WO2005094812A1 - Nateglinide-containing preparation - Google Patents

Abstract

It is intended to provide a nateglinide-containing preparation (in particular a preparation disintegrated in the oral cavity) having a lessened bitterness which is a medicinal composition containing nateglinide as the active ingredient and characterized by further containing at least one member selected from the group consisting of organic acids, inorganic acids, sweeteners and perfumes.

Description

 Nateglinide-containing preparations Technical field

 The present invention relates to a formulation of nateglinide useful as a diabetes drug, and more particularly to an orally disintegrating tablet of nateglinide.

 Nateglinide [N-Dragon Compound: N- (trans-4-isopropylcyclohexylcarbol) -D-phenalanine] has an excellent hypoglycemic effect by oral administration and is known to be useful as a therapeutic drug for diabetes. (Patent Document 1).

 Since nateglinide drug substance has a very strong bitter taste, when used as an oral preparation, it was necessary to mask the bitter taste by coating the surface of the tablet. On the other hand, when considering drugs from the patient's point of view, ease of ingestion is required. Nateglinide is an excellent drug for improving postprandial hyperglycemia, and thus required administration before meals. However, conventional preparations require water to be taken at the same time as the drug at the time of administration, and there has been a demand for a preparation that does not require water at the time of ingestion.

 On the other hand, in recent years, oral preparations that do not require water when taken have been developed. Among these, a preparation called an orally (rapidly) disintegrating tablet in which a drug is disintegrated in the oral cavity and then absorbed in the digestive tract is known.

 By the way, since nateglinide drug substance has an extremely strong bitter taste as described above, when an orally disintegrating tablet is produced by a usual method, it has a bitter taste in the oral cavity at the time of ingestion, which causes discomfort to the user and is not practical. Was a problem. Up to now, there has been known an invention relating to a preparation containing nateglinide, but there is no known invention relating to an orally disintegrating tablet having reduced bitterness. (Patent Documents 2 to 6)

[0002] Patent Document 1: Japanese Patent Publication No. 4 15221

 Patent Document 2: WO98Z22105

 Patent Document 3: WOO 1/21159

 Patent Document 4: WO0lZ47557

 Patent Document 5: WO02Z34254

Patent Document 6: WO02Z40010 Disclosure of the invention

 An object of the present invention is to provide a pharmaceutical preparation containing nateglinide as an active ingredient, which does not cause bitterness and / or a preparation.

 As a result of intensive studies to solve the above-mentioned problems, bitterness was reduced even when disintegrated in the oral cavity by containing nateglinide and at least one of organic or organic acids, sweeteners, and flavors. It has been found that a preparation can be provided, and the present invention has been completed.

 That is, the present invention provides a pharmaceutical composition containing nateglinide as an active ingredient, further comprising at least one selected from the group consisting of an organic acid or an inorganic acid, a sweetener and a flavoring agent. Things. In this case, the organic acid is selected from the group consisting of ascorbic acid, citric acid, anhydrous citric acid, succinic acid, tartaric acid, fumaric acid, and malic acid, and the inorganic acid is sodium hydrogen phosphate or calcium hydrogen phosphate; Preferably, the sweetener is saccharin sodium or aspartame, the flavor is L-menthol or peppermint, and furthermore, the organic acid is caffeic acid, the inorganic acid is sodium hydrogen phosphate, and the sweetener is sodium saccharin sodium. And the flavor is preferably L-menthol.

 Further, the present invention is a pharmaceutical composition containing nateglinide as an active ingredient, which composition further contains an organic or inorganic acid, a sweetener, and a flavor. In this case, the organic acid is ascorbic acid, citric acid, citric anhydride, succinic acid, tartaric acid, fumaric acid, or malic acid, the inorganic acid is sodium hydrogen carbonate or calcium hydrogen phosphate, and the sweetener is sucrose. It is preferable that the flavoring agent is L-menthol or peppermint, and furthermore that the organic or inorganic acid is citric acid of an organic acid or sodium hydrogen phosphate of an inorganic acid. Is preferably saccharin sodium and the flavor is L-menthol.

 Further, the above composition is preferably a pharmaceutical composition which is an orally disintegrating tablet or an orally disintegrating tablet having reduced bitterness.

