KR20180121060A - Once-daily fixed-dose combination capsule formulations comprising sustained release cilostazol and immediate release statin minitablets and preparation method thereof - Google Patents

Abstract

The present invention relates to a once-daily oral composite capsule comprising sustained release cilostazol and immediate release statin minitablets, and a method for manufacturing the same. The cilostazol sustained release minitablets are manufactured by utilizing a specific fixed dose of xanthan gum and ethylcellulose or ethylcellulose and Eudragit RL or RS as a sustained release agent. The statin general release minitablets are manufactured by utilizing immediate release additives with a high shear wet granulation method. By filling the minitablets in a gelatin hard capsule, a composite capsule containing a fixed dose of cilostazol and statin can be provided, which can be taken orally once a day. Therefore, the composite capsule can be widely used as a customized composite formulation for elderly patients with ischemic complex vascular disease accompanied by hyperlipidemia and patients susceptible to diabetes, chronic cardiovascular disease and nephropathy, and can enhance convenience of medication and patient compliance.

Description

[0001] The present invention relates to a once-daily oral capsule preparation comprising a fixed-dose cilostazol emulsion and a statin general-release mini tablet, and a method for preparing the same, preparation method thereof}

The present invention relates to a once-daily oral capsule preparation containing a fixed dose of cilostazol and a statin mini tablet, and a method for preparing the same, and more particularly, to a capsule preparation comprising a cilostazol-releasing mini tablet and The statin-releasing mini-tablets are made up of a statin-releasing mini-tablet and a specific amount of a residual antibiotic and ethylcellulose Ethylcellulose and Eudragit RL were used, statin general release mini tablets were prepared by high shear wet granulation method using immediate release additives and then filled into gelatin hard capsules, and fixed dose cilostazol and statin mini A capsule containing the tablet once a day, which can be taken orally, can be provided.

Ischemic cardiovascular disease caused by metabolic diseases such as hypertension, hyperlipidemia, diabetes, and obesity is characterized by progressive, chronic, and complex, and the prevalence of major causes of death is increasing along with the deterioration of quality of life. In addition, there are many cases of multiple morbidity to other metabolic diseases and various complications. Therefore, it is difficult to cure a single metabolic disease, and it is difficult to manage complications and manage complicated diseases. In order to effectively treat and prevent ischemic cardiovascular diseases, it is required to develop a combination of multiple drugs that can reduce multiple risk factors such as metabolic diseases and associated diseases. Especially, these ischemic cardiovascular diseases have a higher vulnerability (25-49% mortality rate) and limitations in adult drug treatment because they show much higher incidence and multiple morbidity rates in the elderly than in general adults. Therefore, there is a desperate need for the development of a multi-drug combination therapy that meets the physiological and pathological characteristics of the elderly.

The formation of thrombus through activation of platelet aggregation by the interaction of platelet and plasma coagulation factors in arterial blood vessels due to metabolic diseases and vascular injury causes ischemic cardiovascular diseases such as arteriosclerosis, angina pectoris, myocardial infarction and cerebral infarction, Anti-platelet aggregation-inhibiting antiplatelet agents inhibit platelet-mediated thrombus formation and vascular occlusion, thereby being pharmacologically effective in the treatment and prevention of ischemic cardiovascular diseases. In particular, Cilostazol is an antiplatelet agent for the phosphodiesterase III blockade of phosphoric acid, and has vasodilatory, antiproliferative, and lipid-modulating effects. Thus, Cilostazol is effective against chronic diseases such as occlusive atherosclerosis and diabetic peripheral vasculopathy It is frequently used for the improvement of ischemic symptoms due to arterial occlusion and for the prevention of recurrence after cerebral infarction. In addition, cilostazol is effective for prevention of restenosis after vascular surgery, for prevention of acute ischemic stroke secondary to stroke, improvement of inflammation and oxidative stress in hypertensive type 2 diabetic patients, kidney protection of renal disease treatment, It has been clinically proven that drug resistance is much lower than that of aspirin or clopidogrel.

Hyperlipidemia, such as cholesterol or triglyceride, is abnormally elevated in the plasma due to excessive intake of fat and sugar, obesity, diabetes, kidney disease, hypothyroidism, genetic factors, and the like. Thrombosis occurs in the arterial blood vessels and causes ischemic cardiovascular symptoms As a cause, ischemic cardiovascular disease can be prevented by treating hyperlipemia. Statin drugs, which control cholesterol synthesis by HMG-Co A reductase inhibition, are most effective in lowering plasma low-density lipoprotein and preventing cardiovascular disease in patients with metabolic disorders. They are used for the treatment of atherosclerosis, It has been shown to be clinically effective in reducing ischemic cardiovascular events such as myocardial infarction and cerebral infarction and mortality. In particular, it has been found that sodium salt of pravastatin therapy is safe and effective in the treatment of hyperlipidemia and in the management of ischemic cardiovascular disease in many clinical studies, including nephropathy and damage, myopathies and rhabdomyolysis, liver dysfunction and other side effects Was found to be lower than other statins, and it was proved that the risk of diabetes was lowest as well as the prevention of diabetes. Pravastatin sodium, which has a very low interaction with other drugs, is more suitable for adult patients, including elderly patients, who are more susceptible to diabetes, chronic cardiovascular disease, and kidney disease than other statins, and is recommended for use as safe and effective statins.

The combination therapy of cilostazol and statin is currently being used for the treatment and prevention of ischemic cardiovascular disease with ischemic cardiovascular disease and other metabolic diseases with hyperlipidemia accompanied by the cause of hyperlipidemia, It has been found that there is a better clinical treatment and prevention effect than the therapy. Particularly, when pravastatin sodium is used in combination with cilostazol, it is expected to treat and prevent ischemic cardiovascular diseases with hyperlipidemia more safely and effectively in elderly patients, patients suffering from diabetes, chronic cardiovascular diseases and nephropathy. The development of a combination of several combinations of cilostazol and statins can result in the addition of a combination of anticoagulant and antihyperlipidemic and antithrombotic effects of different mechanisms, A single, simplified use of a solid combination drug by both drugs will improve both drug compliance and patient compliance.

Since cilostazol is used in a dose of 100 mg twice a day and statins in a dose of 5 to 80 mg once a day, a fixed dose of cilostazol selected as a specific dose ratio of both drugs To ensure that once daily dosing of statins is effective, both drugs should be appropriately and individually controlled to release and elute each drug from one formulation to maintain or maintain the intrinsic pharmacokinetic behavior (absorption, distribution, metabolism and excretion) of both drugs, To clarify and simplify the formulation and manufacturing method of the drug according to the physical properties of both drugs, to secure the safety of the combination drug by preventing the physicochemical interaction between the drugs and the drugs and the additives to be used, It is necessary to develop an optimized formulation, such as miniaturization of the combined dosage form by minimizing the increase in the size of the formulation due to the drug.

