KR20160121190A - Pharmaceutical composition comprising anagliptin or a pharmaceutically acceptable salt thereof, and metformin or a pharmaceutically acceptable salt thereof and preparation method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating type 2 diabetes and a preparation method of the same, wherein the pharmaceutical composition comprises: an immediate release-type first layer containing anagliptin or a pharmaceutically acceptable salt thereof as an active ingredient; and a controlled release-type second layer containing metformin or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition improves treatment effects and reduces side effects, compared with when either of the components is taken separately, while maintaining the drug elution rate equally desirable as that of an agent containing either of the components alone. Also, the pharmaceutical composition, by using a highly viscous diluting agent and thereby reducing the content of the diluting agent, can reduce the size of tablets and capsules, make patients swallow with ease, improve medication compliance, and therefore can be beneficially used as an effective agent for preventing or treating type 2 diabetes.

Description

FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition comprising anagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof and a method for preparing the same. THEREOF AND PREPARATION METHOD THEREOF}

The present invention relates to a controlled release formulation comprising an immediate release first layer comprising anagliptin or a pharmaceutically acceptable salt thereof as an active ingredient and metformin or a pharmaceutically acceptable salt thereof as an active ingredient Type second layer, and a method for producing the same.

Diabetes is largely divided into insulin-dependent type 1 diabetes and non-insulin-dependent type 2 diabetes. Type 2 diabetes mellitus occurs mainly after the age of 40, and it accounts for most of the diabetic patients in Korea. Type 2 diabetes is called adult type diabetes, and the cause of the disease is not clear yet. However, it is known that genetic factors and environmental factors are involved together. In type 2 diabetes patients, more than 90% Occupies.

Type 2 diabetes is a chronic and progressive disease resulting from the complex pathophysiology of insulin resistance and insulin secretory dysfunction. Therapy usually begins with diet and exercise and leads to a monotherapy of oral antidiabetic drugs. Conventional monotherapy may initially regulate blood glucose in some patients, but it can not control blood glucose adequately during long-term treatment and requires combination therapy within several years after diagnosis.

However, the combination regimen of two or more oral antidiabetic drugs causes discomfort in many patients, resulting in poor compliance with the patient's medication compliance, which results in poor treatment.

Anagglitin is an inhibitor of dipeptidyl peptidase-4 (DDP-4). It activates incretin to achieve a stable blood glucose lowering effect, overcomes the disadvantages of existing drugs such as hypoglycemia and weight gain, Is lower than that of the existing sulfonylurea family.

Metformin is a drug for the treatment of non-insulin dependent diabetes and has a chemically biguanide structure. Metformin is useful for the prevention and treatment of diabetes because it regulates sugar production in the gastrointestinal tract and increases glucose utilization in the muscles. Metformin also has the advantage of not increasing body weight because it also acts to improve lipid metabolism, and it can be advantageously used for preventing and treating diabetic complications (for example, cardiovascular diseases).

Korean Patent Laid-Open Publication No. 2014-0045271 discloses a bilayer pharmaceutical formulation consisting of a first layer comprising metformin and a second layer comprising gemigliptin, wherein said first layer exhibits a sustained release pattern And a sustained-release matrix is prepared by using pregelatinized starch as an excipient in order to exhibit such a sustained-release pattern, and this sustained-release matrix component is disclosed as a double-layer preparation containing preferably 40-80 wt% of metformin hydrochloride .

Metformin, however, is a high-content preparation containing 500 mg or more. As shown in Korean Patent Laid-Open Publication No. 2014-0045271, metformin is a sustained-release formulation containing 40-80% by weight of metformin hydrochloride When the matrix is constituted, the content of the excipient becomes too high and the size of the tablet becomes large, so that convenience of the patient and adherence to the medicament are lowered, thereby failing to achieve the merits of the combined preparation.

Accordingly, the inventors of the present invention have devised a pharmaceutical composition comprising anagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, which has solved the above-mentioned problems, and a method for producing the same. The combination preparation of the present invention is a pharmaceutical composition composed of a first layer comprising an anagliptin component, which is a DDP-4 inhibitor, and a second layer comprising a metformin component, and has a dissolution rate equal to that of a preparation containing each single component However, by using excipients with high viscosity to reduce the amount of excipients and to reduce the size of tablets, the convenience of patients and their compliance with medication were improved.

Korean Patent Publication No. 2014-0045271

It is therefore an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of type 2 diabetes comprising a first layer comprising an immediate release type comprising an anagliptin component and a controlled release second layer comprising a metformin component, .

In order to solve the above-mentioned problems, the present invention relates to an immediate-release first layer comprising anagliptin or a pharmaceutically acceptable salt thereof as an active ingredient, and metformin or a pharmaceutically acceptable salt thereof, Wherein the controlled release second layer comprises hydroxypropylmethylcellulose having a viscosity of from 4000 mPas to 200000 mPas, wherein the controlled release second layer comprises hydroxypropyl methylcellulose having a viscosity of from 4000 mPas to 200000 mPas. ≪ / RTI >

In one embodiment of the present invention, it is preferred that the immediate release first layer and the controlled release second layer constitute a double compression tablet, and the double compression tablet is more preferably a two-layer tablet, but is not limited thereto.

In another embodiment of the present invention, each of the immediate release first layer or the controlled release second layer preferably further comprises a pharmaceutically acceptable additive, but is not limited thereto.

In still another embodiment of the present invention, the immediate release first layer preferably comprises at least one selected from the group consisting of a binder, an excipient, a disintegrant and a glidant, and the immediate release first layer comprises It is more preferable to include at least one selected from the group consisting of povidone as the binder, microcrystalline cellulose as the excipient, crospovidone as the disintegrant and sodium stearyl fumarate as the lubricant, but not limited thereto.

