KR101512386B1 - Complex formulation comprising metformin and mitiglinide and method for preparation thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising mitiglinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof; And a complex preparation comprising metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the methiglidanide component is equivalent to or similar to the dissolution pattern of the single composition of the methiglinide without interfering with the metformin component Wherein the metformin component also has an elution pattern equal to or similar to the elution pattern of the metformin single preparation, and a process for producing the same.

Metizin, metformin, combination preparation, diabetes

Description

TECHNICAL FIELD [0001] The present invention relates to a method for preparing a combination of metizinide and metformin,

The present invention relates to a combination of mitiglinide and metformin for the treatment of diabetes and a method for producing the same.

Metformin, a biguanide-based drug for the treatment of diabetes mellitus, is an oral antidiabetic agent and a blood glucose drug that is mainly used for the treatment of non-insulin dependent diabetes mellitus (NIDDM). Metformin's glucose regulatory mechanism is independent of insulin secretion and inhibits glucose synthesis in the liver, which is related to the effect of reducing fasting blood glucose levels, and is associated with insulin resistance (type 2) diabetic patients Although it can be used as a primary drug, it does not show a therapeutic effect in the improvement of postprandial rapid blood sugar increase in type 2 diabetic patients.

Currently, metformin is commercially available as a tablet of GLUCOPHAGE (Bristol-Myers Squibb Company) as its hydrochloride salt. Commercially available glucophage tablets contain 500 mg, 850 mg, or 1,000 mg of metformin hydrochloride and their administration is done within a range that does not exceed the maximum required dose of 2550 mg per day in terms of both efficacy and tolerance have.

Recently, rapid-acting insulin secretagogues such as nateglinide, repaglinide, and mitiglinide, which are oral hypoglycemic drugs, have been proposed, and a remarkable therapeutic effect Which is attracting attention. It is known that insulin secretion is remarkably lower in type 2 diabetic patients than in healthy persons because of an increase in the early insulin secretion after glucose loading, in particular, a rise in the blood glucose level for 30 minutes after the glucose ingestion. That is, when glucose is loaded into a healthy person, the blood glucose value slowly increases for 30 to 60 minutes, and then slowly falls. However, since insulin secretion is low when glucose is loaded into the diabetic patient, the blood glucose value rapidly increases for 30 to 90 minutes A phenomenon of ascending glucose spike is observed. Therefore, there is a need for a drug that exhibits a blood glucose level close to that of a healthy person by exhibiting drug efficacy early, especially during 30 to 60 minutes. It is known that as a rapid-acting insulin secretagogue, there is a remarkable effect on the improvement of postprandial blood glucose level, especially for the case of mitiglinide.

Presently, mitiglinide is commercially available as a tablet form of GLUFAST (Choong-Wae Pharm) as its calcium hydrate form. The commercially available glutathione tablets contain 5 mg or 10 mg of the microglycine calcium hydrate, and the administration thereof is within a range of 5 to 45 mg of a single dose in consideration of both effects and side effects.

Based on the above facts, metformin and fasting insulin secretagogue, which have the effect of reducing fasting glucose concentration, are combined and administered as a blood glucose drug in combination with a drug exhibiting a remarkable therapeutic effect in improvement of postprandial blood glucose level Is being tried, and as a part of such an attempt, a combination prescription of mitiglinide and metformin is being made. As a patent related to this combination therapy, for example, International Publication No. WO 2007/56387 discloses a pill and a capsule containing metformin and methylglycine.

On the other hand, in combination administration of metformin and mitiglinide, it is preferable that the mitiglinide is firstly applied for rapid regulation of blood glucose after the meal, and metformin is acting later than the mitiglinide due to the nature of the drug such as inhibition of the action mechanism and side effects Therefore, in the case of preparing a combination of metigurin and metformin for co-administration, a design considering the characteristics of the above-mentioned drugs is required. In particular, when a compound is manufactured, the amount of the mitiglinide component is 5 to 10 mg, and the amount of the mitoglinide component is smaller than that of the metformin containing 500 to 1000 mg, so that the mitiglinide must elute before the metformin Nevertheless, a small amount of metiglintide is mixed together in a large amount between metformin components, which inhibits rapid elution due to metformin and exhibits a dissolution pattern similar to metformin. Therefore, it should be taken into account that when the < RTI ID = 0.0 > mitoglynide < / RTI > is made into a single preparation and the dissolution pattern is different,

However, the invention disclosed in the above-mentioned International Publication WO 2007/56387 does not solve the above-mentioned problems, and the improvement is required.

Disclosure of the Invention The present invention has been made to solve the above-mentioned problems of the prior art, and it is an object of the present invention to provide a medicinal composition comprising metygrinide and metformin as main components of a combination preparation, Or a similar dissolution pattern and an excellent dissolution rate, and to provide a method for producing the composite preparation of metglianide and metformin.