Korean Registered Patent No. 10-1008540 (Registered on January 10, 2011)

It is an object of the present invention to provide a once-daily oral dosage-containing complex capsule comprising Cilostazol, an anti-platelet agent, and Statins, a therapeutic agent for hyperlipidemia, which are effective for the prevention or treatment of ischemic vascular disease, To provide a method.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising cilostazol-releasing mini-tablet and statin-releasing mini-tablet, wherein the cilostazol-releasing mini-tablet comprises 50 to 65% by weight of cilostazol, 15 to 30 By weight and ethyl cellulose in an amount of 5 to 20% by weight.

The present invention also relates to a cilostazol-releasing mini-tablet and a statin-releasing mini-tablet, wherein the cilostazol-releasing mini-tablet comprises 50 to 65% by weight of cilostazol, 15 to 30% by weight of ethylcellulose, 5 to 20% by weight of the composition.

In addition, cilostazol, cupolate and ethylcellulose were put into a high-shear granulator and mixed. Then, an ethanol solution of povidone K-30 was sprayed and mixed to prepare cilostazol-releasing granules. Then, a lubricant was added and mixed The first step to prepare cilostazol-releasing mini-tablets using a tablet machine, statins and additives were added to a high-shear granulator, mixed with an ethanol solution of povidone K-30, A second step of preparing statin general-release mini-tablets by adding a lubricant and then adding a lubricant, and a second step of preparing the statin-releasing mini-tablets of the first step and the statin general-release mini-tablets of the second- And a third step of filling the tablets into hard gelatin capsules.

In addition, the present invention relates to a method for producing cilostazol-releasing granules by mixing cilostazol, ethylcellulose and eudragit in a high shear granulator, mixing and spraying an ethanol solution of povidone K-30, , Statins and additives were added to a high shear granulator and mixed. Then, an ethanol solution of povidone K-30 was sprayed on and mixed with statin A second step of preparing a general release granule, adding a lubricant, mixing and then preparing a statin general-release mini tablet using a tablet machine, and a second step of preparing a cilostazol-releasing mini tablet and a second step And a third step of filling the gelatin hard capsule with statin general-release mini tablets.

The composite capsule according to the present invention can be manufactured as a combination preparation containing cilostazol and statin, which are different from each other in the conventional dosage and dosing method, as a fixed dose of cilostazol and statin and can be taken orally once a day , In particular, cilostazol-releasing mini-tablets may be prepared by mixing a specific fixed amount of the residual cholesterol and ethylcellulose Ethylcellulose and Eudragit RL or RS were used, statin general-release mini-tablets were prepared by high shear wet granulation method using immediate release additives and then filled into gelatin hard capsules for 24 hours without initial rapid drug release It is possible to release cilostazol at a constant release rate and accelerate statins without delaying the initial drug release. Therefore, it can be used in the elderly patients with frequent ischemic vascular diseases accompanied by hyperlipidemia, patients with diabetes, patients with chronic cardiovascular disease and patients vulnerable to kidney disease Can be widely used as a customized combination preparation, and the convenience of medication and the patient compliance can be improved.

Figure 1 shows the chromatogram results of cilostazol and pravastatin sodium simultaneously analyzed by high performance liquid chromatography at 254 nm and 238 nm wavelengths.
Figure 2 shows the calibration curve of pravastatin sodium at a wavelength of 254 nm and cilostazol at a wavelength of 238 nm.
FIG. 3 shows the results of (a) cilostazol, (b) pravastatin sodium and (c) cilastazole, pravastatin sodium and mixtures thereof at a wavelength of 254 nm and 238 nm after storage for 3 months at 40 ° C./75% relative humidity. ) And (d) Chromatogram results obtained by simultaneously analyzing a mixture of 5: 1 (w / w) cilostazol and pravastatin sodium by high performance liquid chromatography.
Figure 4 shows cilostazol release dried granules and their mini-tablets.
Figure 5 shows the pravastatin sodium release dry granules and their mini-tablets.
Figure 6 shows mini-tablets of cilostazol and pravastatin sodium and their hard capsule filling.
Figure 7 shows the release profile of the release profile of cilostazol from cilostazol and pravastatin sodium composite capsules in a pH 6.8 phosphate buffer containing 0.5% sodium lauryl sulfate.
Figure 8 shows the release profile of the release profile of cilostazol from cilostazol and pravastatin sodium combined capsules in a pH 1.2 hydrochloric acid buffer containing 0.5% sodium lauryl sulfate.
Figure 9 shows the dissolution profiles of pravastatin sodium from cilostazol and pravastatin sodium composite capsules obtained by performing a dissolution test in water.
Figure 10 shows cilostazol release dried granules and their mini-tablets.
Figure 11 shows the release profile of the release profile of cilostazol from cilostazol and pravastatin sodium combined capsules in a pH 6.8 phosphate buffer containing 0.5% sodium lauryl sulfate.
Figure 12 shows the release profile of the release profile of cilostazol from cilostazol and pravastatin sodium composite capsules in a pH 1.2 hydrochloric acid buffer containing 0.5% sodium lauryl sulfate.
FIG. 13 shows the dissolution profile of pravastatin sodium from cilostazol and pravastatin sodium composite capsules obtained by performing a dissolution test in water.

The present invention relates to a method for the treatment and prevention of ischemic cardiovascular diseases accompanied by hyperlipidemia, which comprises cilostazol release and statin general release mini tablets which can be taken orally once daily as a combination of cilostazol and statin A composite capsule preparation and a method for producing the same are provided.

The term "general release" agent used in the present invention means an agent that does not control the releasing property of the active ingredient from the preparation, and usually indicates a dissolution behavior depending on the physical properties of the active ingredient.

As used herein, the term "mini-tablet" refers to a tablet made by compressing a drug into a uniform shape, but unlike a tablet having a general-sized diameter, the mini-tablet has a very small diameter (usually 3 mm or less) And the smaller the diameter of the mini-tablet, the more the number of mini-tablets that can be injected into the capsule increases.

The term "capsule preparation " used in the present invention means a medicine prepared by filling a capsule in the form of a liquid, a tablet, a powder, a granule, a mini tablet, or a pellet or by encapsulating with a capsule base.

