WO2006016602A1 - Nateglinide-containing preparation reduced in bitterness - Google Patents

Abstract

A peroral solid preparation of the quick-acting short-lasting type which gives no feeling of bitterness and retains properties of nateglinide. The peroral solid preparation reduced in bitterness contains nateglinide and a water-soluble polymer, and is characterized by containing the water-soluble polymer in an amount of 0.3-6 parts by weight, in terms of solid amount, per part by weight of the nateglinide.

Description

 Specification

 Nateglinide-containing preparation with reduced bitterness

 Technical field

 [0001] The present invention relates to an oral solid preparation of nateglinide useful as a diabetic drug.

 Background art

 [0002] Nateglinide [Compound name: N— (Trans-4 isopropyl cyclohexyl carbo- ol) -D-Fu-lualanin] (Japanese Patent Publication No. 4-15221) is rapidly administered by oral administration before meals. It has an excellent effect of being absorbed into blood and improving postprandial hyperglycemia (fast-acting, short-acting type), and is actually used in clinical settings as a treatment for diabetes.

 However, since nateglinide drug substance itself has a very strong bitter taste, when used as an oral preparation, it was necessary to reduce the bitter taste by coating the surface of the tablet.

 By the way, when considering a pharmaceutical from a patient's viewpoint, the ease of ingestion is calculated | required. Nateglinide is an excellent drug to improve postprandial hyperglycemia and therefore requires pre-meal administration. However, conventional preparations require water intake at the same time as the drug at the time of administration, and nateglinide-containing preparations that do not require water at the time of intake have been required. In recent years, oral preparations that do not require water when taken have been developed for oral preparations. Among these, a formulation called an intraoral (fast) disintegrating tablet is known which is disintegrated in the oral cavity and then absorbed in the digestive tract!

 However, since nateglinide drug substance has a very strong bitter taste as described above, when an orally disintegrating tablet is produced by the usual method, it has a bitter taste in the oral cavity at the time of taking it, giving the user unpleasantness and practical use. There was a problem above. In addition, there are several known powers of preparations containing nateglinide so far that have solved the above problems (Patent Documents 2 to 6).

[0003] Patent Document 1: Japanese Patent Publication No. 4 15221

 Patent Document 2: WO98Z22105

 Patent Document 3: WOO 1/21159

Patent Document 4: WO0lZ47557 0

 Disclosure of the invention

 Problems to be solved by the invention

[0004] An object of the present invention is to provide a nateglinide-containing oral solid preparation that does not give a bitter taste and maintains the fast-acting short-term properties of nateglinide.

 Means for solving the problem

[0005] As a result of diligent studies to solve the above problems, it was found that an oral solid preparation with reduced bitterness can be produced by using a specific amount of a water-soluble polymer with respect to nateglinide. It came to complete.

 That is, the present invention is an oral solid preparation containing nateglinide and a water-soluble polymer, characterized by containing 0.3 to 6 parts by weight of the water-soluble polymer in terms of solid content with respect to 1 part by weight of nateglinide. The oral solid preparation is provided.

 The present invention also relates to an oral solid preparation with reduced bitterness containing nateglinide and a water-soluble polymer, comprising 0.3 to 6 parts by weight of the water-soluble polymer in terms of solid content per 1 part by weight of nateglinide. The oral solid preparation is provided.

 The present invention is also an oral solid preparation containing nateglinide and a water-soluble polymer, comprising a step of dissolving nateglinide and a water-soluble polymer in an organic solvent, and a step of forming a granular substance from the obtained solution! Provided is a method for producing an oral solid preparation with reduced bitterness.

 The invention's effect

 [0006] In a preparation containing nateglinide, which is a diabetic drug, it has become possible to provide a preparation that has a bitter taste reduction and also has the fast-acting short-time properties of nateglinide. Can be used by disintegrating in the mouth.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0007] Nateglinide contained in the oral solid preparation of the present invention can be synthesized according to the method described in Japanese Patent Publication No. 4-15221. The crystal form used is not particularly limited. Force H type or B type is preferred. H type is particularly preferred from the viewpoint of stability.

