KR20060093467A - Complex pellets containing hypoglycemic agents, HM-CO reductase inhibitors and enteric-coated aspirin to prevent atherosclerosis in diabetic patients - Google Patents

Abstract

The present invention relates to a composite pellet comprising aspirin, a hypoglycemic agent and an HMG-CoA reductase inhibitor, and specifically a composite having an enteric coating on the outside of the main layer containing aspirin and an outer coating with an HMG-CoA reductase and a hypoglycemic agent. It is about pellets. The composite pellet according to the present invention comprises a main layer coated with 25 to 35% by weight of aspirin in 40 to 55% by weight of inert sugar particles; Enteric base layer coated with 10 to 15% by weight of the enteric base on the outside of the main layer; and 0.2 to 2.5% by weight of sulfonylurea-based hypoglycemic agent and 2.5 to 15% by weight of HMG-CoA reduction on the outside of the enteric base layer Including an outer layer coated with an enzyme inhibitor, wherein the hypoglycemic agent is one drug selected from the group consisting of glibenclamide and glimepiride among sulfonyl urea drugs, HMG-CoA The reductase inhibitor is characterized in that it is one drug selected from the group consisting of simvastatin, atorvastatin calcium and roschvastatin calcium.

Pellets, aspirin, hypoglycemic agents, HMG-CoA reductase inhibitors

Description

Formulation of single dosage form containing hypoglycemic agents, HMG-CoA reductase inhibitors and enteric coated Aspirin for diabetic hypoglycemic agents, HMG-CO reductase inhibitors and enteric-coated aspirin the prevention of atherosclerosis in diabetics}

1 shows a cross section of the layers forming the composite pellet according to the invention.

The present invention relates to a composite pellet comprising aspirin, a hypoglycemic agent and an HMG-CoA reductase inhibitor, and specifically a composite having an enteric coating on the outside of the main layer containing aspirin and an outer coating with an HMG-CoA reductase and a hypoglycemic agent. It is about pellets.

Diabetes is a disease in which glucose, which is obtained by digesting foods due to lack of insulin secretion or decreased cellular reactivity to insulin due to genetic factors, obesity, and poor eating habits, is accumulated in the blood without proper use in our bodies.

Diabetes is classified into insulin dependent type (type 1) and insulin independent type (type 2), and type 2 diabetes accounts for most of Korean diabetes.

Hypoglycemic agents are mainly used to treat diabetes, and oral hypoglycemic agents are generally sulfonyl urea, biguanide, alpha glucosidae inhibitor, and insulin sensitizer. (insulin sensitiser). The sulfonylurea-based diabetic therapeutic agent binds to the beta-cell receptor of the island of Langerhans in the pancreas, inhibits extracellular migration of potassium ions, induces depolarization, increases intracellular migration of calcium ions, and promotes insulin secretion. The main drugs of the sulfonylurea system include chlorpropamide, glibenclamide, glibenclamide, gliclazide, and glimepiride, which are mainly controlled by blood sugar by diet and exercise therapy. Use if not. Metformin is a representative biguanide-based drug that lowers blood sugar by inhibiting glucose absorption in the small intestine, strengthening insulin action in peripheral tissues such as muscle and adipose tissue, and inhibiting angiogenesis in the liver, but sulfonylurea-based drugs Unlikely, it does not increase insulin secretion.

The most clinically problematic problem in the management of type 1 and type 2 diabetes patients is the occurrence of chronic vascular complications. In particular, large vessel complications due to atherosclerosis are known to be the leading causes of death in patients with diabetes. As a cause of atherosclerosis, high cholesterol and thrombus formation can be mentioned, and complications of diabetic patients can be prevented by appropriate management.