 According to the present invention, it has become possible to provide a preparation containing nateglinide, which is a diabetic drug, which does not give a bitter taste even when disintegrated in the oral cavity.

BEST MODE FOR CARRYING OUT THE INVENTION Nateglinide contained in the pharmaceutical composition of the present invention can be synthesized according to the method described in Japanese Patent Publication No. 4-15221 and the like. The crystal form to be used is not particularly limited. H-type or B-type described in Japanese Patent No. 2508949 is preferred, and particularly H-type is particularly preferable in view of stability.

 The organic acid contained in the pharmaceutical composition of the present invention refers to an organic compound having an acid property and in the form of a salt, for example, an alkali metal such as sodium and potassium, and an alkaline earth such as calcium and magnesium. It may be in the form of a salt with a metal or an amine such as triethanolamine. Specific examples include ascorbic acid, citric acid, citric anhydride, succinic acid, tartaric acid, fumaric acid, malic acid and their sodium and potassium salts. Ascorbic acid, citric acid, citric anhydride, tartaric acid and malic acid are more preferable in the form of an acid, and cunic acid is particularly preferable from the viewpoint of reducing bitterness. The inorganic acid contained in the pharmaceutical composition of the present invention refers to an acid containing no carbon atom, which is in the form of a salt, for example, an alkali metal such as sodium and potassium, an alkaline earth metal such as calcium and magnesium, and the like. Alternatively, it may be in the form of a salt with an amine such as triethanolamine. Specific examples include phosphoric acid, carbonic acid, sodium hydrogen phosphate, calcium hydrogen phosphate, calcium carbonate and the like. In a salt form, sodium hydrogen phosphate and calcium hydrogen phosphate are more preferable, and sodium hydrogen phosphate is particularly preferable from the viewpoint of reducing bitterness.

 The sweetener contained in the pharmaceutical composition of the present invention refers to an additive or a seasoning used for imparting sweetness to a pharmaceutical or food, and specifically includes sugars, sugar alcohols, saccharin, saccharin sodium, and aspartame. And saccharin sodium and aspartame are preferred, and saccharin sodium is particularly preferred from the viewpoint of reducing bitterness.

The fragrance contained in the pharmaceutical composition of the present invention refers to a substance added to add aroma to pharmaceuticals, foods, cosmetics, etc., and specifically, L-menthol, peppermint powder, melon, citrus fruits, berries, pineapple, vanilla. And coffee, cola, cider, cider, milk, cinnamon, and L-menthol and peppermint powder are preferred, and L-menthol is particularly preferred from the viewpoint of reducing bitterness. In particular, it is preferable to contain citric acid, saccharin sodium and L-menthol. Examples of the dosage form of the pharmaceutical composition of the present invention include powders, granules, fine granules, tablets, and the like, and preferred examples include granules, fine granules, and tablets. The pharmaceutical composition of the present invention is preferably in the form of a tablet, and the content of nateglinide per tablet is preferably 30 mg or more!

 In formulating the pharmaceutical composition of the present invention, additives used in ordinary oral preparations can be used as other components, and are not particularly limited, but include excipients, disintegrants, binders, Lubricants, coloring agents and the like can be appropriately compounded. When the pharmaceutical composition of the present invention is in the form of an orally disintegrating tablet, it is preferable to further add a disintegrant in order to rapidly disintegrate the tablet in the oral cavity. Disintegrators include sodium carboxymethyl starch, canolemelose, canolemelose sodium, canolemelose kanoresum, cross-force noremelose sodium, crospovidone, low-substituted hydroxypropylcellulose (hydroxypropyl group 5.0 to 16.0%; see Japanese Pharmacopoeia 13th revision D—885 to D888), partially alpha-monostarch, and the like, with carmellose, carboxymethyl starch sodium and crospovidone being particularly preferred. ,.

 The amount of the disintegrant added is preferably 1% by weight to 10,000% by weight, more preferably 5% by weight to 1000% by weight, and still more preferably 10% by weight to 400% by weight, based on nateglinide. is there.