Cilostazol is a drug that is very low in water solubility (3 mg / mL) but high in membrane permeability and therefore classified as BCS (Biopharmaceutics Classification System) class II, administered twice daily at a dose of 100 mg. Cilostazol is low in absorption due to low dissolution rate in vivo, but has a large influence on the dissolution rate of the particle size. Therefore, it can improve absorption and bioavailability through particle control, and there is no change in elution and stability depending on pH in gastrointestinal tract, It has long biological half-life (11.0 ± 4.0 hours), increases absorption by food, and exhibits side effects such as headache if blood concentration exceeds the minimum toxic concentration. Considering this fact, in the development of a combination with pravastatin sodium, cilostazol crystal powders with an average particle size in the range of 20 to 50 μm were used, and a dose of 200 mg per day was administered through a sustained release preparation of cilostazol suitable for once- , It is possible to reduce the effect of food and minimize side effects of headache while maintaining effective blood levels. Stanthine drugs such as atorvastatin, rosuvastatin, lovastatin and pravastatin sodium are administered once a day in a dose of 5 to 80 mg. Therefore, in the development of a combination drug with cilostazol, It would be desirable to design with a general release (immediate release) formulation in which bioequivalence with the conventional formulation of crystalline powder of statins with an appropriate average particle size is ensured according to the water solubility of the selected statins. Pravastatin sodium, which is classified as BCS class III with high water solubility and low membrane permeability, is predominantly absorbed in small intestine such as duodenum, undergoes hepatic metabolism, is unstable at gastrointestinal pH and decreases bioavailability by food, A general release formulation of pravastatin sodium suitable for administration once daily in a dose of 20 mg or 40 mg per day, which can be stabilized under acidic conditions using a crystalline powder having a particle size in the range of 100 to 150 μm, is required.

The present invention adopts the mini-tablet for the design of the combination of cilostazol release and statin general release (fast-release) suitable for once-a-day administration according to the above-mentioned formulation policy, The tablets are separated and filled into hard capsules to be combined to minimize the physicochemical interactions between cilostazol and statin, thereby blocking the incompatibility between the drugs. In addition, cilostazol and statin general release additives, statins and cilostazol Minimizing the physicochemical interactions between the release additives to enhance the stability of the combination and minimizing the mutual influence on the release and dissolution of each drug to achieve a more elaborate profile of the different target release profiles for each drug And the mini-tablets individually release and elute the drug, resulting in a total cilostazol release And the general release of statin can be minimized and the content of cilostazol and statin can be more accurately controlled in the complex, and the size of the complex can be minimized without unnecessary preparation and stabilization, Can provide advantages such as no need for additional manufacturing equipment and unit operation due to its small size.

In order to prepare 24-hour sustained-release mini-tablets of cilostazol, the mini-tablets have a much larger surface area than the matrix-type general tablets per unit mass, so that even when the same release agent is used, There is a need for a cilostazol-releasing mini tablet matrix system capable of slowing the release more strongly from the tablet and further controlling the release for 24 hours, preferably for 24 hours. In the case of agents with a delayed drug release effect in the use of multiple hydrophilic and hydrophobic polymeric sustained release single agents that slow the release of high-dose drugs, although water-soluble, they may not achieve full release within 24 hours with excessive retardation of the initial drug release However, in the case of a base agent having a delayed drug release effect, complete release can be achieved within 24 hours, but there is a problem that the initial release of the drug is excessively accelerated. By overcoming this problem and using a combination of different drug release modifiers that can regulate the release of cilostazol over a 24 hour period and functionally complementary sustained release agents, cilostazol is a 24 hour sustained release mini tablet matrix System should be devised.

As a result of studies on the combination of hydrophilic and hydrophobic polymeric release retarding agents having different physico - chemical characteristics and different characteristics from those of the drug release modulator, the cilostazol mini - tablet 24 - hour release control showed that the hydrophilic high molecular weight polysaccharide, xanthan gum, And ethylcellulose, which is a hydrophobic cellulose ether, or a combination of ethyl cellulose and Eudragit RL or RS, which is a hydrophilic or insoluble amino methacrylate copolymer, is the most preferred 24 hour release control of cilostazol The results of the fitness of the combination with cilostazol and pravastatin sodium were obtained.

The cup dagger swells through rapid hydration before it is dissolved in water and forms a weak gel, which slowly gels and dissolves faster than other hydrophilic matrix-forming polymers that form strong gels. erosion), and after dissolution of the drug, the release of the drug due to dissolution and erosion of the residual pancreas is relatively fast, regardless of the pH, but since drug release can be controlled with no time dependence, It is effective for the release of drug of speed. Water-insoluble and hydrophobic ethylcellulose has the ability to slow the diffusion of dissolved drugs and to slow the release of drug by erosion of ethylcellulose, thereby potentially delaying the release of hydrophilic or hydrophobic drugs. However, compared to early drug release, . With a sustained-release mini tablet matrix system that combines the proper weight ratio of the two polymers with these characteristics, the high drug (200 g) release of cilostazol due to the overall drug diffusion and erosion of the complex base can be simultaneously elaborately and flexibly controlled The release profile of cilostazol at a nearly constant rate was obtained while the disintegration of the sustained-release matrix continued for 24 hours. It is safe to use non-toxic, non-polar, biocompatible, most suitable combination with drug and non-ionic material, stable at pH and temperature, good in flowability and compressibility, and easy to granulate.

Eudragit RL or RS, which is hydrophilic or water-insoluble, is a polymer that shows permeability and weak expansion properties to water irrespective of pH. It is a polymer that dissolves through dissolution matrix formation and releases drug by erosion of Eudragit. can be delayed irrespective of the pH, and in particular, have the property of effectively controlling early initial drug release. Eudragit RL or a combination of the appropriate weight ratio of RS and ethylcellulose simultaneously provides a finely tuned release of high capacity (200 g) cilostazol by diffusion of the co-medication of the combined complex base erosion through a sustained release mini tablet matrix system To reduce the initial release of cilostazol while maintaining the release matrix form and to obtain a release profile of cilostazol at a substantially constant rate for 24 hours. Eudragit RL or RS and ethyl cellulose are safe and non-toxic, non-irritating, biocompatible, compatible with most drugs and non-ionic materials, stable to pH, flowable and compressible, and easy to granulate .

Hereinafter, the present invention will be described in more detail.

The present invention relates to cilostazol-releasing mini-tablets and statin-releasing mini-tablets, wherein said cilostazol-releasing mini-tablets comprise 50-65 wt% cilostazol, 15-30 wt% To 20% by weight of the composition.

The present invention also relates to a cilostazol-releasing mini-tablet and a statin-releasing mini-tablet, wherein the cilostazol-releasing mini-tablet comprises 50 to 65% by weight of cilostazol, 15 to 30% by weight of ethylcellulose, 5 to 20% by weight of the composition.

Preferably, the statin general release mini tablet may comprise 5 to 50% by weight of statins, 5 to 30% by weight of magnesium oxide, 5 to 25% by weight of microcrystalline cellulose and 20 to 40% by weight of crospovidone.

Preferably, the Eudragit may be, but is not limited to, Eudragit RS or Eudragit RL.

Preferably, the cilostazol-releasing mini-tablets may contain, but are not limited to, 200 mg cilostazol daily.

