WO2000010557A1 - Stabilized solid preparations - Google Patents

Abstract

Stabilized solid preparations of (R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride which are excellent as drugs. These stabilized solid preparations of the above compound are characterized by, for example, containing sugar alcohols and starches as fillers.

Description

 Specification

 Stabilized solid dosage technology

 The present invention provides (R) — (1) -3 ′ — (2—amino: I—hydroxyxetil) -14′—fluoromethansulfonanilide hydrochloride having the following structure [I]: (Hereinafter referred to as “the compound of the present application”).

背 景 技 術

Background technology

 The compound of the present invention is an effective therapeutic agent for a disease such as urinary incontinence at a very small dose of 0.2 to 3.Omg per adult, and is currently being developed by the present applicant. It is a known substance.

 Since the dose of the compound of the present invention is extremely small as described above, a solid formulation of the compound of the present invention is secured by adding an excipient and the like in order to secure an appropriate size and weight, and to reduce the weight deviation. It is necessary to granulate.

The compound of the present invention is very stable in itself, and general excipients and the like used in pharmaceutical preparations are inert. The compound of the present invention is It is supposed to be constant. However, it has been found that there is a problem with respect to the stability of the compound of the present invention even when the compound of the present invention is formed into a solid preparation by an ordinary method.

 Disclosure of the invention

 An object of the present invention is to provide a stable solid preparation of the compound of the present invention.

 The present inventors have conducted intensive studies and as a result, have found that the above-mentioned problems can be solved by using a sugar alcohol and starch as excipients, and have completed the present invention.

 One aspect of the present invention is a stabilized solid preparation of the compound of the present invention, which comprises a sugar alcohol and starch as excipients (hereinafter, referred to as “the solid preparation of the present invention”). The solid preparation of the present invention further containing an organic acid can be mentioned as one of the present invention, and the stability thereof is usually higher than that of a preparation not containing an organic acid. The solid preparation of the present invention can further contain at least one selected from the group consisting of a disintegrant, a binder, and a lubricant. In the solid preparation of the present invention, those containing a binder and a lubricant are preferred.

 Examples of the dosage form of the solid preparation of the present invention include tablets, powders, granules, fine granules, and capsules. Tablets are particularly suitable. In the present invention, examples of the “sugar alcohol” as an excipient include mannitol, xylitol, sorbitol, and erythritol. Of these, mannitol is particularly suitable.

Examples of the “starch” as an excipient include corn starch, wheat starch, rice starch, and potato starch. In this, Corn starch is suitable.

 Examples of the “organic acid” include tartaric acid, phthalic acid, lingic acid, citric acid, fumaric acid, and succinic acid. Of these, tartaric acid is suitable.

 Examples of the “disintegrant” include low-substituted hydroxypropyl cellulose, starches and carmellose. Examples of the starch include the same starch as the excipient.

 Examples of "binders" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyridone, starches, arabia gum, gelatin, glucose, sucrose, traga And sodium alginate. Examples of the starch include the same starch as the excipient.

 Examples of the “lubricant” include stearic acid, magnesium stearate, calcium stearate, and talc. In the present invention, as a stabilized solid preparation, the residual ratio of the compound of the present invention is 90% after 3 months under the condition of 60 ° C, or at 40 and 6 months under the condition of 75% relative humidity. The above can be mentioned, preferably those of 95% or more.

The solid preparation of the present invention can be produced by a conventional method according to the selected dosage form after appropriately granulating the compound of the present invention. For example, in the case of tablets, it is preferable to manufacture them by a so-called wet method. Specifically, a prescribed amount of sugar alcohol and starch are charged into a fluidized bed granulator, mixed for a certain period of time, and mixed. Binder with dissolved amount of the compound of the present invention The solution is evenly sprayed on the mixture and granulated. After the granules are sized, a lubricant is added and mixed, and the mixture is compression-molded with a suitable tableting machine to produce the solid preparation (tablet) of the present invention. The solid preparation of the present invention as such a tablet can be subjected to film coating and sugar coating.

