Antidiabetic Agents

Abstract

To provide a composition, useful as a pharmaceutical, containing mitiglinide calcium hydrate and voglibose, and a method for producing the same.SOLUTION: A pharmaceutical composition contains mitiglinide calcium hydrate, voglibose and crystalline cellulose.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition containing mitiglinide calcium hydrate and voglibose, and a method for preparing the same. [Background technology]

[0002] Mitiglinide calcium hydrate binds to sulfonylurea receptors present in pancreatic β cells, releasing insulin from the pancreatic β cells. Mitiglinide calcium hydrate is classified as a fast-acting insulin secretagogue and improves postprandial hyperglycemia in type 2 diabetes.

[0003] Voglibose inhibits α-glucosidase, which breaks down disaccharides into monosaccharides in the intestine, thereby slowing the production and absorption of glucose and improving postprandial hyperglycemia in type 2 diabetes.

[0004] As an example of a tablet containing mitiglinide calcium hydrate and voglibose, Patent No. 4230524 (Patent Document 1) discloses a tablet containing mitiglinide calcium hydrate, voglibose, lactose, corn starch, crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose and magnesium stearate. As an orally disintegrating tablet containing mitiglinide calcium hydrate, JP 2013-127009 A (Patent Document 2) discloses an orally disintegrating tablet in which the bitterness is masked, and JP 2014-1233 A (Patent Document 3) discloses an orally disintegrating tablet which has appropriate hardness and rapid disintegration properties and can be industrially produced using general manufacturing equipment. As an orally disintegrating tablet containing voglibose, JP 2004-2326 A (Patent Document 4) discloses an orally disintegrating tablet which has appropriate hardness and rapid disintegrability and in which loss of voglibose during the formulation process is small. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 4230524 [Patent Document 2] JP 2013-127009 A [Patent Document 3] JP 2014-1233 A [Patent Document 4] JP 2004-2326 A Summary of the Invention

[0006] The present inventors have investigated a composition useful as a medicine, which contains mitiglinide calcium hydrate and voglibose and is useful as a tablet, and have completed the present invention.

[0007] In one aspect, the present invention provides a pharmaceutical composition comprising mitiglinide calcium hydrate, voglibose, and microcrystalline cellulose.

[0008] In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising mitiglinide calcium hydrate, voglibose, and microcrystalline cellulose.

[0009] In one aspect, the present invention provides a granule comprising mitiglinide calcium hydrate, voglibose, and microcrystalline cellulose. [Brief description of the drawings]

[0010] [Figure 1] The effect of the crystalline cellulose content in the tablet on the dissolution (pH 1.2) of mitiglinide calcium hydrate from the tablet is shown. It can be seen that the dissolution of mitiglinide calcium hydrate from the tablet with a crystalline cellulose content of 16% is faster than that from the tablet with a crystalline cellulose content of 6%. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In one aspect, the present invention provides a pharmaceutical composition comprising mitiglinide calcium hydrate, voglibose, and microcrystalline cellulose. The pharmaceutical composition provided by the present invention contains mitiglinide calcium hydrate. The content of mitiglinide calcium hydrate in the pharmaceutical composition provided by the present invention may be 1 to 20% by weight, preferably 5 to 10% by weight, based on the weight of the pharmaceutical composition. When the pharmaceutical composition provided by the present invention is in the form of a tablet (e.g., an orally disintegrating tablet), each tablet may contain 10 mg of mitiglinide calcium hydrate. The pharmaceutical composition provided by the present invention contains voglibose. The content of voglibose in the pharmaceutical composition provided by the present invention may be 0.01 to 1% by weight, preferably 0.03 to 0.3% by weight, based on the weight of the pharmaceutical composition. When the pharmaceutical composition provided by the present invention is in the form of a tablet (e.g., an orally disintegrating tablet), each tablet may contain 0.2 mg of voglibose. Examples of crystalline cellulose used in the pharmaceutical composition provided by the present invention include Ceolus ST-100, Ceolus ST-02, Ceolus FD-101, Ceolus FD-301, Ceolus FD-F20, Ceolus UF-F711 and Ceolus UF-F702 (all manufactured by Asahi Chemical Industry Co., Ltd.). Crystalline cellulose also includes what is called microcrystalline cellulose. The content of crystalline cellulose in the pharmaceutical composition provided by the present invention may be 7 to 30% by weight, preferably 10% by weight or more, more preferably 15 to 30% by weight, based on the weight of the pharmaceutical composition.