The present invention also provides a method of controlling the release of metgylnidium and metformin as described above, whereby metformin acts after the first action of the mitiglinide, thereby controlling the postprandial and fasting blood glucose levels at least similar to the case of taking each single agent And to provide a combined preparation which can be used as an active ingredient.

According to the present invention,

A metformin layer containing metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof; And

A metiglintide layer formed on the outer surface of the metformin layer and containing a mitigliardide, a pharmaceutically acceptable salt thereof, or a hydrate thereof,

Wherein the dissolution rate of the mitiglinide component in the above-mentioned mitiglinide layer is 85% or more within 30 minutes after the administration.

In the combination preparation of the present invention, the above-mentioned mitiglinide component is characterized by a higher dissolution rate within 30 minutes than the metformin component. The dissolution rate of the metformin component is preferably 85% or more within 60 minutes.

In the combination preparation of the present invention, the metformin layer is a granulated and tableted layer further comprising a pharmaceutically acceptable carrier together with metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof,

The above-mentioned mitiglinide layer is characterized in that it is a directly tableted layer further comprising a pharmaceutically acceptable carrier together with a mitiglinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

It is preferable that the granulated and compressed metformin layer forms one layer and the directly tableted methiglinide layer forms one layer to produce a two-layer type.

In addition, in the combination preparation of the present invention, the metformin layer is contained in the form of a tablet further comprising a pharmaceutically acceptable carrier together with metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof; Wherein the microglianide layer further comprises a pharmaceutically acceptable carrier together with a microglycinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof to form a coating layer on the outer surface of the tablet form.

In addition, in the combination preparation of the present invention, the metformin layer is contained in the inner core form, further comprising a pharmaceutically acceptable carrier together with metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof; Wherein the mitoglynide layer further comprises a pharmaceutically acceptable carrier together with a mitiglinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof to form a layer on the outer surface of the inner core type.

The present invention also relates to a pharmaceutical composition comprising a first step of preparing and granulating metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, together with a pharmaceutically acceptable carrier, into granules; And a second step of directly titrating mitiglinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, together with a pharmaceutically acceptable carrier, for the preparation of a combination of mitiglinide and metformin.

In the preparation of the above-mentioned medigrinide and metformin combination agent, since the content of metformin is larger than that of the methiginide, it is preferable to granulate the metformin-containing layer first and then to directly tablet the medigrinide-containing layer However, the present invention is not limited thereto, and the tableting steps of metformin and methylglycine may be changed in the preparation of the combination preparation.

The manufacturing method is characterized in that, in the first step, the granule form forms at least one layer, and the form directly prepared by tableting in the second step forms at least one layer, and is produced in a multilayer form.

In addition, it is more preferable that the granule form in the first step forms one layer, and the directly edible form in the second step forms one layer to produce a two-layer form.

The oral compositions containing the mitiglinide and metformin of the present invention exhibit an elution pattern and an excellent dissolution rate comparable to or similar to those in the respective single preparations without interfering with each other, And it is excellent in the effect of maintaining the fasting blood glucose level at a normal value thereafter.

According to the present invention,

A metformin layer containing metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof; And

A metiglintide layer formed on the outer surface of the metformin layer and containing a mitigliardide, a pharmaceutically acceptable salt thereof, or a hydrate thereof,

Wherein the dissolution rate of the mitiglinide component in the mitiglinide layer is 85% or more within 30 minutes after the administration.

 In the present invention, the < RTI ID = 0.0 > metiglinide < / RTI > component exhibits an elution pattern equal or similar to the single formulation of metiglintin without interference by the components of metformin and the metformin component also exhibits an elution pattern equal or similar to the metformin single preparation do.

(2S) -2-benzyl-3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid] is a non-sulfone compound having the chemical structure represented by the following formula It is an insulin secretagogue.

In the present invention, the mitiglianide component is contained in the form of a mitiglinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and among them, a mitiglinide calcium hydrate can be preferably used.

Metformin is an oral antidiabetic and blood glucose drug mainly used in the treatment of non-insulindependent diabetes mellitus (NIDDM) as a treatment for biguanide type diabetes mellitus, It has a chemical structure.

In the present invention, the metformin component is included in the form of metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and among them, a salt form such as metformin hydrochloride, metformin succinate, metformin fumarate, metformin bromate, metformin p- Chlorophenoxyacetic acid salt or metformin ebonate, and the like, and preferably metformin hydrochloride can be used.

In the combination preparation of the present invention, the above-mentioned mitiglinide component is characterized by a higher dissolution rate within 30 minutes than the metformin component. The dissolution rate of the methiginide component is preferably 85% or more within 30 minutes, and the dissolution rate of the metformin component is preferably 85% or more within 60 minutes. Promoting postprandial insulin secretion in this range may be desirable.

In a combination preparation of the present invention, the weight ratio of metizinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof: metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof is from 1:10 to 200, preferably from 1: 15 to 100, and most preferably 1:20 to 70.