In general, hyperlipidemia refers to an abnormally increased state of lipids such as cholesterol or triglycerides in plasma. Hyperlipidemia, especially hypercholesterolemia, leads to arterial thrombosis, which causes arteriosclerosis, in which lipids build up along the blood vessel walls, which is a clinically important issue because it reduces blood flow and causes ischemic heart disease, angina, and myocardial infarction. Therefore, hyperlipidemia and arteriosclerosis are closely related diseases. By treating hyperlipidemia, arteriosclerosis can be prevented. Various methods have been used to treat hyperlipidemia, but the HMG-CoA reductase inhibitor, a cholesterol synthesis inhibitor, is known as the most effective drug for treating hyperlipidemia. HMG-CoA reductase inhibitors inhibit HMG-CoA reductase, a rate-determining step in the synthesis of cholesterol in liver cells, thereby lowering cholesterol required for the synthesis of bile acids and compensating for atherosclerosis. Phosphorus effect is expressed by increasing the number of LDL (Low Density Lipoprotein) receptors to bring more LDL from the blood and lower the LDL concentration in the blood.

Thrombosis, another mechanism that causes atherosclerosis, is formed by the interaction of platelets and plasma coagulation factors in the wound site of blood vessels, or damaged blood vessels, which also causes atherosclerosis. Aspirin is used as an antipyretic and analgesic drug and has been used as a home medicine. Recent studies have shown that aspirin has various effects besides antipyretic and analgesic effects. The drug is attracting attention recently because it is reported as a preventive drug for thrombosis. This is because acetylsalicylic acid, a component of aspirin, irreversibly acetylates the cyclo-oxygenase of platelets to block the synthesis of thromboxane A2 (thromboxane A2: TXA2), a platelet aggregation derivative. This is because it blocks the sticking.

Therefore, either glycenclamide or glimepiride among sulfonyl urea drugs, hypoglycemic agents, simvastatin, an HMG-CoA reductase inhibitor, and atorvastatin calcium (Atorvastatin Calcium) And when a combination selected from the group consisting of Rosuvastatin calcium and aspirin is contained in one formulation such as tablets or pellets, the administration is simple and clinically the most problematic in diabetics. It may be useful for the prevention and treatment of chronic vascular complications, especially atherosclerosis.

The present invention proposes a combination formulation comprising the components set forth above for diabetics. Therefore, the present invention has the following object.

An object of the present invention is one selected from the group consisting of glybenclamide and glymepyride in sulfonylurea hypoglycemic agents, simvastatin, atorvastatin calcium (Atorvastatin Calcium) and roschvastatin in HMG-CoA reductase inhibitors. It is to provide one formulation comprising aspirin and one drug selected from the group consisting of calcium (Rosuvastatin calcium).

Formulations according to the invention prepared by the above method has the advantage of providing a formulation containing three active drugs in one formulation. One formulation containing the two active drugs shown is provided in the form of double pellets that can be filled into hard capsules. For example, the double pellets form aspirin coated on inert sugar particles, followed by enteric coating to improve gastrointestinal disorders of aspirin, followed by sulfonylurea-based hypoglycemic agents including glymepiride and various HMG-CoAs including simvastatin. Forming a layer containing a reductase inhibitor to form a multi-layered composite pellet, or in the form of tablets with different layers, or enteric-coated aspirin in the form of nuclear tablets and other hypoglycemic agents and HMG-CoA Reductase inhibitors may be prepared in the form of double-nucleated tablets to be contained in the outer layer. The formulations according to the invention may preferably be multilayer pellets or core tablets of the methods set forth above.

The double pellets or double tablets prepared by the above method preferentially dissolve the blood glucose lowering agent and HMG-CoA reductase inhibitor which are present in the outermost layer of the formulation, and the drug is eluted. When enteric coated aspirin reaches the upper part of the small intestine to reduce the amount of lipids such as cholesterol and improve gastrointestinal disorders, it elutes and inhibits the aggregation of platelets to prevent the formation of blood clots to prevent atherosclerosis in diabetics. It can have a significant effect.