[0012] The pharmaceutical composition provided by the present invention may contain additives commonly used in the pharmaceutical technology field, such as excipients, binders, disintegrants, flow agents, sweeteners, lubricants, pH adjusters, surfactants and flavors.

[0013] Examples of excipients that may be used in the pharmaceutical compositions provided by the present invention include sugars such as lactose (e.g., lactose hydrate, anhydrous lactose), glucose, sucrose, fructose, maltose, etc.; sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, D-mannitol, etc.; starches (e.g., corn starch, potato starch, rice starch, wheat starch), crystalline cellulose, magnesium aluminometasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate, and ethylcellulose. The content of the excipient in the pharmaceutical composition provided by the present invention may be 20 to 95% by weight, preferably 30 to 90% by weight or more, and more preferably 30 to 85% by weight, based on the weight of the pharmaceutical composition.

[0014] Examples of binders for use in the pharmaceutical compositions provided by the present invention include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, dextrin, methyl cellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch, agar, and gelatin. The content of the binder in the pharmaceutical composition provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight or more, and more preferably 1 to 3% by weight, based on the weight of the pharmaceutical composition.

[0015] Examples of disintegrants that may be used in the pharmaceutical compositions provided by the present invention include croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and carmellose. The content of the disintegrant in the pharmaceutical composition provided by the present invention may be 0.3 to 20% by weight, preferably 1 to 10% by weight or more, and more preferably 3 to 10% by weight, based on the weight of the pharmaceutical composition.

[0016] Examples of flow agents that may be used in the pharmaceutical compositions provided by the present invention include light anhydrous silicic acid and magnesium aluminometasilicate. The content of the fluidizing agent in the pharmaceutical composition provided by the present invention may be 0.03 to 3 wt %, preferably 0.1 to 3 wt % or more, and more preferably 0.3 to 3 wt %, based on the weight of the pharmaceutical composition.

[0017] Examples of sweeteners that may be used in the pharmaceutical compositions provided by the present invention include sodium saccharin, dipotassium glycyrrhizinate, aspartame®, stevia, thaumatin and sucralose. The content of the sweetener in the pharmaceutical composition provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight or more, and more preferably 0.3 to 3% by weight, based on the weight of the pharmaceutical composition.

[0018] Examples of lubricants that can be used in the pharmaceutical compositions provided by the present invention include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, sucrose fatty acid esters and sodium stearyl fumarate. The content of the lubricant in the pharmaceutical composition provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight or more, and more preferably 1 to 5% by weight, based on the weight of the pharmaceutical composition.

[0019] Examples of pH adjusting agents that may be used in the pharmaceutical compositions provided by the present invention include citrates, phosphates, carbonates, tartrates, fumarates, acetates and amino acid salts. The content of the pH adjuster in the pharmaceutical composition provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight or more, and more preferably 1 to 5% by weight, based on the weight of the pharmaceutical composition.

[0020] Examples of surfactants that may be used in the pharmaceutical compositions provided by the present invention include sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate and poloxamer. The content of the surfactant in the pharmaceutical composition provided by the present invention may be 0.01 to 3 wt %, preferably 0.03 to 1 wt % or more, and more preferably 0.03 to 0.5 wt %, based on the weight of the pharmaceutical composition.

[0021] Examples of flavorings that may be used in the pharmaceutical compositions provided by the present invention include citrus flavors such as lemon, orange, grapefruit, peppermint, spearmint, and menthol.

[0022] In one embodiment, the pharmaceutical composition provided by the present invention comprises mitiglinide calcium hydrate and voglibose as active ingredients, microcrystalline cellulose and mannitol as excipients, hydroxypropyl cellulose as a binder, and crospovidone as a disintegrant. In this embodiment, the weight ratio of microcrystalline cellulose:mitiglinide calcium hydrate may be 1:1-4:1, and the weight ratio of microcrystalline cellulose:hydroxypropyl cellulose may be 3:1-20:1. The pharmaceutical compositions provided by the present invention may be free of corn starch. In one embodiment, the pharmaceutical composition provided by the present invention comprises mitiglinide calcium hydrate and voglibose as active ingredients, microcrystalline cellulose and mannitol as excipients, and hydroxypropyl cellulose as a binder, and further comprises crospovidone as a disintegrant, but does not contain corn starch.