 The water-soluble polymer contained in the oral solid preparation of the present invention is a polymer having a weight average molecular weight of preferably about 1,000 to about 2 million, more preferably about 10,000 to about 200,000, and at 25 ° C. The solubility in water or any aqueous medium such as an aqueous solution showing acidity or alkalinity is preferably 0.1 lgZlOOmL or more.

 Specifically, methylcellulose and hydroxypropyl pill cellulose described in the Japanese Pharmacopoeia or the US Pharmacopoeia (including 53.4-77.5% of hydroxypropoxyl group when dry product is quantified), hydroxypropyl methylcelluloses (For example, hydroxypropyl methyl senol p-ace 2208, 2906, 2910), positive bi-redo, n (f column; t is p-bi-no-redo, N K2 5, K30, Κ90, etc.), copolydon, polybulu alcohol , Aminoalkyl metaatreate copolymer, polyburacetal jetylaminoacetate, etc., preferably methinoresenorelose, hydroxypropinoresenorelose, hydroxypropinoremethinoresenolate 2910 .

 The amount of the water-soluble polymer added is 0.3 to 6 parts by weight, preferably 0.5 to 3 parts by weight, in terms of solid content, per 1 part by weight of nateglinide.

 It is preferable to further add a disintegrating agent to the oral solid preparation of the present invention in order to maintain the fast-acting short-time nature of nateglinide. Disintegrants include sodium carboxymethyl starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose (5. 0 to 16.0% included (see Japanese Pharmacopoeia 13th revision D— 885 to D—888), partially alpha-ized starch, etc., with crospovidone, carmellose and croscarmellose sodium being particularly preferred.

 The amount of the disintegrant added is preferably 0.01 to 16 parts by weight, and preferably 0.1 to 4 parts by weight with respect to 1 part by weight of nateglinide.

 The oral solid preparation of the present invention is preferably in the form of an orally disintegrating tablet.

In the oral solid preparation of the present invention, additives used in normal oral preparations can be used as other ingredients, and although not particularly limited, sugars, starches, crystalline cell mouths and the like are added. excipients; binder; a lubricant, such as magnesium stearate, talc; _P H adjusting agent; Coloring agents; flavoring agents such as saccharides and menthol can be blended.

 In order to produce an oral solid preparation with reduced bitterness according to the present invention, it can be produced by using a conventional method. For example, a mixture or granulated product of nateglinide and a water-soluble polymer is used as a tablet, capsule or It can be provided as a formulation such as granules or powders. When the oral solid preparation of the present invention is provided as a tablet, it is provided as a tablet by optionally adding a disintegrant or other additives to a mixture or granulated product of nateglinide and a water-soluble polymer and then compressing the tablet. it can. Specifically, the powder obtained by mixing the composition with an appropriate mixer can be produced by tableting, or can be produced by dry granulation (such as compaction granulation) or wet granulation (fluidized bed). (Granulation method, agitation granulation method, extrusion granulation method, etc.) or a spray-drying method, etc., and a granulated product is prepared. Can be manufactured by locking.

 In the case of the wet granulation method, nateglinide and the water-soluble polymer used in the present invention are usually dissolved in a suitable organic solvent. Examples of the organic solvent that can be used include ethanol, ethanol water having an ethanol content of 10 to 90%, and a mixed solvent of dichloromethane and ethanol (mixing ratio (volume ratio) = for example, 1: 9 to 9: 1). .

 In the wet granulation method, a layer is formed by coating core particles composed of a disintegrant or the like with a solution in which nateglinide and a water-soluble polymer are dissolved in an organic solvent together with other components as necessary. Thus, the granular material can be obtained as a granulated product.

 In the wet granulation method, core particles containing excipients such as crystalline cellulose are coated with nateglinide to form an inner layer of nateglinide, and the resulting granular material is further combined with other components as necessary. An outer layer is formed by coating with a water-soluble polymer that can be used in the present invention, and finally a granular material can be obtained as a granulated product.