According to the method of the present invention, the patient was uncomfortable with taking multiple doses by taking the blood glucose lowering agent, the HMG-CoA reductase inhibitor, and the aspirin, respectively, but the medication compliance of the patients was improved by the preparation according to the present invention. The therapeutic effect of

The configuration of the present invention for achieving the object set forth below will be described in detail.

According to a suitable embodiment of the present invention, the composite pellet of the present invention comprises a main layer coated with 25 to 35% by weight of aspirin in 40 to 55% by weight of inert sugar particles; An enteric base layer coated with 10 to 15% by weight of an enteric base on the outside of the main layer; and a 0.2 to 2.5% by weight hypoglycemic agent and 2.5 to 15% by weight of a HMG-CoA reductase inhibitor on the outside of the enteric base layer Wherein the hypoglycemic agent is one drug selected from the group consisting of glybenclamide and glymepiride among sulfonyl urea drugs, and the HMG-CoA reductase inhibitor is simvastatin, atorvastatin calcium And roschvastatin calcium.

According to another suitable embodiment of the present invention, the enteric coating base is phthalic acid hydroxypropyl methyl cellulose, polyethylene glycol 6000, methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose acetate succinate, At least one selected from the group consisting of polyvinylacetate phthalate, cellulose acetate trimellitate, carboxymethylcellulose, and shellac.

According to another suitable embodiment of the present invention, it further comprises 0.1 to 1% by weight of a stabilizer, and the stabilizer is tocopherol, dibutylhydroxytoluene, butylhydroxyanisole and the like ascorbic acid, sodium sulfite, At least one antioxidant selected from the group consisting of sodium pyrosulfite and sodium hydrogen sulfite.

According to another suitable embodiment of the present invention, it may further comprise 5 to 15% by weight of hydroxypropyl cellulose or a derivative thereof and 0.5 to 2% by weight of polyethylene glycol.

According to another suitable embodiment of the present invention, hard gelatin filled with the composite pellet of claim 1 may be provided.

According to another suitable embodiment of the invention, said hard gelatin capsules may contain 80 to 100 mg of aspirin per capsule.

According to another feature of the invention, the hard gelatin capsules may contain 1 to 8 mg of sulfonylurea-based hypoglycemic agents per capsule.

According to another feature of the invention, the hard gelatin capsules may contain 10 to 40 mg of HMG-CoA reductase inhibitor per capsule.

According to another suitable embodiment of the present invention, the composite pellet of the present invention may be prepared for oral administration.

The invention is described in detail below by way of example and not by way of limitation.

1 shows a cross section of the layers forming the composite pellet according to the invention.

As shown in FIG. 1, the composite pellet of the present invention has an enteric coating layer and a sulfine-containing core, an aspirin-containing layer coated on the core, an aspirin-containing layer, an enteric base, and coated on the outside of the aspirin-containing layer. And a sulfonylurea-based hypoglycemic agent and an HMG-CoA-reductase inhibitor-containing layer comprising a polyvinylurea-based hypoglycemic agent and an HMG-CoA reductase inhibitor and coated on the outside of the enteric coating layer.

Looking at the composition ratio of the layers formed by the above method, aspirin 25 to 35% by weight, a sulfonylurea-based hypoglycemic agent 0.2 to 2.5%, HMG-CoA reductase inhibitor 2.5 to 15% by weight, hydroxypropyl cellulose Or derivatives 5 to 15% by weight, polyethylene glycol 0.5 to 2% by weight, enteric coating base 10 to 15% by weight, stabilizer 0.1 to 1% by weight, inert sugar particles may be 40 to 55% by weight. The layers may form one pellet as a whole or may be filled inside the capsule.

Aspirin, sulfonylurea-based hypoglycemic agents and HMG-CoA reductase inhibitors do not achieve the expected efficacy as drugs, and side effects may occur when the upper limit is exceeded. In addition, when the enteric coating base is less than 10% by weight, it does not function as an enteric coating base, when it exceeds 15% by weight it takes a lot of time in the pellet manufacturing process, it has a disadvantage that can not expect rapid dissolution in the intestine. And when the stabilizer is less than 0.1% by weight does not function as a stabilizer, when the amount exceeds 1% by weight has a problem that can lower the stability rather.