Preferably, the statin may be selected from the group consisting of pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin and salts thereof, but is not limited thereto.

Preferably, the statin general release mini tablet may contain, but is not limited to, 10 to 40 mg of pravastatin sodium daily dose.

Preferably, the composite capsule may be administered orally once a day.

Preferably, the composite capsule may be a hard gelatin capsule of No. 1 to 00, more preferably a gelatin hard capsule of No. 1 to No. 0, but is not limited thereto.

Preferably, the cilostazol-releasing mini-tablets have an average diameter of from 1.5 to 3.0 mm and an average weight of from 3.5 to 8.0 mg, the average diameter of the statin general-release mini tablets is 1.5 to 3.0 mm, 8.5 mg, and the average weight of the composite capsule may be 350 to 500 mg, but is not limited thereto.

In addition, cilostazol, cupolate and ethylcellulose were put into a high-shear granulator and mixed. Then, an ethanol solution of povidone K-30 was sprayed and mixed to prepare cilostazol-releasing granules. Then, a lubricant was added and mixed The first step to prepare cilostazol-releasing mini-tablets using a tablet machine, statins and additives were added to a high-shear granulator, mixed with an ethanol solution of povidone K-30, A second step of preparing statin general-release mini-tablets by adding a lubricant and then adding a lubricant, and a second step of preparing the statin-releasing mini-tablets of the first step and the statin general-release mini-tablets of the second- And a third step of filling the tablets into hard gelatin capsules.

In addition, the present invention relates to a method for producing cilostazol-releasing granules by mixing cilostazol, ethylcellulose and eudragit in a high shear granulator, mixing and spraying an ethanol solution of povidone K-30, , Statins and additives were added to a high shear granulator and mixed. Then, an ethanol solution of povidone K-30 was sprayed on and mixed with statin A second step of preparing a general release granule, adding a lubricant, mixing and then preparing a statin general-release mini tablet using a tablet machine, and a second step of preparing a cilostazol-releasing mini tablet and a second step And a third step of filling the gelatin hard capsule with statin general-release mini tablets.

Preferably, the additive in the second step may be, but is not limited to, an additive for general release (rapid release).

Preferably, the additive of the second step may be at least one selected from the group consisting of magnesium oxide, microcrystalline cellulose and crospovidone, but is not limited thereto.

Preferably, the third stage cilostazol-releasing mini-tablet contains a daily dose of cilostazol of 200 mg, and the statin general-release mini-tablet may contain 10 to 40 mg of statin daily dose, It is not limited.

Preferably, the composite capsule of the third step can be administered orally once a day.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example  One: With cilostazol Of pravastatin sodium  Simultaneous method

In the present invention, simultaneous quantitative analysis of cilostazol and pravastatin sodium was established using gradient reverse-phase high performance liquid chromatography (HPLC), and the content of each drug in this combination preparation, Content uniformity, release and elution.

A Fortis C18 reversed phase column (150 X 4.6 mm, 5 μm particle size) was used in stationary phase at 30 ° C with an Agilent 1260 Infinity HPLC system equipped with a UV detector and four pumps and the mobile phase was 0.08 (Solvent A) and pure acetonitrile (solvent B) in which M phosphoric acid buffer and acetonitrile were mixed in an amount of 80: 20% (v / v) Gradient elution sequence: 100 → 85% solvent A: 0 → 15% linear gradient with solvent B for 2 min; 85% Solvent A: isopropyl alcohol for 15 minutes with solvent B for 4 minutes; 85 → 50% Solvent A: 15 → 50% Solvent B linear gradient for 2 minutes; 50% solvent A: isocratic for 10 minutes with 50% solvent B; 50 → 100% solvent A: 50 → 0% linear gradient for 2 minutes with solvent B; 100% Solvent A: Equilibration re-equilibration for 3 minutes with 0% Solvent B (23 minutes total travel time).

The known or unspecified amount of cilostazol, pravastatin sodium, or a formulation containing both drugs is diluted with a certain amount of benzophenone, an internal standard of cilostazol, and ethylparaben, an internal standard of pravastatin sodium (ethylparaben) were dissolved in methanol for 5 minutes, and then filtered using a 0.22 μm nylon membrane filter. Each 10 μL of the solution was injected into the HPLC system to obtain cilostazol at 254 nm, Pravastatin sodium obtained chromatogram results at 238 nm.

As a result, referring to FIG. 1, it was possible to obtain a chromatogram result of each concentration having a high resolution and a symmetric pravastatin sodium UV absorption peak.

Cilostazol in the concentration range of 5.0 to 300.0 μg / mL, benzophenone in the concentration of 20.0 μg / mL, pravastatin sodium in the concentration range of 5.0 to 100.0 μg / mL and ethyl paraben in the concentration of 30.0 μg / mL were dissolved in methanol, The standard curve of cilostazol was prepared by obtaining a linear change in the ratio of the peak area of cilostazol to the peak area of benzophenone with respect to the change in the known concentration, The calibration curve of pravastatin sodium was obtained by linearly changing the peak area of pravastatin sodium relative to the peak area of ethylparaben with respect to the concentration of the base. Using the calibration curves of cilostazol and pravastatin sodium, the concentration of each drug in the preparation and release sample containing unspecified cilostazol and pravastatin sodium could be analyzed simultaneously.

Example  2: With cilostazol Of pravastatin sodium  Evaluation of drug-drug compatibility

After 3 months (7 days, 14 days, 28 days and 90 days) in the accelerated stability test conditions (40 ° C temperature / 75% relative humidity) to evaluate the fitness of cilostazol and pravastatin sodium drug, HPLC analysis was performed.

A mixture of cilostazol, pravastatin sodium or a physical mixture of cilostazol and pravastatin sodium in a weight ratio of 5: 1 was placed in a brown glass vial, and a stability test chamber, The changes in appearance of each sample and the appearance of impurities such as decomposition products and changes in the content of each drug were analyzed using the established HPLC simultaneous analysis method. The results are shown in FIG.

As a result, referring to Table 1 and FIG. 3, there was no apparent change in appearance over time, no occurrence of unidentified degradation product, no significant change in the identified substance, and no remarkable change in the two drug contents No change was found, so the combination of cilostazol and sodium pravastatin was considered to be appropriate.

