KR102362342B1 - Composite tablet comprising vildagliptin and metformin - Google Patents

Abstract

One aspect of the present invention is as an active ingredient
5 to 15% by weight of vildagliptin or a pharmaceutically acceptable salt thereof; and
85 to 95% by weight of metformin or a pharmaceutically acceptable salt thereof;
83 to 92% by weight of metformin is in the form of granules, the granules comprising 20.5 to 25.0% by weight of a pharmaceutically acceptable binder based on the dry weight of the granules,
a tablet comprising 75.0 to 85.0% by weight on a dry weight basis of an active ingredient consisting of vildagliptin, metformin, or each pharmaceutically acceptable salt; and
A manufacturing method thereof is provided.

Description

Composite tablet comprising vildagliptin and metformin

The present invention relates to a complex tablet containing vildagliptin and metformin, and more particularly, to a complex tablet capable of securing the stability of vildagliptin and metformin while ensuring superior uniformity of the formulation of vildagliptin and metformin is about

Metformin is a widely prescribed drug for lowering blood sugar in NIDDM patients with type 2 diabetes, and is marketed in the form of a hydrochloride salt (glucophage, Bristo-Myers Squibb Company). Metformin acts on diabetic patients through effects such as increased sensitivity to insulin in human peripheral tissues, inhibition of glucose absorption in the intestine, inhibition of hepatic glucose synthesis, inhibition of fatty acid absorption, and the like. Suitable dosages of metformin include a unit dose of 500 mg two to three times daily (which may be increased up to five times a day), or 850 mg once or twice a day ( Non-Patent Document 1).

Vildagliptin is a DPP-IV inhibitor class hypoglycemic agent and inhibits the inactivation of GLP-1 and GIP by DPP-IV, thereby enabling GLP-1 and GIP to promote insulin secretion in pancreatic beta cells. , by inhibiting the secretion of glucagon by alpha cells, it has a hypoglycemic action. Vildagliptin is commercially available in the form of a basic compound (Gaves Chung, Novartis, Korea).

In addition, a combination tablet of metformin and vildagliptin has been developed and is being marketed (Gavsmet tablets, 50/500, 50/850, 50/1000 mg, Novartis Korea Co., Ltd.) (Patent Document 1).

Since a high dose of metformin has to be used in the complex tablet, it is manufactured by a wet granulation method of high dose drug loading. In addition, metformin has very low flowability, so it is difficult to tablet with content uniformity unless flowability is improved by granulation. It is also known that there are physical problems such as poor compressibility and friability of tablets. Therefore, metformin in the composite tablet was formulated by wet granulation. Since vildagliptin is sensitive to moisture, in order to secure the stability of the active ingredient, it is not included in the wet granules of metformin, but is mixed and compressed directly into the wet granules of metformin to prepare a complex tablet. did That is, the metformin was formulated in such a way that vildagliptin was not present at all in the inner case of the tablet, which is the inside of the wet granulation, but was present outside the wet granule, that is, in the outer case of the tablet (Patent Document 1).

1. Korean Patent Registration 1391085

1. Martindale, The Complete Drug Reference

One aspect of the present invention is to provide a composite tablet containing metformin and vildagliptin, which has excellent formulation uniformity and high formulation strength, while ensuring excellent stability of the active ingredient.

Another aspect of the present invention is to provide a method for manufacturing the complex tablet.

Other objects and advantages of the present application will become more apparent from the following detailed description in conjunction with the appended claims. Content not described in this specification will be omitted because it can be sufficiently recognized and inferred by those skilled in the art within the technical field of the present application or a similar technical field.

One aspect of the present invention is

as an active ingredient

5-15% by weight of vildagliptin or a pharmaceutically acceptable salt thereof; and

85 to 95% by weight of metformin or a pharmaceutically acceptable salt thereof;

83-92% by weight of metformin is in the form of granules, the granules comprising 20.5-25.0% by weight of a pharmaceutically acceptable binder based on the dry weight of the granules,

Provided is a complex tablet comprising 75.0 to 85.0 wt% of an active ingredient consisting of vildagliptin, metformin, or each pharmaceutically acceptable salt on a dry weight basis.

