JP5664993B2 - Solid formulation containing glimepiride - Google Patents

Description

  The present invention relates to a solid preparation containing glimepiride which is a drug for diabetes.

  Glimepiride has the chemical name 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl] -phenylsulfonyl] -3- (trans-4-methyl). Cyclohexyl) -urea is a sulfonylurea hypoglycemic agent. It is widely used to improve type 2 diabetes because of its pharmacological actions such as insulin secretion stimulating action on pancreatic beta cells and sugar uptake promotion in peripheral tissues.

  Glimepiride is currently marketed as a tablet, but its solubility in water is low, and in order to produce a solid preparation, improvement in solubility is required, and a technique for improving solubility has been reported. In Patent Document 1, a preparation containing 2% or more of glimepiride finely pulverized so as to have an average particle diameter of 10 μm or less, Patent Document 2 discloses a technique of dry-grinding glimepiride together with a binder, and Patent Document 3 includes glimepiride. Techniques for granulating using a liquid suspended or dispersed in a solution containing hydroxypropylcellulose or hydroxypropylmethylcellulose are described.

JP 2007-31377 A JP 2008-169135 A JP 2009-57331 A

However, pulverization, particularly pulverization to 2 μm or less, requires complicated pulverization, and there is a problem in terms of handling and stability, such as easy scattering when the particle size is small. Further, the technique of mixing and pulverizing as in Patent Document 2 depends on the equipment, and there is a risk that metallic contaminants may be generated from the equipment.
Accordingly, an object of the present invention is to improve the solubility of glimepiride without excessive pulverization and to provide a solid preparation that is stable for a long period of time.

  Therefore, as a result of various studies to improve the solubility of glimepiride and to develop a solid preparation having good stability, the present inventor has formulated glimepiride with a fatty acid ester type nonionic surfactant to formulate glimepiride. In addition to the improvement in solubility, the generation of degradation products is significantly suppressed even when stored for a long period of time compared with the case of blending finely pulverized glimepiride, and a stable solid preparation can be obtained for a long period of time. As a result, the present invention has been completed.

  That is, the present invention provides a glimepiride-containing solid preparation containing (A) glimepiride and (B) a fatty acid ester type nonionic surfactant.

  Since the solid preparation of the present invention has improved solubility of glimepiride in water, the dissolution property from the preparation into water is improved. Further, even when stored under high temperature and high humidity conditions, generation of decomposition products (impurities) is suppressed, and the product is stable for a long time.

It is a figure which shows the decomposition | disassembly product (sulfonamide body) generation | occurrence | production suppression effect by long-term storage of this invention solid formulation.

  The active ingredient of the solid preparation of the present invention is (A) glimepiride. Glimepiride has the chemical name 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl] -phenylsulfonyl] -3- (trans-4-methyl). Cyclohexyl) -urea having the structure of the following formula (1).

  The average particle size of glimepiride used in the present invention may be about 1 to 30 μm, more preferably about 1 to 10 μm, and particularly preferably about 2.5 to 10 μm from the point that fine pulverization is not required. Glimepiride having such an average particle diameter is preferably pulverized and sized by a normal pulverizing means such as a vibration mill, a rod mill, a ball mill, a hammer mill, and a jet mill. Here, the value measured by the laser diffraction / light scattering method is used as the average particle diameter.

  The content of glimepiride in the solid preparation of the present invention is preferably 0.4 to 6% by mass, more preferably 0.5 to 2% by mass, from the viewpoints of dissolution and ingestion.

  The solid preparation of the present invention contains (B) a fatty acid ester type nonionic surfactant in addition to glimepiride. In the preparation of glimepiride, an anionic surfactant such as sodium lauryl sulfate (Comparative Example 2) or polyoxyethylene glycol (Comparative Example 1) does not provide sufficient improvement in solubility, and the fatty acid ester type nonionic surfactant The solubility is improved by blending the agent. Examples of the fatty acid ester type nonionic surfactant to be used include polyoxyethylene fatty acid esters and sucrose fatty acid esters, and among these, polyoxyethylene fatty acid esters are more preferable. Of these nonionic surfactants, those that are solid at room temperature (25 ° C.) are more preferred from the viewpoint of solubility of glimepiride and long-term storage stability.