The combined preparation of the present invention may be prepared in any form used in this field, but it is preferably prepared from tablets.

In particular, in the combination preparation of the present invention, the metformin layer is a granulated and tableted layer further comprising a pharmaceutically acceptable carrier together with metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof,

It is preferred that the above-mentioned mitigliide layer is a directly tableted layer further comprising a pharmaceutically acceptable carrier together with a mitiglinide formed in powder form, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

In the case of forming such a layer as described above, it is advantageous to avoid interferences between drugs in the elution of the mitiglinide component and the metformin component, and to control the elution in accordance with the action mechanism and the application characteristics of each of the drugs.

Further, it is more preferable that the metformin layer granulated and compressed as described above forms one layer, and the directly tableted methiglinide layer forms one layer to be a two-layer type.

In the above, each layer is made of a composite material by a tableting method using pressure, and a pressure range of 0.5 ton to 3 ton is preferable, but 1 ton to 2.5 ton is more preferable.

Wherein the granulated and tableted metformin layer comprises metformin, a pharmaceutically acceptable salt thereof or a hydrate thereof in an amount of from 10 to 98% by weight and a pharmaceutically acceptable carrier selected from the group consisting of excipients, lubricants, disintegrating agents and binding agents Characterized in that it comprises at least one selected component.

As the above-mentioned pharmaceutically acceptable carrier, at least one component selected from the group consisting of excipients, lubricants, disintegrating agents and binding agents may be contained in an amount of 2 to 90% by weight.

Examples of the excipient include crystalline cellulose or cellulose derivatives, corn starch, cyclodextrin, precipitated calcium carbonate, polyvinyl alcohol, calcium hydrogen phosphate, sodium starch glycolate, methylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose Lactose, mannitol, etc. Examples of the lubricant include magnesium stearate, calcium stearate, light silicic anhydride, com- pitol, stearic acid, talc and the like. Examples of the disintegrant include croscarmellose sodium, glycolic acid starch sodium, crospovidone, Corn starch, alginic acid, sodium alginate, carboxymethylcellulose magnesium and aluminum silicate, sodium hydrogencarbonate, and the like. The binder may include hydroxypropylcellulose, low-substituted hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose, eudragit, wax, carbomer, and the like.

In addition, the above-mentioned direct-pressed layer, the methylgly- linide layer, comprises 0.1 to 50% by weight of mitiglinide, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable carrier, And at least one component selected from the group consisting of

As the above-mentioned pharmaceutically acceptable carrier, at least one component selected from the group consisting of excipients, lubricants, and disintegrators may be contained in an amount of 50 to 99.90% by weight.

Examples of the excipient include ruddy presses, crystalline cellulose or cellulose derivatives, corn starch, cyclodextrin, precipitated calcium carbonate, polyvinyl alcohol, calcium hydrogen phosphate, sodium starch glycolate, hydroxypropylmethylcellulose, Examples of the lubricant include magnesium stearate, calcium stearate, light silicic anhydride, com- pitol, stearic acid, talc, sodium laurate and the like, and disintegrators include croscarmellose sodium, glycol Corn starch, alginic acid, sodium alginate, carboxymethylcellulose magnesium and aluminum silicate, sodium hydrogen carbonate, and the like.

In the combination preparation of the present invention, the pharmaceutically acceptable carrier may further include those conventionally used in this field besides those exemplified above.

The present invention relates to a combination of a mitiglinide and a metformin, wherein the components of the mitiglinide component and the metformin are not interfered with each other and each elution pattern is controlled differently, Or a similar elution pattern and an excellent dissolution rate, it is possible to use the composition of the known single agent of the methiglianide and the composition of the known single agent of metformin as it is.

In the combination preparation of the present invention, the metformin layer is contained in tablet form, further comprising a pharmaceutically acceptable carrier together with metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof; The above-mentioned mitiglianide layer may further comprise a pharmaceutically acceptable carrier together with a mitiglinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof to form a coating layer on the outer surface of said tablet form. In the case of forming such a layer as described above, it is advantageous to avoid interferences between drugs in the elution of the mitiglinide component and the metformin component, and to control the elution in accordance with the action mechanism and the application characteristics of each of the drugs.

Also, the metformin layer is comprised in the inner core form, further comprising a pharmaceutically acceptable carrier together with metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof; The above-mentioned methiglianide layer may further comprise a pharmaceutically acceptable carrier together with a mitiglinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof to form a layer on the outer surface of said inner core type. In the case of forming such a layer as described above, it is advantageous to avoid interferences between drugs in the elution of the mitiglinide component and the metformin component, and to control the elution in accordance with the action mechanism and the application characteristics of each of the drugs.

The composition of the above-mentioned tablet form, coat layer, inner core form, and outer layer mentioned above can be applied without limitation as long as it is commonly used in this field.