As another embodiment of the pellet according to the present invention aspirin 25 to 35% by weight, sulfonylurea-based hypoglycemic agent 0.2 to 2.5%, HMG-CoA reductase inhibitor 2.5 to 15% by weight, hydroxypropyl cellulose or derivatives thereof 5 to 15 Weight%, polyethylene glycol 0.5 to 2% by weight, enteric coating base 10 to 15% by weight, stabilizer 0.1 to 1% by weight, various excipients for tablets to be tableted, such as extenders or binders prepared using 40 to 55% by weight Double tablets may be provided.

In the present invention, aspirin may be used by dissolving 20 to 50% by weight of the total weight, but in order to express the optimal effect for the purpose of preventing thrombosis, it is preferable to use up to 25 to 35% by weight. At this time, a suitable solvent may be used by mixing one or two or more selected from the group consisting of acetone, ethanol, dichloromethane, isopropyl alcohol and purified water, in particular, the most preferred solvent is acetone 30 to 100 It is preferable to dissolve using the drainage amount. At this time, when the amount of the solvent is less than 30 times the amount of the main drug can not expect complete dissolution, when more than 100 times the amount of solvent may cause delay of the working time and drug instability is not preferable. In addition, in order to prevent the formation of blood clots and to prevent atherosclerosis, aspirin is required to take a steady dose of aspirin, which is a gastrointestinal disorder in order to solve the enteric coating. It must be absorbed. In order to have an enteric coating having the above effect, at least 10 to 20% by weight of the enteric coating base to the total weight should be coated. In the case of coating according to the present invention according to the present invention, a film layer having a thickness of about 10 micrometers is formed on the surface of the formulation. If the coating layer is thinner than the above thickness, the coating layer does not exhibit resistance to an acidic solution. If the coating layer is thicker than this, it is not preferable because the coating layer may have a delay in working time and a dissolution rate in the intestine.

In the outer layer of the enteric-coated preparation, a sulfonylurea blood glucose lowering agent and an HMG-CoA reductase inhibitor layer are formed. Usually, it is preferable to contain 0.2 to 2.5% by weight and 2.5 to 15% by weight relative to the total weight. . In addition, since HMG-CoA reductase inhibitor is a fermentation product, it is possible to enhance the stability of the drug by adding 0.1 to 1% by weight of antioxidant.

The equipment used to make the double pellets in the present invention is a GPCG1 fluid bed coating machine from Glatt, Germany, but known coating machines known in the art can be used. The operating conditions of the equipment are controlled by inlet air temperature 50 ℃, outlet air 40 ℃, air flow rate 7m / sec, nozzle diameter 1.0mm, spray pressure 1.3bar, coating liquid inlet rate 25g / min, and under each condition Was carried out.

Hereinafter, the present invention will be described in detail through examples and comparative examples, but the examples presented are not intended to limit the scope of the present invention. In addition, inert sugar particles, which are components added in Examples and Comparative Examples, are selected and used so that the approximate particle size has a constant size with a diameter of 0.2 ~ 0.6 mm.

Example

Example 1

The composition ratios of the preferred aspirin, glimepiride and simvastatin composite pellets according to the present invention are shown in Table 1.

Table 1. Composition of aspirin, glymepiride and simvastatin composite pellets

                                                 (Unit: Gram, 1,000 Capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Glymepire Simvastatin Butylhydroxyanisole hydroxypropylmethylcellulose phthalate hydroxypropylmethyl- cellulose polyethylene glycol 6000 talc 155 100---10-1 1 ------40 4 4 --2 20 1 10-1 1 Total (weight, grams) 267 315 350

The method of forming each layer shown in Table 1 is as follows.