As the sucrose fatty acid ester, sucrose C ₈ -C ₂₄ fatty acid ester is preferable. Examples of the polyoxyethylene fatty acid ester include polyoxyethylene C ₈ -C ₂₄ fatty acid ester. Specifically, polyoxyethylene capric acid ester, polyoxyethylene lauric acid ester, polyoxyethylene myristic acid ester, Examples thereof include oxyethylene palmitate, polyoxyethylene stearate, polyoxyethylene oleate and the like. Of these, polyoxyethylene C ₈ -C ₂₀ fatty acid esters are more preferred, and polyoxyethylene stearic acid esters are particularly preferred. Moreover, the polyoxyethylene number of polyoxyethylene fatty acid ester is 5-100, Furthermore, 5-80 are preferable. For pharmaceutical use, those having a polyoxyethylene number of about 40 for oral administration can be used as JP polyoxyl stearate 40, polyoxyl stearate 45 or polyoxyl stearate 55 having a polyoxyethylene number of 45 or 50, respectively. Is available.

  The content of the fatty acid ester type nonionic surfactant in the solid preparation of the present invention is 0.2 to 1.2% by mass, and further 0.3 to 0.00% in terms of the solubility of glimepiride and long-term storage stability. 8 mass% is preferable. Moreover, it is preferable to contain 0.1-1 mass part and also 0.15-0.5 mass part of fatty-acid-ester type nonionic surfactants per 1 mass part of glimepiride from the same point.

In the solid preparation of the present invention, various additives such as excipients, binders, disintegrants and lubricants can be used in addition to the glimepiride and fatty acid ester type nonionic surfactants.
Examples of excipients include lactose hydrate, D-mannitol, erythritol, etc., binders include povidone, crystalline cellulose, hypromellose, methylcellulose, hydroxypropylcellulose and the like, and disintegrants such as sodium starch glycolate, corn starch, Potato starch, partially pregelatinized starch, pregelatinized starch, low-substituted hydroxypropylcellulose, agar, crospovidone, etc. Lubricants include talc, light anhydrous silicic acid, magnesium stearate, calcium stearate, macrogol 6000, etc. Is mentioned.

  The solid preparation of the present invention may contain the above components, but it is preferable to add a fatty acid ester type nonionic surfactant when granulating glimepiride for obtaining the effects of the present invention. Accordingly, the dosage form of the solid preparation of the present invention is preferably a granulated product such as a fine granule or a granule, a compression molded product of a granulated product such as a tablet, or a capsule filled with the granulated product.

  For the preparation of such a granulated product, for example, glimepiride may be mixed with a fatty acid ester type nonionic surfactant and other additives, and a necessary amount of water may be added and granulated by a conventional method. The obtained granulated product may be used as it is as fine granules or granules, and may be coated as necessary. Moreover, the tablet should just tablet a granulated material with a normal tableting machine. The tablet may be further subjected to film coating or the like.

  In the solid preparation of the present invention, glimepiride is considered to have a surface coated with a fatty acid ester type nonionic surfactant. In the state where a solvent is present around the preparation, the fatty acid ester type nonionic surfactant is rapidly dissolved, improving the wettability and solubility of glimepiride. In the case where the solvent is not present around the preparation or is present in a very small amount, it is considered that the fatty acid ester type nonionic surfactant does not dissolve but protects glimepiride from the environment and improves the stability.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this at all.

Example 1
8.8 g of glimepiride (average particle size: 9.87 μm), 359.5 g of lactose hydrate, 75.0 g of crystalline cellulose, and 40.0 g of sodium starch glycolate were mixed with a high-speed agitation granulator FS-GS-1J (Fukae Powtech Co., Ltd.) In addition, after premixing, 10.0 g of povidone and 1.5 g of polyoxyl stearate 40 were dissolved in 60 mL of water, and then a binding solution containing 2.5 g of light anhydrous silicic acid was added and granulated. The granule was dried at 50 ° C. with a shelf dryer PH-201 (manufactured by Tabai). The granules were sized with a sieve having an opening of 500 μm, put into a V-type mixer, mixed with 2.5 g of magnesium stearate, and tableted powder was obtained. This tableting powder was tableted by adjusting the tablet mass of HT-AP6 (manufactured by Hata Iron Works) to 170 mg so as to obtain a tablet containing 3 mg of glimepiride in one tablet.