In one embodiment of the present invention, the controlled-release second layer preferably contains not more than 15% by weight of a pharmaceutically acceptable additive based on the second layer, but is not limited thereto.

In the pharmaceutical composition of the present invention, it is preferable that the controlled release second layer includes at least one selected from the group consisting of a binder and a glidant, and the controlled release second layer preferably comprises povidone, More preferably at least one selected from the group consisting of magnesium stearate, but is not limited thereto.

According to the present invention, the amount of hydroxypropylmethylcellulose contained in the controlled release second layer may vary within a given range to achieve the desired release profile, depending on its viscosity.

In one embodiment of the present invention, when the viscosity of hydroxypropylmethylcellulose is 200000 mPas, the controlled-release second layer may contain 10 to 70 mg of metformin hydrochloride per 1000 mg of metformin hydrochloride, preferably 30 mg of metformin hydrochloride Do.

For example, the hydroxypropylmethylcellulose is contained in the controlled release second layer in an amount of 1 wt% to 5 wt%, but is not limited thereto.

In one embodiment of the present invention, the pharmaceutical composition preferably has an outer film coating, wherein the coating base of the outer film coating is selected from the group consisting of hydroxypropylmethylcellulose, yellow iron oxide, titanium oxide, polyethylene glycol 400, talc, Iron oxide and black iron oxide, but it is not limited thereto.

In another embodiment of the present invention, the first layer of anagliptin or a pharmaceutically acceptable salt thereof is contained in an amount of 25 to 400 mg, more preferably 50 to 200 mg, It is not limited.

In another embodiment of the present invention, the metformin or the pharmaceutically acceptable salt thereof of the controlled release second layer is preferably contained in an amount of 125 to 4000 mg, more preferably 250 to 2000 mg Most preferably 500 to 1000 mg, but is not limited thereto.

The present invention also relates to a pharmaceutical composition comprising: (a) preparing a mixture constituting an immediate release first layer comprising anagliptin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; And (b) preparing a mixture constituting a controlled-release second layer comprising metformin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the medicament for preventing or treating type 2 diabetes is < RTI ID = 0.0 > Wherein the mixture constituting the controlled release second layer prepared in the step (b) contains not more than 35% of particles having a particle size of not more than 150 mu m and has a humidity (LOD) of 1.0 to 3.0% Or a pharmaceutically acceptable salt thereof. The present invention also provides a method of producing a pharmaceutical composition for the prevention or treatment of type 2 diabetes.

In an embodiment of the present invention, the mixture may contain not more than 30% of particles having a particle size of not more than 135 탆, but the present invention is not limited thereto and the LOD may preferably be 1.0 to 2.0% But is not limited thereto.

In another embodiment of the present invention, the step (b) may further include (c) coating the outer layer with a pharmaceutical composition as a coating base, wherein the coating base of the outer layer coating is selected from the group consisting of hydroxypropyl But is not limited to, at least one selected from the group consisting of methyl cellulose, yellow iron oxide, titanium oxide, polyethylene glycol 400, talc, red iron oxide and black iron oxide.

In yet another embodiment of the present invention, the pharmaceutically acceptable additive of step (a) preferably comprises at least one member selected from the group consisting of a binder, an excipient, a disintegrant and a glidant, Povidone, microcrystalline cellulose as the excipient, crospovidone as the disintegrant, and sodium stearyl fumarate as the lubricant, but is not limited thereto.

In another embodiment of the present invention, the pharmaceutically acceptable additive in step (b) preferably includes at least one selected from the group consisting of a binder, an excipient and a glidant, and the povidone, the excipient More preferably at least one selected from the group consisting of hydroxypropyl methylcellulose and magnesium stearate as the lubricant, but not limited thereto.

In another embodiment of the present invention, the hydroxypropyl methylcellulose preferably has a viscosity of 4000 mPas to 200000 mPas, and it is preferable that the hydroxypropylmethyl cellulose is contained in the controlled release type second layer in an amount of 1 to 5% by weight But is not limited thereto.

In another embodiment of the present invention, the immediate release first layer of anagliptin or a pharmaceutically acceptable salt thereof is included preferably in 25 to 400 mg, but is not limited thereto.

In another embodiment of the present invention, metformin or pharmaceutically acceptable salt thereof of the controlled-release second layer is preferably included in the range of 125 to 4000 mg, but is not limited thereto.

An immediate release first layer comprising the anagliptin of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and a controlled release second layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient The present invention provides a pharmaceutical composition for the prevention or treatment of type 2 diabetes, which improves the therapeutic effect and alleviates adverse effects and reduces the content of the excipient by using a high viscosity excipient while ensuring a dissolution rate equivalent to that of the preparation containing each single component By reducing the size of the tablets, the convenience of taking the patients and the compliance with the medicines were improved.

FIG. 1 is a schematic diagram showing the manner in which a bilayer tablet containing anagliptin and metformin hydrochloride is eluted in water within 5 to 30 minutes.
2 is a graph showing dissolution profiles at pH 1.2 of Example 3 of the present invention and Comparative Example 1. Fig.
3 is a graph showing dissolution profiles at pH 4.0 of Example 3 of the present invention and Comparative Example 1. Fig.
4 is a graph showing dissolution profiles at pH 6.8 of Example 3 and Comparative Example 1 of the present invention.
5 is a graph showing dissolution profiles in water of Example 3 of the present invention and Comparative Example 1. Fig.
6 is a graph showing dissolution profiles at pH 1.2 of Example 3 and Comparative Example 2 of the present invention.
7 is a graph showing dissolution profiles at pH 4.0 of Example 3 and Comparative Example 2 of the present invention.
8 is a graph showing dissolution profiles at pH 6.8 of Example 3 and Comparative Example 2 of the present invention.
9 is a graph showing dissolution profiles in water of Example 3 and Comparative Example 2 of the present invention.