Note 1 coating (inner layer)

155 grams of inert sugar particles are placed in a fluidized bed coater and run to fluidize the particles to be coated. At the same time, 10 grams of hydroxypropylmethylcellulose and 1 gram of polyethylene glycol 6000 were dissolved in 2,000 grams of ethanol and methylene chloride mixed in a 1: 1 mass ratio, 100 grams of aspirin was dissolved in the solution, and 1 gram of talc was added. Stir. The drug is coated on the sugar particles while spraying the coating solution containing Note 1 through the fluidized bed coater.

Enteric coating

40 grams of phthalic acid hydroxypropylmethylcellulose and 4 grams of polyethylene glycol were added to 1,000 grams of ethanol and methylene chloride mixed in a 1: 1 mass ratio to completely dissolve. Then, 4 grams of talc was added thereto, followed by stirring and dispersing. Enteric coating is performed.

Note 2 coating (outer layer)

10 grams of hydroxypropylmethylcellulose and 1 gram of polyethylene glycol 6000 were dissolved in 2,000 grams of a mixture of ethanol and methylene chloride 1: 1, followed by 1 gram of butylhydroxyanisole, 2 grams of glymepiride, and 20 grams of simvastatin. Dissolve, add 1 gram of talc, and stir to prepare the coating solution 2. Subsequently, the pellet is coated with the medicine 2 by spraying the finished pellet.

Example 2

Composite pellets were prepared containing the amounts of aspirin, glimepiride and simvastatin in the amounts shown in Table 2.

Table 2. Composition of aspirin, glymepiride and simvastatin composite pellets

                                               (Unit: Gram, 1,000 Capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Glymepire Simvastatin Butylhydroxyanisole hydroxypropylmethylcellulose phthalate hydroxypropylmethyl- cellulose polyethylene glycol 6000 talc 122 100---10-1 1 ------40 4 4 --2 40 2 20-2 2 Total (weight, grams) 234 282 350

Each layer shown in Table 2 was formed in the following manner.

Note 1 coating (inner layer)

122 g of inert sugar particles were used in the same manner as in Example 1 coating.

Enteric coating

It was carried out in the same manner as in the enteric coating of Example 1.

Note 2 coating (outer layer)

20 grams of hydroxypropylmethylcellulose and 2 grams of polyethylene glycol 6000 were dissolved in 4,000 grams of ethanol and methylene chloride mixed in a 1: 1 mass ratio. To this solution, completely dissolve, add 2 grams of talc, and stir to prepare the coating solution. Subsequently, the pellets coated with the main medicine 2 were obtained by spraying the enteric coated pellets.

Example 3

Composite pellets were prepared containing the amounts of aspirin, glimepiride and simvastatin in the amounts shown in Table 3.

 Table 3. Composition of aspirin, glymepiride and simvastatin composite pellets

                                                (Unit: Gram, 1,000 Capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Glymepire Atovastatin Calcium Butylhydroxyanisole Hydroxypropylmethylcellulose Phthalate Hydroxypropylmethyl- Cellulose Polyethyleneglycol 6000 Talc 171.5 100---10-1 1 ------40 4 4 --2 10 0.5 5-0.5 0.5 Total (weight, grams) 283.5 331.5 350

Each layer shown in Table 3 was formed according to the following method.

Note 1 coating (inner layer)

Prepared in the same manner as the coating of Note 1 of Example 1, 171.5 grams of inert sugar particles were used.

Enteric coating

It was prepared in the same manner as in the enteric coating of Example 1.

Note 2 coating (outer layer)

5 grams of hydroxypropylmethylcellulose and 0.5 grams of polyethylene glycol 6000 were dissolved in 1,000 grams of ethanol and methylene chloride mixed at a mass ratio of 1: 1, followed by 0.5 grams of butylhydroxyanisole and 2 grams of glymepiride, and Atoba Add 10 grams of statin calcium, dissolve completely, add 0.5 grams of talc, and stir to prepare the main solution. Subsequently, the pellets coated with the main medicine 2 were obtained by spraying the enteric coated pellets.