Another aspect of the present invention is

As a method for manufacturing a complex tablet according to an aspect of the present invention,

preparing metformin granules by granulating 83 to 92 wt% of metformin or a pharmaceutically acceptable salt thereof in the tablet together with a binder;

mixing the remaining content (8-17 wt%) of metformin, vildagliptin or a pharmaceutically acceptable salt thereof, and the metformin granules;

preparing an uncoated tablet by adding a lubricant to the mixture and mixing, followed by compression tableting; and

It provides a manufacturing method comprising the step of coating the uncoated tablet.

The composite tablet comprising metformin and vildagliptin according to an aspect of the present invention can secure excellent storage stability of the active ingredient, and the uniformity of the formulation of all the composite ingredients is significantly superior to that of the conventional formulation, and the formulation strength is Therefore, it is possible to provide a combination tablet containing metformin and vildagliptin, which is pharmaceutically preferable compared to conventional formulations.

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

All technical terms used in the present invention, unless otherwise defined, have the same meaning as commonly understood by one of ordinary skill in the relevant field of the present invention.

The contents of all publications incorporated herein by reference are hereby incorporated by reference in their entirety.

Each description and embodiment disclosed in this application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present application fall within the scope of the present application. In addition, it cannot be seen that the scope of the present application is limited by the detailed description described below.

In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention. Also, the term “comprising” is intended to be inclusive and means that there may be additional elements in addition to those listed.

As used herein, the term “comprising” is used in the same way as it is commonly used.

It is understood that all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, etc. used herein are modified in all instances by the term “about” unless otherwise specified. Accordingly, the numbers set forth herein are approximations that may vary depending on the desired properties to be obtained by the present invention. As used herein, the term “about” is a specified value or within 1% to 2%. For example, “about 10%” means 9.8% to 10.2%. In another example, “about 100° C.” means 98° C. to 102° C.

The present inventors studied to develop a complex tablet containing metformin and vildagliptin, which is pharmaceutically superior to conventional formulations. As a result, when a part of metformin is prepared as granules, but the rest of the metformin is not contained in the granules, and a composite tablet is prepared by mixing and tableting the metformin granules together with vildagliptin, the uniformity of formulation of the vildagliptin component and Composite tablets were developed by confirming that the strength of the composite tablet could be significantly improved compared to the conventional formulation, and the stability of the active ingredient could also be secured.

One aspect of the present invention is

as an active ingredient

5-15% by weight of vildagliptin or a pharmaceutically acceptable salt thereof; and

85 to 95% by weight of metformin or a pharmaceutically acceptable salt thereof;

83 to 92% by weight of metformin is in the form of granules, the granules comprising 20.5 to 25.0% by weight of a pharmaceutically acceptable binder based on the dry weight of the granules,

Provided is a tablet containing 75.0 to 85.0% by weight of an active ingredient consisting of vildagliptin, metformin, or each pharmaceutically acceptable salt on a dry weight basis.

As used herein, the “inner shell” of the tablet refers to the metformin granule portion, and the “outer shell” of the tablet refers to the outside of the metformin granules. That is, the inner case of the composite tablet according to the above aspect is metformin granules, and the outer case includes all of the remaining metformin and vildagliptin.

The pharmaceutically acceptable salts of vildagliptin include, but are not limited to, known acid addition salts of vildagliptin such as hydrochloride, nitrate, and acetate. It is intended to include all of the above salts and free base forms collectively. In one embodiment, the vildagliptin is vildagliptin nitrate.

The pharmaceutically acceptable salts of metformin include hydrochloride, metformin (2:1) fumarate, metformin (2:1) succinate, bromate, p-chlorophenoxy acetate or embonate, and mono- and dibasic carboxylic acids Including, but not limited to, other known acid addition salts of metformin, hereinafter, unless otherwise indicated, "metformin" is collectively referred to as including all of the above salts and free base forms. In one embodiment, the metformin is metformin hydrochloride.