[0023] In one embodiment, the pharmaceutical composition provided by the present invention is a tablet.In a preferred embodiment, the pharmaceutical composition provided by the present invention is an orally disintegrating tablet.When the pharmaceutical composition provided by the present invention is an orally disintegrating tablet, it can be disintegrated in the oral cavity within 60 seconds, preferably within 45 seconds, more preferably within 30 seconds. In one embodiment, the pharmaceutical composition provided by the present invention is an orally disintegrating tablet, which can disintegrate within 60 seconds, preferably within 45 seconds, and more preferably within 30 seconds, when tested using purified water (without a disc) according to the disintegration test method (general test method of the Japanese Pharmacopoeia). In one embodiment, the pharmaceutical composition provided by the present invention is an orally disintegrating tablet, which exhibits appropriate hardness and rapid disintegration. In one embodiment, the pharmaceutical composition provided by the present invention is in the form of a tablet, which exhibits good dissolution properties of the active ingredients mitiglinide and voglibose. In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and the hardness thereof may be 10 to 200 N, preferably 30 to 150 N. More specifically, there is the hardness after tablet formation (initial hardness) and the hardness of the tablet after moisture absorption stored at 40° C. and a relative humidity of 75% for a predetermined period of time (moisture hardness), and when measured with a hardness tester PC-30 (Okada Seiko Co., Ltd.), the hardness of the tablet of the present invention may be 50 to 100 N in initial hardness and 30 N or more (e.g., 30 to 40 N) in hygroscopic hardness. In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and the thickness of the tablet can be set arbitrarily taking into consideration ease of handling and swallowing, but the change in tablet thickness after storage at 40°C and a relative humidity of 75% can be within 12%, preferably within 9%, and more preferably 6%. In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and when a dissolution test is performed according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) at a rotation speed of 50 rpm using Solution 1 (pH 1.2) as the test solution, the dissolution rate after 15 minutes can be 85% or more. In one embodiment, a tablet which is a pharmaceutical composition provided by the present invention is packed in a PTP sheet and further packed in an aluminum bag, and any one or all of the tablet thickness, hardness, and disintegration time do not change from the start of the test for at least 6 months under an environment of 40°C / relative humidity 75%. The pharmaceutical compositions provided by the present invention may be used to treat diabetes (eg, type 2 diabetes).

[0024] In one aspect, the present invention provides a method for producing the pharmaceutical composition provided by the present invention. For example, the pharmaceutical composition provided by the present invention can be prepared by the steps of: (i) wet granulating a mixture containing mitiglinide calcium hydrate, voglibose, and microcrystalline cellulose to obtain a granule; (ii) mixing the granules obtained in (i), a disintegrant and a lubricant; and (iii) compressing the mixture obtained in (ii) into tablets. It can be manufactured in. In the above step (i), the mixture containing mitiglinide calcium hydrate, voglibose and crystalline cellulose may further contain hydroxypropyl cellulose. In the above step (ii), the disintegrant may be crospovidone, the lubricant may be talc and calcium stearate, and D-mannitol, light anhydrous silicic acid and sucralose may be further mixed. In the above step (iii), the pressure during tableting is 1 to 60 kN / cm 2 may be also possible.

[0025] In one aspect, the present invention provides a granulated product obtained in the above step (i). The granules obtained in step (i) above may contain 10 to 40% by weight of crystalline cellulose, the weight ratio of crystalline cellulose to mitiglinide may be 1:1 to 4:1, and the weight ratio of crystalline cellulose to hydroxypropyl cellulose may be 3:1 to 20:1.

[0026] The present invention will be further described below with reference to examples, but the present invention is not limited to these. EXAMPLES