Example 4

Composite pellets were prepared comprising aspirin, glymepiride and atorvastatin calcium, including amounts as set forth in Table 4.

Table 4. Composition of aspirin, glymepiride and atorvastatin calcium complex pellets

                                                (Unit: Gram, 1,000 Capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Glymepire Atovastatin Calcium Butylhydroxyanisole Hydroxypropylmethylcellulose Phthalate Hydroxypropylmethyl- Cellulose Polyethyleneglycol 6000 Talc 155 100---10-1 1 ------40 4 4 --2 20 1 10-1 1 Total (weight, grams) 267 315 350

Each layer shown in Table 4 was prepared in the following manner.

Note 1 coating (inner layer)

Prepared in the same manner as in Example 1 coating of Example 1, only 155 grams of inert sugar particles were used.

Enteric coating

It was prepared in the same manner as in the enteric coating of Example 1.

Note 2 coating (outer layer)

20 grams of atorvastatin calcium was prepared in the same manner as in Example 2 coating.

Example 5

Composite pellets were prepared comprising the amounts of aspirin, glimepiride and atorvastatin calcium in the amounts shown in Table 5.

Table 5. Composition of aspirin, glymepiride and atorvastatin calcium complex pellets (unit: gram, 1,000 capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Glymepire Atovastatin Calcium Butylhydroxyanisole Hydroxypropylmethylcellulose Phthalate Hydroxypropylmethyl- Cellulose Polyethyleneglycol 6000 Talc 122 100---10-1 1 ------40 4 4 --2 40 2 20-2 2 Total (weight, grams) 234 282 350

Each layer shown in Table 5 was prepared in the following manner.

Note 1 coating (inner layer)

122 g of inert sugar particles were used in the same manner as in Example 1 coating.

Enteric coating

It was prepared in the same manner as in the enteric coating of Example 1.

Note 2 coating (outer layer)

40 g of atorvastatin calcium was prepared in the same manner as in Example 2 coating.

Example 6

Composite pellets were prepared comprising the amounts of aspirin, glymepyride and roschvastatin calcium in the amounts shown in Table 6.

Table 6. Composition of Aspirin, Glimepiride and Rochevastatin Calcium Complex Pellets

                                                (Unit: Gram, 1,000 Capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Glymepiride Roschvastatin Calcium Butylhydroxyanisole Hydroxypropylmethylcellulose Phthalate Hydroxypropylmethyl- Cellulose Polyethyleneglycol 6000 Talc 171.1 100---10-1 1 ------40 4 4 --2 10.4 0.5 5-0.5 0.5 Total (weight, grams) 283.1 331.1 350

Each layer shown in Table 6 was prepared by the following method.

Note 1 coating (inner layer)

Prepared in the same manner as in coating 1 of Example 1, 171.1 grams of inert sugar particles were used.

Enteric coating

It was prepared in the same manner as in the enteric coating of Example 1.

Note 2 coating (outer layer)

Prepared in the same manner as in Example 2 coating of Example 3, using 10.4 grams of Rochevastatin calcium.

Example 7

Composite pellets were prepared comprising aspirin, glimepiride and roschvastatin calcium as shown in Table 7.

Table 7. Composition of Aspirin, Glimepiride and Rochevastatin Calcium Complex Pellets

                                                (Unit: Gram, 1,000 Capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Glymepiride Roschvastatin Calcium Butylhydroxyanisole Hydroxypropylmethylcellulose Phthalate Hydroxypropylmethyl- Cellulose Polyethyleneglycol 6000 Talc 154.2 100---10-1 1 ------40 4 4 --2 20.8 1 10-1 1 Total (weight, grams) 266.2 314.2 350

Each layer shown in Table 7 was prepared in the following manner.

Note 1 coating (inner layer)

154.2 grams of inert sugar particles were prepared, in the same manner as in coating Example 1 of Example 1.

Enteric coating

It was prepared in the same manner as in the enteric coating of Example 1.