In one embodiment, the complex tablet may include vildagliptin nitrate and metformin hydrochloride as active ingredients.

83 to 92 wt% of metformin contained in the composite tablet is present in the form of granules, and the granules may be specifically wet granules. Since metformin contained in the composite tablet has a high unit dose, it is preferable to formulate it as wet granules. When manufactured by wet granulation, a large amount of metformin can be manufactured more compactly, thereby increasing patient compliance with the complex tablet.

The granules of metformin further include a pharmaceutically acceptable binder for the preparation of the granules. The binder may be present in an amount of 20.5 to 25% by weight based on the dry weight of the granules. Such pharmaceutically acceptable binders include, for example, starch, cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose, hydroxylpropylmethyl cellulose, sucrose, dextrose, corn syrup, polysaccharides, gelatin, and these may be selected from any combination of In one embodiment, the pharmaceutically acceptable binder may be hydroxylpropylmethyl cellulose.

The metformin granules, vildagliptin and the remaining amount of metformin, and a pharmaceutically acceptable excipient may be used together to form the complex tablet. The remaining amount of metformin is 8 to 17% by weight of the total metformin contained in the complex tablet.

In one embodiment, the remaining quantity of metformin, ie, metformin present in the external form of the tablet, is about 10-15% by weight of the total metformin contained in the composite tablet.

In one embodiment, the remaining quantity of metformin, ie, metformin present in the external form of the tablet, is about 15% by weight of the total metformin contained in the composite tablet.

Conventional metformin granules and vildagliptin-containing composite tablets have only vildagliptin as an active ingredient in the external tablet of the granule, and metformin is used only for the preparation of granules and is present only in the granules, i.e., in the internal phase, and does not exist at all in the trauma. form that does not Compared to such a conventional formulation, in the present application, 8 to 17% by weight of metformin, which is a part of metformin, is not used in the formation of granules of metformin, but is mixed with metformin granules, vildagliptin, and pharmaceutically acceptable excipients and compressed tabletting. 8-17% by weight, which is part of metformin, is in the form present in the trauma of the tablet. As such, since 8 to 17% by weight of metformin is present in the trauma of the tablet, the content uniformity of vildagliptin has a significantly higher effect than that of the conventional composite tablet (see Experimental Example 1). On the other hand, when the content of metformin exceeds 17 wt %, it was found that there is a disadvantage in that the mass deviation of metformin is increased (see Experimental Example 2). Therefore, when 8 to 17% by weight, which is a part of metformin, is present in the external wound of the tablet, it is possible to provide a complex tablet with excellent uniformity of formulation of both vildagliptin and metformin. In addition, when the metformin conditions were satisfied, it was confirmed that the hardness was high and the crushability was low, which was pharmaceutically desirable (see Experimental Example 3).

The composite tablet may be a tablet in which the determination value of the content uniformity test of vildagliptin according to the Korean Pharmacopoeia general test method is 6.6 or less, and the determination value of the mass deviation test of metformin is 3 or less. The lower the determination value, the better the formulation uniformity. Due to the technical characteristics, the composite tablet of the present application can provide a composite tablet having significantly superior formulation uniformity compared to the conventional composite tablet.

The pharmaceutically acceptable excipient may be any excipient known in the art for use in the manufacture of tablets, and may be selected from diluents, disintegrants, binders, glidants, coating agents, and any combination thereof. However, the present invention is not limited thereto.

In one embodiment, the excipient may include a lubricant and a coating agent.

In one embodiment, the lubricant may be present in an amount of 0.2 to 0.6% by weight based on the total weight of the tablet; and/or the coating agent may be present in an amount of 1.2 to 3.5% by weight.

The diluent may be selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethyl cellulose, and any combination thereof, but is not limited thereto; The disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and any combination thereof, but is not limited thereto; The binder may be selected from, but not limited to, the group consisting of povidone, hypromellose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, copovidone, and any combination thereof; And/or the lubricant may be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and any combination thereof, but is not limited thereto.