Example  3: Preparation of composite capsules containing cilostazol-releasing mini-tablets and pravastatin sodium-releasing mini-tablets (combined use of a cup-dagger and ethylcellulose)

3-1) In the high shear wet granulation method  by Cilostazol Standing release  Manufacture of mini tablets

A. Formulation

Formulation number
(Based on 200 mg cilostazol daily) Weight (mg) F1 F2 F3 F4 Cilostazol
(Crystalline powder having an average particle diameter of 20 to 50 [mu] m) 200 200 200 200 Xanthan gum (Grinsted ^® Xanthan Ultra) :
Ethylcellulose (Ethocel ^TM Std 100FP Premium) 60:60 80:40 90:30 96:24 (1: 1) (2: 1) (3: 1) (4: 1) Povidone K-30 (Kollidon ^® 30)
- 3% (w / v) solution in 100% ethanol (90 nu) - 2.7 2.7 2.7 2.7 Magnesium stearate 7.3 7.3 7.3 7.3 Total 330 330 330 330

B. Recipe

A predetermined amount of cilostazol, xanthan gum and ethylclellulose previously prepared in a 40 mesh sieve is placed in a high shear granulator (e.g., Key KG5 high shear granulator) and stirred at a speed of 75 rpm , And a 100% ethanol solution (binding solution) of 3% (w / v) povidone K-30 was maintained at a rate of 3 g / min Lt; RTI ID = 0.0 > cilostazol < / RTI > wet granules. The wet granules were dried by wet-milling in a 20 mesh (850 μm) sieve, dried at 40 to 50 ° C to a dry weight loss of 2.0% or less for at least 2 hours, To produce cilostazol release dried granules as shown in Fig. 4 (left).

According to the analysis of the drug content of the cilostazol-releasing dry granules, magnesium stearate, which is an amount of 200 mg cilostazol-equivalent amount of a lubricant, is added and mixed with a mixer (for example, a tubular mixer or a bin-blender) For 5 minutes to prepare a final mixture of cilostazol.

The final mixture was compressed using a 2 mm squeeze mini punch and a die equipped with a die (e.g., Sejong GRC-7S rotary tablet machine) to obtain a yarn having a weight of 4 to 6 mg and a tablet hardness of 1 to 3 kp Starzol-releasing mini-tablets were prepared as shown in Figure 4 (right).

3-2) In the high shear wet granulation method  by Pravastatin sodium  Manufacture of General Purpose Mini Tablets

A. Formulation

Formulation (Pravastatin sodium daily dose 40 mg) Weight (mg) Pravastatin sodium
(Crystalline powder having an average particle size of 100 to 150 mm) 40 Magnesium oxide 15 ^{Microcrystalline cellulose PH-101 (Avicel ®} PH-101) 10 Crospovidone (Kollidon ^® CL) 30 Povidone K-30 (Kollidon ^® 30)
- 2% (w / v) solution in 100% ethanol (70 mL) - 1.4 Sodium stearyl fumarate 3.6 Total 100

B. Recipe

A predetermined amount of pravastatin sodium, magnesium oxide, microcrystalline cellulose and crospovidone previously prepared in a 40 mesh sieve is placed in a high shear granulator (for example, Key KG5 high shear granulator) (W / v) povidone K-30 in a 100% ethanol solution (the combined solution was maintained at a stirring speed of 75 rpm for 3 minutes and then maintained at a stirring speed of 200 to 300 rpm and a sedimentation rate of 3000 to 4000 rpm) ) Was added to the mixed powder at a rate of 3 g / min to prepare pravastatin sodium wet granules. The wet granules were dried by wet-milling in a 20 mesh (850 μm) sieve, dried at 40 to 50 ° C to a dry weight loss of 2.0% or less for at least 2 hours, 5 (left), pravastatin sodium release dry granules were prepared.

Sodium stearyl fumarate, an amount of a lubricant equivalent to 40 mg pravastatin sodium per unit, was added to the pravastatin sodium-releasing dry granules according to the drug content analysis, and a mixer (e.g., tubular mixer or bin-blender) For 5 minutes to prepare a final mixture of pravastatin sodium.

The final mixture was compressed using a 2 mm squeeze-shaped mini punch and a die equipped with a die (e.g., Sejong GRC-7S rotary tablet machine) to obtain pravastatin sodium having a weight of 4 to 6 mg and a tablet hardness of 1 to 3 kp A general release mini tablet was prepared as shown in Figure 5 (right).

3-3) Cilostazol Standing release  Mini tablets and Pravastatin sodium  Preparation of Composite Capsules Containing General Release Mini Tablets

A. Recipe

6, according to the analysis of the average weight and drug content of the prepared cilostazol-releasing mini tablets, 95% to 105% of the target weight (330 mg) (or 95% of cilostazol daily dose 200 mg To 100% of the target weight (100 mg) according to the analysis of the average weight and drug content of the cilostazol-releasing mini-tablets having the weight within the above range Or 95% to 105% of a pravastatin sodium daily dose of 40 mg) pervastatin sodium-releasing mini-tablets were loaded into a No. 0 gelatin hard capsule, ranging from 95 to 105% of the total target weight of the mini tablets (430 mg) To prepare a cilostazol-pravastatin sodium composite capsule containing the active ingredient.

Example  4: Cilostazol Standing release  Granules and mini tablets and Pravastatin sodium  Characterization of generic emulsion granules and mini tablets (combined use of a cup dagger and ethylcellulose)

4-1) In the high shear wet granulation method  by Cilostazol Standing release  And Pravastatin sodium  Characteristics of general release granules

The drug content of the prepared granules was determined by < simultaneous analysis of cilostazol and pravastatin sodium in Example 1 >, and loss on drying was carried out by heating to 25O &lt; 0 &gt; C to 105 & Toledo HB43-S halogen moisture analyzer). The average particle diameter was measured using a laser scattering method. The apparent density was determined by weighing using a 100 mL cylinder. The compression density was 100 mL cylinder, and then the volume was determined by measuring the volume by tapping 100 times. The flowability was determined by calculating the Carr's Compressibility of the Carr's Compressibility by the following Equation 1 using the apparent density and the compression density value.

[Equation 1]

As a result, referring to the following Table 4, the contents of each drug in the cilostazol and pravastatin sodium granules (F1 to F4) were in good agreement with the formulation, and the ethanol used in the drying of the wet granules was almost eliminated The average apparent particle size was 400 μm and the particle size distribution was narrow. The apparent bulk density, compressive density and compressibility values of the granules showed the mixing properties, compressibility and flowability of the granules. It was evaluated that it was suitable for the manufacturing process such as mixing with other additives, tableting of mini-tablet and filling of capsule.

