabilizers, pH adjusting agents, dissolution aids, colorants, fragrances, etc. without departing from the effects of the present invention. have. The content thereof is preferably 100 to 30,000 parts by weight, more preferably 100 to 20,000 parts by weight based on 100 parts by weight of simsimvastatin.

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 mixtures 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 monorate, glyceryl monostearate, Glyceryl palmitostearate, polyethylene glycol and the like can be used.

The stabilizer may be an alkali metal salt, a salt of alkaline earth metal, or an alkalizing agent which is a mixture thereof, and preferably calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium oxide, magnesium carbonate, sodium citrate, or the like. Ascorbic acid, citric acid, butylated hydroxy anisole, butylated hydroxy toluene and tocopherol derivatives may also be used.

The pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and a basicizing agent such as precipitated calcium carbonate, ammonia water, meglumine.

The dissolution aid can be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium and the like.

In addition to the various additives selected from colorants and flavorings, pharmaceutically acceptable additives may be selected and used to formulate the formulations of the present invention.

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 formulation may form a film-like coating layer on the outer surface of the tablet, if necessary. That is, the amlodipine / simvastatin pharmaceutical formulation of the present invention can be used in the form of uncoated tablets without a coating layer, and when the coating layer is formed on the surface of the tablet containing the active ingredient to form a coated tablet, the stability of the active ingredient is further improved. There are advantages to be secured.

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 using the above-described components, and may be applied to methods such as a fluidized bed coating method and a fan coating method. Can be. It is preferable to use a pan coating method.

The coating layer may be a coating agent, a coating aid or a mixture thereof. Specifically, the coating layer may be a coating agent such as cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, fats, and the like. Gelatin and the like can be used, and one or two or more kinds selected from polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, and the like can be used as the coating aid.

At this time, when formulated as a coated tablet, the coating layer is preferably included in the range of 0.5 to 15% by weight of the total weight of the tablet.

The formulation may be filled with capsules as necessary, and the material of the capsule may be one or a mixture of two or more selected from gelatin, succinate gelatin, hydroxypropylmethylcellulose.

2. Delayed release block

In the present invention, the delayed-release compartment refers to a compartment in which the active ingredient is released after a certain time of release of the prior-release compartment active ingredient. The delayed-release compartment comprises (1) the pharmacologically active ingredient amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof, and (2-1) a release controlling substance and / or (2-2) an osmotic pressure regulator and a semipermeable membrane coating base. It may include, and if necessary, (3) may further include a pharmaceutically acceptable additive. The delayed-release compartment according to the invention may be taken simultaneously with a commercially available rapid release simvastatin preparation.

(1) pharmacologically active ingredients

The pharmacologically active component of the delayed-release compartment includes amlodipine, the (S) isomer thereof, (R) isomer and pharmaceutically acceptable salts, and preferred salts include maleic acid salt of amlodipine and besylate salt of amlodipine. Can be mentioned.

The active ingredient in the delayed-release compartment may comprise about 1 mg to about 40 mg, preferably about 2 mg to about 20 mg, as amlodipine in the unit formulation.

Amlodipine has a time of about 40% or less of the total amount of amlodipine in the unit formulation reaching release within about 2 hours, preferably within about 3 hours, more preferably within about 4 hours after initiation of the release of simvastatin. Delay the onset of drug efficacy.

(2-1) Release Control Substances

The delayed-release compartment in the pharmaceutical formulation of the present invention comprises at least one release controlling substance selected from enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof, preferably a mixture of enteric polymers and hydrophilic polymers. Or a water-insoluble polymer.

In the delayed-release compartment of the present invention, the release controlling substance comprises about 0.1 to 100 parts by weight based on 1 part by weight of amlodipine. If the release control material is less than 0.1 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 9 hours of the delay time is too long when more than 100 parts by weight.

In the delayed-release compartment of 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, such as an enteric cellulose derivative, an enteric acrylic acid copolymer, Enteric maleic acid-based copolymers, enteric polyvinyl derivatives, and mixtures thereof. Here, 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 benzoate phthalate, cellulose prop At least one selected from cationate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxyethyl cellulose phthalate, methyl hydroxyethyl cellulose and mixtures thereof; The enteric acrylic acid copolymer may be a styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer, butyl styrene-acrylate-acrylic acid copolymer, methacrylic acid-methyl methacrylate copolymer (eg, Eudragit L 100, Eudragit S, Degussa, Germany), methacrylic acid and ethyl acrylate copolymer (e.g. Eudragit L 100-55, Degussa, Germany), methyl methacrylate-methacrylic acid-acrylic acid At least one selected from octyl copolymer and mixtures thereof; The enteric maleic acid-based copolymer may be a vinyl acetate-maleic anhydride copolymer, a styrene-maleic anhydride copolymer, a styrene-maleic acid monoester copolymer, a vinyl methyl ether-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, or a vinyl butyl ether At least one selected from maleic anhydride copolymer, acrylonitrile-methyl methacrylate-maleic anhydride copolymer, butyl styrene-maleic-maleic anhydride copolymer and mixtures thereof; The enteric polyvinyl derivative may be at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, polyvinyl acetal phthalate and mixtures thereof, preferably polyvinylacetate phthalate, hydroxypropyl methyl cellulose It may be at least one selected from phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylate, methyl methacrylate) copolymer and poly (methacrylate, ethyl acrylate) copolymer.

The enteric polymer according to the present invention may be included in an amount of about 0.1 to 20 parts by weight, preferably about 0.5 to 10 parts by weight relative to 1 part by weight of amlodipine, and when it is less than 0.1 parts by weight, it is easily dissolved at a pH of less than 5, 20 If the amount is more than the weight part, there is a problem in that the total weight of the preparation is unnecessarily large or excessively delayed dissolution.

In the delayed-release compartment of the present invention, water-insoluble polymer refers to a polymer that does not dissolve in pharmaceutically acceptable water that controls the release of the drug, for example polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate -Methyl methacrylate) copolymer, poly (ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose tri And at least one selected from the group consisting of acylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof, preferably polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate- Methyl methacryl Rate) copolymer, poly (ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate) copolymer, ethyl cellulose, cellulose acetate, more preferably polyvinyl acetate, poly (ethyl acrylate-methyl methacrylate) Late-trimethylaminoethyl methacrylate) copolymer, polymethacrylate copolymer, poly (ethyl acrylate-methyl methacrylate) copolymer, and the like can be used.

The water-insoluble polymer according to the present invention may be included in about 0.1 to 30 parts by weight, preferably about 0.5 to 20 parts by weight relative to 1 part by weight of amlodipine, and when less than 0.1 parts by weight, there is a problem in that the release of the drug is not controlled. In the case of more than 30 parts by weight, there is a problem that excessive dissolution is delayed.

In the delayed-release compartment of the invention, hydrophobic compounds refer to substances which are insoluble in the pharmaceutically acceptable water controlling the release of the drug, such as fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and And at least one selected from the group consisting of mixtures thereof. Wherein the fatty acid and fatty acid esters are at least one selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, stearic acid and mixtures thereof; Fatty alcohols are one or more selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol and mixtures thereof; Waxes are one or more selected from carnauba wax, beeswax, microcrystalline wax, and mixtures thereof; The inorganic substance may use at least one selected from talc, precipitated calcium carbonate, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, bum and mixtures thereof, preferably fatty acid esters, glyceryl Palmitostearate, glyceryl stearate, glyceryl bihenate, More preferably, glyceryl stearate, glyceryl bihenate can be used.