[0027] (Example 1 and Comparative Example 1: Production of tablets) The amounts of ingredients are shown in Table 1. Granulation drying process Mitiglinide calcium hydrate, D-mannitol, crystalline cellulose, and hydroxypropyl cellulose were mixed using a high-speed agitation granulator. Then, a solution of voglibose in water was added and granulated. After crushing the coarse granules using a granulator, the mixture was dried at 50°C using an air-blowing incubator. Sizing ~ Mixing granulation process The granules were sized using a granulator, D-mannitol, crospovidone, light anhydrous silicic acid and sucralose were added and mixed using a mixer, followed by adding talc and calcium stearate and mixing using a mixer to obtain granules for tableting. Tableting process The granules for tableting were compressed using a tableting machine so that each tablet contained 10 mg of mitiglinide calcium hydrate and 0.2 mg of voglibose, to obtain tablets. The average initial hardness of the obtained tablets was 64 N, the tablet thickness was 2.6 mm, and when tested using purified water (without an auxiliary disk) according to the disintegration test method (general test method of the Japanese Pharmacopoeia), the disintegration time was 22 seconds. [Table 1] Dissolution Test (Test Example 1: Dissolution test of mitiglinide calcium hydrate) A dissolution test was carried out on the tablets obtained in Example 1 and Comparative Example 1 using the Japanese Pharmacopoeia dissolution test fluid No. 1 (pH 1.2) as the test fluid, according to the Japanese Pharmacopoeia general test method dissolution test method No. 2 (paddle method) at 50 rpm. The results are shown in Figure 1. The results in FIG. 1 show that Example 1, in which crystalline cellulose was added at 16%, exhibited a more excellent dissolution behavior than Comparative Example 1, in which crystalline cellulose was added at 6%. [Industrial Applicability]

[0028] The pharmaceutical composition provided by the present invention is useful as a therapeutic agent for diabetes.

Claims

1. An orally disintegrating tablet, It contains 10 mg of mitiglinide calcium hydrate, 0.2 mg of voglibose, and crystalline cellulose and excipients. the content of the mitiglinide calcium hydrate is 5 to 10% by weight relative to the orally disintegrating tablet, and the weight of the orally disintegrating tablet is 100 mg or more and 200 mg or less; The content of the crystalline cellulose is 7 to 30% by weight based on the orally disintegrating tablet, the weight ratio of said crystalline cellulose to said mitiglinide calcium hydrate is greater than 1:1 to 4:1; In a dissolution test according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) using a rotation speed of 50 rpm and a test liquid of Solution 1 (pH 1.2), the dissolution rate of mitiglinide calcium hydrate after 15 minutes is 85% or more. An orally disintegrating tablet (excluding orally disintegrating tablets containing corn starch) comprising 10 mg of the mitiglinide calcium hydrate, 0.2 mg of the voglibose, a granule containing the crystalline cellulose and an excipient, and a powder containing the excipient D-mannitol.

2. 2. The orally disintegrating tablet according to claim 1, further comprising a binder.

3. The orally disintegrating tablet according to claim 2, wherein the excipient and / or binder is D-mannitol and / or hydroxypropyl cellulose.

4. The orally disintegrating tablet according to any one of claims 1 to 3, further comprising crospovidone as a disintegrant.

5. The orally disintegrating tablet according to any one of claims 1 to 4, further comprising at least one agent selected from the group consisting of a flow agent, a sweetener, and a lubricant.

6. The orally disintegrating tablet according to claim 5, wherein the glidant is light anhydrous silicic acid.

7. The orally disintegrating tablet according to any one of claims 1 to 6, which is for treating diabetes.

8. A method for producing an orally disintegrating tablet, comprising: (i) wet granulating a mixture containing 10 mg of mitiglinide calcium hydrate, 0.2 mg of voglibose, microcrystalline cellulose and an excipient to obtain a granule; (ii) mixing the granules obtained in (i), D-mannitol as an excipient, a disintegrant and a lubricant; and (iii) compressing the mixture obtained in (ii) into tablets, the orally disintegrating tablet produced contains 5 to 10% by weight of mitiglinide calcium hydrate and has a weight of 100 mg or more and 200 mg or less; The orally disintegrating tablet produced contains 7 to 30% by weight of crystalline cellulose, and further comprises the weight ratio of said crystalline cellulose to said mitiglinide calcium hydrate is greater than 1:1 to 4:1; It contains 10 mg of mitiglinide calcium hydrate, 0.2 mg of voglibose, and crystalline cellulose and excipients. A method for producing an orally disintegrating tablet (excluding orally disintegrating tablets containing corn starch) in which the dissolution rate of mitiglinide calcium hydrate after 15 minutes in a dissolution test conducted according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) at a rotation speed of 50 rpm using Liquid 1 (pH 1.2) as the test liquid is 85% or more.

9. The method according to claim 8, wherein the granules obtained in (i) contain 10 to 40% by weight of crystalline cellulose.

10. The method according to claim 8 or 9, wherein the granules obtained in (i) further contain hydroxypropyl cellulose.

11. The method according to any one of claims 8 to 10, wherein the granules obtained in (i) further contain hydroxypropyl cellulose, and the weight ratio of crystalline cellulose to hydroxypropyl cellulose is 3:1 to 20:1.

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