The present invention also relates to a pharmaceutical composition comprising a first step of preparing and granulating metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, together with a pharmaceutically acceptable carrier, into granules; And a second step of directly titrating mitiglinide, a pharmaceutically acceptable salt thereof, or hydrate thereof, together with a pharmaceutically acceptable carrier, to a method for preparing a combination of mitiglinide and metformin.

In the preparation of the above-mentioned medigrinide and metformin combination agent, since the content of metformin is larger than that of the methiginide, it is preferable to granulate the metformin-containing layer first and then to directly tablet the medigrinide-containing layer However, the present invention is not limited thereto, and the tableting steps of metformin and methylglycine may be changed in the preparation of the combination preparation.

 The manufacturing method is characterized in that, in the first step, the granule form forms at least one layer, and the form directly prepared by tableting in the second step forms at least one layer, and is produced in a multilayer form.

In addition, it is preferable that the granule form in the first step forms one layer, and the directly edible form in the second step forms one layer to produce a two-layer form.

In the above, each layer is made of a composite material by a tableting method using pressure, and a pressure range of 0.5 ton to 3 ton is preferable, but 1 ton to 2.5 ton is more preferable.

The pharmaceutical composition of the present invention can be taken orally. Desirable dosages of the combination of the present compounds of the present invention and the metformin compound depend on the condition and the weight of the patient, the degree of disease, the type of drug, and the period of time, but can be appropriately selected by those skilled in the art. The preferred dosage is in the range of 5 to 22 mg / metformin and 250 to 1000 mg of metizinide in a single dose, and the administration can be carried out once a day and several times.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. However, the following examples and test examples are provided for illustrating the present invention, and the present invention is not limited thereto, and various modifications and changes may be made.

Example  1-1 to 1-4: With mitiglinide  Multi-layered tablets of metformin ( Double layer )

Carrying Table 3-4 to the granulation and tableting the metformin composition, the appointed proximity to other glycidyl arsenide composition directly to the powder prepared in accordance with Table 1-2 prepared in accordance with the bi-layer tablet in accordance with Table 5 (Examples 1-1 to 1-4).

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Rudy Press 70.0 mg Microcrystalline cellulose  70.0 mg Sodium starch glycolate  6.0 mg Magnesium stearate  5.0 mg Low substituted hydroxypropylcellulose  8.0 mg

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Rudy Press 70.0 mg Microcrystalline cellulose  70.0 mg Hydroxypropylcellulose  6.0 mg Magnesium stearate  5.0 mg Low substituted hydroxypropylcellulose  8.0 mg

Metformin composition ingredient 1 weight per unit Metformin   500.0 mg Lactose    83.3 mg Pregelatinized starch    16.7 mg Hydroxypropylmethylcellulose    72.0 mg Povidone    23.0 mg Magnesium stearate    7.5 mg

Metformin composition ingredient 1 weight per unit Metformin   500.0 mg Lactose    83.3 mg Pregelatinized starch    16.7 mg Hydroxypropylmethylcellulose    144.0 mg Povidone    23.0 mg Magnesium stearate    7.5 mg

Manufacturing prescription (Table 1) + (Table 3) Example 1-1 (Table 1) + (Table 4) Examples 1-2 (Table 2) + (Table 3) Example 1-3 (Table 2) + (Table 4) Examples 1-4

Test Example 1: The multi-layered defined dissolution test prepared in Examples 1-1 to 1-4

The tablets prepared in Examples 1-1 to 1-4 were subjected to a dissolution test in distilled water. The dissolution test method was the same as in Test Example 1 above. As a result of the test, in the tablets of Examples 1-1 to 1-4, the respective layers did not affect the dissolution rate of each other, and it was possible to control dissolution of metiglintide and metformin differently. That is, the dissolution rate of the mitiglinide was 85% or more within 30 minutes, and metformin released more than 85% after the dissolution of the mitiglinide (see FIGS. 1 and 2).

Example  2-1 to 2-4: In metformin tablets Mitiglinide  Coated Coating  Produce

The coated tablets of Examples 2-1 to 2-4 were prepared by coating the metformin tablets prepared according to Tables 8 to 9 with the mitigliide compositions prepared according to Tables 6 to 7 according to the prescription of Table 10.

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Hydroxypropylcellulose 200.0 mg PEG 5.0 mg

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Hydroxypropylmethylcellulose 200.0 mg Sodium lauryl sulfate 5.0 mg

Metformin composition ingredient 1 weight per unit Metformin   500.0 mg Lactose    83.3 mg Pregelatinized starch    16.7 mg Hydroxypropylmethylcellulose    34.0 mg Povidone    23.0 mg Magnesium stearate    7.5 mg

Metformin composition ingredient 1 weight per unit Metformin   500.0 mg Lactose    83.3 mg Pregelatinized starch    16.7 mg Hydroxypropylmethylcellulose    72.0 mg Povidone    23.0 mg Magnesium stearate    7.5 mg

Manufacturing prescription (Table 6) + (Table 8) Example 2-1 (Table 6) + (Table 9) Example 2-2 (Table 7) + (Table 8) Example 2-3 (Table 7) + (Table 9) Examples 2-4

Test Example  2: Example  2-1 to 2-4 Coating definition  Dissolution test

The tablets prepared in Examples 2-1 to 2-4 were subjected to a dissolution test in distilled water. The dissolution test method was the same as in Test Example 1 above. As a result of the test, in the coated tablets of Examples 2-1 to 2-4, the tablet portion and the coated portion did not affect the dissolution rate of each other, and it was possible to control the elution of the metiglintide and the metformin differently (FIGS. 3 and 4) 4).