The hydrophobic compound according to the present invention may be included in an amount of about 0.1 to 20 parts by weight, preferably about 0.5 to 10 parts by weight relative to 1 part by weight of amlodipine, and when less than 0.1 part by weight, there is a problem in that the release of the drug is not controlled. If the amount is more than the weight part, there is a problem that excessive dissolution is delayed.

The hydrophilic polymer may be a polymer, which is dissolved in pharmaceutically acceptable water for controlling the release of a drug, such as sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, and carboxyvinyl polymers. It can be used selectively, and specifically, as a sugar, dextrin, polydextrin, dextran, pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, Amylose, amylopectin and the like can be selected and used as the cellulose derivative. , Hi Roxyethyl methyl cellulose can be selected and used, and guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum and the like can be selected. Casein, zein, and the like can be selected and used; polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, and the like can be selected and used; and poly (butyl methacryl) as a polymethacrylate copolymer Latex, (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer, poly (methacrylate-methylmethacrylate) copolymer, poly (methacrylate-ethylacrylate) copolymer and the like Polyethylene glycol, polyethylene oxide, etc. may be selected and used as the polyethylene derivative, and It is used as a fertilizer Carbomer carbonyl polymer, and preferably uses a starch, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, xanthan gum, polyvinyl alcohol, or carbomers.

The hydrophilic polymer according to the present invention may be included in an amount of about 0.05 to 30 parts by weight, preferably about 0.5 to 20 parts by weight relative to 1 part by weight of amlodipine, and when less than 0.05 parts by weight, there is a problem in that the release rate is not controlled, and 30 weights. In the case of excessive excess, there is a problem in that the release rate is not controlled, and in the case of more than 30 parts by weight, dissolution is excessively delayed.

Preferred release controlling materials of the present invention include polyvinylacetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer, carboxyvinyl polymer, ethylcellulose, cellulose acetate, One or more selected from the group consisting of carboxymethyl cellulose sodium, polyethylene oxide, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose phthalate; Or at least one selected from the group consisting of carboxyvinyl polymer, hydroxypropylmethylcellulose, and hydroxypropylmethylcellulose phthalate; Or carboxyvinyl polymer and hydroxypropylmethylcellulose.

(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 delayed-release compartment of the present invention, the osmotic pressure control agent refers to a component used to control the release rate of a drug using the principle of osmotic pressure, for example magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, ammonium acetate And at least one selected from the group consisting of lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate and mixtures thereof. Preferably sodium chloride, potassium chloride, sodium phosphate, potassium phosphate can be used. Here, the osmotic pressure regulator may be included in an amount of about 0.01 parts by weight to 10 parts by weight, preferably about 0.05 parts by weight to 5 parts by weight, with respect to 1 part by weight of amlodipine, and when less than 0.01 parts by weight, sufficient time difference release property may not be obtained. In the case of more than 10 parts by weight, drug release is delayed and no significant clinical effect is obtained.

In the delayed-release compartment of the present invention, the semi-permeable membrane coating base is a pharmaceutically usable coating base, which is formulated into the coating layer of the pharmaceutical formulation to be used to form a film which allows some components to pass but not others. It is also possible to use the above-mentioned water insoluble polymer. In the present invention, the semipermeable membrane coating base is, for example, polyvinyl acetate, polymethacrylate copolymer, poly (ethyl acrylate, methyl methacrylate) copolymer, poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl meth) Methacrylate) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof Or more species. Preferably, cellulose acetate, polyvinyl acetate, cellulose acetate, ethyl cellulose, polymethacrylate copolymer can be used.

Here, the semi-permeable membrane coating base may be included in about 0.01 parts by weight to 10 parts by weight, preferably about 0.05 parts by weight to 1.25 parts by weight with respect to 1 part by weight of amlodipine, and less than 0.01 parts by weight is difficult to have a sufficient delay time In the case of more than 10 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, disintegrants, lubricants, pH adjusting agents, antifoam agents other than those mentioned as pharmaceutically acceptable (2-1) or (2-2) substances within the scope of not impairing the effects of the present invention. , Additives commonly used, such as dissolution aids, may be further formulated using within a range not departing from the nature of delayed release.

For example, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof may be used as a diluent; As a binder, starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, povidone, gelatin, Or mixtures thereof.

As a disintegrant, starch or modified starches, such as sodium starch glycolate, corn starch, potato starch, or 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 and the like can be used.

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

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

In the pharmaceutically acceptable additive of the present invention, as a dissolution aid, polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docuate sodium and the like 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.

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 preferably, purified water or ethanol may be used.

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

The pharmaceutical formulation of the present invention may be in the form of a two-phase matrix tablet obtained by compression-compressing the delayed-release compartment and the prior-release compartment after homogeneous mixing. Preferably, the delayed-release compartment is prepared in the form of granules. will be.

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 consisting of a pre-release compartment surrounding the outside of the tablet, the film coating layer of the film coating layer as it is dissolved Simvastatin will be eluted 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 consisting 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-controlling agent inside the tablet for delayed release, followed by compression, and then coated the surface of the tablet with a semipermeable membrane coating agent to form an inner core. It is a dosage form in which 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 pharmaceutical preparations 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 formulations of the present invention may further form a coating layer on the exterior of the delayed release compartment and / or the prior release compartment. In other words, the surface of the particles, granules, pellets, or tablets consisting of delayed-release compartments and / or pre-release compartments may be coated for the purpose of release control or formulation stability.

In addition, the pharmaceutical preparation of the present invention may be in the form of a kit comprising a delayed-release compartment and a prior-release compartment, and specifically, the present invention prepares 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 taken at the same time by filling together with a foil, a blister, a bottle, and the like.

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

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

The coating layer may be formed by using a coating agent, a coating aid, or a mixture thereof. Specifically, the coating agent may include cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, fats, Gelatin, or a mixture thereof, and the like, and a coating aid may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, or a mixture thereof. The coating layer may be included in the range of about 0.5 to 15 weight percent (% w / w) relative to the total weight of the tablet.

The present invention also provides a pharmaceutical formulation according to the present invention for evening administration.

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

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 applies to hypertension or complications of those with metabolic syndrome, such as hypertension or diabetes, obesity, hyperlipidemia, coronary artery disease, etc.

The pharmaceutical preparations of the present invention may be formulated according to the respective diseases or according to the components by using the time-dose dosing principle disclosed by Chrontherpeutics (2003, Peter Redfern, PhP), as appropriate methods in the art, Specifically, it may be produced by a method comprising the following steps.

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

The second step 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 pharmaceutical formulation of the present invention may be prepared by the above process, and the formulation method of the third step 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 compressed into a predetermined amount to prepare tablets as they are or additionally coated, and then separately dissolve and disperse simvastatin in an aqueous film coating solution. By coating on the tablet outer layer obtained in the first step it can be prepared orally administered film coating tablet containing the active ingredient in the film coating.

Preparation of multi-layered tablets

The granules obtained in the first step as they are or are additionally coated and dried with a release controlling substance and the granules obtained in the second step can be prepared in double tablets using a tablet press. Coated multi-layered tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release aid layer as needed, or by formulation 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 amlodipine and the release control material and, if necessary, pharmaceutically acceptable additives in water, an organic solvent, or a mixed solvent and coat the spherical granules with sugar, and release the release control material alone or as necessary. Capsules may be prepared by dissolving in water, an organic solvent or a mixed solvent using more than one species, coating, drying, granulating obtained in the second step or tablets obtained in the third step, and then mixing the capsules and filling the capsule with a capsule filler. have.

