JPH0597670A - Preparation for oral administration - Google Patents

Abstract

PURPOSE:To obtain a preparation for oral administration useful for treating diabetes, comprising ultrafine powder of a benzoxazole derivative as an active ingredient. CONSTITUTION:The objective preparation for oral administration comprises a compound of the formula (R is phenyl or naphthyl; Alk is lower alkylene) or its salt as ultrafine powder having about 6mum average particle diameter. The compound of the formula has extremely increased bioavailability by making into ultrafine powder and is processed into a preparation for oral administration having improved absorption characteristics. The compound is ground into ultrafine state by using a jet mill, etc., 5-[(2,4-Dioxothiazolidin-5-yl) methyl]-2-[4-(dimethylamino)benzyl]benzoxazole may be cited as the compound of the formula.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for oral administration with improved absorbability, and more particularly to a preparation for oral administration for treating diabetes.

[0002]

2. Description of the Related Art Although the number of diabetic patients is increasing worldwide and various treatment methods have been shown, an oral therapeutic drug for oral diabetes, which is effective by oral administration, reduces the burden on diabetic patients and facilitates treatment. It is extremely important to do. Oral antidiabetic drugs started with organic acid preparations and became popular due to the development of sulfonylurea compounds and sulfapyrimidine drugs, but new oral antidiabetic drugs are constantly being sought in order to effectively treat the increasing number of diabetic patients. Has been.

As a novel medicinal compound effective as a therapeutic drug for diabetes, the present applicant has proposed the general formula [I]

[Chemical 2] (However, R represents a phenyl group or a naphthyl group which may have a substituent, and Alk represents a lower alkylene group.) Provided a benzoxazole derivative (JP-A 64-56675). These benzoxazole derivatives have an excellent insulin sensitivity enhancing effect and are useful compounds as therapeutic agents for diabetes, but there is a problem that they are poorly absorbed in the digestive tract upon oral administration.

[0004]

The object of the present invention is to provide a novel oral administration preparation for treating diabetes.

[0005]

[Means for Solving the Problems] The present inventors have diligently aimed at achieving stable and high bioavailability,
As a result of repeated research, they have found that the bioavailability of the benzoxazole derivative [I] can be dramatically increased if it is used as ultrafine particles, and the present invention has been completed. That is, the present invention is an oral preparation for the treatment of diabetes, which contains, as an active ingredient, an ultrafine powder of the benzoxazole derivative represented by the above general formula [I] or a pharmaceutically acceptable salt thereof.

As the benzoxazole which is an active ingredient of the oral preparation of the present invention, R in the general formula [I] is substituted with 1 to 3 groups selected from a halogen atom, a di (lower alkyl) amino group and a pyrrolidino group. And a compound which is a phenyl group or a naphthyl group which may be
Examples of the halogen atom include chlorine atom, fluorine atom, iodine atom and bromine atom, and examples of the di (lower alkyl) amino group include dimethylamino group and diethylamino group. Among these, the most preferable compound as the active ingredient of the present invention is 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- [4- (dimethylamino) benzyl] benzoxazole, 5-
[(2,4-Dioxothiazolidin-5-yl) methyl] -2-[(2-naphthyl) methyl] benzoxazole, 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2 Examples include-(4-chlorobenzyl) benzoxazole or 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- (4-pyrrolidinobenzyl) benzoxazole.

These benzoxazole derivatives [I]
Can be used for the purposes of the present invention either in free form or in the form of its pharmaceutically acceptable salt. As the salt, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, acid addition salts such as hydrochloride and sulfate can be used.

The ultrafine powder in the present invention has an average particle size of about 6 μm or less, preferably about 4 μm or less,
A powder of about 3 μm or less is particularly preferable. Such finely powdered benzoxazole derivatives are described, for example, in the above-mentioned JP-A-6-26.
It can be prepared by pulverizing a crystal of a benzoxazole compound having an average particle size of about 20 μm, which is synthesized by the method described in the Example of 4-56675, by an appropriate method. The pulverization may be performed by using any device as long as it can achieve a desired particle size, that is, a particle size of about 6 μm or less, for example, a jet mill, a hammer mill, a rotary ball mill, a vibrating ball mill, a shaker mill, a rod mill. , A tube mill or the like. When using a ball mill or a bead mill, either dry pulverization or wet pulverization may be used.