Example  3-1 to 3-4: With mitiglinide  Metformin Nucleus  Produce

According to the prescription of Table 15, the metiglintide compositions prepared according to Tables 11 to 12 were used as outer layers and the metformin composition prepared according to Tables 13 to 14 was used as the inner core, .

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Rudy Press 120.0 mg Microcrystalline cellulose  12.0 mg Sodium starch glycolate  50.0 mg Magnesium stearate  93.4 mg Low substituted hydroxypropylcellulose  20.9 mg

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Rudy Press 120.0 mg Microcrystalline cellulose  12.0 mg Hydroxypropylmethylcellulose  10.0 mg Magnesium stearate  93.4 mg Low substituted hydroxypropylcellulose  20.9 mg

Metformin composition ingredient 1 weight per unit Metformin   500.0 mg Lactose    83.3 mg Pregelatinized starch    16.7 mg Hydroxypropylmethylcellulose    34.0 mg Povidone    23.0 mg Magnesium stearate    7.5 mg

Metformin composition ingredient 1 weight per unit Metformin   500.0 mg Lactose    83.3 mg Pregelatinized starch    16.7 mg Hydroxypropylmethylcellulose    68.0 mg Povidone    23.0 mg Magnesium stearate    7.5 mg

Manufacturing prescription (Table 11) + (Table 13) Example 3-1 (Table 11) + (Table 14) Example 3-2 (Table 12) + (Table 13) Example 3-3 (Table 12) + (Table 14) Example 3-4

Test Example  3: Example  3-1 to 3-4 Nuclear  Dissolution test

The tablets prepared in Examples 3-1 to 3-4 were subjected to a dissolution test in distilled water. The dissolution test method was the same as in Test Example 1 above. As a result of the test, the inner layer of the outer layer made of the mediglnide in the core of Examples 3-1 to 3-4 and the inner core made of metformin did not affect the dissolution rate of each other, and the elution of the mitiglinide and metformin was controlled differently (See Figs. 5 and 6).

Example  5-1 to 5-4: The dissolution profile of metformin is controlled as in the case of single agent Mitiglinide  Controlled dissolution rate With mitiglinide  Metformin Multilayer tablet  Produce

The metformin compositions prepared according to Table 20 below were granulated and tableted and the metiglintide compositions prepared according to Tables 16-19 were directly tabletted with the powders to compress and wet the metigurinide layer and the metformin layer according to Table 21, To prepare two-layer formulations (Examples 4-1 to 4-4).

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Rudy Press 70.0 mg Microcrystalline cellulose  70.0 mg Sodium starch glycolate  6.0 mg Magnesium stearate  5.0 mg Low substituted hydroxypropylcellulose  8.0 mg

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Rudy Press 70.0 mg Microcrystalline cellulose  70.0 mg Hydroxypropylmethylcellulose  10.0 mg Magnesium stearate  5.0 mg Low substituted hydroxypropylcellulose  8.0 mg

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Rudy Press 70.0 mg Microcrystalline cellulose  70.0 mg Hydroxypropylmethylcellulose  20.0 mg Magnesium stearate  5.0 mg Low substituted hydroxypropylcellulose  8.0 mg

Methylglynide composition ingredient 1 weight per unit Mitiglinide 10.0 mg Rudy Press 70.0 mg Microcrystalline cellulose  70.0 mg Hydroxypropylmethylcellulose  30.0 mg Magnesium stearate  5.0 mg Low substituted hydroxypropylcellulose  8.0 mg

Metformin composition ingredient 1 weight per unit Metformin   500.0 mg Lactose    83.3 mg Pregelatinized starch    16.7 mg Hydroxypropylmethylcellulose    72.0 mg Povidone    23.0 mg Magnesium stearate    7.5 mg

Manufacturing prescription (Table 16) + (Table 20) Example 4-1 (Table 17) + (Table 20) Example 4-2 (Table 18) + (Table 20) Example 4-3 (Table 19) + (Table 20) Example 4-4

Test Example  4: Example  The multi-layered positive dissolution test prepared in 4-1 to 4-4

The tablets prepared in Examples 4-1 to 4-4 were subjected to a dissolution test in distilled water. The dissolution test method was the same as in Test Example 1 above. The test results of Examples 4-1 to 4-4 are shown in Tables 22 to 25, respectively (see Figs. 7 and 8).