 Also in the case of the spray drying method, nateglinide and the water-soluble polymer used in the present invention are usually dissolved in a suitable organic solvent. As the organic solvent, the same solvents as described for the wet granulation method can be used.

 Regarding tableting, when producing orally disintegrating tablets, it is preferable to tablet at low pressure, preferably 50 NZm 2 or less.

Furthermore, the tablets can be film-coated as necessary. Film co For example, hydroxypropylmethylcellulose 2910 can be used as the tempering agent.

 [0010] When the oral solid preparation of the present invention is provided as a granule or powder, the dry granulation method is also used.

 (Compressed granulation method, etc.) or wet granulation method (fluidized bed granulation method, stirring granulation method, extrusion granulation method, etc.) or a normal granulation method such as spray-drying production method. .

 The oral solid preparation of the present invention produced by these methods can be ingested without the need for water compared to conventional preparations, has reduced bitterness when disintegrated in the oral cavity, and is compared with the current nateglinide tablets. It is a preparation that can ensure bioequivalence in in vitro evaluation.

[0011] In the oral solid preparation of the present invention, in particular, the oral solid preparation in the form of a powder containing 1 part by weight of aminoalkyl methacrylate copolymer E in terms of solid content with respect to 1 part by weight of nateglinide. Favored ,.

 In particular, a core containing carmellose and crospovidone, and an outer layer composed of 1 to 2 parts by weight of hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose or polybulurpyrrolidone in terms of solid content per 1 part by weight of nateglinide Oral solid preparations in the form of a powder containing are also preferred. Here, the oral solid preparation in which the outer layer is composed of 2 parts by weight of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose or polybutylpyrrolidone in terms of solid content with respect to 1 part by weight of nateglinide is particularly preferred. Particularly preferred are oral solid preparations which are also composed of 1 part by weight of hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone in terms of conversion.

 In particular, it is an oral solid preparation in the form of granules containing a crystalline cellulose core, an inner layer of nateglinide, and an outer layer of 0.7 parts by weight of aminoalkyl methacrylate copolymer E in terms of solid content with respect to 1 part by weight of nateglinide. Also preferred.

In particular, nateglinide, orally in the form of a tablet, containing 1.1 parts by weight of methylcellulose and croscarmellose sodium in terms of solid content with respect to 1 part by weight of nateglinide, and having a hardness of 20-30 N / m ² Solid formulations are also preferred where oral solid formulations with 1 part by weight methylcellulose and 0.1 parts by weight croscarmellose sodium are more preferred Among these, an oral solid preparation in which nateglinide is dispersed in a water-soluble polymer is preferable. As a method for producing such an oral solid preparation, for example, it is preferable to use a solvent removal method in which nateglinide and a water-soluble polymer are dissolved in an organic solvent and then the solvent is removed. An oral solid preparation with reduced bitterness containing nateglinide and a water-soluble polymer, comprising the steps of dissolving nateglinide and a water-soluble polymer in an organic solvent and forming a particulate material from the resulting solution (e.g. spray drying). The method of manufacturing is preferred U ヽ.

[0012] When the oral solid preparation of the present invention is in the form of granules, the average particle size of the particles is preferably 0.05 to 0.85 mm.

When the oral solid preparation of the present invention is in the form of an orally disintegrating tablet, its hardness is preferably 50 NZm ² or less, more preferably ²⁰ to 30 NZm ² .

 The oral solid preparation of the present invention is preferably a preparation that is rapidly disintegrated by saliva in the oral cavity and can be swallowed as it is. But of course it can be taken with water. It is desirable that the preparation of the present invention disintegrates within 60 seconds when placed in the oral cavity.

 Example

[0013] Examples 1 to 6

 Nateglinide and the water-soluble polymer shown in Table 1 were mixed thoroughly in a 1: 1 ratio, and nateglinide-containing powder preparation was obtained by crushing with a crushing granulator (Roller 1 Compactor 1 and Turbo Industries). When the taste evaluation of this powder formulation was carried out in the same manner as the taste evaluation described later, the bitterness was reduced.