More specifically, pulverization by a jet mill is performed by, for example, injecting compressed air of about 6 kg / cm ² to collide the raw material crystals with a ceramic collision plate to pulverize, and fine powder is preliminarily given a predetermined clearance. It can be carried out by classifying and collecting with a cyclone set to. Grinding with a sample mill can be performed, for example, with a clearance of 1 mm, a screen punch of 1 mm, and a hammer rotation speed of about 12000.
It can be carried out by pulverizing under the condition of rpm and collecting the fine powder which has passed through the screen. Further, for example, in the case of a stainless steel vibrating ball mill with an internal capacity of 100 ml having four stainless steel balls having a diameter of 9 mm,
It can be crushed by processing at a frequency of about 1200 rpm for about 30 minutes to 2 hours. Further, for example, porcelain balls about 40
In the case of using a porcelain rotary ball mill with an internal capacity of 1000 ml containing the individual pieces, the crushing may be carried out by rotating at a rotation speed of about 120 rpm for about 20 to 40 hours.

At the time of pulverization, the raw material crystals of the benzoxazole compound may be pulverized by simple pulverization or mixed pulverization with a pulverization aid, but in order to prepare the ultrafine particle compound necessary for the present invention. Are preferably mixed and pulverized using a grinding type pulverizer such as a vibrating ball mill or a rotary ball mill. As the grinding aid used for the mixing and grinding, for example, mannitol, xylitol, lactose, glucose and other sugars, as well as hydroxypropyl starch, carboxymethyl starch and the like can be used, and the amount thereof is 1 part by weight of the benzoxazole compound. It is preferably about 1 to 50 parts by weight. In this case, the mixed pulverized product may be used as it is as a formulation raw material, or a finely divided benzoxazole compound isolated by dissolving and removing a pulverization auxiliary from water in the mixed pulverized product may be used as a formulation raw material. You can also

To give a specific example, among the benzoxazole derivatives of the present invention, the average particle diameter of 5-
[(2,4-dioxothiazolidin-5-yl) methyl] -2-[(2-naphthyl) methyl] benzoxazole average particle size (50
% Diameter) was about 6 μm, the average particle diameter in the case of jet mill pulverization was about 3 μm, and the average particle diameter in the case of mannitol mixed pulverization was about 0.5 to 1 μm. Of the above methods,
The mixing and grinding method using a grinding aid such as mannitol is described in detail in Japanese Patent Application Laid-Open No. 3-66613 filed by the present applicant.

The ultrafine-grained benzoxazole derivative thus obtained showed an increase in plasma concentration in an absorptive test conducted in dogs, as shown in Experimental Examples described later, and the increase was untreated. It was about 30 times more than the bulk powder. These results show that the ultrafine-particle drug of the present invention can be an effective therapeutic drug for diabetes in oral administration. However, the present invention is not limited to a specific pulverization method, and the use of an ultrafine benzoxazole derivative having a particle diameter of about 6 μm or less obtained by another method can achieve the above object. , Will be apparent to those skilled in the art. Therefore, the present invention also includes a preparation for oral administration using the ultrafine particle benzoxazole obtained by any method.

The finely-divided benzoxazole derivative having a particle size within a predetermined range or a mixed pulverized product containing the same prepared as above may be used as it is or in an excipient, according to a conventional method for formulation.
It can be used as a powder by mixing with a lubricant, a coloring agent and the like. Alternatively, it can be granulated and used as a fine granule or a granule. The above granulation operation can be carried out by a conventional method in this technical field, specifically, a wet granulation method, a dry granulation method, a spray granulation method, or the like. When the wet granulation method is used, for example, a finely-divided benzoxazole derivative or a mixed pulverized product thereof, or a mixture of an excipient, a disintegrating agent, a lubricant, and the like appropriately mixed therein is kneaded with a binder solution and stirred to form a mixture. It can be carried out by granulating by a granulation method, a high speed stirring granulation method, a fluidized bed granulation method, an extrusion granulation method, a tumbling granulation method, etc., and then sizing and drying. Further, in the case of the dry granulation method, using a normal dry granulation device, pressure is applied to the finely divided benzoxazole derivative, a mixed pulverized product thereof, or a mixture containing an appropriate binder, excipient, disintegrating agent, or the like. Can be carried out by adding to form a lump and then crushing into suitable particles. Further, in the case of the spray granulation method, a finely divided benzoxazole derivative, a mixed pulverized product thereof alone or a mixture of the same with an appropriate excipient, binder, disintegrating agent or the like is dissolved or suspended in an appropriate solvent and sprayed. It can be carried out.

