JPH1077234A - Solid preparation for oral administration and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a solid preparation for oral administration, containing fine powder nitrendipine readily absorbable without an absorption promoter, comprising fine powder nitrendipine having a specific particle diameter as an active ingredient. SOLUTION: This preparation comprises fine powder nitrendipine having an average particle diameter equal to or smaller than several μm, preferably <=6μm, more preferably >=43μm. The crystalline fine powder nitrendipine is obtained only by pulverizing crystalline raw powder nitrendipine. The nitrendipine is also obtained by transferring amorphous nitrendipine by external energy such as heat or pressure or in the presence of water by a well-known method. This fine powder nitrendipine thus obtained is made into a granular state by a fluidized bed or a high-speed stirring granulation method and tableted to give a solid preparation for oral administration. Preferably, 5-10 pts.wt. (the total amount of 80 pts.wt.) of the fine powder nitrendipine is contained in the solid preparation. Even in the case of the oral administration of the solid preparation, improvement in availability in vivo is expected.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an oral solid preparation and a method for producing the same, and more particularly, to an oral solid preparation containing fine powder nitrendipine which can be easily absorbed without an absorption enhancer, and a method for producing the same. .

[0002]

2. Description of the Related Art The antihypertensive action resulting from the calcium antagonism of dihydropyrrolidines is already known (GB 135891).
issue). Many typical members of this class exhibit very low solubility in aqueous media. Nitrendipine is also difficult to achieve optimal blood concentrations due to its very low solubility of 2 mg / liter in aqueous media. To overcome this, active compounds with low solubility are usually
It is known that improvement can be achieved by adding a large amount of a solubilizing agent or an absorption promoter.

In fact, it is known that the solubility is improved by adding sodium lauryl sulfate and polyvinylpyrrolidone as adjuvants (JP-A-61-68).
431) and JP-A-60-197860, 0.5 to 1 part by weight of polyvinylpyrrolidone and 0.05 to 1 part by weight of sodium lauryl sulfate per 1 part by weight of nitrendipine.
Formulations containing 0.5 parts by weight have been proposed.

[0004] However, since hypertension is usually administered for a long period of time, its bioavailability is improved by pharmaceutical formulation, while additives (such as solubilizing agents) are contained as much as possible. It is preferable to formulate the formulation without using it.

[0005]

According to the present invention, there is proposed a solid oral preparation having improved oral absorbability, which comprises fine powder nitrendipine having an average particle size of several μm or less as an active ingredient. Further, according to the present invention, there is provided a method for producing a solid oral preparation, wherein nitrendipine finely ground to an average particle size of several μm or less is granulated by a fluidized bed or a high-speed stirring granulation method, and further tableted.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The nitrendipine in the present invention has an average particle size of several μm or less, preferably 6 μm or less, more preferably 3 μm or more. The raw powder of nitrendipine has strong cohesiveness among particles, about 3 μm
This is because it is difficult to prepare fine particles having a particle size of about or less. Such fine powder nitrendipine is obtained by using a homogenous powder of crystalline or non-crystalline nitrendipine (average particle size of about 20 μm) by a mechanical grinding method such as a ball mill or a hammer mill, for example, using a Hosokawa micron (pin mill 160Z type). And finely pulverized into fine powder having an average particle size of several μm or less. Crystalline fine powder nitrendipine can be obtained by simply pulverizing with crystalline bulk powder, and non-crystalline nitrendipine can be obtained by external energy such as heat, pressure, or water. It can be obtained by transferring by a known method and pulverizing.

The solid preparation containing the fine powder nitrendipine in the present invention includes a fine powder; a powder, fine granules or granules appropriately sized and granulated from the fine powder; these fine powders, powders and fine granules Or, all of those which can be used for oral use, such as tablets formulated using granules, are included.
In this solid preparation, fine powder nitrendipine is preferably 5 to 10 parts by weight (total amount is 80 parts by weight).
It may also contain pharmaceutically acceptable carriers or excipients, and optionally one or more various additives such as binders, disintegrants, lubricants, colorants and the like. In the present invention,
It is not necessary to include an absorption enhancer or a solubilizing agent which should be avoided when considering long-term administration of a substance having surfactant properties or a polyhydric propylene derivative. This increases the rate of dissolution of nitrendipine due to its fine powder form, achieves a desired blood concentration, and is equivalent without containing an absorption enhancer or a solubilizing agent as conventionally used. Or higher bioequivalence can be obtained. When the solid preparation optionally contains one or more additives such as a binder, a disintegrant, a lubricant, and a colorant, the amount can be adjusted within a range usually used. .