Elution time 0 5 10 15 30 45 60 90 Mitiglinide 0 78.12 92.12 99.15 99.42 99.44 99.41 99.45 Metformin 0 21.45 39.36 62.72 84.12 97.35 100.54 101.2

Elution time 0 5 10 15 30 45 60 90 Mitiglinide 0 32.67 54.37 69.18 85.43 94.71 100.67 100.58 Metformin 0 18.42 36.41 60.22 83.47 98.73 99.44 100.87

Elution time 0 5 10 15 30 45 60 90 Mitiglinide 0 13.74 29.98 48.36 75.43 90.35 98.57 102.12 Metformin 0 16.88 36.84 59.39 85.91 97.35 100.54 101.2

Elution time 0 5 10 15 30 45 60 90 Mitiglinide 0 6.34 23.75 36.46 55.42 73.52 86.08 95.34 Metformin 0 21.45 34.36 62.72 84.12 97.35 100.54 101.2

Test Example  5: Example  4-1 to 4-4 Multi-layer definition Postprandial blood glucose Degradability  compare

The multi-layered tablets of Examples 4-1, 4-2, 4-3, and 4-4 were administered to a rat with diabetes to evaluate postprandial glucose lowering ability. As a result, in Example 4-1 and 4-2 multi-layer tablets in which the dissolution rate of the microgranide was more than 85% for 30 minutes, the effect of lowering the postprandial blood glucose level to normal was confirmed. In Examples 4-3, It was confirmed that the 4-4 multi-layered tablets did not lower the postprandial blood glucose level to normal.

Test Example  6: Mitiglinide Single agent  Comparison of dissolution rate according to type

(One) Mitiglinide  Preparation of a single preparation

Depending on the form of the single formulation of mitiglinide (Table 26), wet granule prescription -2 (Table 28), wet granule prescription -3 (Table 29), and wet granule prescription -4 Table 30). ≪ tb >< TABLE >

Prescribing of mitiglinide directly ingredient 1 weight per unit Mitiglinide 10.0 mg Lactose (Direct Tablets) Lactose 70.0 mg Microcrystalline cellulose  70.0 mg Sodium starch glycolate  6.0 mg Magnesium stearate  5.0 mg Low substituted hydroxypropylcellulose  8.0 mg

- Preparation method: Miliginide, lactose for direct (direct tableting), sodium starch glycolate, microcrystalline cellulose and low-substituted hydroxypropylcellulose were mixed, and the mixture was stirred with magnesium stearate and tableted.

Mitiglinide wet granule prescription -1 ingredient 1 weight per unit Mitiglinide 10.0 mg Lactose 70.0 mg Microcrystalline cellulose  70.0 mg Sodium starch glycolate  6.0 mg Magnesium stearate  5.0 mg Low substituted hydroxypropylcellulose  8.0 mg

- Preparation method: Prepared by granulating a solution obtained by dissolving methylglynide, lactose, sodium starch glycolate, microcrystalline cellulose and low-substituted hydroxypropylcellulose in distilled water as a binder, filtering with magnesium stearate and titrating.

Mitiglinide Wet Granule Prescription -2 ingredient 1 weight per unit Mitiglinide 10.0 mg Lactose 70.0 mg Microcrystalline cellulose  70.0 mg Sodium starch glycolate  6.0 mg Magnesium stearate  5.0 mg Hydroxypropylcellulose  8.0 mg

- Preparation method: Prepared by granulating a solution of mitiglinide, lactose, starch glycolic acid starch, microcrystalline cellulose and hydroxypropylcellulose in distilled water as a binder, filtering with magnesium stearate and titrating.

Mitiglinide wet granule prescription -3 ingredient 1 weight per unit Mitiglinide 10.0 mg Lactose 70.0 mg Microcrystalline cellulose  70.0 mg Sodium starch glycolate  6.0 mg Magnesium stearate  5.0 mg Pregelatinized starch  8.0 mg

- Preparation method: Prepared by granulating a solution of mitiglinide, lactose, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch in distilled water as a binding agent, filtering with magnesium stearate and titrating.

Mitiglinide Wet Granule Prescription -4 ingredient 1 weight per unit Mitiglinide 10.0 mg Lactose 70.0 mg Microcrystalline cellulose  70.0 mg Sodium starch glycolate  6.0 mg Magnesium stearate  5.0 mg Povidone  8.0 mg

- Preparation Method: Meatiglinide, lactose, sodium starch glycolate, and microcrystalline cellulose were prepared by granulating a solution of povidone in distilled water as a binding agent, filtering with magnesium stearate and titrating.