(2) simvastatin and pharmaceutically acceptable additives are dissolved or suspended in water, organic solvents or mixed solvents, coated on spherical sugar granules, dried, and then mixed with release control pellets containing amlodipine in (1). Capsules may be prepared by filling the capsules with a filler.

[Product] Kit Preparation

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

The complex drug system of the present invention as described above is formulated with a combination of amlodipine and simvastatin as the active ingredient to be administered only once in the evening time, it is easier to take medication than when formulating each active ingredient separately, In addition, metabolic interference between drugs does not occur, thereby reducing side effects, and blood pressure control and lipid control effects of each drug appear to be improved than their own effects alone.

In the present invention, in order to confirm the concept of the invention, a simple clinical trial comparing the time-administration group and the simultaneous administration group of simvastatin and amlodipine was conducted. As a result, it was confirmed that the expression and safety of the time-administration group were significantly improved than the simultaneous administration group.

In other words, if the difference in the gastrointestinal elution and absorption time of simvastatin and amlodipine, respectively, it would be possible to prevent the increase of the blood concentration of simvastatin and prevent the accumulation effect, thereby preventing the side effects of the increase in the blood concentration and prevent the side effects. It was confirmed that it could be prevented.

As described above, the present invention provides a so-called time difference dosage regimen (Chronotherapeutics) that maximizes the therapeutic effect on the basis of xenobiotics to improve the side effects that can occur in combination with heterologous drugs from a pharmacokinetic point of view. As a formulated formulation, simvastatin and amlodipine, which affect or receive the same enzyme, the cytochrome P 450 series enzyme, are used as active active ingredients, and time-release substances are controlled to control the time they are eluted in the body. Differentiated use allows the active ingredient to be delivered at a certain rate and at a certain rate of time, which is why pharmacological, clinical, scientific and economical methods for the prevention and treatment of chronic circulatory disease Useful pharmaceutical preparations can be realized.

In addition, according to the present invention by configuring the release rate of the drug differently can prevent the antagonism and side effects between the drugs and at the same time can obtain a synergistic effect of the drug.

In addition, according to the present invention, since both agents can be taken at a time, it is easy to guide the medication and the medication of the patient.

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

Example  One: Nuclear Justice  Produce

1) Preparation of Amlodipine Delayed-Release Compartments

Next, amlodipine maleate and microcrystalline cellulose were apologized with No. 35 with the ingredients and contents shown in Table 2, mixed with a double cone mixer, and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately added to purified water. The binder solution (10% w / w) was melted and sprayed to form granules and dried. Carbomer 71G was added to the granules in powder form, and magnesium stearate was added and mixed in a final double cone mixer. The final mixture was compressed into tablets using a rotary tableting machine (MRC-30: Sejong), It was.

2) Preparation of simvastatin pre-release compartments

Next, simvastatin, microcrystalline cellulose, and mannitol were apples in No. 35 with the ingredients and contents shown in Table 2, and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid are dissolved in purified water to prepare a binding solution (10% w / w), and the mixture is added to a high-speed mixer with the main ingredient mixture, and then combined and granulated using an oscillator with No. 20 sieve. Dried at 60 ° C. and formed into a No. 20 sieve. Butylated hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed, and magnesium stearate was added to the final mixture in a double cone mixer.

3) tableting and coating

Using a nucleated tablet tableting machine (RUD-1: Kilian), the amlodipine inner core was compressed into a composition containing simvastatin as an outer layer, and then a high coater (SFC-30N, Sejong Machinery, Korea) was used as the ingredients and contents described in Table 2. A nucleated tablet was prepared by forming a film coating layer.

Example  2 : Nuclear Justice  Produce

1) Preparation of amlodipine delayed-release compartment (inner core)

Next, amlodipine maleate and microcrystalline cellulose were apologized with No. 35 with the ingredients and contents shown in Table 2, mixed with a double cone mixer, and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately added to purified water. The binder solution (10% w / w) was melted and sprayed to form granules and dried. Again, the granules were coated by spraying a hydroxypropylmethylcellulose phthalate solution (20% w / w) dissolved in a 1: 1 mixture of ethanol and methylene chloride. 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-30: Sejong), which was used as an inner core.

2) Preparation of simvastatin pre-release compartments

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

3) tableting and coating

Amlodipine-simvastatin nucleated tablets were prepared according to 3) tableting and coating method of Example 1 with the ingredients and contents described in Table 2.

Example  3: Nuclear Justice  Produce

1) Preparation of amlodipine delayed-release compartment (inner core)

Next, amlodipine malate and microcrystalline cellulose were apologized with No. 35 sieve and mixed in a double cone mixer, and fed into a high-speed mixer, fed with Colicoat SR30D, and granulated with No. 20 sieve using an oscillator. This was dried at 60 ° C. using a hot water dryer, and then re-assembled into No. 20 sieve. Magnesium stearate was added thereto, followed by final mixing in a double cone mixer, and the final mixture was compressed into tablets using a rotary tablet press (MRC-30: Sejong) and used as an inner core.

2) Preparation of Chamvastatin Prior-Release Compartment

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

3) tableting and coating

Amlodipine-simvastatin nucleated tablets were prepared according to 3) tableting and coating method of Example 1 using the ingredients and contents shown in Table 2.

Example  4: preparation of multilayer tablets

1) Preparation of amlodipine delayed-release compartment (inner core)

Next, amlodipine maleate and microcrystalline cellulose were apologized with No. 35 with the ingredients and contents shown in Table 2, mixed with a double cone mixer, and separately prepared by dissolving hydroxypropylmethylcellulose in purified water (10% w / w). Granules were formed and dried. Again, the granules were sprayed onto the granules by spraying a hydroxypropylmethylcellulose phthalate solution dissolved in a 1: 1 mixture of ethanol and methylene chloride. Magnesium stearate was added thereto and mixed in a final double cone mixer.

2) Preparation of simvastatin pre-release compartments

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

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, and the composition containing amlodipine is placed in a secondary powder feeder and tableted under conditions that can minimize the incorporation between layers, and a high coater (SFC-30N, Sejong Machinery Co., Ltd.) , Korea) to form a film coating layer to prepare a multi-layered tablet.

Example  5: preparation of multilayer tablets

1) Preparation of amlodipine delayed-release compartments

Next, amlodipine maleate and microcrystalline cellulose were apologized with No. 35 with the ingredients and contents shown in Table 2, mixed with a double cone mixer, and separately prepared by dissolving hydroxypropylmethylcellulose in purified water (10% w / w). Granules were formed and dried. Again, the granules were sprayed onto the granules by spraying Eudragit RS PO solution (20% w / w) dissolved in a 1: 1 mixture of ethanol and methylene chloride. Magnesium stearate was added thereto and mixed in a final double cone mixer.

2) Preparation of Chamvastatin Prior-Release Compartment

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

3) tableting and coating

Amlodipine-simvastatin multi-layered tablets were prepared according to the 3) tableting and coating method of Example 4 with the ingredients and contents described in Table 2.

Example  6: Preparation of two-phase matrix tablet

1) Preparation of amlodipine delayed-release compartments

Next, amlodipine maleate and microcrystalline cellulose were appled into No. 35 and mixed with the ingredients and contents shown in Table 2, and then fed into a high-speed mixer, and colicoat SR30D was added and then associated. After the association, granulation was carried out using an oscillator in No. 20 sieve, which was dried at 60 ° C. using a hot water dryer, and then re-established in No. 20.

2) Preparation of simvastatin pre-release compartments

Next, simvastatin, microcrystalline cellulose, and mannitol were apples in No. 35 with ingredients and contents shown in Table 2, and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid are dissolved in purified water to prepare a binding solution (10% w / w), and the mixture is added to a high-speed mixer with the mixture of the main components, and then united. It was dried at 60 ℃ using and sizing again to No. 20 sieve, and butylated hydroxyanisole was added thereto and mixed.