Example 2
A tablet was obtained in the same manner as in Example 1 except that polyoxyl 40 stearate in Example 1 was changed to sucrose fatty acid ester.

Comparative Example 1
A tablet was obtained in the same manner as in Example 1 except that polyoxyl 40 stearate in Example 1 was changed to polyoxyethylene glycol 400.

Comparative Example 2
A tablet was obtained in the same manner as in Example 1 except that polyoxyl 40 stearate in Example 1 was changed to sodium lauryl sulfate.

Example 3
5.9 g of glimepiride (average particle size: 9.87 μm), 386.9 g of lactose hydrate, 50.0 g of crystalline cellulose, and 40.0 g of sodium starch glycolate were mixed with a high-speed agitation granulator FS-GS-1J (Fukae Powtech Co., Ltd.) In addition, after premixing, 10.0 g of povidone and 2.5 g of polyoxyl stearate 40 were dissolved in 60 mL of water, and then a binder solution added with 2.5 g of light anhydrous silicic acid was added and granulated. The granule was dried at 50 ° C. with a shelf dryer PH-201 (manufactured by Tabai). The granules were sized with a sieve having an opening of 500 μm, put into a V-type mixer, mixed with 2.5 g of magnesium stearate, and tableted powder was obtained. This tableting powder was tableted by adjusting the tablet mass of HT-AP6 (manufactured by Hata Iron Works) to 85 mg so as to obtain a tablet containing 1 mg of glimepiride in one tablet.

Comparative Example 3
Glimepiride (average particle size 2.37 μm) subjected to jet milling 5.9 g, lactose hydrate 386.9 g, crystalline cellulose 50.0 g, sodium starch glycolate 40.0 g, povidone 10.0 g, light anhydrous silicic acid 2.5 g and 2.5 g of magnesium stearate were added and mixed to obtain a mixed powder.

Test Example 1 (Dissolution test of Examples 1 and 2 and Comparative Examples 1 and 2)
One glimepiride tablet was taken and a dissolution test was performed according to the Japanese Pharmacopoeia Second Method (Paddle Method). The rotational speed of the paddle was 50 rpm, and the test solution was purified water and a McIlvaine buffer solution having a pH of 6.0.
High-performance liquid chromatography was used to measure glimepiride in the sample.
The test results are shown in Table 1 below.

  In the case of using a McIlvaine buffer having a pH of 6.0 as a test solution, the elution rate at 60 minutes is generally 40% higher than that of Comparative Example 2 using sodium lauryl sulfate, which is often used as a solubilizer. And Examples 1 and 2 using sucrose fatty acid ester showed an elution rate close to 2 times. Compared with other comparative examples, a high solubilizing effect was exhibited.

Test Example 2 (Storage stability comparison test of Example 3 and Comparative Example 3)
Glimepiride has a structure represented by the formula (1), and a sulfonamide compound represented by the formula (2) exists as an impurity generated during storage.
Put the tableting powder before the tableting process of Example 3 and Comparative Example 3 into a glass bottle, put it in a white box without closing the lid, conduct a storage test under the condition of 40 ° C. and 75% RH, and increase the sulfonamide body. Compared.

  The test results are shown in Table 2 below and FIG.

  Compared to Comparative Example 3 in which pulverization was performed, Example 3 was stable because the formation of sulfonamide after storage for 6 months was suppressed to one third.

Claims (3)

(A) Glimepiride having an average particle size of 2.5 to 10 μm, and (B) Glimepiride-containing solid preparation containing polyoxyl 40 stearate (except for an orally rapidly disintegrating tablet containing polyvinyl alcohol) .   The solid preparation containing glimepiride according to claim 1, which is a granulated product, a compression-molded product or a capsule thereof.   (A) The glimepiride containing solid formulation of Claim 1 or 2 which contains 0.1-1 mass part of (B) polyoxyl 40 stearates with respect to 1 mass part of glimepiride with an average particle diameter of 2.5-10 micrometers.

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