(2) Elution test

The dissolution test of the above-prepared < RTI ID = 0.0 > mitiglinide < / RTI > The dissolution test method was the same as in Test Example 1 above. The dissolution test results for the above-prepared mitiglinide preparations are shown in Table 31 (direct tableting prescription) and Table 32 (wet granule prescription 1 to 4) (see FIG. 9).

time 0 2 5 10 15 Dissolution rate (%) 0 43.2 78.12 92.12 99.15

time 0 2 5 10 15 Granule-1 0 27.4 62.41 86.45 94.34 Granule-2 0 8.03 48.12 75.12 89.15 Granule-3 0 30.75 67.78 87.23 94.21 Granule-4 0 5.48 34.24 62.12 79.98

As described above, it was confirmed that the initial dissolution rate of the microgranide was slightly lowered as a result of granulation using the wet granule binder.

Comparative test example  One: Mitiglinide Timetable  And metformin single positive dissolution test

The currently commercially available titles of metiglidin and those of metformin were subjected to a dissolution test in the same manner as in Test Example 1, respectively.

(Gluplast, Choongwae Pharma) and metformin-containing preparation (Glucophage, Merck Co., Ltd.) were identified.

 As a result of the test, currently commercially available methiginide and metformin single-definition elution are different from each other, the dissolution of the single definition of the methiginide is very fast, and the metformin single-definition elution has a somewhat later elution pattern than that of the single-definition elution of the metiglinide (See Fig. 10).

Comparative Example  1-1 to 1-4: With mitiglinide  Metformin together Granulated  Manufacture of tablets

Lactose, corn starch and crystalline cellulose were granulated with povidone K30 according to the prescriptions of Tables 33 to 36 below, and the low-substituted hydroxypropylcellulose, magnesium stearate, talc, and light anhydrous silicic acid were mixed To prepare tablets of Comparative Examples 1-1 to 1-4.

Comparative Example 1-1 ingredient 1 weight per unit Mitiglinide  10.0 mg Metformin  500.0 mg Lactose  143.0 mg Corn starch  20.0 mg Crystalline cellulose   55.0 mg Low substituted hydroxy cellulose   12.0 mg Povidone K30   12.0 mg Magnesium stearate  16.0 mg Talc  16.0 mg Light anhydrous silicic acid  16.0 mg

* Povidone K30 1.5% when used as a main ingredient granule

Comparative Example 1-2 ingredient 1 weight per unit Mitiglinide  10.0 mg Metformin  500.0 mg Lactose  131.0 mg Corn starch  20.0 mg Crystalline cellulose   55.0 mg Low substituted hydroxypropylcellulose   12.0 mg Povidone K30   24.0 mg Magnesium stearate  16.0 mg Talc  16.0 mg Light anhydrous silicic acid  16.0 mg

* Povidone K30 3.0% when using the main ingredient granules

Comparative Example 1-3 ingredient 1 weight per unit Mitiglinide  10.0 mg Metformin  500.0 mg Lactose  107.0 mg Corn starch  20.0 mg Crystalline cellulose   55.0 mg Low substituted hydroxy cellulose   12.0 mg Povidone K30   48.0 mg Magnesium stearate  16.0 mg Talc  16.0 mg Light anhydrous silicic acid  16.0 mg

* Povidone K30 6.0% when using the main ingredient granules

Comparative Example 1-4 ingredient 1 weight per unit Mitiglinide  10.0 mg Metformin  500.0 mg Lactose  83.0 mg Corn starch  20.0 mg Crystalline cellulose   55.0 mg Low substituted hydroxy cellulose   12.0 mg Povidone K30   72.0 mg Magnesium stearate  16.0 mg Talc  16.0 mg Light anhydrous silicic acid  16.0 mg

* When using the main ingredient granule, povidone K30 9.0%

Comparative test example  2: Comparative Example  Elution test of tablets prepared in 1 to 4

The tablets prepared in Comparative Examples 1-1 to 1-4 were subjected to a dissolution test in distilled water. The dissolution test method was the same as in Test Example 1 above. Test results In Comparative Examples 1-1 to 1-4, the dissolution profiles of metizinide and metformin were similar in the case of the preparation in which both the metizinide and metformin were granulated, and the dissolution profiles of the two components could not be controlled differently (Fig. 11 And Fig. 12).

Comparative Example  2-1 to 2-3: With mitiglinide  Metformin is taken separately Granulation  Together Tender  Manufacture of tablets

Metformin and hydroxypropylmethylcellulose were granulated with a fluidized bed granulator to prepare metformin granules according to the prescriptions of Tables 37 to 39, and granules of metigulinide, lactose, corn starch and crystalline cellulose were granulated with distilled water, Cellulose, ruddy press, croscarmellose sodium, glycolic acid starch sodium, magnesium stearate, and talc were mixed to prepare Comparative Examples 2-1 to 2-3 Tablets were prepared.