3) After mixing, tableting and coating

Each of the final compositions prepared above was mixed with a double cone mixer, starch glyconate sodium 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-30: Sejong) and then formed into a film coating layer using a high coater (SFC-30N, Sejong Machinery, South Korea) to prepare a two-phase matrix tablet.

Example  7: Preparation of two-phase matrix tablets

1) Preparation of granules as amlodipine delayed-release compartments

Next, amlodipine maleate and microcrystalline cellulose were apologized to No. 35 with the ingredients and contents shown in Table 2, and mixed in a double cone mixer. The mixture was poured into a fluidized bed granulator (GPCG 1: Glatt) and sprayed with a binder solution (10% w / w) prepared by dissolving hydroxypropylmethylcellulose in purified water separately to form granules and dried. Again, the granules were sprayed onto the granules by spraying Eudragit RS PO solution (20% w / w) dissolved in a 1: 1 mixture of ethanol and methylene chloride.

2) Preparation of Chamvastatin Prior-Release Compartment

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

3) tableting and coating

Amlodipine-simvastatin biphasic matrix tablets were prepared according to 3) postmixing, tableting and coating methods of Example 6 with the ingredients and contents listed in Table 2.

Example  8: Preparation of Two-Phase Matrix Tablets

1) Preparation of Amlodipine Delayed-Release Compartments

Next, amlodipine maleate and microcrystalline cellulose were apologized to No. 35 with the ingredients and contents shown in Table 2, and mixed in a double cone mixer. The mixture was poured into a fluidized bed granulator (GPCG 1: Glatt), and a binder (10% w / w) prepared by dissolving hydroxypropylmethylcellulose in purified water was sprayed to form granules and dried. Again, the granules were coated by spraying a hydroxypropylmethylcellulose phthalate solution (20% w / w) dissolved in a 1: 1 mixture of ethanol and methylene chloride.

2) Preparation of simvastatin pre-release compartments

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

3) tableting and coating

Amlodipine-simvastatin biphasic matrix tablets were prepared according to 3) postmixing, tableting and coating methods of Example 6 with the ingredients and contents listed in Table 2.

Example  9: two-phase capsule formulation

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

Next, the ingredients and contents shown in Table 2 and 1) of Example 8 were prepared according to the preparation method of the amlodipine delayed-release compartment.

2) 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 2) simvastatin pre-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. It was. The final mixed mixture was put into a powder feeder and filled into No. 1 gelatin hard capsules using a capsule charger.

Example  10: two phase capsule formulation

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

Next, amlodipine malate and microcrystalline cellulose were apologized with No. 35 sieve with the ingredients and contents shown in Table 2, mixed with a double cone mixer, and then poured into a fluidized bed granulator (GPCG 1: Glatt) and sprayed with colicoat SR30D to form granules. And dried.

2) 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 2) simvastatin pre-release compartment of Example 6.

3) Mixing and Capsule Filling

Amlodipine-simvastatin biphasic capsules were prepared according to the method of 3) mixing and capsule filling in Example 9 with the ingredients and contents shown in Table 2.

Example  11: Nuclear Justice  Produce

1) Preparation of amlodipine delayed-release compartment (inner core)

Next, amlodipine besylate, microcrystalline cellulose, and dicalcium phosphate were mixed with a No. 35 sieve with the ingredients and contents shown in Table 3, mixed with a double cone mixer, and then added to a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethyl separately. The binding solution (10% w / w) made by dissolving cellulose in purified water was sprayed to form granules and dried. Carbomer 71G was added to the granules in powder form, and magnesium stearate was added thereto and mixed in a final double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-30: Sejong).

In the above tablet, hydroxypropylmethylcellulose phthalate and acetylated monoglyceride were added to a 1: 1 mixture of ethanol and methylene chloride, and the dissolved solution was used as a coating solution (20% w / w) and a high coater (SFC-30N, Sejong Machinery, Korea) was used to form a film coating layer to prepare the inner core.

2) Preparation of simvastatin pre-release compartments

Next, simvastatin, microcrystalline cellulose, corn starch and lactose into apples No. 35 were mixed with the ingredients and contents shown in Table 3 and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid are dissolved in purified water to prepare a binding solution (10% w / w), and the mixture is added to a high-speed mixer with the main ingredient mixture, and then combined and granulated using an oscillator with No. 20 sieve. Dried at 60 ° C. and formed into a No. 20 sieve. 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.

3) tableting and coating

Using a nucleated tablet tableting machine (RUD-1: Kilian), tableting the amlodipine inner core with a composition containing simvastatin as an outer layer, and then coating the film with the ingredients and contents shown in Table 3 as a high coater (SFC-30N, Sejong Machinery, Korea) A layer was formed to prepare a nucleated tablet.

Example  12: Preparation of Multi-Layered Tablets

1) Preparation of Amlodipine Delayed-Release Compartments

Next, the binding solution prepared by dissolving amlodipine besylate, microcrystalline cellulose and dicalcium phosphate as a No. 35 sieve with a component and content shown in Table 3 and mixing with a double cone mixer, and separately dissolving hydroxypropylmethylcellulose in purified water (10% w / w) was sprayed to form granules and dried. Again, the granules were coated by spraying a coating solution (20% w / w) composed of hydroxypropylmethylcellulose phthalate and acetylated monoglyceride dissolved in a 1: 1 mixture of ethanol and methylene chloride. Magnesium stearate was added thereto and mixed in a final double cone mixer.

2) Preparation of Chamvastatin Prior-Release Compartment

It was prepared according to the ingredients and contents shown in Table 3 below and the preparation method of 2) simvastatin pre-release compartment of Example 1.

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, and the composition containing amlodipine is placed in a secondary powder feeder and tableted under conditions that can minimize the incorporation between layers, and a high coater (SFC-30N, Sejong Machinery Co., Ltd.) , Korea) to form a film coating layer with the ingredients and contents shown in Table 3 to prepare a multilayer tablet.

Example  13: Preparation of Capsule

1) Preparation of amlodipine delayed-release compartment (purification)

Next, amlodipine besylate and microcrystalline cellulose were mixed with a No. 35 sieve according to the ingredients and contents shown in Table 3, mixed in a double cone mixer, and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately added to purified water. The binder solution (10% w / w) was melted and sprayed to form granules and dried. Carbomer 71G was added to the granules in powder form, and magnesium stearate was added thereto and mixed in a final double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-30: Sejong). In the above tablet, hydroxypropylmethylcellulose phthalate and acetylated monoglycerides were dissolved in a 1: 1 mixture of ethanol and methylene chloride, and the solution dissolved as a coating solution (20% w / w) was coated with a high coater (SFC-30N, Sejong Machine, Korea) was used to form a film coating layer to prepare a tablet.

2) Preparation of simvastatin pre-release compartments (tablets)

Next, simvastatin, microcrystalline cellulose, and mannitol were apples in No. 35 with ingredients and contents shown in Table 3, and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid are dissolved in purified water to prepare a binding solution (10% w / w), and the mixture is added to a high-speed mixer with the main ingredient mixture. Dried at 60 ° C. and formed into a No. 20 sieve. Butylated hydroxyanisole, sodium starch glyconate, colloidal silicon dioxide were mixed, and magnesium stearate was added and finally mixed in a double cone mixer, and then the final mixture was rotary tablet press (MRC-30: Sejong). It was compressed using. The tablets were coated with a high coater (SFC-30N, Sejong Machinery, Korea) using a coating solution (20% w / w) prepared by dissolving and dispersing hydroxypropyl cellulose 2910, polyethylene glycol 6000, titanium oxide and talc in 80% ethanol. ).