The present invention includes an immediate release first layer comprising anagliptin or a pharmaceutically acceptable salt thereof as an active ingredient and a controlled release second layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient The present invention provides a pharmaceutical composition for the prevention or treatment of type 2 diabetes mellitus, which achieves an elution equivalent to that of each single preparation.

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

The present invention relates to a controlled release formulation comprising an immediate release first layer comprising anagliptin or a pharmaceutically acceptable salt thereof as an active ingredient and metformin or a pharmaceutically acceptable salt thereof as an active ingredient Wherein the controlled release second layer comprises hydroxypropylmethylcellulose having a viscosity of from 4000 mPas to 200000 mPas. The present invention also relates to a pharmaceutical composition for the prevention or treatment of type 2 diabetes.

The term "type 2 diabetes" is defined as a condition in which the subject's fasting blood glucose or serum glucose concentration exceeds 125 mg / dl (6.94 mmol / l). Measurement of blood glucose levels is a standard process for routine medical analysis. When performing the titration test, the blood sugar level of diabetes will exceed 200 mg (11.1 mmol / l) per 1 ㎗ of plasma 2 hours after ingesting 75 g of glucose on an empty stomach.

In the glucose tolerance test, 75 g / d is orally administered to the testee 10 to 12 hours after the fasting, and the glucose level is recorded immediately before the ingestion of the saccharide and 1 hour and 2 hours after ingestion of the saccharide. In a healthy subject, the blood sugar level before the ingestion of glucose was 60 to 110 mg per 1 ㎗ of plasma, less than 200 mg per 1 ㎗ after 1 hour of ingestion of sugar, and 140 mg per 1 ㎗ after 2 hours to be. When the value after 2 hours is 140 to 200 mg, this is regarded as abnormal glucose tolerance.

"Pharmaceutically acceptable salts" of the present invention are all possible salts that can be readily used by those skilled in the art.

Specifically, the pharmaceutically acceptable salts of anagliptin include acetic acid salts, adipic acid salts, L-ascorbic acid salts, L-aspartic acid (L- aspartic acid, capric acid, decanoic acid, carbonic acid, citric acid, fumaric acid, galactaric acid, mucic acid, D D-glucoheptonic acid salt, D-gluconic acid salt, D-glucuronic acid salt, glutamic acid salt, glutaric acid salt, ) Salts, glycerophosphoric acid salts, glycolic acid salts, hippuric acid salts, hydrochloric acid salts, DL-lactic acid salts, lauric acid ( lauric acid, maleic acid, (-) - L-malic acid, palmitic acid, phosphoric acid, sebacic acid, sebacic acid salt, stearic acid salt, succinic acid salt, (+) - L-tartaric acid salt, thiocyanic acid salt, alginic acid, benzenesulfonic acid salt, benzoic acid salt, benzoic acid salts, (+) - camphoric acid salts, caprylic acid, octanoic acid salts, cyclamic acid salts, dodecylsulfuric acid salts, Ethane-1,2-disulfonic acid salt, 2-hydroxy-ethanesulfonic acid salt, ethanesulfonoic acid salt, gentisic acid salt, a gentisic acid salt, a 2-oxo-glutaric acid salt, an isobutyric acid salt, a lactobionic acid salt, a malonic acid salt, Methanesulfonic acid salt, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid salt, 1-hydroxy-2- 1-hydroxy-2-naphthoic acid salt, nicotinic acid salt, oleic acid salt, L-pyroglutamic acid, (-) - L-pyroglutamic acid, (-) - L-pyroglutamic acid, ) Salt, p-toluenesulfonic acid salt, but is not limited thereto.

Pharmaceutically acceptable salts of metformin include, but are not limited to, acetate, adipate, L-ascorbate, L-aspartate, caprate, carbonate, citrate, fumarate, myristate, D- Glucuronic acid salt, D-glucuronic acid salt, glutamic acid salt, glutaric acid salt, glycerophosphate, glycolic acid salt, hippurate salt, hydrochloride salt, DL-lactate salt, maleate salt, (+) - L-tartaric acid salt, thiocyanic acid salt, alginic acid, benzenesulfonic acid salt, benzoic acid salt, (+) - camphoric acid salt, caprylic acid salt, cyclic acid salt, cyclic acid salt, But are not limited to, salts such as hydrochloric acid, hydrobromic acid, hydrobromic acid, hydrobromic acid, tartaric acid, tartaric acid, tartaric acid, Acid salts, methanesulfonates, naphthalene-1,5-disulfonates, naphthalene-2-sulfonates, 1-hydroxy- (-) - L-pyroglutamic acid salt, p-toluenesulfonic acid salt, but is not limited thereto, and is preferably a hydrochloride salt.

The term "pharmaceutical composition" as used herein refers to a mixture of compositions of the present invention and other chemical components such as diluents or carriers. The pharmaceutical composition may be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term " immediate release type "as used in the present invention means the" general release "of Korean Pharmacopoeia, and the general release preparation is a preparation which does not control the release property of the active ingredient separately from the preparation. It means to show the behavior.

The term " controlled release type "used in the present invention means the same as the" release control "of Korean Pharmacopoeia.