[0008] Pharmaceutically acceptable carriers or excipients include:
For example, sucrose, D-mannitol, maltose, glucose, fructose, glucose, powdered reduced maltose syrup, lactose,
Corn starch, wheat starch, potato starch, rice starch, inositol, ethyl cellulose, xylitol, crystalline cellulose, synthetic aluminum silicate, β-cyclodextrin, D-sorbitol, low-substituted hydroxypropylcellulose, dextrin, calcium lactate, hydroxypropyl starch, Examples include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pectin, methyl cellulose and the like.

Examples of the binder include crystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, corn starch paste, wheat starch paste, potato starch paste, rice starch paste, starch syrup, carboxymethylcellulose, sodium carboxymethylcellulose, Gum arabic, corn starch, wheat starch,
Potato starch, rice starch, sodium alginate,
Xanthan gum, soft silicic anhydride, dextrin, tragacanth powder, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, macrogol, ethylcellulose, gelatin, glucose,
White sugar, starch syrup and the like.

[0010] Disintegrators include, for example, carboxymethyl starch, pregelatinized starch, sodium carboxymethyl starch, hydrous silicon dioxide, guar gum, crystalline cellulose, corn starch, wheat starch, potato starch, rice starch, lactose, low-substituted hydroxypropyl Cellulose, hydroxymethylethylcellulose,
Hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, D-mannitol, methylcellulose, carboxymethylcellulose calcium, calcium carbonate and the like.

Examples of the lubricant include magnesium stearate, purified talc, stearic acid, calcium stearate and the like. As a coloring agent, turmeric extract, yellow iron oxide, carbon black, caramel, β-carotene,
Carotene liquid, licorice extract, food blue 1, food yellow 4, food yellow 5, food yellow 4, aluminum lake, food red 102, food red 2, food red 3,
Copper chlorophyll, red bean, riboflavin and the like can be mentioned.

The method for producing a solid preparation containing fine powder nitrendipine of the present invention is characterized in that nitrendipine finely ground to an average particle size of several μm or less as described above is optionally mixed with the above-mentioned excipients and the like. Can be formulated into powders, fine granules, granules or tablets using a conventional method known per se. For example, finely powdered nitrendipine can be made into a fine granule or granule having a desired particle size by using a fluid bed known per se or by a high-speed stirring granulation method,
In addition, fine powder nitrendipine as it is, or fine-grained,
After granulation, it can be formulated by a known tableting method. Further, the obtained solid preparation may be optionally coated.

[0013]

EXAMPLES Example 1 Formulation Formulation of the raw powder of nitrendipine (manufactured by Ohara Pharmaceutical Co., Ltd.) having an average particle diameter of about 19.6 μm was pulverized three times with a pin mill (160Z type) manufactured by Hosokawa Micron, and the average particle diameter was adjusted. About 5.8 μm of fine powder nitrendipine was obtained. The particle size of the fine powder nitrendipine was measured using a Shimadzu laser diffraction particle size distribution analyzer (SALD-2000A).
The average particle size was determined.

100 g of this fine powder of nitrendipine, 1136 g of lactose, 240 g of crystalline cellulose and 80 g of partially pregelatinized starch were placed in a fluid bed granulator (manufactured by Powrex Co., Ltd.) and mixed in a dry state. This was granulated by a wet granulation method in which 640 ml of an aqueous solution containing 32 g of hydroxypropyl cellulose was sprayed by a spray method. After completion of the spraying operation, the granules were dried at 40 ° C. for about 0.5 hours and sieved with a 30-mesh JIS standard sieve.

Subsequently, 12 g of magnesium stearate was added to and mixed with the obtained nitrendipine in the form of granules, and the mixture was compression-formed with a rotary tableting machine (diameter: 6 mm) to thereby obtain a tablet A ₅ (tablet of nitrendipine) of 80 mg per tablet. 5mg
Content). Next, 90 g of hydroxypropyl methylcellulose 2910, 54 g of titanium oxide, and talc 6
g and yellow iron sesquioxide 0.75 g were dissolved or dispersed in 50% ethanol, and the coating tablets (NO-16-D, manufactured by Kikusui Seisakusho Co., Ltd.) were sprayed on the tablets to spray film-coated tablets A. ₅ manufactured.