The particles thus obtained can be used as they are as a powder, fine granules or granules by adding various additives as required, and further according to a conventional method such as tableting or filling into capsules, for example, tablets. , And can be used in dosage forms such as capsules. Among the preparations suitable for oral administration of the present invention, fine granules, granules and tablets may be further subjected to surface coating such as film coating and sugar coating according to a conventional method, if desired.

The excipients, binders, disintegrants, lubricants and the like which can be used in the above formulation are not particularly limited as long as they are suitable for the formulation for oral administration. As the excipient, for example, sucrose, lactose, starch, sorbitol, mannitol, crystalline cellulose, calcium hydrogen phosphate, calcium citrate, calcium sulfate and the like can be used, and as the binder, for example, polyvinylpyrrolidone,
Cellulose derivatives (methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), gelatin, starch paste, gum arabic, sodium alginate, sucrose, polyvinyl alcohol, polyethylene glycol, methyl acrylate / methacrylic acid copolymer, etc. can be appropriately used. .. Examples of the disintegrant include starch, kaolin,
Cellulose, sodium alginate, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose,
Carboxymethyl cellulose calcium, crystalline cellulose, internally crosslinked sodium carboxymethyl cellulose and the like, and lubricants such as alkali metal stearate, alkali metal lauryl sulfate, talc, precipitated calcium carbonate, synthetic aluminum silicate, silicon oxide, magnesium oxide. Etc. can be given. When the binder is used as a solution, the solvent may be, for example, methanol, ethanol, water or the like.

The thus-obtained preparation for oral administration of the present invention exhibits excellent various properties that allow the benzoxazole derivative to exert its beneficial effects effectively, and in particular, it has excellent properties as a therapeutic drug for oral diabetes. is there.

[0017]

[Action]

Experimental Example 1 Drugs having various particle sizes were administered to dogs, the drug concentration in plasma was measured, and the relationship between the particle size and the drug concentration in plasma was investigated. [Drug] 5-[(2,4-dioxothiazolidine-5-
Ill) methyl] -2-[(2-naphthyl) methyl] benzoxazole untreated bulk powder (particle size about 20 μm), and particles obtained by sample milling, jet milling and ball milling Diameter 6 μm, 3 μm
And 0.6 μm powder was used. (However, 0.6μ
The powder of m contained mannitol because the mannitol mixed grinding method was used to obtain a desired particle size. )

[Experimental Method] 50 mg of each of the above particles was added to 5 parts of water.
It was suspended in 0 ml and administered to 4 dogs. [Results and Discussion] The results are as shown in FIG. 1 and Table 1.

[0019]

[Table 1]

As is clear from FIG. 1, the particle size is about 0.6.
The plasma concentration of the drug was very high when the powder of 3 μm, 3 μm and 6 μm was administered, but the plasma concentration of the drug was very high when the unground powder of 20 μm was administered. It turns out to be low. In addition, the maximum plasma concentration (Cm
ax) and the degree of increase in the area under plasma concentration (AUC) are as shown in Table 1, and both parameters, which are indices of absorbability, have a particle size of about 6 μm when the untreated bulk powder is 1.
Was several times, 3 μm powder was more than 10 times, and 0.6 μm powder was about 30 times. Therefore, it is clear that the drug absorbability is remarkably increased by miniaturization, and it was found that such pharmaceutical processing is extremely effective for obtaining high bioavailability.