3) Capsule filling

The amlodipine tablet of step 1) and the simvastatin tablet of step 2) were filled into No. 3 hard gelatin capsules using a capsule charger.

Example  14: Preparation of Capsule

1) Preparation of amlodipine delayed-release compartment (purification)

Next, the ingredients and contents shown in Table 3 and 1) of Example 13 were prepared according to the preparation method of the amlodipine delayed-release compartment.

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

Next, simvastatin, microcrystalline cellulose, lactose, corn starch were apples into No. 35 sieve with the ingredients and contents shown in Table 3 and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid are dissolved in purified water to prepare a binder solution (10% w / w), and the mixture is added to a high-speed mixer with the main component mixture, and then granulated using an oscillator with a No. 20 sieve. After drying at 60 ℃ using was again established as No. 20 sieve. Butylated hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed, and magnesium stearate was added to the final mixture in a double cone mixer.

3) Capsule filling

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

Example  15: Coating Definition  Produce

1) Preparation of amlodipine delayed-release compartment (purification)

Next, the ingredients and contents shown in Table 3 and 1) of Example 11 were prepared according to the preparation method of the amlodipine delayed-release compartment.

2) Preparation of simvastatin pre-release coating solution

Next, simvastatin, butylated hydroxyanisole, hydroxypropylmethylcellulose 2910, colloidal silicon oxide, polyethylene glycol 6000, titanium oxide, and talc were dissolved and dispersed in 80% ethanol using the ingredients and contents shown in Table 3 below. An extruded simvastatin coating solution (20% w / w) was prepared.

3) Primary coating

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

4) secondary coating

The film coating layer composition of Table 3 was dissolved in a mixture of 80% ethanol and purified water to prepare a film coating solution, and then a second coating was performed on the first coated tablet to prepare a film coated tablet.

Example  16: Simvastatin  - Amlodipine Osmotic Nuclear Justice  Produce

1) Preparation of amlodipine delayed-release compartments (purification)

Next, amlodipine besylate, microcrystalline cellulose, and sodium chloride were mixed with a No. 35 sieve with the ingredients and contents shown in Table 3, mixed with a double cone mixer, and magnesium stearate was added thereto, followed by final mixing with a double cone mixer. It was compressed using (MRC-30: Sejong). After tableting, colicoat SR 30D as a semipermeable membrane coating base and triethyl citrate as a plasticizer were dispersed in purified water (20% w / w), and then coated on the inner core using a high coater (SFC-30N, Sejong Machinery, Korea). An osmotic inner core was prepared.

2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table 3 below and the preparation method of 2) simvastatin pre-release compartment of Example 11.

3) tableting and coating

Simvastatin vesicles-amlodipine osmotic nucleated tablets were prepared in the same manner as in Example 11, 3) tableting and coating.

Example  17: Blister  Packing Of kit  Produce

To prepare the ingredients and contents shown in Table 3, but was prepared in the same manner as in Example 13 except that the amlodipine tablets and simvastatin tablets of Example 13 to be packaged in a blister packaging container for simultaneous use instead of filling the capsules at the same time .

Example  18: Nuclear Justice  Produce

1) Preparation of (S) -Amlodipine Delayed-Release Block (Inner Core)

Next, the (S) -amlodipine besylate and microcrystalline cellulose were apologized with No. 35 sieve with the ingredients and contents shown in Table 4, mixed with a double cone mixer, and then added to a fluidized bed granulator (GPCG 1: Glatt), and separately hydroxypropyl cellulose. Was dissolved in purified water to spray a binding solution (10% w / w) to form granules, and dried. Carbomer 71G was added to the granules as a powder and mixed in a double cone mixer for 10 minutes. Magnesium stearate, which was sieved through a No. 35 sieve, was added and finally mixed for 4 minutes. The final mixture was compressed into tablets at a speed of 30 revolutions per minute using a rotary tablet press (MRC-30: Sejong) to prepare a (S) -amlodipine inner core.

2) Preparation of simvastatin pre-release compartments

Next, simvastatin, microcrystalline cellulose, and mannitol were sieved through a No. 20 sieve with the ingredients and contents shown in Table 4, followed by mixing for 10 minutes in a high speed mixer. Separately, hydroxypropyl cellulose and citric acid were dissolved in purified water to prepare a binding solution (10% w / w). While adding the binding solution to the mixture, granulation was completed by granulation, drying, and formulation to complete the preparation. Butylated hydroxyanisole and sodium starch glycolate, previously sieved through a No. 35 sieve, were administered to a double cone mixer with the above granules, mixed for about 10 minutes, and magnesium stearate was sieved through a No. 35 sieve. After administration to the double cone mixer, the final mixing for about 4 minutes to complete the preparation of simvastatin layer granules.

3) tableting and coating

A nucleated tablet was prepared by using a nucleated tablet tableting machine (RUD-1: Kilian) to compress the amlodipine inner core at a rate of 30 revolutions per minute using a composition containing simvastatin as an outer layer. Separately, the film coating layer composition of Table 4 was dissolved in a solvent to prepare a film coating solution. The nucleated tablet prepared above was administered to a high coater (SFC-30N, Sejong Machinery, Korea) and coated with a film coating solution to complete nucleated tablet manufacturing.

Example  19: Nuclear Justice  Produce

Prepared with the ingredients and contents shown in the following Table 4, except that the poly (methacrylate, methyl methacrylate) copolymer after the preparation of the core tablet of Example 18 was further coated with a solution (20% w / w) purified water dispersion And was prepared in the same manner as in Example 18.

Example  20: Preparation of Capsule

1) Preparation of (S) -Amlodipine Delayed-Release Block (Tablet)

Next, (S) -amlodipine besylate and microcrystalline cellulose were mixed with a No. 35 sieve according to the ingredients and contents shown in Table 4, mixed with a double cone mixer, and added to a fluidized bed granulator (GPCG 1: Glatt), and hydroxy separately. The binding solution (10% w / w) made by dissolving propyl cellulose in purified water was sprayed to form granules, followed by drying. Carbomer 71G was added to the granules as a powder and mixed in a double cone mixer for 10 minutes. Magnesium stearate, which was sieved through a No. 35 sieve, was added and finally mixed for 4 minutes. (S) -Amlodipine tablets prepared by tableting the final mixture at a rate of 30 revolutions per minute using a rotary tableting machine (MRC-30: Sejong) were prepared. The poly (methacrylate, methyl methacrylate) copolymer was added to purified water. Coating with dispersed solution (20% w / w) completed the preparation of (S) -amlodipine tablets.

2) Preparation of simvastatin pre-release compartments (tablets)

Next, simvastatin, microcrystalline cellulose, and mannitol were sieved through a No. 20 sieve with the ingredients and contents shown in Table 4, followed by mixing for 10 minutes in a high speed mixer. Separately, hydroxypropyl cellulose and citric acid were dissolved in purified water to prepare a binding solution (10% w / w). While adding the binder solution to the mixture, granulation was completed by granulation, drying, and formulation. Butylated hydroxyanisole, which was previously sieved through a No. 35 sieve, sodium starch glycolate, and colloidal silicon dioxide were administered together with the above granules in a double cone mixer, mixed for about 10 minutes, and magnesium stearate was added thereto. After sieving through a No. 35 sieve and administering to a double cone mixer, final mixing was performed for about 4 minutes to complete the preparation of simvastatin layer granules. Simvastatin tablets prepared by tableting the granules at a speed of 30 revolutions per minute using a rotary tablet press (MRC-30: Sejong) were coated with the film layer components of Table 8 to complete the preparation of simvastatin tablets.