In one embodiment, the excipient may include hydroxypropyl methyl cellulose, magnesium stearate, and Opadry.

The complex tablet may contain about 50 mg of vildagliptin nitrate as a base and about 500 to 1,000 mg of metformin hydrochloride per unit tablet. In one embodiment, about 50 mg of vildagliptin nitrate as a base, and about 500, about 850 mg, or about 1,000 mg of metformin hydrochloride may be included.

The combination tablet can be used for the treatment of any disease or condition that is effective due to the combined administration of vildagliptin and metformin. The disease is, for example, non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft, calcitonin-osteoporosis, heart failure, glucose metabolism insufficiency, IGT (glucose tolerance failure), Alzheimer's disease, Parkinson's disease, hyperlipidemia, diabetic myocardial For the treatment of a disease or condition selected from a condition, left or right ventricular hypertrophy, hypertrophic medial hypertrophy in arteries, large vessels or both, mesenteric vasculature, mesangial hypertrophy, neurodegenerative disorder, cognitive impairment, and any combination thereof. can be used

As a result of a stability test for the complex tablet of the present application under severe conditions, it was confirmed that the total content of related substances of vildagliptin was significantly lower than that of the conventionally marketed complex tablet, Gavsmet (see Experimental Example 4). Therefore, the composite tablet of the present application can be provided as a composite tablet having remarkably excellent formulation uniformity and formulation hardness while ensuring the stability of the active ingredient over time.

Another aspect of the present application is

As the manufacturing method of the complex tablet according to the present application,

preparing metformin granules by granulating 83 to 92 wt% of metformin or a pharmaceutically acceptable salt thereof in the tablet together with a binder;

mixing the remaining content (8-17 wt%) of metformin, vildagliptin or a pharmaceutically acceptable salt thereof, and the metformin granules;

preparing an uncoated tablet by adding a lubricant to the mixture and mixing, followed by compression tableting; and

It provides a manufacturing method comprising the step of coating the uncoated tablet.

For the details of the manufacturing method, the description of the complex tablet according to all aspects of the present application may be applied as it is.

According to one embodiment of the present invention, in the above production method, metformin granules may be prepared by a wet granulation method. The manufacturing method of the wet granulation method is not particularly limited, and any wet granulation method known in the art may be used.

The vildagliptin or a pharmaceutically acceptable salt thereof mixed with the metformin granules may be present in the form of particles or powder. The form of the particles of vildagliptin can be prepared by conventionally known solvent granulation. The solvent may be selected from, for example, but not limited to, ethanol, isopropanol, ethyl acetate, glycofurol, propylene glycol, and any combination thereof. Vildagliptin in powder form may be prepared by a method known in the art, or may be obtained commercially (Kyungwong Pharmaceutical).

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1 and 2

Tablets containing the ingredients of Examples 1 and 2 of Table 1 were prepared. Specifically, it was prepared as follows.

Metformin hydrochloride-1 and hydroxypropylmethyl cellulose were mixed together and wet granulated. After drying the prepared granules, they were sized. Then, metformin hydrochloride granules were mixed with metformin hydrochloride-2 and vildagliptin nitrate. Magnesium stearate was added to the mixture and mixed, followed by compression tableting to prepare uncoated tablets. The prepared uncoated tablet was coated using Opadry to complete the complex tablet.

comparative example One

A complex tablet was prepared in the same manner as in Examples 1 and 2, except that the content of metformin hydrochloride-2 was 0.

comparative example 2

A complex tablet was prepared in the same manner as in Examples 1 and 2, except that the content of metformin hydrochloride-2 was 20% by weight based on the total weight of metformin hydrochloride in the tablet.

[Table 1]

Example 3 and 4

Composite tablets were prepared in the same manner as in Examples 1 and 2, except for containing the components in the amounts shown in Examples 3 and 4 in Table 2 below.