 The amount of other additives to nateglinide when producing the pharmaceutical composition of the present invention is not particularly limited as long as the object of the present invention can be achieved. 0.01-2000 wt%, 0.01-4500 wt% for inorganic acids, 0.01-45,000 wt% for sweeteners, 0.001-200 wt% for flavors, preferably 0.1-500 wt% for organic acids, 0.1-500 for inorganic acids % By weight, 0.1-500% by weight of sweetener and 0.01-50% by weight of flavor. More preferably, the content is 1 to 200% by weight of an organic acid, 1 to 200% by weight of an inorganic acid, 1 to 100% by weight of a sweetener, and 1 to 15% by weight of a flavor. The total amount of soybean curd of these soups is 0.001 ~

The content is 50,000% by weight, preferably 0.01 to 5000% by weight, more preferably 0.1 to 1000% by weight, and still more preferably 1 to 500% by weight.

In particular, cunic acid is added to nateglinide by 100 to 200% by weight, Pharmaceutical compositions containing up to 200% by weight and 5 to 15% by weight of L menthol are preferred. By producing the above composition, a nateglinide-containing pharmaceutical composition having reduced bitterness can be provided. The pharmaceutical composition of the present invention can ensure bioequivalence in in vitro evaluation with current nateglinide tablets.

[0006] The method for producing the pharmaceutical composition of the present invention can be produced by tableting a simple mixture of a drug and an additive, and the powder before tableting can be produced by dry granulation or wet granulation. Granulation method and fluidized bed granulation method can be used.

On the other hand, in order to produce an orally disintegrating tablet having reduced bitterness using the above composition, it can be produced by using a usual method.For example, a mixture of the composition or a granulated product is produced under low pressure, for example, A tableting method at 50 NZm ² or less can be used. Specifically, after the composition is mixed with an appropriate mixer, it can be manufactured by low-pressure tableting, or can be produced by dry granulation (pressure granulation, etc.) or wet granulation (fluid bed granulation). Granules can be prepared by a usual granulation method such as a granulation method, a stirring granulation method, etc.) and tableted under low pressure.

Orally disintegrating tablets produced by these methods can be ingested without the need for water as compared with the conventional preparations, and have a reduced bitterness even when disintegrated in the oral cavity. The orally disintegrating tablet preferably has a hardness of 50 NZm ² or less, more preferably ²⁰ to 30 NZm ² . It is a drug that is rapidly disintegrated by saliva in the oral cavity and can be swallowed with saliva. The formulations of the present invention can disintegrate within 60 seconds.

 Example

 Next, the present invention will be described in more detail with reference to Examples and Comparative Examples.

 (Examples 1 to 21)

 The compound shown in Table 1 and the compounding ratio of the weight were added to a miller (Mirther IMF700G, Iwatani Corporation) and mixed for 2 minutes to obtain a mixed powder.

 (Comparative Examples 1-2)

 The compound shown in Table 1 and the compounding ratio of the weight were added to a miller (Mirther IMF700G, Iwatani Corporation) and mixed for 2 minutes to obtain a mixed powder.

[0008] [Table 1]

(Example 22)

 The mixed powders obtained in Examples 1 to 21 and Comparative Examples 1 and 2 were subjected to taste evaluation by sensory evaluation. The evaluation was performed in five stages. Table 2 shows the evaluation criteria and Table 3 shows the taste evaluation results.

 [0010] [Table 2] Stage Bitterness Aftertaste Aftertaste

 5 Not bitter at all None preferred

3 Slightly bitter Somewhat incompatible Neither bitter or bitter

 1 is unpleasant

Strong [0011] [Table 3]

[0012] As can be seen from Table 3, bitterness could be reduced by adding at least one of organic acids, inorganic acids, sweeteners and flavors.

 Furthermore, it was recognized that the combination of these improved not only bitterness but also aftertaste.

 (Examples 22 to 24)

After adding the appropriate amount of purified water and granulating with a stirring granulator (Dalton, Power-Pander PK150) at the compound and blending ratio (weight) described in the granulation section in Table 4, the fluidized bed dryer ( Dried in Freund Industries, FLO-1). After forcible sieving with a sieve opening of lmm, the compound described in the post-addition part in Table 4 is mixed in a bag to prepare granules for tableting. The obtained granules for tableting were tableted at a low pressure (20 to 30 NZm ² ) with a tableting machine (Hata Tekkosho, HTAP38LII, φ7.5 mm) to obtain orally disintegrating tablets.