3) Filling capsule

Using the capsule charger, the (S) -amlodipine tablets and simvastatin tablets were simultaneously filled into gelatin hard capsules of No. 3 to complete the capsule preparation.

Example  21: Preparation of Capsule

1) Preparation of (S) -amlodipine delayed-release compartment (purification)

To prepare the (S)-amlodipine tablets by the method of Example 20-1) with the ingredients and contents shown in the following Table 4.

2) Preparation of simvastatin layer prior-release compartment (granule)

Next, simvastatin, microcrystalline cellulose, and mannitol were sieved through a No. 20 sieve with the ingredients and contents shown in Table 4, followed by mixing for 10 minutes in a high speed mixer. Separately, hydroxypropyl cellulose and citric acid were dissolved in purified water to prepare a binding solution (10% w / w). While adding the binder solution to the mixture, granulation was completed by granulation, drying, and formulation. Butylated hydroxyanisole, sodium starch glycolate, and colloidal silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a double cone mixer together with the above granules, and then mixed for about 10 minutes, and magnesium stearate was mixed. After sieving through a No. 35 sieve and administering to a double cone mixer, final mixing was performed for about 4 minutes to complete the preparation of simvastatin layer granules.

3) Capsule filling

Using the capsule charger, the above (S) -amlodipine tablets and simvastatin granules were simultaneously filled into hydroxypropylmethylcellulose hard capsules of No. 1 to complete the capsule preparation.

Example  22: Blister  Packing Of kit  Produce

Prepared with the ingredients and contents shown in the following Table 4, except that the (S)-amlodipine tablets and simvastatin tablets of Example 20 to be packaged in the PTP packaging to be used in the co-package instead of the simultaneous filling in a capsule It was prepared as follows.

Example  23: Preparation of coated tablet

1) Preparation of (S) -Amlodipine Delayed-Release Block (Tablet)

Following the ingredients and contents shown in Table 4, (S) -amlodipine and microcrystalline cellulose were apples into No. 35 sieve, mixed with a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropyl cellulose was separately added. The binding solution (10% w / w) dissolved in purified water was sprayed to form granules, followed by drying. Carbomer 71G was added to the granules as a powder and mixed in a double cone mixer for 10 minutes. Magnesium stearate, which was sieved through a No. 35 sieve, was added and finally mixed for 4 minutes. (S) -Amlodipine tablets prepared by tableting the final mixture at a speed of 30 revolutions per minute using a rotary tablet press (MRC-30: Sejong) were prepared in the poly (methacrylate, methyl methacrylate) in Table 4 below. Coalescing was coated with a solution (20% w / w) dispersed in purified water to complete the preparation of (S)-amlodipine tablets.

2) Preparation of simvastatin coating solution

Next, simvastatin, butylated hydroxyanisole, hydroxypropylmethylcellulose 2910, and colloidal silicon oxide were dissolved in a mixture of ethanol and methylene chloride 1: 1 to prepare a simvastatin coating solution.

3) Primary coating

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

4) 2nd coating

After dissolving the film coating layer composition of Table 4 in a solvent to prepare a film coating solution to prepare a film-coated tablet by a secondary coating on the first coated tablets.

[Table 2]

Table 3

Table 4

Experimental Example  One : Nuclear Justice  Comparative dissolution test comparative dissolution profile test )

A comparative dissolution test of the amlodipine maleate / simvastatin nucleated tablet of Example 1 and the reference drug (Zoko: simvastatin monotherapy, MSD, Jean Novasque: amlodipine monotherapy, Pfizer) was performed. In the case of the amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid from 2 hours. The dissolution test method for each component is as follows, and the results are shown in FIG.

According to FIG. 1, simvastatin component of the nucleated tablet of the present invention showed nearly equivalent dissolution characteristics compared to that of control, whereas amlodipine component had a dissolution rate of up to about 3 hours within about 30%, and the control formulation in 1 hour. Compared with the already eluted 99% eluted was significantly delayed.

As described above, the nucleotablet of amlodipine maleate / simvastatin of the present invention, unlike the amlodipine single agent, the initial release of amlodipine is much slower than simvastatin, thus significantly lowering the chance of metabolism in the liver before simvastatin.

[Amlodipine Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 75 revolutions / min

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

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

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

[Simvastatin test method]

Dissolution test basis: 'Simvastatin tablet' in USP 29

Test method: Paddle method, 50 revolutions / minute

Test solution: 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 257nm)

Experimental Example  2: comparative dissolution test of multilayer tablets ( comparative dissolution profile test )

Comparative dissolution tests of the pharmaceutical preparations of amlodipine maleate / simvastatin of Examples 4 and 5 and the anti-treatment agent (Zoko: simvastatin single agent, Novask: amlodipine single agent) were performed. The dissolution characteristics of the simvastatin and amlodipine components were measured by the method of Experimental Example 1. In the dissolution test of the amlodipine components, the dissolution test was performed by changing the elution solution from artificial gastric fluid to artificial intestinal fluid at 2 hours. The results are shown as shown in FIG.

2, simvastatin component of the multi-layered tablet of the present invention showed almost the same elution characteristics as compared to the control preparation joko, while the amlodipine component of all the dissolution rate of up to about 3 hours within about 40%, the control formulation of 1 hour Compared to the already eluted 99% eluted was found to be significantly delayed eluted.

As described above, the multilayer tablet of amlodipine maleate / simvastatin of the present invention is unlikely to be metabolized in the liver before simvastatin because the initial release of amlodipine is much slower than simvastatin, unlike the amlodipine single agent, which is the reference drug.

Experimental Example  3: Nuclear Justice  Comparative dissolution test comparative dissolution profile test )

The comparative dissolution test of the amlodipine besylate / simvastatin nucleated tablet of Example 11 and the reference drug (Zoko: simvastatin monotherapy, MSD, Jean Novasque: amlodipine monotherapy, Pfizer) was performed. In the case of the amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid from 2 hours. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in Figure 3 attached.

3, simvastatin component of the nucleated tablet of the present invention showed almost the same elution characteristics as compared to the control formulation joko, while the amlodipine component of all the dissolution rate up to about 3 hours within about 40%, the control formulation is 1 hour Compared to the already eluted 99% eluted was found to be significantly delayed eluted.

As described above, the nucleotablet of amlodipine besylate / simvastatin of the present invention, unlike the amlodipine single agent, the initial release of amlodipine is much slower than simvastatin, thereby lowering the probability of metabolism in the liver before simvastatin.

Experimental Example  4: 2 phase Capsule  Comparative dissolution test comparative dissolution profile test )

The comparative dissolution test of the amlodipine besylate / simvastatin capsule of Example 13 and the control drug (Zoko: simvastatin monotherapy, MSD, Jean Novasque: amlodipine monotherapy, Pfizer) was performed. In the case of the amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid from 2 hours. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in Figure 4 attached.

According to FIG. 4, the simvastatin component of the biphasic capsule formulation of the present invention exhibited almost the same dissolution characteristics as compared to the control formulation joko, whereas the amlodipine component had a dissolution rate of about 3 hours or less within about 30% and the control formulation was 1 hour. Compared with the nearly 99% eluted in the bed, it was confirmed that there was a significant delay.

As described above, the capsule containing the amlodipine besylate / simvastatin complex tablet of the present invention is unlikely to be treated with amlodipine single agent, so the initial release of amlodipine is much slower than simvastatin, and thus the probability of metabolism in the liver is lower than that of simvastatin.