More specifically, in the case of the composition of the present invention, the anagliptin component contained in the "immediate release type" first layer upon oral administration is immediately released, the dissolution of the drug is completed within 30 minutes, and the "controlled release" The metformin component contained in the layer means that the release is sufficiently delayed in the stomach so that the elution is completed within a total of 2 hours after oral administration.

The pharmaceutical compositions of the present invention may be in the form of tablets, capsules, powders, dropping pills, pulvis, boluses, tinctures or poultices. Preferred tablets may be conventional tablets, coated tablets, dispersible tablets, foamable tablets, and the like, and may be multiple compressed tablets, such as double capsules, tablet presses, multi-layer tablets, and the like. Preferred capsules are conventional capsules, enteric coated capsules, and the like.

In one example, it is preferred that the immediate release first layer and the controlled release second layer constitute a double compression tablet, and the double compression tablet is more preferably a two-layer tablet.

The "double compression tablet" is a type of multiple compression tablets, and multiple compression tablets are prepared by compressing the packing two or more times. As a result, multi-layer tablets may be produced. Inside tablets may be nucleated, Or may be a press-formed tablet.

Specifically, the two-layer tablet of the present invention was prepared for the purpose of allowing stepwise release of drug by allowing anagliptin component and metformin component, which are different components, to be contained in each layer.

In one example, the immediate release first layer or the controlled release second layer may each further comprise a pharmaceutically acceptable additive.

For example, the controlled release second layer preferably comprises no more than 15% by weight, based on the second layer, of a pharmaceutically acceptable additive, but is not limited thereto.

The term "pharmaceutically acceptable" as used herein is defined as a carrier or diluent that does not impair the biological activity and properties of the composition.

The term "additive " as used in the present invention means an excipient, a binder, a disintegrant, a lubricant, a colorant or a fragrance, but is not limited thereto.

The excipients refer to additives which impart a suitable volume to the prescription composition to make tablets of the desired size.

Examples of the excipient include microcrystalline cellulose, lactose, starch, white sugar, mannitol, sorbitol, calcium carbonate, sucrose, lactose or gelatin. Lt; / RTI >

The binders refer to additives that increase the inter-granular tackiness of the formulated powders, facilitate granulation, and maintain the physical form of the final molding.

Examples of the binder include povidone, magnesium aluminum silicate. But are not limited to, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, and low-substituted hydroxypropylcellulose. have.

The disintegrants refer to additives which, when administered, facilitate disintegration of the tablet into small particles so that the drug can be used well.

Examples of the disintegrant include, but are not limited to, crospovidone, agar, starch, alginic acid or its sodium salt, anhydrous calcium hydrogen phosphate, and the like, and may be substituted with a pharmaceutically acceptable disintegrant.

The lubricants allow the tablet granules to flow well into the die of the tablet machine, prevent the punch and die from abrasion, and prevent the filler material from sticking to the punch and die. It also means an additive giving gloss to the surface of tablets.

Examples of the lubricant include sodium stearyl fumarate, silica, talc, stearic acid or a magnesium salt or calcium salt thereof, polyethylene glycol, magnesium aluminate metasilicate, etc., but not limited thereto, and may be substituted with a pharmaceutically acceptable lubricant .

In addition, generally known boiling salts, absorbents, coloring agents, flavoring agents, sweeteners and the like may be used together according to circumstances.

In one example, the immediate release first layer may comprise at least one selected from the group consisting of binders, excipients, disintegrants, and glidants, preferably the immediate release first layer is selected from the group consisting of povidone, Microcrystalline cellulose as the disintegrant, crospovidone as the disintegrant, and sodium stearyl fumarate as the lubricant.

For example, the controlled release second layer may comprise at least one selected from the group consisting of a binder and a glidant, and preferably the controlled release second layer comprises povidone as the binder and magnesium stearate as the glidant And at least one selected from the group consisting of.

For example, the hydroxypropylmethylcellulose may be included in the controlled release second layer in an amount of 1 to 5 wt%.

The pharmaceutical composition provided in the present invention may have an outer film coating, and the coating base of the outer film coating may be composed of hydroxypropylmethylcellulose, yellow iron oxide, titanium oxide, polyethylene glycol 400, talc, red iron oxide and black iron oxide And may include at least one selected from the group consisting of those listed above.

For the outer film coating, conventional coating agents can be used. Specifically, Opadry (TM), hydroxypropyl methylcellulose, and Eudragit series can be used.

In one embodiment, the immediate release first layer of anagliptin or a pharmaceutically acceptable salt thereof may be included in an amount of 25 to 400 mg, preferably 50 to 200 mg.

In another example, the controlled-release second layer metformin or a pharmaceutically acceptable salt thereof may be included at 125-4000 mg, preferably 250-2000 mg, and most preferably 500-1000 mg. mg. < / RTI >

The pharmaceutical compositions of the present invention facilitate administration of the compounds into the organism. There are a variety of techniques for administering the compounds, including the following oral, rectal, vaginal, intranasal, ocular, buccal, sublingual or parenteral subcutaneous, intramuscular, intravenous Intrathecal administration, intradermal administration, epidural administration, and the like. Oral administration is preferred.

A preferred dosage of anagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition provided herein is not particularly limited as long as the condition and the weight of the patient, the degree of disease, the form of the drug, The route of administration, and the period of time, but can be appropriately selected by those skilled in the art.

In general, the dosage of anagliptin is 25 to 400 mg, preferably 50 to 200 mg, more preferably 100 mg per one dose.