[0014] [Table 4] Example 2 2 Class 2 3 Implementation '51 2 4

 Natec "Lini 30 30 30

 30 30 30

 Grain saccharin sodium 30 30 30

 L-Tole 3 3 3

 Department D-Man-Tall 30 30 30

 Post-crystalline cellulose 30 30 30

 Mac stearate "nesium 1.5.1.5.1.5

 Carmellose 45

 Carpho "Ximethylsta" Sanoa 22

 Crosshairs 13

The orally disintegrating tablets obtained in the above Examples were evaluated for taste and measured for orally disintegrating time according to the evaluation criteria described in Table 2. The taste was evaluated on a five-point scale. Oral disintegration time The disintegration time when this tablet was put in the oral cavity was measured. Table 5 shows the evaluation results. As shown in Table 5, the orally disintegrating tablets containing an organic acid (or inorganic acid), a sweetener, and a flavoring agent in the same mixing ratio as the mixed powder and a disintegrant are added. It has the same bitterness-reducing effect as, and has a fast disintegration property with an oral disintegration time of 60 seconds or less.

[Table 5] Example 22 Example 2 23 Example 2 4

 Taste 5 5 5

 Aftertaste 3 3 3

 Aftertaste 3 2 3

 11 10 11

 50 seconds 51 seconds, 33 seconds

Claims

The scope of the claims  [I] The pharmaceutical composition described above, which further comprises at least one selected from the group consisting of an organic or inorganic acid, a sweetener and a flavor, in a pharmaceutical composition containing nateglinide as an active ingredient.  [2] The organic acid is selected from the group consisting of ascorbic acid, citric acid, citric anhydride, succinic acid, tartaric acid, fumaric acid, and malic acid, and the inorganic acid is selected from sodium hydrogen phosphate and hydrogen phosphate. The pharmaceutical composition according to claim 1, wherein the sweetener is any of sodium saccharin or aspartame, and the flavor is either L-menthol or peppermint.  [3] The pharmaceutical composition according to claim 1, wherein the organic acid is cacaic acid, the inorganic acid is sodium hydrogen phosphate, the sweetener is sodium saccharin, and the flavoring power is L-menthol. [4] The pharmaceutical composition according to claim 1, further comprising an organic or inorganic acid, a sweetener, and a flavor. 5. The pharmaceutical composition according to claim 3, wherein the organic acid or the inorganic acid is citric acid, an organic acid, the sweetener is saccharin sodium, and the flavor is menthol. 6. The pharmaceutical composition according to claim 3, wherein the organic acid or the inorganic acid is an inorganic acid sodium hydrogen phosphate, the sweetener is saccharin sodium, and the flavor is L-menthol. [7] A claim comprising at least one selected from the group consisting of an organic acid or an inorganic acid, a sweetener and a flavorant, and the total amount thereof is 0.001 to 50,000% by weight based on nateglinide. Term 7. The pharmaceutical composition according to any one of 1 to 6. [8] The composition according to claim 1, comprising 0.01 to 2000% by weight of an organic acid, 0.01 to 4500% by weight of an inorganic acid, 0.01 to 45,000% by weight of a sweetener, and 0.001 to 200% by weight of nateglinide. 7. The pharmaceutical composition according to any one of claims 1 to 7. [9] The pharmaceutical composition according to any one of claims 1 to 8, which contains 100 to 200% by weight of citrate, 050 to 200% by weight of sodium saccharin, and 5 to 15% by weight of 1-menthol based on nateglinide. object.  [10] The pharmaceutical composition according to any one of claims 1 to 9, which is an orally disintegrating tablet.  [11] The pharmaceutical composition according to claim 10, which is an orally disintegrating tablet having reduced bitterness. 12. The pharmaceutical composition according to claim 10, further comprising a disintegrant. [13] The pharmaceutical composition according to claim 12, wherein the disintegrant is selected from the group consisting of sodium carboxymethyl starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone and a low-substituted hydroxypropylcellulose. object.  [14] The pharmaceutical composition according to any one of claims 11 to 13, which is disintegrated in the oral cavity by saliva within 60 seconds.