Experimental Example  5: clinical trial ( clinical study )

In this experiment, commercially available 'Zokoco' (simvastatin 20 mg, MSD) and 'Novask tablet' (Besilic acid amlodipine 6.944 mg, Pfizer) and the experimental group 'Zokoco' and 'Novask tablet' are examples of the present invention. Clinical trials were carried out as shown in Table 5 to have the effect as a composition according to the present invention by administering a time difference to have the same release time as in the composition provided by.

Table 5

This experiment was conducted to reduce the number of domestic and international clinical trial criteria and the number of experiments for the approval of medicines for the purpose of marketing, while supporting the effects of the invention. It became.

Detailed results of the comparative clinical trials are shown in Table 6 and FIGS. 5 to 7.

Table 6

At the time of blood pressure drop, the time-difference group showed lower blood pressure than the co-administration group in the blood pressure measurement at 41 days in systolic and diastolic blood pressure.

2. The lower level of total cholesterol and LDL-cholesterol showed the lowest lipid status at 41 days than the simultaneous treatment group.

3. The most important lipid of hyperlipidemia, the neutral lipid lowering state was superior to the timed group, and the concurrent group showed no neutral lipid lowering effect. Statins are inhibitors of cholesterol synthesis, but the cholesterol synthesis reaction itself is known to have a rate of neutral lipid lowering in the range of 8% -25% because it regulates the rate of lipid protein synthesis. Compared with this figure, the neutral hypolipidemic effect in this clinical trial was 20% in the time-differentiated group, whereas the concurrent-treated group showed little effect.

This can be interpreted that the co-administration group antagonizes each other by enzymes in the liver, and simvastatin is released into the blood, thereby lowering the neutral lipid.

4. It is well known that lipid improvement requires an increase in HDL levels.

5. Biomarker changes in blood at day 41 of dosing to evaluate the safety of drug therapy

1) S-GPT, S-GOT, CPK, γ-GPT and alkaline phosphatase levels showed safer biomarks.

2) This may be inferred due to the unnecessary inflammation-induced response of simvastatin, because more simvastatin spills into the blood than the simultaneous administration group.

6. Clinical adverse events were observed in 3 patients with mild adverse events in only 2 patients. One case of diarrhea occurred in the time-administered group, and one case of fatigue and cough in one patient.

The changes in blood concentrations of drugs through this comparative clinical trial are as follows.

1) Blood concentrations of simvastatin β-hydroxy acids: In the blood concentrations of simvastatin β-hydroxy acids, which should be low in blood, we found that the time-difference was 40% lower than other concomitant or simvastatin monotherapy. Number (Table 7 and FIG. 5).

This is a pharmacokinetic proof that timed dosing can provide better lipid lowering action and lower side effects.

Table 7

2) Sum of simvastatin and simvastatin β-hydroxy acid: As shown in Table 8 and FIG. 6, the sum of blood concentrations of simvastatin and simvastatin β-hydroxy acid is different from that of simvastatin in the liver. It can be seen as overwhelmingly high, demonstrating that timed dosing may have better lipid lowering effects and lower side effects than do simultaneous dosing.

Table 8

3) Blood concentration of amlodipine: The concentration of amlodipine in blood is directly related to the lowering of blood pressure and has an additional effect of increasing lipid lowering effect.

Table 9

As shown in Figures 5 to 6, the difference in the time between absorption of simvastatin and amlodipine in the gastrointestinal tract, the blood concentration of simvastatin and simvastatin β-hydroxy acid, which is an active type change significantly decreased compared to the control group, It has been confirmed that the side effects of lysis can be prevented, and this also results in that the composition according to the present invention causes simvastatin to be first absorbed by timed administration and converted to the active form in the liver, and the inactive metabolite is metabolized by the cytochrome P450 3A4 enzyme. It has been shown that the inhibitory action of amlodipine on cytochrome P450 3A4 has no effect on simvastatin by being excreted and excreted with sufficient absorption time difference and subsequent administration of amlodipine to the gastrointestinal tract.

In addition, as shown in FIG. 7, the time-dose group was simultaneously administered at 7 pm throughout the test group due to a delay of about 4 to 5 hours of Tmax (drug reaching time of drug) of amlodipine, but was administered at 12 pm. It can be seen that the same delayed blood pressure lowering effect as shown. Thus, it can be seen that the composition according to the present invention has an optimal blood pressure lowering effect during the period from morning to midday of the administration day when the average blood pressure peaks, unlike the conventional simultaneous administration group.

Thus, as in the pharmaceutical preparations of amlodipine and simvastatin according to the present invention, the time-divided administration not only significantly reduces the side effects of simvastatin than when single-agents are administered at the same time, as well as amlodipine administered for the purpose of lowering blood pressure. It can be seen that the clinical optimal effect of the expression.

Table 10 shows the results of measuring blood lipid concentrations between the co-administration group of amlodipine and simvastatin and the time-division group according to the present invention. It was found that the lag group significantly lowered blood levels of simvastatin's LDL-cholesterol and total cholesterol, compared to the simultaneous administration of Novask tablets (6.944 mg of besyl acid amlodipine) and joco tablets (simvastatin 20 mg). Could confirm. This is not affected by the inhibition of cytochrome P450 3A4 enzyme by amlodipine in the time-dose group, and is due to the inhibition of HMG-CoA reductase, which converts the entire drug to the active form in the liver and increases blood cholesterol levels.

Table 10

On the other hand, Table 11 and Table 12 are the results of measuring blood pressure between the co-administration group of amlodipine and simvastatin and the time difference administration group according to the present invention. The blood pressure lowering effect of amlodipine was found to be significantly lowered in the mean seat systolic blood pressure and mean seat diastolic blood pressure in the time-differentiated group. This is because the increase in amlodipine blood concentration in the time-differentiated group is shown in FIG. It shows the appearance. As a result of the delayed drug release of amlodipine administered for the purpose of lowering blood pressure with a time difference of about 4 hours as intended by the present invention, it was proved that the time-differentiated group had an excellent blood pressure-lowering effect compared to the simultaneous-dose group.

Table 11

Table 12

In conclusion, the anti-hyperlipidemic effect of simvastatin at the same dose was higher when the pharmaceutical preparations of amlodipine and simvastatin according to the present invention were administered at the same time than when a single formulation of amlodipine and simvastatin were administered simultaneously. As well as being exerted better, the elevated blood pressure-lowering effect of amlodipine administered for the purpose of lowering blood pressure has been demonstrated, and it can be seen that the expression of the optimal effect by prolonged release time is predicted.

As described above, the present invention provides a so-called time difference dosage regimen (Chronotherapeutics) that maximizes the therapeutic effect on the basis of xenobiotics to improve the side effects that can occur in combination with heterologous drugs from a pharmacokinetic point of view. It is formulated as an active ingredient by using a combination of amlodipine and simvastatin, which are components that affect or inhibit enzyme activity, the same enzyme, cytochrome P 450-based enzymes, by controlling the time they are eluted in the body. It is possible to deliver at a certain rate at a timed interval, so that the pharmacological, clinical, scientific and economically more useful functional time-dose pharmaceutical preparations in the prevention and treatment of chronic circulatory diseases than in the case of a combination prescription in which the drug components are taken separately at the same time Can be realized.

In addition, according to the present invention by configuring the release rate of the drug differently can prevent the antagonism and side effects between the drugs and at the same time can obtain a synergistic effect of the drug.

In addition, according to the present invention, since both agents can be taken at a time, it is easy to guide the medication and the medication of the patient.