Metformin is typically administered at a dose of about 500 mg per day, using about 100 mg to 500 mg or 200 mg to 850 mg (one to three times a day), or from about 300 mg to 1000 mg once or twice, mg to 2000 mg to 2500 mg, or the delayed-release metformin may be provided at a dose of about 100 mg to 1000 mg or preferably 500 mg to 1000 mg or once daily at a dose of about 500 mg to 2000 mg once or twice a day do. The specific dose content may be metformin hydrochloride 250, 500, 625, 750, 850 and 1000 mg.

The dosage of the active ingredient in the composition according to the invention may vary, but the amount of active ingredient may be such that an appropriate dosage form is obtained. Thus, the selected dose and the selected dosage form will depend on the desired therapeutic effect, route of administration, and duration of treatment. A suitable dosage range for the co-administered product is a maximal tolerated dose to a lower dose, for example 1/10 of the maximum tolerated dose, for a single formulation.

The present invention also provides methods for treating type 2 diabetes, particularly by administering to a host in need of such treatment a therapeutically effective amount of one of the pharmaceutical compositions of the present invention.

For example, a host requiring such treatment is a human.

The pharmaceutical composition may be administered once daily (QD), twice daily (BID), three times daily (TID), or four times daily.

The present invention also relates to a pharmaceutical composition comprising: (a) preparing a mixture constituting an immediate release first layer comprising anagliptin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; And (b) preparing a mixture constituting a controlled-release second layer comprising metformin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the medicament for preventing or treating type 2 diabetes is < RTI ID = 0.0 > Wherein the mixture constituting the controlled release second layer prepared in the step (b) contains not more than 35% of particles having a particle size of not more than 150 mu m and has a humidity (LOD) of 1.0 to 3.0% Or a pharmaceutically acceptable salt thereof. The present invention also provides a method of producing a pharmaceutical composition for the prevention or treatment of type 2 diabetes.

In an embodiment of the present invention, the mixture may contain not more than 30% of particles having a particle size of not more than 135 탆, but the present invention is not limited thereto and the LOD may preferably be 1.0 to 2.0% But is not limited thereto.

The method for preparing a pharmaceutical composition of the present invention may further include (c) after the step (b), (c) coating an outer film with a pharmaceutical composition as a coating base, wherein the coating base of the outer film coating is a hydroxypropyl And may include at least one selected from the group consisting of methyl cellulose, yellow iron oxide, titanium oxide, polyethylene glycol 400, talc, red iron oxide and black iron oxide, and preferably includes all of the above materials.

For example, the pharmaceutically acceptable additive of step (a) may include at least one selected from the group consisting of a binder, an excipient, a disintegrant, and a glidant. Preferably, the adjuvant is povidone, Cellulose, crospovidone as the disintegrant, and sodium stearyl fumarate as the lubricant.

In another example, the pharmaceutically acceptable additive in step (b) may include at least one member selected from the group consisting of a binder, an excipient and a glidant, and preferably includes povidone as the binder, hydroxypropyl Methyl cellulose, magnesium stearate as the lubricant, and the like.

Preferably, the hydroxypropylmethylcellulose may have a viscosity of 4000 mPas to 200000 mPas, and the hydroxypropylmethylcellulose may be contained in the controlled release second layer in an amount of 1 to 5% by weight.

The present invention will now be described in more detail by way of non-limiting examples. However, the following examples are intended to further illustrate the present invention, and the scope of the present invention is not limited by the following examples. The following examples can be appropriately modified and changed by those skilled in the art within the scope of the present invention.

Example

Example  1-3. Anagliptin and  Metformin hydrochloride complex two-layer definition manufacture

Tablets were prepared according to the ingredients and contents in Table 1 below. Table 1 shows the content per one tablet.

At this time, the coating layer can be produced in an amount of about 3.0 to 3.5% of the double layer, and is produced using hyrommelose, yellow iron oxide, titanium oxide, polyethylene glycol 400, talc, red iron oxide, black iron oxide, ethanol and purified water.

division ingredient Example 1
(100/500 mg) Example 2
(100/850 mg) Example 3
(100/1000 mg) amount
(mg) amount
(mg) amount
(mg) Twin
(Not yet) Ana
Glutinin layer Anagliptin 100.00 100.00 100.00 Povidone 7.40 7.40 7.40 Pending
cellulose 57.25
57.25
57.25
Crospovidone 18.50 18.50 18.50 Fumaric acid
Sodium stearyl 1.85
1.85
1.85
ethanol 13.70 13.70 13.70 gun 185.00 185.00 185.00 Mat
Formic hydrochloride layer Metformin hydrochloride 500.00 850.00 1000.00 Povidone 30.00 51.00 60.00 Hydroxy
Propyl methylcellulose
(HPMC K200M CR) 15.00
25.50
30.00
Magnesium stearate 3.75 6.38 7.50 Purified water 87.50 148.75 175.00 gun 548.75 932.88 1097.50 gun 733.75 1117.88 1282.50

(a) Preparation of a mixture comprising anagliptin

Anagliptin is combined with the binding solution containing povidone and ethanol to form a mixture. The mixture is then dried and set. The microcrystalline cellulose composition, crospovidone, is mixed in the formed mixture and then stoichiometrically mixed with sodium stearyl fumarate.

The detailed preparation process of the mixture containing anagliptin is as follows.

(b) Preparation of a mixture comprising metformin hydrochloride

Metformin hydrochloride is aprated and mixed with povidone to form a mixture. Then, the mixture is combined with a binding liquid containing povidone and purified water, granulated, and dried. The dried mixture is mixed with hydroxypropylmethylcellulose K200M CR and the mixture is stirred with magnesium stearate.