Formulation number Release granules from cilostazol Pravastatin sodium
General release granule F1 F2 F3 F4 Drug content (%) (n = 6) 99.8 + - 0.4 99.7 ± 0.6 99.6 ± 0.5 100.1 + - 0.4 100.1 + - 0.4 Loss on drying (%) (n = 3) 1.6 ± 0.05 1.5 ± 0.06 1.7 ± 0.04 1.5 + 0.04 1.5 ± 0.06 Particle size (μm) (n = 3) 340.5 ± 32.1 382.1 ± 37.5 420.7 ± 43.2 396.3 ± 42.4 425.2 ± 39.3 Apparent density (g / mL) (n = 3) 0.39 + 0.03 0.38 + 0.04 0.38 + 0.03 0.37 + 0.04 0.39 + 0.02 Tap density (g / mL) (n = 3) 0.44 + 0.04 0.45 + 0.03 0.44 + 0.04 0.43 + 0.04 0.45 + 0.03 Compression of Carr (%) 11.4 15.6 13.6 14.0 13.3

4-2) Cilostazol Standing release  And Pravastatin sodium  Characteristics of General Purge Mini Tablets

Each drug content of the mini-tablets prepared was determined by &quot; simultaneous assay of cilostazol and pravastatin sodium &quot; in Example 1 by changing 10 of 30 randomly taken tablets 6 times, and the mass deviation, tablet thickness and tablet hardness For each of the 20 mini-tablets randomly sampled, measurements were made using a microbalance, a vernier caliper (eg Mitumitu 530 vernier caliper) and a hardness tester (eg Erweka TBH 125 hardness tester) (Copley FR 1000 friability tester) was used to determine the degree of damage and weight loss (%).

As a result, referring to the following Table 5, it was found that the contents of each drug in all the cilostazol and pravastatin sodium mini tablet formulations (F1 to F4) were very consistent with the formulation and the deviation of the low tablet weight (less than 8% The thickness of the tablets was approximately 1.5 mm and the hardness was within the target range (1 to 3 kp). The degree of fatigue of the tablets was within the range of 1 to 3 kp. Respectively.

Formulation number Cilostazol release mini tablets Pravastatin sodium release mini tablets F1 F2 F3 F4 Drug content (%) (n = 6) 101.1 ± 0.3 100.4 ± 0.5 99.7 ± 0.5 99.5 + - 0.4 99.8 ± 0.3 Mass deviation (mg) (n = 20) 5.3 ± 0.2 5.1 ± 0.2 4.9 ± 0.3 4.8 ± 0.3 5.5 ± 0.2 Tablet thickness (mm) (n = 20) 1.53 + 0.03 1.50 + 0.04 1.48 + 0.03 1.47 + 0.04 1.45 ± 0.03 Purified hardness (kp) (n = 20) 1.5 ± 0.1 1.5 ± 0.1 1.4 ± 0.1 1.4 ± 0.1 2.5 ± 0.1 (%) (N = 3) 0.54 + 0.08 0.53 + 0.07 0.54 + 0.08 0.52 + 0.07 0.68 ± 0.12

Example  5: Cilostazol Standing release  And Pravastatin sodium  Evaluation of Drug Release Profile of Composite Capsules Containing Generic Discharged Mini Tablets With a dagger Of ethyl cellulose  Complex use)

5-1) Compound capsule Cilostazol  Emission profile

The cilostazol release test from the cilostazol-pravastatin sodium composite capsule was carried out using a dissolution tester (for example, Agillent 708-DS dissolution apparatus) according to Method 2 (paddle method) 900 mL of distilled water) in pH 6.8 phosphate buffer containing 0.5% sodium lauryl sulfate for 24 hours, then in pH 1.2 hydrochloric acid buffer containing 0.5% sodium lauryl sulfate for 4 hours in each of six vessels, 37 Lt; 0 &gt; C and a paddle speed of 75 rpm. 2 mL test solutions were taken at 0.5, 1, 2, 4, 6, 8, 12, 16, 20 and 24 hours in pH 6.8 phosphate buffer and 0.5, 1, 2 and 4 hours in pH 1.2 hydrochloric acid buffer, respectively. After filtration through a nylon membrane filter, the concentration of released cilostazol was determined by HPLC simultaneous analysis.

As a result, referring to FIG. 7 and FIG. 8, it can be seen that all the F1 to F4 preparations of cilostazol mini tablets prepared by the combined use of a cup-cutter and ethyl cellulose (with a fixed amount of 120 mg per 200 mg of cilostazol) The release rate of cilostazol was 24 hours from the sol-pravastatin sodium composite capsule, and the initial release rate was slowed by increasing the ratio of the residual sludge in the sum of the residual sludge and ethyl cellulose, The rapid characterization was observed in comparison with the low preparation. The release of cilostazol at a slightly higher rate at pH 1.2 than at pH 6.8 is a result of the slightly slow release of the drug over acidic conditions. F1 to F4 mini-tablets showed a sustained release pattern of cilostazol at a substantially constant rate for 24 hours, 62-67% cumulative release at 12 hours, 95-97% cumulative release at 20 hours, and 100% F3 and F4 formulations, which showed complete cumulative release, were found to be optimal for cilostazol once a day.

5-2) Compound capsule Pravastatin sodium  Dissolution profile

The pravastatin sodium dissolution test from the cilostazol-pravastatin sodium composite capsule was also conducted using a dissolution tester (e.g., Agillent 708-DS dissolution apparatus) according to the dissolution test method 2 (paddle method) of Korean Pharmacopoeia 11 The test solution (900 mL of distilled water) was run for 120 minutes in six vessels at a temperature of 37 ± 0.5 ° C and a paddle speed of 50 rpm. 2 mL of each test solution was taken at 5, 10, 15, 30, 60, and 120 minutes, filtered through a 0.22 μm nylon membrane filter, and the sodium concentration of the eluted pravastatin was determined by HPLC simultaneous analysis.

As a result, referring to FIG. 9, the pravastatin sodium general release mini tablet had a dissolution rate of pravastatin sodium of 80% or more within 15 minutes from the cilostazol-pravastatin sodium composite capsules containing the cilostazol mini tablet of all F1 to F4 formulations And almost complete dissolution at 60 minutes or more. Thus, it was confirmed that the dissolution of pravastatin sodium was sufficiently satisfied with the dosage of once-a-day dosing (release of 80% or more at 30 minutes).

5-3) Cilostazol - Pravastatin sodium  Compositions of Composite Capsules (Composite) Profile (Composite)

As a result of drug release test of composite capsules containing cilostazol-releasing mini-tablet and pravastatin sodium-releasing mini-tablet produced by high shear granulation method using a combination of a cup dagger and ethylcellulose, F3 or F4 Composite capsules containing the cilostazol-releasing mini-tablet and pravastatin sodium-releasing mini-tablet were identified as a combination product showing cilostazol release and pravastatin sodium release profile suitable for once-daily administration of cilostazol and pravastatin sodium .