 Examples 7-12

 Nateglinide and the water-soluble polymer shown in Table 2 were dissolved in an organic solvent (ethanol, 50% ethanol water, or dichloromethane Z ethanol = 6: 4) so that the solid content was 10% by weight. Sprayed with a spray dryer (GS310, Yamato Kagaku) to obtain a spray-dried nateglinide-containing powder formulation.

 Examples 13-16

A solution of nateglinide and the water-soluble polymer shown in Table 3 dissolved in an organic solvent (dichloromethane Zethanol = 6: 4) was mixed using a fluid bed granulator (FLO-1 type, Freund Industries). 3 was sprayed in the fluidized bed to the powder described in the addition part during granulation to obtain a granulated product. Additives described in the post-addition part were added to the obtained granulated product to obtain a nateglinide-containing powder formulation.

 Example 17

 Water-soluble polymers listed in Table 4 are fluidized-bed granulator (FLO— 1) on the core particles layered by spraying ethanol aqueous solution of nateglinide onto spherical core particles of crystalline cellulose (Selfia CP507, Asahi Kasei Co., Ltd.). Type, Freund Sangyo Co., Ltd.) to obtain nategrid-containing film-coated granules.

 Taste evaluation

 Taste evaluation by sensory evaluation was performed on the powder formulations obtained in Examples 1 to 17 above. Evaluation was conducted by dissolving a preparation corresponding to 10 mg of nateglinide in the oral cavity to evaluate the taste. In addition, the evaluation was performed in five stages. Table 5 shows the evaluation criteria, and Tables 2 to 4 show the taste evaluation results.

 [0014] [Table 1]

 In the table, the amount of each component added.

 Hydroxypropyl-no-ufci-relose 2910 (Brand name TC ~ 5R,! Km)

 Aminoalmethacryl L ~ Tocoho. U Ma ~ E (trade name Eudraginto E-100, Rame

 Methyl Cell Kouichisu (trade name S "4, manufactured by Shin-Etsu Chemical Co., Ltd.)

 Polyvinyli JW Riddon (Brand name Corrid O, BASF Ne)

 Copolidon (trade name Copoli A A64, BASF¾

 Hydroxypropyl Cell Koichi 2910 (trade name HPC- SL, Nippon Soda)

[0015] [Table 2]

[0016] [Table 3]

[0017] [Table 4] Method of addition Ingredient Example 1 7

 Nazgerinito '50

 Crystalline cellulose 300

Aminoalkylmethacrylate § click ¹ Le - ^DOO] e. Lima-Ε

 Core particle part Water-soluble polymer

 35

 Etazur

 Solvent

 350

 Taste evaluation Bitterness 5

 Aftertaste 4

 Aftertaste 4

 Total score 13

 In the table, the amount of each ε added indicates weight Ρ.

 The water-soluble polymers are as shown in Table 2 footnotes.

[0018] [Table 5]

[0019] As described above, the formulation of the present invention provides an oral solid formulation containing nateglinide with low bitterness.

 As a result of sensory evaluation, the strength and bitterness specific to nateglinide could be reduced by dispersing nateglinide in the water-soluble polymer.

 Example 18

 A solution of nateglinide and the polymer shown in Table 6 dissolved in an organic solvent (dichloromethane Z ethanol = 6: 4) was prepared using the fluidized bed granulator (FLO-1 type, Freund Corporation) as shown in Table 6. It was sprayed in the fluidized bed to the powder described in the addition part at the time of granulation to obtain a granulated product. Additives described in the post-addition part were added to the resulting granulated product, and nateglinide-containing orally disintegrating tablet preparations were obtained by low-pressure tableting.

 For the orally disintegrating tablets obtained in the above examples, taste evaluation by sensory evaluation (1 tablet dissolved in the oral cavity) and bioequivalence evaluation by in vitro evaluation (dissolution test, aseptic) 90 mg tablet ). Table 6 shows the evaluation results.

[0020] [Table 6] Table 6

 In the table, the amount of component added is in parts by weight unless otherwise specified. The water-soluble polymers are as shown in Table 2 footnotes.