The detailed preparation process of the mixture containing metformin hydrochloride is shown in Table 2 below.

fair ingredient Equipment used Condition (standard) Apple Metformin hydrochloride O / S 30-60 mesh mix Povidone K-90 Mixer 30-60 rpm, 10-40 minutes Union Povidone K-90 / water Allied machine 30-90 seconds Primary drying - dryer LOD 2.5 ~ 3.5 Granulation - Power mill 0.5-2.0 mm circular screen Secondary drying - dryer LOD 1.0 ~ 2.0 Formulations - Granulator 10-30 mesh After mixing Hydroxypropyl
Methyl cellulose
(HPMC) K200M CR Mixer 30-60 rpm, 10-40 minutes The Magnesium stearate Mixer 30-60 rpm, 1-10 minutes

(c) Anagglitin and metformin hydrochloride complex two-layer tableting / coating / packaging process

The two-layered tablets are prepared in accordance with the General Rules for the Purification of Pharmacopoeia and are prepared using purified water (pharmacopoeial) and ethanol (Japan Pharmacopeia) as a binding solvent.

The mixture containing the anagliptin of step (a) and the metformin hydrochloride of step (b) was tableted with a two-layer tablet machine (Sejong Pharmatech) to form a two-layer tablet, do.

Comparative Example  One. Anagliptin  Preparation of single agent

Ana article riptin used a leg guard ^® tablet (JW Choongwae ㈜) containing 100 mg Ana article riptin as single agents.

Comparative Example  2. Preparation of metformin hydrochloride single preparation

1000 mg of Glucophage ^占 containing 1000 mg of metformin hydrochloride as a single preparation of metformin hydrochloride (Merck Co.) was used.

Comparative Example  3. Anagliptin and  Metformin hydrochloride complex Double layer  Setting of drying conditions during manufacture

The procedure of Example 3 was repeated except that the humidity (LOD) after secondary drying in step (b) of Example 3 was set to less than 1.0%.

Comparative Example  4. Anagliptin and  Metformin hydrochloride complex Double layer  Setting of drying conditions during manufacture

Example 3 was prepared in the same manner as in Example 3, except that the humidity (LOD) after the secondary drying in the step (b) of Example 3 was made to exceed 3.0%.

Comparative Example  5. Change the additive type Anagliptin and  Metformin hydrochloride complex two-layer definition manufacture

Was prepared in the same manner as in Example 3, except that hydroxypropylmethylcellulose K100M CR (viscosity 100000 mPas) was used in the preparation of the mixture containing metformin hydrochloride. The detailed ingredients and contents are shown in Table 3, and the contents in Table 3 indicate the content per one tablet.

Comparative Example 5 mg / T % Metformin hydrochloride 1000.0 91.1 Povidone (K-90) 60.0 5.5 HPMC K100M CR 30.0 2.7 Magnesium stearate 7.5 0.7 gun 1097.5 100.0

Comparative Example  6. Change the additive content Anagliptin and  Metformin hydrochloride complex two-layer definition manufacture

Was prepared in the same manner as in Example 3, except that 20 mg of hydroxypropylmethylcellulose K200M CR (viscosity 200000 mPas) was used as an additive. The detailed ingredients and contents are shown in Table 4, and the contents in Table 4 indicate the content per one tablet.

Comparative Example  7. Change the additive content Anagliptin and  Metformin hydrochloride complex two-layer definition manufacture

Was prepared in the same manner as in Example 3, except that 40 mg of hydroxypropylmethylcellulose K200M CR (viscosity 200000 mPas) as an additive was used. The detailed ingredients and contents are shown in Table 4, and the contents in Table 4 indicate the content per one tablet.

　
　 Comparative Example 6 Comparative Example 7 mg / T % mg / T % Metformin hydrochloride 1000.0 92.0 1000.0 90.3 Povidone (K-90) 60.0 5.5 60.0 5.4 HPMC K200M CR 20.0 1.8 40.0 3.6 Magnesium stearate 7.5 0.7 7.5 0.7 Total (lower) 1087.5 100.0 1107.5 100.0

Comparative Example  8-12. By varying the additive content Anagliptin and  Metformin hydrochloride complex two-layer definition manufacture

Were prepared in the same manner as in Example 3 according to the ingredients and contents in Table 5 below. The content of Table 5 represents the content per one tablet. The viscosity of the following HPMC K4M CR is 4000 mPas.

Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 mg / T % mg / T % mg / T % mg / T % mg / T % Metformin hydrochloride 1000.0 86.9 1000.0 90.0 1000.0 92.5 1000.0 92.5 1000.0 92.5 Povidone
(K-90) 36.0 3.1 36.0 3.2 36.0 3.3 36.0 3.3 36.0 3.3 HPMC
K4M CR 100.0 8.7 60.0 5.4 40.0 3.7 30.0 2.8 20.0 1.9 Magnesium stearate 15.0 1.3 15.0 1.4 15.0 1.4 15.0 1.4 15.0 1.4 gun 1151.0 100.0 1111.0 100.0 1081.0 100.0 1081.0 100.0 1081.0 100.0

Test Example  One. Anagliptin  Dissolution test

Anagliptin components of the combination preparation of Example 3 and the single preparation of Comparative Example 1 were subjected to a comparative dissolution test using an elution machine under the following conditions.

≪ Dissolution condition >

Test method: Korean Pharmacopoeia second method (paddle method)

Amount of eluate: 900 mL

Conditions: 50 rpm, 37 +/- 0.5 DEG C

Device: Device 2

The results of the dissolution test are shown in Table 5 (Example 3, Comparative Example 1) and Figs. 2 to 5.