Note 2 coating (outer layer)

Prepared in the same manner as in Example 2 coating of Example 1, 20.8 grams of Rochevastatin calcium was used.

In order to evaluate the adequacy of the embodiment according to the present invention, a composite pellet was prepared as in the comparative example below.

Comparative example

Comparative Example 1

Composite pellets were prepared containing the amounts of aspirin, glimepiride and simvastatin in the amounts shown in Table 8.

Table 8. Composition of Aspirin, Glimepiride and Simvastatin Complex Pellets

                                                (Unit: Gram, 1,000 Capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Simvastatin Glymepiride Butylhydroxyanisole Hydroxypropylmethylcellulose Phthalate Hydroxypropylmethyl- Cellulose Polyethyleneglycol 6000 Talc 179 100---10-1 1 ------20 2 2 --20 2 1 10-1 1 Total (weight, grams) 291 315 350

Each layer shown in Table 8 was prepared by the following method.

Note 1 coating (inner layer)

179 grams of inert sugar particles were prepared, in the same manner as in coating Example 1 of Example 1.

Enteric coating

Prepared in the same manner as in the enteric coating of Example 1, 20 grams of hydroxypropyl methyl cellulose was used.

Note 2 coating (outer layer)

Prepared in the same manner as in Example 2 coating of Example 1.

Comparative Example 2

Composite pellets were prepared containing the amounts of aspirin, glimepiride and simvastatin in the amounts shown in Table 9.

Table 9. Composition of Aspirin, Glymepyride and Simvastatin Complex Pellets

                                                 (Unit: Gram, 1,000 Capsules)

Name Inner floor (about 1st floor) Enteric coating layer Outer layer (about 2nd floor) Inert Sugar Particles Aspirin Glymepire Simvastatin Butylhydroxyanisole hydroxypropylmethylcellulose phthalate hydroxypropylmethyl- cellulose polyethylene glycol 6000 talc 156 100---10-1 1 ------40 4 4 --2 20-10-1 1 Total (weight, grams) 268 316 350

Each layer shown in Table 9 was prepared by the following method.

Note 1 coating (inner layer)

156 grams of inert sugar particles were prepared, in the same manner as in coating Example 1 of Example 1.

Enteric coating

It was prepared in the same manner as in the enteric coating of Example 1.

Note 2 coating (outer layer)

It was prepared in the same manner as in Coating 2 of Example 1, except that butylhydroxyanisole was not used.

In order to compare the working effect of the embodiment according to the present invention with the comparative example, the following experiment was carried out.

Experiment example

Experimental Example 1

The dissolution test of Examples 1-7 was performed to determine the percent drug release rate of glymepiride in the oral complex pellet formulation of aspirin, glymepiride and HMG-CoA reductase inhibitor.

Elution time % Release Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 30 minutes 98.7 97.5 97.2 98.3 99.5 98.3 99.5

Experimental Example 2

The dissolution test of Examples 1-7 was performed to determine the percent drug release of HMG-CoA reductase inhibitors in oral complex pellet formulations of aspirin, glymepiride and HMG-CoA reductase inhibitors.

Elution time % Release Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 30 minutes 96.7 99.3 97.3 98.1 98.9 97.8 99.7

Experimental Example 3

In order to determine the acid resistance of enteric-coated aspirin in oral complex pellet preparations of aspirin and HMG-CoA reductase inhibitors, dissolution tests of Examples 1-7 and Comparative Example 1 were carried out in 0.1 M / L hydrochloric acid solution.

Elution time % Release Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Comparative Example 1 120 minutes 3.2 4.5 4.7 3.2 2.7 3.8 4.7 41.3

As described above, the product coated with phthalic acid hydroxypropyl methyl cellulose, which is an enteric coating base, over 10% of the total weight (Example 1-7) was hardly eluted under gastric fluid conditions, but was less than 10% as in Comparative Example 1. The coated product was not resistant to gastric juice conditions and a large amount was eluted.