[Table 2]

Experimental example One: Formulation uniformity comparative test ( Vildagliptin )

The formulation uniformity test for vildagliptin was performed according to the content uniformity test (film-coated tablet) of the formulation uniformity test method of the 10th revision general test method of the Korean Pharmacopoeia. Measurements were repeated 3 times for each of 10 samples.

The conditions of the content uniformity test analysis are as follows.

<Conditions for content uniformity test analysis>

1) Detector: UV absorbance spectrometer (measurement wavelength: 212nm)

2) Column: YMC_Triart C18 (4.6 mm × 250mm, 5um) or equivalent column

3) Column temperature: 25℃

4) Injection volume: 10uL

5) Analysis time: 8 minutes

6) Flow rate: 1.0 mL/min

7) Mobile phase: A solution of 0.5 g sodium chloride and 0.5 g sodium heptanesulfonate dissolved in 1 L purified water, adjusted to pH 3.85 with phosphoric acid, and methanol mixed at a ratio of 550: 450 (V/V)

The determination value was calculated by multiplying the standard deviation value obtained through the measurement by the determination coefficient (2.4 when n=10).

The results are shown in Table 3 below.

[Table 3]

Experimental example 2: Formulation uniformity comparative test ( metformin )

The formulation uniformity test for metformin was performed according to the mass deviation test (solid formulation) of the formulation uniformity test method of the 10th revision general test method of the Korean Pharmacopoeia. The procedure was repeated 3 times for each of 10 samples. The determination value was calculated by multiplying the standard deviation value obtained through the measurement by the determination coefficient (2.4 when n=10).

The results are shown in Table 4 below.

[Table 4]

As a result of the experiment in Table 3, Example 2 showed the best value of vildagliptin content uniformity of about 2 or less, and Example 1 and Comparative Example 2 had about 6.6 or less, which was good. In the case of Comparative Example 1, it was found to exceed 7, indicating that the content uniformity of vildagliptin was relatively poor.

In addition, as a result of the experiment in Table 4, the mass deviation determination value of metformin was very excellent as Examples 1, 2, and Comparative Example 1 were about 2 or less, but in Comparative Example 2, it was found to be about 5 or more, so the mass uniformity of metformin It was found that the sex was relatively very low.

Taken together, it was found that the composite tablets of Examples 1 and 2 were able to secure excellent formulation uniformity of both vildagliptin and metformin.

Experimental example 3: the hardness of the formulation and friability exam

The hardness of the tablets was measured using a durometer as a measure of the physical strength of the tablets, and at least 10 tablets were measured and the average value was recorded.

As a method of measuring the friability of compression-molded tablets without peeling, 10 tablets that were accurately weighed were tested for friability by 100 rotations (240 seconds) with a Friabilator. The fine powder adhering to the tablet was removed, and the mass was precisely weighed in the same manner as before the start of the test, and the weight loss due to crushing was calculated as a percentage of the initial weight. The results are shown in Table 5 below.

[Table 5]

According to the experimental results, it was confirmed that the composite tablets of Examples 1 and 2 had significantly higher hardness and lower friability than Comparative Examples 1 and 2, and had excellent pharmaceutically excellent physical properties.

Experimental example 4: Stability test

Example 2 The content of related substances was measured after leaving the reagent and control drug Gavsmet tablets together for 2 weeks under severe conditions (50±2℃, 80±5% RH). The analysis conditions for related substances are as follows.

<Metformin hydrochloride related substance analysis conditions>

1) Detector: UV absorbance spectrometer (measurement wavelength: 218nm)

2) Column: ZORBAX SB-Phenyl 4.6 mm × 250 mm. 5 μm or equivalent column

3) Column temperature: 30℃

4) Injection volume: 5uL

5) Analysis time: 35 minutes

6) Flow rate: 1.0 mL/min

7) Mobile phase:

A (pH 2.5 phosphate buffer solution): A solution in which 6 g of potassium phosphate and 4 g of sodium hexanesulfonate were put in 1 L purified water, and the pH was adjusted to 2.5 with phosphoric acid.