Eluent pH sample Time (minutes) 0 5 10 15 30 pH 1.2 Comparative Example 1 0.0 64.1 93.5 98.1 99.3 Example 3 0.0 72.4 86.3 93.3 99.0 Difference 0.0 8.3 7.2 4.8 0.3 pH 4.0 Comparative Example 1 0.0 60.7 90.2 97.0 100.5 Example 3 0.0 70.1 90.1 97.5 100.2 Difference 0.0 9.4 0.1 0.5 0.3 pH 6.8 Comparative Example 1 0.0 68.0 90.7 97.1 100.1 Example 3 0.0 70.3 86.8 98.4 104.6 Difference 0.0 -2.3 3.9 -1.3 -4.5 water Comparative Example 1 0.0 47.4 85.8 94.1 97.8 Example 3 0.0 64.4 87.0 94.5 99.4 Difference 0.0 -17.0 -1.2 -0.4 -1.6

As shown in Table 6, the anagliptin component disintegrates and dissolves within 30 minutes.

Test Example  2. Dissolution test of metformin hydrochloride

A metformin hydrochloride component of the combination preparation of Example 3 and the single preparation of Comparative Example 2 was subjected to a dissolution test in the same manner as in Test Example 1.

The results of the dissolution test are shown in the following Table 7 (Example 3, Comparative Example 2) and FIGS. 6 to 9.

Eluent pH sample Time (minutes) 0 5 10 15 30 45 60 90 120 pH 1.2 Comparative Example 2 0.0 18.0 27.7 35.3 52.3 64.3 73.3 88.0 101.8 Example 3 0.0 11.7 22.4 31.6 55.2 68.4 77.5 89.4 101.4 Difference 0.0 6.3 5.3 3.7 2.9 4.1 4.2 1.4 0.4 pH 4.0 Comparative Example 2 0.0 17.7 26.9 33.9 50.1 61.5 70.4 89.8 102.9 Example 3 0.0 13.1 19.4 28.2 48.0 64.6 76.2 92.5 100.9 Difference 0.0 4.6 7.5 5.7 2.1 3.1 5.8 2.7 2.0 pH 6.8 Comparative Example 2 0.0 20.8 34.1 44.8 70.5 87.8 96.1 101.2 102.4 Example 3 0.0 15.3 25.3 37.7 64.7 86.3 95.9 99.9 100.8 Difference 0.0 5.5 8.8 7.1 5.8 1.5 0.2 1.3 1.6 water Comparative Example 2 0.0 18.6 28.8 36.6 55.2 70.3 82.0 97.8 102.2 Example 3 0.0 14.9 23.6 32.6 56.2 74.2 85.3 96.7 102.1 Difference 0.0 3.7 5.2 4.0 1.0 3.9 3.3 1.1 0.1

As shown in Table 7, the metformin hydrochloride component disintegrates and dissolves within 2 hours.

Test Example  3. Dissolution test of metformin hydrochloride according to kinds and contents of additives

The change in dissolution rate of metformin hydrochloride was tested at pH 6.8 in the same manner as in Test Example 1 for the composite two-layered tablets of Comparative Examples 5 to 12 prepared by changing the kind and content of hydroxypropylmethylcellulose as an additive. The test results are shown in Table 8 below.

sample Time (minutes) 0 5 10 15 30 45 60 90 120 Example 3 0.0 11.7 22.4 31.6 55.2 68.4 77.5 89.4 101.4 Comparative Example 2 0.0 18.0 27.7 35.3 52.3 64.3 73.3 88.0 101.8 Comparative Example 5 0.0 14.3 27.7 39.2 64.3 81.2 88.9 92.7 94.2 Comparative Example 6 0.0 13.0 27.6 40.4 67.3 83.1 90.4 94.8 96.7 Comparative Example 7 0.0 10.1 18.9 28.2 48.5 60.8 69.2 78.8 84.7 Comparative Example 8 0.0 16.3 29.2 38.4 55.8 65.6 72.0 81.2 87.7 Comparative Example 9 0.0 16.9 28.2 37.7 59.4 73.4 82.2 91.1 96.0 Comparative Example 10 0.0 14.6 28.7 42.1 74.9 94.5 101.1 102.9 103.2 Comparative Example 11 0.0 20.2 35.3 47.7 78.6 94.4 99.0 103.2 103.5 Comparative Example 12 0.0 21.9 42.7 59.6 88.7 97.7 99.8 101.2 101.3

As can be seen from the results of Table 8, when the low viscosity hydroxypropylmethyl cellulose (4000 mPas) is used in a content range similar to high viscosity hydroxypropylmethyl cellulose (200000 mPas or more), the dissolution rate is not easily controlled, A dissolution rate similar to that of the preparation could not be obtained.

Therefore, the present inventors have found that a tablet having a high content of metformin of 500 mg or more (500 to 1000 mg) has a large tablet size, thereby achieving a dissolution profile equivalent to that of a single preparation for improving the convenience of taking the patient and the compliance with the medication, High viscosity hydroxypropylmethylcellulose of 200,000 mPas was used in the combination according to one embodiment of the present invention in order to improve convenience of use and compliance with medicines.

Test Example  4. The hardness / Massono / Unparalleled  exam

The hardness of the tablets was measured using a hardness tester (manufacturer: ERWEKA).

The durability of the tablets was measured by using a friabilator (ERWEKA) at 100 rpm and 25 rpm for 4 minutes. This device measures the fatigue of the tablet by rolling and dropping the tablets inside the drum. The tablet was rotated at a constant number of revolutions and the mass reduction was measured by adding the tablets before and after the rotation. The resistance to mass loss is the ability of the tablet to withstand breakage during handling, packaging and shipping. In most products, it is estimated that the fatigue rate of the tablet should be 1% of its mass.