[0021]

【Example】

Example 1 (1) Crystals of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- [4- (dimethylamino) benzyl] benzoxazole were made of stainless steel balls 4
An average particle size of 6 was obtained by crushing for 1 hour with a vibrating ball mill (made by Specs Co., Ltd.) having an internal capacity of 100 ml.
Obtaining μm particles. The average particle diameter was measured by a laser diffraction type Cirrus particle size meter or a centrifugal sedimentation type distribution meter (the same applies hereinafter). (2) 100 parts by weight of this product, 54.8 parts by weight of lactose and 18 parts by weight of calcium carboxymethyl cellulose are mixed, and a water-containing ethanol solution containing 5.4 parts by weight of hydroxypropyl cellulose is added and kneaded. The kneaded product is treated with a JIS standard sieve of 24 mesh, and the material passed through the sieve is dried at 45 ° C. for 3 hours. After drying, 1.8 parts by weight of magnesium stearate is added and mixed, and the mixture is compression-molded with a rotary tableting machine (diameter 8 mm) to obtain tablets of 180 mg per tablet.

Example 2 (1) Crystals of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2-[(2-naphthyl) methyl] benzoxazole were sample milled (Fuji Paudal Co.). Made) clearance 1mm, screen punch 1mm,
Particles having an average particle diameter of 6 μm are obtained by pulverizing 5 times under the condition of a hammer rotation speed of 12000 rpm. (2) In the same manner as in Example 1 except that the above particles are used,
180 mg tablets are obtained per tablet.

Example 3 (1) 100 parts by weight of crystals of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- (4-chlorobenzyl) benzoxazole and 100 parts by weight of mannitol, About 1 porcelain ball (diameter 5 to 20 mm) is placed in a porcelain ball mill with an internal capacity of 1000 ml and about 1
By pulverizing for a time, particles having an average particle diameter of about 4 μm are obtained. (2) 100 parts by weight of this product, 54.8 parts by weight of lactose and 18 parts by weight of low-substituted hydroxypropylcellulose are mixed, and a water-containing ethanol solution containing 5.4 parts by weight of polyvinylpyrrolidone is added and kneaded. Thereafter, the same treatment as in Example 1 is carried out to obtain 180 mg tablets per tablet.

Example 4 (1) Crystals of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- [4- (dimethylamino) benzyl] benzoxazole and 100 ml of distilled water were porcelain. The particles are placed in a ball mill (the same as that used in Example 3- (1)), pulverized for 24 hours, and then spray-dried at an intake air temperature of 140 ° C. to obtain particles having an average particle diameter of about 3 μm. (2) 50 parts by weight of this product and 47 parts by weight of corn starch are mixed, and a water-containing ethanol solution containing 3 parts by weight of hydroxypropyl cellulose is added and kneaded. The kneaded product is dried at 45 ° C. for 15 minutes and then crushed. 3 at 45 ° C again
The powder is obtained by drying for an hour and treating with a No. 30 standard sieve.

Example 5 (1) Crystals of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2-[(2-naphthyl) methyl] benzoxazole were jet milled (manufactured by Pneumatic). ) Under an air pressure of about 6 kg / cm ² to obtain particles having an average particle size of about 3 μm. (2) 100 parts by weight of this product, 300 parts by weight of lactose and 75 parts by weight of corn starch are mixed, and a hydrous ethanol solution containing 25 parts by weight of hydroxypropyl cellulose is added and kneaded. After drying the kneaded product at 45 ° C. for 15 minutes, the kneaded product is crushed. Dry again at 45 ° C for 3 hours and
The powder is obtained by treating with a No. 0 standard sieve.

Example 6 A hard gelatin capsule was filled with the powder obtained in Example 5,
Get a capsule.

Example 7 (1) 10 parts by weight of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2-[(2-naphthyl) methyl] benzoxazole and 100 parts by weight of mannitol were mixed. Then, the mixture is placed in a vibration ball mill made of stainless steel (made by Specs; internal volume 100 ml, 2 stainless steel balls) and mixed and pulverized for 60 minutes to obtain particles having an average particle diameter of about 0.6 μm as a mixed and pulverized product. (2) To 110 parts by weight of the mixed pulverized product produced above, 30 parts by weight of corn starch are added and mixed, and a hydrous ethanol solution containing 10 parts by weight of dextrin is added and kneaded. The kneaded product is dried at 45 ° C. for 15 minutes and crushed.
Granules are obtained by treating with a No. 12 standard sieve.