 V ro evaluation (dissolution test) is evaluated with J P 1 'J P 2 test solution described in Japanese Pharmacopoeia

[0021] As shown in Table 6, it was confirmed that the strong bitterness peculiar to nateglinide was reduced and the dissolution was equivalent in the Vitro evaluation. From this, it is understood that an orally disintegrating tablet that can reduce the bitter taste of nateglinide and ensure bioequivalence with the current nateglinide tablet has been developed.

 [0022] Comparative Example 1

 One tablet of nateglinide (“Fastic” 90 mg tablet) that is currently on the market was dissolved in the oral cavity and taste evaluation was performed. As a result of the evaluation, the bitterness was very strong, so the tablet was discharged on the way. The aftertaste also remained for several hours.

[0023] [Table 7] Fusui 90m

Note: The bitterness was so strong that it was discharged without dissolving the whole amount. Comparative Example 2

 Dissolve 10 mg of nateglinide drug substance corn starch 10 mg (containing nateglinide lmg) in the mouth and follow the taste evaluation described above! I evaluated it.

 As a result, the bitterness was 1, the presence or absence of aftertaste: 3, the aftertaste: 1, and the total: 5.

 The bitterness was strong and the aftertaste remained for several hours.

Claims

The scope of the claims  [I] An oral solid preparation containing nateglinide and a water-soluble polymer, wherein the water-soluble polymer is contained in an amount of 0.3 to 6 parts by weight in terms of solid content with respect to 1 part by weight of nateglinide. Oral solid formulation.  [2] An oral solid preparation with reduced bitterness containing nateglinide and a water-soluble polymer The oral solid preparation comprising 0.3 to 6 parts by weight of a water-soluble polymer in terms of solid content with respect to 1 part by weight of nateglinide. [3] The oral solid preparation according to claim 1 or 2, which contains 0.5 to 3 parts by weight of a water-soluble polymer in terms of solid content with respect to 1 part by weight of nateglinide. [4] The water-soluble polymer may be selected from methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcelluloses, polyvinylpyrrolidone, copolydon, polyvinyl alcohol, and aminoalkyl metaacrylate copolymer. The oral solid preparation according to any one of the above. 5. The oral solid preparation according to any one of claims 1 to 3, wherein the water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose 2910.  6. The oral solid preparation according to any one of claims 1 to 5, further comprising a disintegrant. [7] Disintegrants are selected from the group forces of sodium carboxymethyl starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose and partially alpha-unified starch The oral solid preparation according to claim 6. 8. The oral solid preparation according to any one of claims 1 to 7, wherein the preparation is in the form of an orally disintegrating tablet.  [9] The oral solid preparation according to claim 8, which disintegrates within 60 seconds by saliva in the oral cavity.  [10] The oral solid preparation according to claim 9, which contains 1 part by weight of aminoalkyl methacrylate copolymer E in terms of solid content with respect to 1 part by weight of nateglinide and is in the form of powder. [II] Solid containing carmellose and crospovidone and 1 part by weight of nateglinide 11. The oral solid preparation according to claim 10, which is in the form of a powder containing 1 part by weight of an outer layer composed of 1 part by weight of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone. 12. The condylar form comprising a crystalline cellulose core, an inner layer of nateglinide, and an outer layer of 0.7 parts by weight of an aminoalkyl methacrylate copolymer E in terms of solid content with respect to 1 part by weight of nateglinide. Oral solid formulation. [13] A tablet of nateglinide, containing 1 part by weight of methylcellulose and 0.1 part by weight of croscarmellose sodium in terms of solid content with respect to 1 part by weight of nateglinide and having a hardness of 20 to 30 NZm ² The oral solid preparation according to claim 12, which is in a form. [14] A method for producing an oral solid preparation containing nateglinide and a water-soluble polymer, comprising a step of dissolving nateglinide and a water-soluble polymer in an organic solvent, and a step of forming a granular substance from the obtained solution. 15. The production method according to claim 14, wherein the organic solvent is ethanol, ethanol water having an ethanol content of 10 to 90%, or a mixed solvent of dichloromethane and ethanol.