 The total content of sugar alcohols and starches in one preparation can be in the range of 70 to 99.999 w / w%, preferably in the range of 90 to 98 w / w%. The content ratio (weight ratio) of the sugar alcohol to the starch is preferably in the range of 1: 9 to 9: 1, and more preferably in the range of 6: 4 to 4: 6.

 The concentration of the compound of the present application in one preparation varies depending on the dosage form and is not particularly limited, but is preferably in the range of 0.001 to 5 w / w%, and more preferably in the range of 0.1 to 1 w / w%. .

 The solid preparation of the present invention can be provided as a therapeutic agent for urinary incontinence and the like.o

 BEST MODE FOR CARRYING OUT THE INVENTION

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

Example 1

Inject 290 g of mannitol (excipient) and 193 g of cornstarch (former) into a fluid bed granulator (MP-01; Baurec, same hereafter), mix for 3 minutes, and mix Then, 180 g of a 7% polyvinyl alcohol solution (binder) in which 3 g of the present compound was dissolved was sprayed and granulated. This granulated product is sized with a feather mill (FM-1; Hosokawa Miclon; the same applies hereinafter), and 2.3 g of magnesium stearate (lubricant) is added to the granulated product. The mixture was then mixed using a V-type mixer, and the mixed granules were compression-molded with a tableting machine (Clean Press Collect 12HUK; Kikusui Seisakusho, the same applies hereinafter) at a compression pressure of 700 kg heavy Z punch and 1 tablet. 130.3 mg of the solid preparation of the present invention (tablet) was prepared.

Example 2

 Mannitol and potato starch were employed as excipients, and a formulation of the present invention (tablet) was prepared in the same manner as in Example 1.

Example 3

 250 g of xylitol (excipient) and 233 g of starch (former) are put into a fluidized bed granulator, mixed for 3 minutes, and then a 7% solution of polyvinyl alcohol in which 1 g of the compound of the present invention is dissolved. (Binder) 180 g was sprayed and granulated. 3.5 g of magnesium stearate (lubricant) was added to the granulated product, mixed with a V-type mixer, and passed through a 24-mesh sieve to prepare a solid preparation (granules) of the present invention.

Example 4

 270 g of mannitol (shape preparation) and 213 g of starch (excipient) are put into a fluidized bed granulator, mixed for 3 minutes, and then polyvinyl alcohol in which 1.5 g of the compound of the present invention is dissolved. 180 g of a 7% solution (binder) was sprayed and granulated. Magnesium stearate (lubricant) (2.7 g) was added to the granulated product and mixed with a V-type mixer. The mixture was filled into the first capsule, and 260 mg of the solid preparation (capsule) of the present invention per capsule was obtained. It was prepared.

Example 5

290 g mannitol (excipient) and 193 g corn starch (excipient) Into a fluidized bed granulator and mixed for 3 minutes, and then spray 180 g of a 7% solution of polyvinyl alcohol (binder) in which 3 g of the compound of the present invention and 0.8 g of tartaric acid (organic acid) are dissolved. And granulated. After granulating the granules with a fuser mill, 2.3 g of magnesium stearate (lubricant) was added, and the mixture was mixed with a Bohle container mixer (PM100, Kotobuki Giken Kogyo Co., Ltd.). Using a tablet machine, 130.5 mg per tablet of the solid preparation of the present invention (tablets) was prepared by compression molding with a compression pressure of 700 kg heavy punch.

Example 6

 2900 g of mannitol (excipient) and 1930 g of corn starch (excipient) were charged into a fluidized bed granulator (WSG-5, Glatt-Okawara Seisakusho) and mixed for 3 minutes. Thereafter, 1800 g of a 7% polyvinyl alcohol solution (binder) in which 30 g of the compound of the present invention was dissolved was sprayed and granulated. The granulated product is sized with a comil (QC-197S, ゥ LEC), 23 g of magnesium stearate (lubricant) is added, mixed with a V-type mixer, and mixed. The granules thus obtained were compression-molded with a tableting machine at a compression pressure of 700 kg / punch to prepare 130.3 mg of the solid preparation of the present invention (tablets) per tablet.