Comparative Example 2-1 ingredient 1 weight per unit Metformin  250.0 mg Hydroxypropylmethylcellulose  125.0 mg Mitiglinide  10.0 mg Lactose  50.0 mg Corn starch  10.0 mg Crystalline cellulose   15.0 mg Low substituted hydroxy cellulose   50.0 mg Rudy Press  250.0 mg Croscarmellose sodium   70.0 mg Magnesium stearate  10.0 mg Talc   10.0 mg

* 50% refined tablet of hydroxypropylmethylcellulose during metformin granulation

Comparative Example 2-2 ingredient 1 weight per unit Metformin  250.0 mg Hydroxypropylmethylcellulose  250.0 mg Mitiglinide  10.0 mg Lactose  50.0 mg Corn starch  10.0 mg Crystalline cellulose   15.0 mg Low substituted hydroxy cellulose   50.0 mg Rudy Press  250.0 mg Croscarmellose sodium   70.0 mg Magnesium stearate  10.0 mg Talc   10.0 mg

* 100% refined tablet with hydroxypropyl methylcellulose at the time of metformin granulation

Comparative Example 2-3 ingredient 1 weight per unit Metformin  250.0 mg Hydroxypropylmethylcellulose  500.0 mg Mitiglinide  10.0 mg Lactose  50.0 mg Corn starch  10.0 mg Crystalline cellulose   15.0 mg Low substituted hydroxy cellulose   50.0 mg Rudy Press  250.0 mg Sodium starch glycolate   70.0 mg Magnesium stearate  10.0 mg Talc   10.0 mg

* Metformin granules 200% tablets of hydroxypropyl methylcellulose

Comparative test example  3: Comparative Example  The elution test of tablets prepared in 2-1 to 2-3

The tablets prepared in Comparative Examples 2-1 to 2-3 were subjected to a dissolution test in distilled water. As the dissolution test method, it was tested according to the paddle method No. 2 in the Korean Pharmacopoeia dissolution test method. As a result of the test, it was difficult to control the dissolution of metizinide and metformin differently in the tablets of Comparative Examples 2-1 to 2-3 (see Figs. 13 and 14).

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing dissolution test results of mitiglinide in the multi-layered tablet preparation of Examples 1-1 to 1-4 of the present invention. FIG.

Fig. 2 is a graph showing the dissolution test results of metformin among the multi-layered tablet preparations of Examples 1-1 to 1-4 of the present invention.

FIG. 3 is a graph showing dissolution test results of mitiglinide in the coated combination complex preparations of Examples 2-1 to 2-4 of the present invention.

FIG. 4 is a graph showing the dissolution test results of metformin among the coated combination preparations of Examples 2-1 to 2-4 of the present invention.

FIG. 5 is a graph showing dissolution test results of mitiglinide in the combination preparations of Examples 3-1 to 3-4 of the present invention.

FIG. 6 is a graph showing the dissolution test results of metformin among the pharmaceutical preparations of Examples 3-1 to 3-4 of the present invention.

Fig. 7 is a graph showing dissolution test results of mitiglinide in the multi-layered tablet preparation of Examples 4-1 to 4-4 of the present invention.

8 is a graph showing the dissolution test results of metformin among the multi-layered tablet preparations of Examples 4-1 to 4-4 of the present invention.

9 is a graph showing dissolution test results of a single preparation of mtigranide of Examples 5-1 to 5-5 of the present invention. [Example 5-1: Direct tableting prescription, Example 5-2: Wet granule prescription -1, Example 5-3: Wet granule prescription -2, Example 5-4: Wet granule prescription -3, Example 5-5: Wet granule prescription -4.

FIG. 10 is a graph showing the results of dissolution test on currently commercially available titles of metiglidin and metformin.

Fig. 11 is a graph showing the results of a comparison between the tablets of Comparative Example 1-1 to 1-4 of the present invention in the form of a tablet obtained by granulating both the mitiglinide and metformin The graph shows the dissolution test results of the mitiglinide in the combination preparation.

Fig. 12 is a graph showing the results of a comparison between the tablets of Comparative Examples 1-1 to 1-4 of the present invention in the form of granules of metiglintide and metformin The graph shows the dissolution test results of metformin among the combined preparations.

Fig. 13 shows the results obtained by granulating separately the Comparative Examples 2-1 to 2-3 of the present invention, The graph shows the dissolution test results of the mitiglinide in the combination preparation.

Fig. 14 is a graph showing the dissolution test results of metformin among the combined preparations which were separately granulated and tableted together as Comparative Examples 2-1 to 2-3 of the present invention.

Claims (15)

delete delete delete delete delete delete delete delete delete delete delete delete delete Metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, as a granule together with a pharmaceutically acceptable carrier; And a second step of directly tabletting the mitiglinide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, together with a pharmaceutically acceptable carrier, on the tableting layer formed in the first step, and a second step of mixing the metiglianide and metformin complex ≪ / RTI > 15. The method of claim 14, wherein in the first step, the granule form forms at least one layer, and the form directly prepared by tableting in the second step forms at least one layer, And a method for producing the metformin combination preparation.

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