Example 2: Formulation 200 g of fine powder nitrendipine, lactose 1036 g, crystalline cellulose 240 prepared in the same manner as in Example 1
g and partially pregelatinized starch (80 g) were placed in a high-speed stirring granulator (manufactured by Powrex Co., Ltd.), 280 ml of an aqueous solution containing 32 g of hydroxypropylcellulose was added, granulated, dried and sieved in the same manner as in Example 1. did.

[0017] Subsequently, the nitrendipine of the resulting granular form, and mixed with magnesium stearate 12g, by compression molding on a rotary tableting machine (diameter 6 mm), tablets A ₁₀ 1 tablet 80 mg (nitrendipine 10m
g). Then film coated using the coating liquid as described above, to produce film-coated tablets A _10.

Example 3 Dissolution Rate A dissolution test was performed using the nitrendipine tablets A ₅ and A ₁₀ (film coated tablets) obtained in Examples 1 and 2. As a comparative example, tablets B ₅ and B ₁₀ (film-coated tablets, each containing 5 mg and 10 mg of nitrendipine) and tablets C containing sodium lauryl sulfate and polyvinylpyrrolidone, which are dissolution aids, were formed using the original powder of nitrendipine. A similar test was performed using (conventional product). Table 1 shows the components and contents of each tablet, and Table 2 shows the dissolution rate and 75% dissolution rate of each tablet.

[0019]

[Table 1]

[0020]

[Table 2]

According to Table 2, the dissolution rate of the tablet A containing the fine powder of nitrendipine of the present invention is superior to that of the tablet B composed of the powdered nitrendipine powder. Was found to be significantly improved. Further, the tablet A of the present invention showed the same dissolution rate as the conventional product C containing a dissolution aid for sodium lauryl sulfate and polyvinylpyrrolidone.

Example 4: Dissolution rate The film-coated tablets (containing 10 mg of nitrendipine) obtained in Example 2 were subjected to the Japanese Pharmacopoeia general test method and the second dissolution test method (paddle method), that is, The above tablets were added to 900 ml of a test solution of the Japanese Pharmacopoeia 2nd method containing 0.5% polysorbate 80,
The dissolution rate was measured by eluting at 100 rpm.

FIG. 1 shows the results. In addition, as a comparative example, it measured similarly about the film-coated tablet (containing 10 mg of nitrendipine) and the conventional product (containing 10 mg of nitrendipine) which consist of the raw powder of nitrendipine.
As apparent from FIG. 1, the fine powdered nitrendipine tablet of the present invention has a remarkably improved dissolution rate as compared with the raw powdered nitrendipine tablet, and exhibits a dissolution rate similar to or higher than that of the conventional product. I understood.

Example 5: Bioequivalence test The film-coated tablets (containing 10 mg of nitrendipine) obtained in Example 2 were orally administered to humans (n = 14), and the bioequivalence was evaluated for two months. It was examined by the drug crossover method.

FIG. 2 shows the result. As a comparative example, a conventional product (containing 10 mg of nitrendipine) was similarly measured. As is apparent from FIG. 2, the tablet containing the finely powdered nitrendipine in the present invention is:
It was found that the bioavailability was equivalent to that of a conventional preparation containing a solubilizing agent.

[0026]

According to the present invention, the dissolution rate can be remarkably improved without using a solubilizing agent by pulverizing nitrendipine to an average particle size of several μm or less. In addition, even when the solid preparation according to the present invention is taken internally, an improvement in bioavailability is expected.

[Brief description of the drawings]

FIG. 1 is a graph showing the dissolution rates of the preparation of the present invention and its comparative product.

FIG. 2 is a graph showing changes in plasma concentration after oral administration of the preparation of the present invention and a comparative product thereof.

Claims (4)

[Claims] 1. An oral solid preparation having improved oral absorbability, comprising a fine powder of nitrendipine having an average particle size of several μm or less as an active ingredient. 2. The solid preparation according to claim 1, wherein the solid preparation is a powder, a fine granule, a granule or a tablet. 3. A solid formulation comprising a pharmaceutically acceptable carrier or excipient without the use of dissolution aids and / or absorption enhancers, optionally used binders, lubricants, disintegrants or pigments. The solid preparation according to claim 1, which is formulated. 4. A method for producing a solid oral preparation, wherein nitrendipine finely ground to an average particle size of several μm or less is granulated by a fluidized bed or a high-speed stirring granulation method, and further tableted.