B: acetonitrile

<Vildagliptin nitrate related substance analysis conditions>

1) Detector: UV absorbance spectrometer (measurement wavelength: 200nm)

2) Column: ZORBAX Eclipse Plus C8 4.6 mm × 150 mm. 3.5 μm or equivalent column

3) Column temperature: 50℃

4) Injection volume: 10uL

5) Analysis time: 25 minutes

6) Flow rate: 1.0 mL/min

7) Mobile phase:

A (pH 3.0 phosphate buffer solution): A solution of 2.5 g of ammonium dihydrogen phosphate in 1 L purified water and adjusted to pH 3.5 with phosphoric acid

B (methanol: acetonitrile) = 60: 40

As a result, related substances of metformin hydrochloride were not found, and related substances of vildagliptin nitrate were shown in Table 6 below. According to the results in Table 6 below, it was confirmed that the composite tablet of Example 2 according to the present application had significantly lower production amount of related substances compared to the commercially available reference drug Gavsmet tablet, and thus the stability was significantly improved.

[Table 6]

So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (12)

as an active ingredient
5 to 15% by weight of vildagliptin or a pharmaceutically acceptable salt thereof; and
85 to 95% by weight of metformin or a pharmaceutically acceptable salt thereof;
83 to 92% by weight of metformin or a pharmaceutically acceptable salt thereof is in the form of wet granules, and the wet granules contain 20.5 to 25.0% by weight of a pharmaceutically acceptable binder based on the dry weight of the wet granules,
A tablet comprising vildagliptin, metformin, or 75.0 to 85.0% by weight on a dry weight basis of the active ingredient consisting of each pharmaceutically acceptable salt. The tablet according to claim 1, comprising vildagliptin nitrate and metformin hydrochloride as the active ingredients. delete The tablet of claim 1 , wherein the binder is selected from starch, cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose, hydroxylpropylmethyl cellulose, sucrose, dextrose, corn syrup, polysaccharides and gelatin. . The tablet according to claim 1, wherein the tablet contains 10 to 20% by weight of a pharmaceutically acceptable excipient. The tablet according to claim 5, wherein the excipient is selected from a diluent, a disintegrant, a binder, a lubricant, and a coating agent. The tablet according to claim 6, wherein the excipients include a binder, a lubricant, and a coating agent. 8. The tablet of claim 7, wherein the excipients include hydroxypropyl methyl cellulose, magnesium stearate, and Opadry. The tablet according to claim 1, wherein the tablet contains 50 mg of vildagliptin nitrate as a base and 500 to 1,000 mg of metformin hydrochloride per unit tablet. The tablet according to claim 1, wherein the determination value of the content uniformity test of vildagliptin according to the Korean Pharmacopoeia general test method is 6 or less, and the determination value of the metformin mass deviation test is 3 or less. The method of claim 1 , wherein non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft, calcitonin-osteoporosis, heart failure, glucose metabolic insufficiency, IGT (glucose tolerance failure), Alzheimer's disease, Parkinson's disease, hyperlipidemia, diabetic cardiomyopathy , left or right ventricular hypertrophy, hypertrophic medial hypertrophy in arteries, large vessels or both, mesenteric vasculature hypertrophy, mesangial hypertrophy, neurodegenerative disorder or cognitive impairment. A method for preparing a tablet according to any one of claims 1, 2, and 4 to 11, comprising:
preparing wet granules of metformin by wet granulating 83 to 92 wt% of metformin or a pharmaceutically acceptable salt thereof in the tablet together with a binder;
mixing the remaining content of 8 to 17% by weight of metformin or a pharmaceutically acceptable salt thereof, vildagliptin or a pharmaceutically acceptable salt thereof, and the prepared metformin wet granules;
preparing an uncoated tablet by adding a lubricant to the mixture and mixing, followed by compression tableting; and
A manufacturing method comprising the step of coating the uncoated tablet.