There are a variety of problems associated with tableting in the manufacture of tablets. The main drawbacks are capping (laminating), laminating (tablets are stripped horizontally, Peeling phenomenon).

Drying is divided into two stages. The primary drying is to control the particle size by the granulation process while maintaining a certain level of humidity (LOD), and the secondary drying is to adjust the humidity to maximize the qualification .

If the particle size is too small (more than 30% of fine particles below 125 μm), the compressibility of the tablet deteriorates.

When the final dryness is less than 1.0%, problems occur in hardness / shrinkage / saturation. If the LOD is 3.0% or more, the fluidity of the granules may be poor and the lamination may occur and the possibility of laminating with anagliptin is high. The basis for setting the drying conditions is shown in detail in Table 9 below.

fair LOD (%) Granularity fair LOD (%) Hardness Massono Unparalleled Primary drying <2.5 <125um 30% or more Secondary drying Comparative Example 3
(&Lt; 1.0) <10KP > 0.3% Capping 2.5 to 3.0 <125um 30% or less Example 3
1.0 to 3.0 > 15KP <0.2% No problem 3.0 to 3.5 <125um 30% or less > 3.5 Mesh clogging Comparative Example 4
> 3.0 <10KP <0.2% Laminating

Claims (21)

An immediate release type first layer comprising anagliptin or a pharmaceutically acceptable salt thereof as an active ingredient and a controlled release second component comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, Layer,
Wherein the controlled release second layer comprises hydroxypropylmethylcellulose having a viscosity of from 4000 mPas to 200000 mPas. The method according to claim 1,
Wherein the immediate release first layer and the controlled release second layer comprise a double compression tablet. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; The method according to claim 1,
Wherein the immediate release first layer and the controlled release second layer each comprise a pharmaceutically acceptable additive. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; The method of claim 3,
Wherein the controlled-release second layer comprises no more than 15% by weight of a pharmaceutically acceptable additive on a second layer basis. The method of claim 3,
Wherein the immediate release first layer comprises at least one selected from the group consisting of a binder, an excipient, a disintegrant, and a glidant. The method of claim 5,
Wherein the immediate release first layer comprises at least one selected from the group consisting of povidone as the binder, microcrystalline cellulose as the excipient, crospovidone as the disintegrant, and stearyl sodium fumarate as the lubricant. A pharmaceutical composition for preventing or treating diabetes. The method of claim 3,
Wherein the controlled-release second layer comprises at least one member selected from the group consisting of a binder and a glidant. The method of claim 7,
Wherein the controlled release second layer comprises at least one member selected from the group consisting of povidone and magnesium stearate as the binding agent. The method according to claim 1,
Wherein the hydroxypropylmethylcellulose is contained in the controlled release second layer in an amount of 1 wt% to 5 wt%. The method according to claim 1,
The pharmaceutical composition for the prevention or treatment of type 2 diabetes according to claim 1, wherein the immediate release first layer of anagliptin or a pharmaceutically acceptable salt thereof comprises 25 to 400 mg. The method according to claim 1,
The pharmaceutical composition for the prevention or treatment of type 2 diabetes according to claim 1, wherein the controlled-release second layer metformin or a pharmaceutically acceptable salt thereof comprises 125 to 4000 mg. (a) preparing a mixture constituting an immediate release first layer comprising anagliptin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; And
(b) a pharmaceutical composition for the prevention or treatment of type 2 diabetes comprising preparing a composition constituting a controlled release second layer comprising metformin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive A process for producing
Wherein the mixture constituting the controlled release second layer prepared in the step (b) contains 35% or less of particles having a particle size of 150 mu m or less and the LOD is 1.0 to 3.0% A method for the manufacture of a pharmaceutical composition for the prevention or treatment of type 2 diabetes. The method of claim 12,
Wherein the mixture contains not more than 30% of particles having a particle size of not more than 135 mu m. The method of claim 12,
The pharmaceutically acceptable additive of step (a) comprises at least one member selected from the group consisting of a binder, an excipient, a disintegrant, and a glidant, and a method for producing a pharmaceutical composition for the prevention or treatment of type 2 diabetes . 15. The method of claim 14,
The pharmaceutically acceptable additive of step (a) may include at least one selected from the group consisting of povidone as the binder, microcrystalline cellulose as the excipient, crospovidone as the disintegrant, and stearyl sodium fumarate as the lubricant Wherein the pharmaceutical composition for preventing or treating type 2 diabetes is administered orally. The method of claim 12,
Wherein the pharmaceutically acceptable additive of step (b) comprises at least one member selected from the group consisting of a binder, an excipient and a glidant. 18. The method of claim 16,
The pharmaceutically acceptable additive of step (b) comprises at least one selected from the group consisting of povidone as the binder, hydroxypropylmethyl cellulose as the excipient and magnesium stearate as the lubricant. A method for the manufacture of a pharmaceutical composition for the prevention or treatment of diabetes. 18. The method of claim 17,
Wherein the hydroxypropyl methylcellulose has a viscosity of 4000 mPas to 200,000 mPas. 18. The method of claim 17,
Wherein the hydroxypropylmethylcellulose is contained in the controlled release second layer in an amount of 1 wt% to 5 wt%. The method of claim 12,
Wherein the immediate release first layer of anagliptin or a pharmaceutically acceptable salt thereof comprises 25 to 400 mg. &Lt; RTI ID = 0.0 &gt; 25. &lt; / RTI &gt; The method of claim 12,
Wherein the controlled release second layer metformin or a pharmaceutically acceptable salt thereof is comprised between 125 and 4000 mg. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;

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