1 is a graph showing the comparative elution curves of amlodipine / simvastatin nucleated tablets prepared according to Example 1 and a control drug (Zoko: simvastatin monotherapy, MSD, Jean Novasque: amlodipine monotherapy, Pfizer).

FIG. 2 is a graph showing the comparative elution curves of the pharmaceutical preparation of amlodipine / simvastatin prepared in accordance with Examples 4 and 10 and the control drug (Zoko: simvastatin monotherapy, Novask: amlodipine monotherapy).

FIG. 3 is a graph showing the comparative elution curves of amlodipine besylate / simvastatin nucleated tablets prepared according to Example 11 and a control drug (Zoko: simvastatin monotherapy, Novask: amlodipine monotherapy).

Figure 4 is a graph showing a comparative dissolution curve of the amlodipine besylate / simvastatin capsules prepared according to Example 13 and the control drug (Zoko: simvastatin single, Novasque: amlodipine single).

5 is a graph comparing blood concentrations of simvastatin β-hydroxy acids between experimental groups as a clinical test result according to Experimental Example 5.

Figure 6 is a graph comparing the blood concentrations of simvastatin β-hydroxy acid and simvastatin between the experimental groups as a clinical test result according to Experimental Example 5.

Figure 7 is a graph comparing the blood concentration of amlodipine between the time difference administration group and the simultaneous administration group as a clinical test result according to Experimental Example 5.

Claims (36)

Prior-release compartments comprising simvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient; And a delayed-release compartment comprising amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. The pharmaceutical formulation according to claim 1, wherein simvastatin is released at least 80% of the total amount of simvastatin in the formulation within 1 hour after the start of release thereof. The pharmaceutical formulation of claim 1, wherein the amlodipine is released 1 hour after initiation of simvastatin release and release is complete within 8 hours. 4. The pharmaceutical formulation of claim 3, wherein amlodipine is released within 40% of the total amount of the unit formulation within 3 hours after initiation of simvastatin release. The pharmaceutical formulation of claim 1, wherein the simvastatin is in the range of 1 to 160 mg in the pharmaceutical formulation. The pharmaceutical formulation of claim 1, wherein the amlodipine is included in the range of 1-40 mg in the pharmaceutical formulation. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises one or more release controlling substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof. 8. A pharmaceutical formulation according to claim 7, wherein said release controlling substance comprises an enteric polymer and a hydrophilic polymer. The pharmaceutical preparation of claim 7 or 8, wherein the enteric polymer is at least one 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. . The method of claim 9, 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 One or more selected from eight phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxyethyl cellulose phthalate, methyl hydroxyethyl cellulose and mixtures thereof; The enteric acrylic acid copolymer may be a styrene-acrylic acid copolymer, a methyl acrylate-acrylic acid copolymer, a methyl methacrylate acrylic acid copolymer, a butyl styrene-acrylate-acrylic acid copolymer, a methacrylic acid-methyl methacrylate copolymer, or methacrylic acid. At least one selected from acid and ethyl acrylate copolymers, methyl acrylate-methacrylic acid and octyl acrylate copolymers and mixtures thereof; 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, butyl styrene-maleic-maleic anhydride copolymer and mixtures thereof; Or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, and polyvinyl acetal phthalate and mixtures thereof. The method of claim 9, wherein the enteric polymer is polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylate, methyl methacrylate) copolymer and poly ( Methacrylate, ethyl acrylate) copolymers and mixtures thereof. 8. The method of claim 7, wherein the water-insoluble polymer is polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate-methyl methacrylate) copolymer, poly (ethylacrylate-methyl methacrylate-trimethylaminoethyl Methacrylate), at least one selected from copolymers, ethyl cellulose, cellulose esters, cellulose ethers, cellulose acylates, cellulose dicylates, cellulose triacylates, cellulose acetates, cellulose diacetates, cellulose triacetates, and mixtures thereof. Pharmaceutical preparations. The method of claim 12, wherein the water-insoluble polymer is polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate-methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethyl Methacrylate), at least one selected from copolymers of ethylcellulose, cellulose acetate, and mixtures thereof. The pharmaceutical preparation according to claim 7, wherein the hydrophobic compound is at least one selected from fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances and mixtures thereof. The method of claim 14, wherein the fatty acid and fatty acid esters are selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, stearic acid and mixtures thereof. Above; The fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof; The waxes are at least one selected from carnauba wax, beeswax, microcrystalline wax and mixtures thereof; The inorganic substance is at least one selected from talc, precipitated calcium carbonate, calcium monohydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, bum and mixtures thereof. The hydrophilic polymer of claim 7 or 8, wherein the hydrophilic polymer is one selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl copolymers, and mixtures thereof. Pharmaceutical formulations. 17. The saccharide according to claim 16, 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 mixtures thereof; The cellulose derivative is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose and their At least one selected from a mixture; The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, xanthan gum and mixtures thereof; The protein is at least one selected from gelatin, casein, zein and mixtures thereof; The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate and mixtures thereof; The polymethacrylate copolymers include poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer, poly (methacrylate-methylmethacrylate) copolymer and poly ( At least one selected from methacrylic acid-ethylacrylate) copolymers, and mixtures thereof; The polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide and mixtures thereof; The carboxyvinyl polymer is a carbomer. The pharmaceutical composition of claim 16, wherein the hydrophilic polymer is selected from the group consisting of starch, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, xanthan gum, polyvinyl alcohol or carboxyvinyl polymer, and mixtures thereof. Formulation. The pharmaceutical formulation of claim 7 or 8, wherein the release controlling substance is contained in an amount of 0.1 to 100 parts by weight based on 1 part by weight of amlodipine. The pharmaceutical formulation according to claim 1, wherein the formulation is 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. The pharmaceutical formulation of claim 1, wherein the 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 consisting of a prior-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. The pharmaceutical formulation of claim 23, wherein the nucleated tablet is an osmotic nucleated tablet. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a capsule comprising particles, granules, pellets, or tablets consisting of delayed-release compartments, and particles, granules, pellets, or tablets consisting of prior-release compartments. The pharmaceutical formulation of claim 1, further comprising a coating layer on the exterior of at least one of the delayed-release compartment or the prior-release compartment. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises an osmotic pressure regulator and is coated with a semipermeable membrane coating base. 28. The method of claim 27, wherein the osmotic agent is selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, ammonium acetate, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate, and mixtures thereof At least one pharmaceutical agent selected. 28. The method of claim 27, wherein the semipermeable membrane coating base is polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylamino Ethyl methacrylate) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof At least one pharmaceutical agent selected from the group consisting of. The pharmaceutical formulation according to claim 1, which is in the form of a coated tablet further comprising a coating layer on the outside. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a kit comprising a delayed release compartment and a prior release compartment. The pharmaceutical formulation of claim 1, wherein the formulation is for evening administration. 33. A method for treating cardiovascular disease, comprising administering the pharmaceutical formulation of any one of claims 1 to 32 to a mammal. The method of claim 7, wherein the release control material is polyvinylacetate, polymethacrylate copolymer, poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate) copolymer, carboxyvinyl polymer, ethyl cellulose Or cellulose acetate, carboxymethylcellulose sodium, polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose phthalate. 8. The pharmaceutical formulation of claim 7, wherein the release controlling substance is at least one selected from the group consisting of carboxyvinyl polymer, hydroxypropylmethylcellulose, and hydroxypropylmethylcellulose phthalate. 9. A pharmaceutical formulation according to claim 7 or 8 wherein said release controlling substance comprises carboxyvinyl polymer and hydroxypropylmethylcellulose.

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