Experimental Example 4

The dissolution test of Examples 1-7 was performed to determine the drug release rate (%) of enteric-coated aspirin in oral complex pellet preparations of aspirin and HMG-CoA reductase inhibitors.

Elution time % Release Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 45 minutes 92.3 91.5 90.2 92.8 93.1 91.7 92.7

Experimental Example 5

In order to measure the stability of HMG-CoA reductase inhibitors in oral complex pellet preparations of aspirin and HMG-CoA reductase inhibitors, the content tests of Examples 1-7 and Comparative Example 2 were conducted.

Storage condition content(%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Comparative Example 2 Room temperature, 90 days 99.8 98.5 99.7 99.9 98.9 97.2 98.2 98.9 40 ° C 75% RH, 90 days 98.9 98.5 98.7 98.1 98.5 97.1 98.1 94.8

As described above, in Comparative Example 2 without using a butylhydroxyanisole as a stabilizer, the stability was lower than that in Examples 1-7.

In the present invention, diabetes mellitus is prescribed in a number of drugs separately to prevent atherosclerosis and then to take the patient to take the exact time of administration as well as the complex method of taking the drug compliance was very poor. However, the composite pellet according to the present invention is easy to take by formulating a single formulation of a sulfonylurea-based hypoglycemic agent, an HMG-CoA reductase inhibitor, and aspirin, which are widely used for the prevention of atherosclerosis of diabetic Chinese characters, in a single formulation. It has the advantage of maximizing the therapeutic effect.

In addition, drugs that are not currently formulated globally but are administered in combination for the treatment of patients in the form of the formulations according to the invention will allow for the continuous development of very effective and easy to take formulations. .

Claims (9)

In a composite pellet containing aspirin, sulfonylurea-based hypoglycemic agents and HMG-CoA reductase inhibitors, A main layer coated with a drug comprising 25 to 35% by weight of aspirin in 40 to 55% by weight of inert sugar particles relative to the total weight; An enteric base layer coated on the outside of the main layer with an enteric base of 10 to 15% by weight relative to the total weight; And And an outer layer coated on the outside of the enteric base layer with a drug comprising 0.2 to 2.5% by weight of sulfonylurea-based hypoglycemic agent and 2.5 to 15% by weight of HMG-CoA reductase inhibitor. Ponyurea-based hypoglycemic agent is one drug selected from the group consisting of glymepiride and glybenclamide, and HMG-CoA reductase inhibitor is one drug selected from the group consisting of simvastatin, atorvastatin calcium and roschvastatin calcium Composite pellet for oral administration, characterized in that. The method of claim 1, wherein the enteric coating agent is phthalic acid hydroxypropyl methyl cellulose, polyethylene glycol 6000, methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose acetate succinate, polyvinylacetate A composite pellet characterized in that one or more selected from the group consisting of phthalate, cellulose acetate trimellitate, carboxymethyl cellulose and shellac. The composite pellet according to claim 2, wherein the enteric coating base comprises 10 to 15% by weight of phthalic acid hydroxypropylmethylcellulose and 1 to 1.5% by weight of polyethylene glycol 6000. The method according to claim 1, wherein the HMG-CoA reductase inhibitor-containing layer is 0.1 to 1% by weight of tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid, sodium sulfite, sodium pyrosulfite and sodium hydrogen sulfite Composite pellets further comprising one or two or more antioxidants selected from the group consisting of. The composite pellet according to claim 4, wherein the antioxidant comprises 0.2 to 0.3 wt% of butylhydroxyanisole relative to the total weight. Hard gelatin capsules filled with the composite pellet of claim 1. The hard gelatin capsule of claim 6, which contains 80 to 100 mg of aspirin per capsule. The hard gelatin capsule of claim 6 which contains 1 to 8 mg of sulfonylurea-based hypoglycemic agents per capsule. The hard gelatin capsule of claim 6 which contains 10 to 40 mg of HMG-CoA reductase inhibitor per capsule.

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