Example 7

Sorbitol (shaping agent) 267.8 g, potato starch (excipient) 191.3 g and low-substituted hydroxypropylcellulose (disintegrant) 23 g were charged into a fluidized bed granulator and mixed for 3 minutes. Thereafter, 180 g of a 7% solution (binder) of hydroxypropyl cellulose in which 3 g of the compound of the present invention was dissolved was sprayed and granulated. This granulated product is sized with a X-mill, then 2.3 g of magnesium stearate (lubricant) is added and mixed with a V-type mixer. Then, the mixed granules were compression-molded with a tableting machine at a compression pressure of a 700 kg heavy punch to prepare 130.5 mg of the solid preparation of the present invention (tablet) per tablet.

Example 8

 270 g of erythritol (excipient) and 213 g of corn starch (excipient) were put into a fluidized bed granulator, mixed for 3 minutes, and thereafter, a polyvinyl alcohol in which 1.5 g of the present compound was dissolved. The mixture was granulated by spraying 180 g of a 7% solution (binder). 2.7 g of magnesium stearate (lubricant) is added to the granulated product and mixed with a V-type mixer to fill No. 1 capsule to prepare 260 mg of the solid preparation of the present invention (capsule) per capsule. Comparative Example 1

 Lactose (excipient) 290 g and corn starch (excipient) 193 g were charged into a fluidized bed granulator and mixed for 3 minutes. Thereafter, 180 g of a 7% polyvinyl alcohol solution (binder) in which 3 g of the compound of the present invention was dissolved was sprayed and granulated. The granules are sized with a fuser mill, and 1.5 g of magnesium stearate (lubricant) is added and mixed with a V-type mixer. The mixed granules are 700 kg heavy punch with a tableting machine. The tablets were compression-molded at a compression molding pressure of 13.4 mg to prepare a solid preparation (tablet) for comparison test of 130.4 mg per tablet. Comparative Example 2

Lactose (excipient) 350 g and microcrystalline cellulose (excipient) 33 g were charged into a fluidized bed granulator and mixed for 3 minutes. Thereafter, 180 g of a 7% solution (binder) of hydroxypropylcellulose in which 3 g of the compound of the present invention was dissolved was sprayed and granulated. After sieving this granulated product with a fuser mill, stir 1.5 g of magnesium phosphate (lubricant) was added and mixed with a V-type mixer. The mixed granules were compression-molded with a tableting machine at a compression molding pressure of 700 kg weight / punch. 4 mg of a comparative solid preparation (tablet) was prepared. Test Example 1 (Formulation change test)

 A mortar of each of the excipients of mannitol, xylitol, sorbitol, erythritol, sugar alcohol, corn starch, wheat starch, potato starch, lactose, or crystalline cellulose, and the compound of the present invention in a ratio of 5: 1. The abuse test was performed under severe conditions (at 60), and the residual ratio of the compound of the present invention after 3 days in a solid state was measured. For reference, 2 mg of each of the above excipients and 2 mg of the compound of the present invention were dissolved in 2 ml of water, and the compound of the present invention was dissolved in a solution state under severe conditions (60 ° C) for 15 hours. The residual rate of the product was measured. The results are shown in Table 1.

 Separately, the stability of the present compound itself in the solid state at 60 (residual rate of the present compound) was measured over one month. The results are shown in Table 2. table 1

 Solid state solution state

 60 ° C, 60 days after 3 days. C, after 15 hours

 Mannitol 9 9% 9 9%

 Xylitol 9 9% 1 0 0%

 Sorbitol 9 9% 1 0 0%

 Erythritol 9 9% 100%

 Corn starch 9 9% 9 9%

 Wheat starch 9 9% 9 9%

 Potato starch 9 9% 9 9%

 Lactose 80% 100%

Microcrystalline cellulose 90% 98% Table 2

 As is clear from Table 1, in the solid state, sugar alcohols and starches had high stability of the compound of the present invention, and other excipients affected the stability of the compound of the present invention.