Example  6: Cilostazol Standing release  Mini tablets and Pravastatin sodium  Preparation of Composite Capsules Containing General Release Mini Tablets With ethyl cellulose Eudragit RL (amino methacrylate copolymer type A)

6-1) In the high shear wet granulation method  by Cilostazol Standing release  Manufacture of mini tablets

A. Formulation

Formulation number
(Based on 200 mg cilostazol daily) Weight (mg) F5 F6 F7 Cilostazol
(Crystalline powder having an average particle diameter of 20 to 50 mm) 200 200 200 Ethylcellulose (Ethocel ^TM Std 100FP Premium) :
Polymethacrylate (Eudragit ^® RL PO) 60:60 80:40 90:30 (1: 1) (2: 1) (3: 1) Povidone K-30 (Kollidon ^® 30)
- 3% (w / v) solution in 100% ethanol (90 mL) - 2.7 2.7 2.7 Magnesium stearate 7.3 7.3 7.3 Total 330 330 330

B. Recipe

A predetermined amount of cilostazol, ethylcellulose and Eudragit RL PO preformed in a 40 mesh sieve is placed in a high shear granulator (eg Key KG5 high shear granulator), maintained at a stirring speed of 75 rpm and 3 The mixture was mixed with a 100% ethanol solution (binding solution) of 3% (w / v) povidone K-30 at a rate of 3 g / min while maintaining the stirring blade at a speed of 200 to 300 rpm and a sedimentation machine at a speed of 3000 to 4000 rpm Lt; RTI ID = 0.0 &gt; cilostazol &lt; / RTI &gt; wet granules. The wet granules were wet-milled into a 20 mesh (850 μm) sieve, dried and dried at 40 to 50 ° C. for at least 2 hours to a dry weight loss of 2.0% or less, and re-shaped into 30 mesh (600 μm) As shown in Fig. 10 (left), cilostazol release dried granules were prepared.

According to the analysis of the drug content of the cilostazol-releasing dry granules, magnesium stearate, which is an amount of 200 mg cilostazol-equivalent amount of a lubricant, is added and mixed with a mixer (for example, a tubular mixer or a bin-blender) For 5 minutes to prepare a final mixture of cilostazol.

The final mixture was compressed using a 2 mm round standard concave mini punch and a die equipped with a die (e.g., Sejong GRC-7S rotary tablet machine) to obtain a siloxane having a weight of 4 to 6 mg and a tablet hardness of 1 to 3 kp A sol-gel release mini tablet was prepared as shown in Figure 10 (right).

6-2) In the high shear wet granulation method  by Pravastatin sodium  Manufacture of General Purpose Mini Tablets

The pravastatin sodium general release mini tablet was prepared by the same formulation and preparation as in Example 3-2).

6-3) Cilostazol Standing release  Mini tablets and Pravastatin sodium  Preparation of Composite Capsules Containing General Release Mini Tablets

A composite capsule comprising cilostazol-releasing mini-tablet and pravastatin sodium-releasing mini-tablet was prepared in the same manner as in Example 3-3).

Example  7: Cilostazol Standing release  Granules and mini tablets, and Pravastatin sodium  Characterization of Generic Release Granules and Mini Tablets With ethyl cellulose Eudragit RL (amino methacrylate copolymer type A)

7-1) In the high shear wet granulation method  by Cilostazol Standing release  And Pravastatin sodium  Characteristics of general release granules

The drug content, the dry weight loss, the average particle size, the apparent density, the compressive density and the compressibility of the pravastatin sodium-releasing granules were analyzed in the same manner as in Example 4-1).

As a result, referring to Table 7 below, the contents of each drug in all the cilostazol and pravastatin sodium granules (F5 to F7) were in good agreement with the formulation, and the ethanol used in drying the wet granules was almost eliminated The average apparent particle size was 400 μm and the particle size distribution was narrow. The apparent bulk density, compressive density and compressibility values of the granules showed the mixing properties, compressibility and flowability of the granules. It was evaluated that it was suitable for the manufacturing process such as mixing with other additives, tableting of mini-tablet and filling of capsule.

Formulation number Release granules from cilostazol Pravastatin sodium
General release granule F5 F6 F7 Drug content (%) (n = 6) 101.2 ± 0.4 99.8 ± 0.5 100.2 ± 0.6 99.8 ± 0.6 Loss on drying (%) (n = 3) 1.5 ± 0.05 1.6 ± 0.07 1.6 ± 0.05 1.4 ± 0.07 Particle size (μm) (n = 3) 390.2 + - 38.5 410.5 ± 47.1. 419.2 ± 50.2. 417.3 ± 42.7 Apparent density (g / mL) (n = 3) 0.33 + 0.04 0.32 ± 0.04 0.35 + 0.03 0.38 + 0.03 Compression density (g / mL) (n = 3) 0.38 + 0.03 0.37 + 0.04 0.41 + 0.03 0.44 + 0.04 Compression of Carr (%) 13.2 13.5 13.6 14.6

7-2) Cilostazol Standing release  And Pravastatin sodium  Characteristics of General Purge Mini Tablets

The drug content, mass deviation, tablet thickness, tablet hardness and degree of fibrillation of cilostazol release and pravastatin sodium general release mini tablets were analyzed in the same manner as in Example 4-2).

As a result, referring to the following Table 8, it was found that the contents of each drug in all the cilostazol and pravastatin sodium mini tablet formulations (F5 to F7) were very consistent with the formulation, The thickness of the tablets was observed to be approximately 1.4 mm, the hardness was within the desired range (1 to 3 kp), the degree of grinding was within the range of pharmacopoeia, and the strength of the tablets was appropriate Respectively.

Formulation number Cilostazol release mini tablets Pravastatin
General Release Mini Tablet F5 F6 F7 Drug content (%) (n = 6) 100.6 ± 0.5 99.7 ± 0.4 100.4 ± 0.6 100.3 ± 0.5 Mass deviation (mg) (n = 20) 5.3 ± 0.3 5.4 ± 0.4 5.4 ± 0.3 5.5 ± 0.1 Tablet thickness (mm) (n = 20) 1.43 + 0.03 1.39 + 0.03 1.38 + 0.04 1.44 ± 0.04 Purified hardness (kp) (n = 20) 1.4 ± 0.1 1.3 ± 0.1 1.3 ± 0.1 2.5 ± 0.1 (%) (N = 3) 0.48 ± 0.09 0.52 + - 0.10 0.45 ± 0.08 0.65 ± 0.11

Example  8: Cilostazol Standing release  And Pravastatin sodium  Evaluation of Drug Release Profile of Composite Capsules Containing Generic Discharged Mini Tablets With ethyl cellulose Eudragit  RL (amino 메록acrylate  copolymer type A)

8-1) Compound capsule Cilostazol  Emission profile

Release of cilostazol from the cilostazol-pravastatin sodium composite capsule was tested in the same manner as in Example 5-1) to determine release profiles.