Example 8 (1) Crystals of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- (4-pyrrolidinobenzyl) benzoxazole are referred to as Example 1- (I). Similarly, the particles are pulverized with a vibrating ball mill to obtain particles having an average particle size of 6 μm. (2) 50 parts by weight of this product, 46.1 parts by weight of lactose and 9 parts by weight of carboxymethyl cellulose calcium are mixed, and a water-containing ethanol solution containing 4 parts by weight of hydroxypropyl cellulose is added and kneaded. The kneaded product was treated with a JIS standard sieve of 24 mesh, and passed through the sieve at 45 ° C.
Dry for 3 hours. After drying, 0.9 part by weight of magnesium stearate is added and mixed, and the mixture is compression-molded with a rotary tableting machine (diameter 8 mm) to obtain 110 mg tablets per tablet.

Example 9 (1) 10 parts by weight of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- (4-pyrrolidinobenzyl) benzoxazole and 90 parts by weight of mannitol were mixed. In the same manner as in Example 7- (I), the particles are pulverized with a vibrating ball mill to obtain particles having an average particle diameter of about 0.6 μm as a mixed pulverized product. (2) 27.5 parts by weight of mannitol and 15 parts by weight of low-substituted hydroxypropylcellulose are added to 100 parts by weight of the mixed pulverized product produced above and mixed, and hydrous ethanol containing 7.5 parts by weight of hydroxypropylcellulose is added thereto. Add the solution and knead. The kneaded product is dried at 45 ° C. for 15 minutes and crushed. Granules are obtained by treating with a No. 12 standard sieve.

[0030]

INDUSTRIAL APPLICABILITY Since the preparation for oral administration of the present invention has a stable and high bioavailability for effectively exerting the drug effect of the benzoxazole derivative, it has excellent properties as a preparation for treating diabetes. Is to have.

[0031]

[Brief description of drawings]

FIG. 1 is a graph showing the drug concentration in plasma when untreated raw powder and ground powder in Experimental Example 1 were administered to dogs.

Claims (8)

[Claims] 1. A compound represented by the general formula [I]: (However, R is a phenyl group or naphthyl group which may have a substituent, and Alk is a lower alkylene group.) As an active ingredient, an ultrafine powder of a benzoxazole derivative or a pharmaceutically acceptable salt thereof is used. A formulation for oral administration containing. 2. The preparation according to claim 1, wherein the ultrafine powder is a powder having an average particle size of about 6 μm or less. 3. In the general formula [I], R is a phenyl group or a naphthyl group which may be substituted with 1 to 3 groups selected from a halogen atom, a di (lower alkyl) amino group and a pyrrolidino group. The formulation according to claim 1 or 2. 4. The preparation according to claim 1, wherein R in the general formula [I] is a halogen-substituted phenyl group, a di (lower alkyl) amino group-substituted phenyl group, a pyrrolidino-substituted phenyl group or a naphthyl group. 5. The active ingredient is 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- [4- (dimethylamino) benzyl] benzoxazole or a pharmaceutically acceptable salt thereof. The formulation according to claim 4, which is an ultrafine powder. 6. An active ingredient in excess of 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2-[(2-naphthyl) methyl] benzoxazole or a pharmaceutically acceptable salt thereof. The preparation according to claim 4, which is a fine powder. 7. An ultrafine powder of the active ingredient 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- (4-chlorobenzyl) benzoxazole or a pharmaceutically acceptable salt thereof. The formulation according to claim 4, which is 8. An ultrafine particle of the active ingredient, 5-[(2,4-dioxothiazolidin-5-yl) methyl] -2- (4-pyrrolidinobenzyl) benzoxazole or a pharmaceutically acceptable salt thereof. The formulation according to claim 4, which is a powder.