Test Example 2 (Stability test in formulation)

 For each of the preparations of Examples and Comparative Examples, the residual ratio of the compound of the present invention was measured after 3 months under severe conditions (60 ° C.). Table 3 shows the results.

Prescription amount (mg) (Continuation of Table 3)

 Formulation Amount (mg) The preparations of the present invention containing sugar alcohols and starches as excipients all retained the stability of the compound of the present invention sufficiently, but lactose and starch, lactose and crystalline cellulose None of the preparations according to the comparative examples using as an excipient could sufficiently maintain the stability of the compound of the present invention. The preparation of the present invention also contained an organic acid such as tartaric acid. The preparation of the present invention retained the stability of the compound of the present invention higher than the preparation of the present invention containing no such acid.

Claims

The scope of the claims  (1) It is characterized by containing sugar alcohols and starches as excipients. (R) — (1)-3 '1 (2-amino 1-hydroxethyl) 1 4 '' Stabilized solid preparation of monofluoromethansulfonanilide hydrochloride.  (2) The (R)-(-) 1-3 'one (2-amino1) according to claim 1, wherein the sugar alcohol is mannitol, xylitol, or sorbitol or erythritol. —Hydroxityl) A stabilized solid preparation of 4'-fluoromethansulfonanilide hydrochloride.  (3) The (R)-(1) -3'-1 (2-amino-1-hydroxethyl) according to claim 1, wherein the starch is corn starch, wheat starch, rice starch, or potato starch. 1) 4 '— A stabilized solid preparation of fluoromethansulfonanilide hydrochloride.  (4) The (R)-(-)-3 '-(2- (amino-1-hydroxyxetil) -14'-fluoro according to any one of claims 1 to 3, further comprising an organic acid. A stabilized solid formulation of methanesulfonyl chloride hydrochloride.  (5) The organic acid is tartaric acid, phthalic acid, lingic acid, citric acid, fumaric acid, or succinic acid according to claim 4, wherein (R)-(-)-3 '-(2-amino No. 1-hydroxyl) 1 '4'-Fluorometansulfonanilide hydrochloride stabilized solid preparation. (6) The (R) -1- (1) -3 according to any one of claims 1 to 5, further comprising at least one selected from the group consisting of a disintegrant, a binder, and a lubricant. 'I- (2-amino-1-hydroxyxetil) I 4'-alpha α-rometansulfonanilide hydrochloride stabilized solid preparation. (7) The (R)-(1-)-3 '-(2-amino-1-) according to claim 6, wherein the disintegrant is low-substituted hydroquinyl propylcellulose, starch or carmellose. Hydroxetil) 1 4'-Fluorometanes A stabilized solid preparation of lefonanilide hydrochloride.  (8) The binder is hydroxypropylcellulose, hydroxypropyl mouth methylcellulose, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, starches, arabia gum, gelatin, glucose, sucrose, (R) — (I) — 3 ′ — (2-amino 1 — Hydroxitytyl) 4 ′ — Fluorometansulfananily according to claim 6, which is tragacanth or sodium alginate. Stabilized solid preparation of dohydrochloride.  (9) The (R) according to claim 6, wherein the lubricant is stearic acid, magnesium stearate, calcium stearate, or talc. (1)-3 '-(2-amino 1-hydroxyxethyl) 1-4'-Fluoromethansulfonanilide hydrochloride stabilized solid preparation.  (10) (R) according to any one of claims 1 to 9, wherein the solid preparation is a tablet, a powder, a granule, a fine granule, or a capsule. (2-amino 1-hydroxyxetil) A stabilized solid preparation of 1'4'-fluoromethansulfonanilide hydrochloride.  (11) (R) after 3 months at 60 ° C or after 6 months at 40 ° C and 75% relative humidity (R) ― (-)-3 ' (Mino 1-hydroxyxethyl) 1'-Stabilized solid preparation of the drug, characterized in that the residual ratio of fluoromethanesulfonanilide hydrochloride is 90% or more.