As a result, referring to FIG. 11 and FIG. 12, it can be seen that in all preparations F5 to F7 of cilostazol mini tablet prepared by using ethyl cellulose and Eudragit RL in combination (using a fixed amount of 120 mg per 200 mg of cilostazol) Release characteristics of cilostazol for 24 hours from the cilostazol-pravastatin sodium composite capsule, and the initial release rate was slowed and the terminal release rate was increased as the ratio of ethyl cellulose was increased in the total amount of ethyl cellulose and eudragit RL It was observed that the characteristics were faster than those with low ratio of ethylcellulose. The similarity of release rate of cilostazol at pH 6.8 and pH 1.2 is a result of reflecting the drug release characteristics regardless of the pH of the test solution, both for ethyl cellulose and for Eudragit RL. The sustained release pattern of cilostazol was continuously shown for 24 hours in the formulations of F5 to F7 mini tablets, with 68-72% cumulative release at 12 hours, 92-94% cumulative release at 20 hours and 97-99% cumulative release at 24 hours The F6 and F7 formulations that showed release were found to be optimal for cilostazol once a day.

8-2) Compound capsule Pravastatin sodium  Dissolution profile

The dissolution profiles of pravastatin sodium from cilostazol-pravastatin sodium composite capsules were also tested in the same manner as in Example 5-2).

As a result, referring to FIG. 13, the pravastatin sodium general release mini tablet had a dissolution rate of pravastatin sodium of 85% or more within 15 minutes from the cilostazol-pravastatin sodium composite capsules containing the cilostazol mini tablet of all the F5 to F7 formulations , And almost complete dissolution at 60 minutes or more. Thus, it was confirmed that the dissolution of pravastatin sodium was sufficiently satisfied with the dose of once-a-day dosing (elution of 80% or more at 30 minutes).

8-3) Cilostazol - Pravastatin sodium  Compositions of Composite Capsules (Composite) Profile (Composite)

As a result of drug release test of composite capsules containing cilostazol-releasing mini-tablet and pravastatin sodium-releasing mini-tablet produced by high shear granulation method using a combination of ethyl cellulose and Eudragit RL, F6 Or a composite capsule comprising a cilostazol-releasing mini-tablet of the F7 formulation and a pravastatin sodium-releasing mini-tablet, which is suitable for once-daily administration of cilostazol and pravastatin sodium, and which exhibits a cilostazol release and a pravastatin sodium dissolution profile Respectively.

Example  9: Drug-additive compatibility (Drug- excipient  compatibility evaluation

(7 days, 14 days, and 28 days) under accelerated stability test conditions (40 ° C temperature / 75% relative humidity) to evaluate the fitness of the cilostazol or pravastatin sodium drug and the additives used in the combination preparation, &Lt; / RTI &gt; and HPLC analysis was performed.

Cilostazol or pravastatin sodium was added to each of 11 different additives such as xanthan gum (Grindsted Xanthan Ultra), polyethylene oxide (PEO, Polyox TM WSR 303), carbomer (Carbopol 971P) , Amino methacrylate copolymer type A (Eudragit® RS PO), ethylcellulose (Ethocel ™ Std 100FP Preminum), microcrystalline cellulose (MCC, Avicel® PH-101), cross- (1: 5) of one of the following: crospovidone, Kollidon® CL, Kollidon® 30, magnesium oxide, sodium stearyl fumarate, magnesium stearate, The physically mixed mixture in the weight ratio was placed in a brown glass vial and stored in a stability test chamber in which the accelerated stability test conditions were maintained for a specified period of time, Whether the appearance and drug content change of the related substances (impurities), such as seafood and analyzed.

As a result, referring to Table 9 below, no significant significant change in each drug content was observed in the mixture between each drug and additive, and no significant change in the identified soft substance was observed with the appearance of undetermined degradation products Cilostazol and pravastatin sodium were evaluated to be suitable for combination with the additives used in the formulation.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

The scope of the present invention is defined by the appended claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included within the scope of the present invention.

Claims (13)

Wherein the cilostazol-releasing mini tablet comprises 50 to 65% by weight of cilostazol, 15 to 30% by weight of a residual knife and 5 to 20% by weight of ethylcellulose, &Lt; / RTI &gt; Wherein the cilostazol-releasing mini tablet comprises 50 to 65% by weight of cilostazol, 15 to 30% by weight of ethylcellulose and 5 to 20% by weight of ethyl cellulose % &Lt; / RTI &gt; The composite capsule preparation according to claim 2, wherein the Eudragit is any one of Eudragit RS and Eudragit RL. 3. The composite capsule preparation according to claim 1 or 2, wherein the cilostazol-releasing mini tablet contains a daily dose of 200 mg of cilostazol. 3. The capsule preparation according to claim 1 or 2, wherein the statin is selected from the group consisting of pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin and salts thereof. . 3. The composite capsule preparation according to claim 1 or 2, wherein the statin general-release mini tablet contains a daily dose of pravastatin sodium of 10 to 40 mg. The composite capsule preparation according to claim 1 or 2, wherein the composite capsule is administered by oral administration once a day. The composite capsule preparation according to claim 1 or 2, wherein the composite capsule is a gelatin hard capsule. 3. The method according to claim 1 or 2, wherein the cilostazol-releasing mini-tablets have an average diameter of 1.5 to 3.0 mm and an average weight of 3.5 to 8.0 mg, and the mean diameter of the statin general- The average weight is 4.0 to 8.5 mg, and the average weight of the composite capsule is 350 to 500 mg. Cilostazol, cupolate and ethylcellulose were put into a high-shear granulator and mixed. Then, an ethanol solution of povidone K-30 was sprayed and mixed to prepare cilostazol-releasing granules. Then, a lubricant was added and mixed A first step of preparing a cilostazol-releasing mini tablet using a tablet machine;
Statin and additives were mixed in a high shear granulator and mixed with an ethanol solution of povidone K-30 to prepare statin general release granules. Then, a lubricant was added and mixed, A second step of preparing a tablet; And
And a third step of filling the gelatin hard capsule with the cilostazol-releasing mini-tablet of the first step and the statin general-release mini tablet of the second step. Cilostazol, ethylcellulose and eudragit were put into a high-shear granulator and mixed. Then, an ethanol solution of povidone K-30 was sprayed and mixed to prepare cilostazol-releasing granules, followed by addition of a lubricant A first step of preparing a cilostazol-releasing mini tablet using the following tablet machine;
Statin and additives were mixed in a high shear granulator and mixed with an ethanol solution of povidone K-30 to prepare statin general release granules. Then, a lubricant was added and mixed, A second step of preparing a tablet; And
And a third step of filling the gelatin hard capsule with the cilostazol-releasing mini-tablet of the first step and the statin general-release mini tablet of the second step. 12. The method according to claim 10 or 11, wherein the cilostazol-releasing mini-tablet of the third step contains a daily dose of 200 mg of cilostazol, and the statin general-release mini-tablet contains 10 to 40 mg of statin daily dose &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. 12. The method of claim 10 or 11, wherein the composite capsule of the third step is administered orally once a day.

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