JPH08127533A - Composition for oral solid pharmaceutical preparation - Google Patents

Abstract

PURPOSE: To obtain the subject pharmaceutical preparation improved in the absorbability for sulfonamide-based antiinflammatory agent. CONSTITUTION: This oral solid pharmaceutical preparation comprises a sulfonamide-based anti-inflammatory agent such as N-(5-amino-4-nitro-2- phenoxyphenyl)methanesulfonamide or N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide and at least one kind of alkaline substance. The alkaline substance is pref. sodium bicarbonate, magnesium oxide, magnesium hydroxide, calcium carbonate or magnesium carbonate, being formulated at 0.1-10 (pref. 0.5-5) pts.wt. per pt.wt. of the sulfonamide-based antiinflammatory agent. In this pharmaceutical preparation, the elutability of the antiinflammatory agent in water or acidic solution is highly improved, and in addition, not only rapid efficacy but absorbability in vivo of the antiinflammatory is markedly improved.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a composition containing a sulfonamide anti-inflammatory agent. More specifically, the present invention relates to a composition for internal solid preparations having improved absorbability, which is characterized by blending one or more alkaline substances.

[0002]

2. Description of the Related Art Generally, it is known that in the case of a poorly soluble drug, fine pulverization (10 μm or less) is used as a technique for improving dissolution and absorption, but a sulfonamide anti-inflammatory agent is not sufficient. It was Further, conventionally, a method of improving absorption by increasing pH in the stomach by taking an acidic anti-inflammatory agent such as ibuprofen, ketoprofen, diclofenac and a large amount of a suspension of magnesium hydroxide (850 mg) together is known. [J. Clin. Phar
macol. , 31, 263 (1991)]. But,
This method requires a simultaneous administration of magnesium hydroxide together with an anti-inflammatory agent, and is not a simple administration method. In addition, there is a preparation in which an oxycam anti-inflammatory agent is mixed with an antacid, and immediate effect is expected [JP-A-3-240729].
issue]. However, there is no known technique for solid preparations for oral administration in which the absorbability of sulfonamide anti-inflammatory agents is improved.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a solid preparation for oral administration which has improved absorbability of a sulfonamide anti-inflammatory agent.

[0004]

[Means for Solving the Problems] The present inventors have found a formulation with good dissolution and excellent absorbability by incorporating an alkaline substance into a sulfonamide anti-inflammatory agent,
The present invention has been completed based on this finding.

That is, the present invention is a composition for internal solid preparations, which comprises a sulfonamide anti-inflammatory agent and one or more alkaline substances.

The anti-inflammatory agent used in the present invention is N- (5
-Amino-4-nitro-2-phenoxyphenyl) methanesulfonamide, N- (2-cyclohexyloxy-
It is a sulfonamide-based anti-inflammatory agent such as 4-nitrophenyl) methanesulfonamide and nimeslide, and it is preferable that the particle size is fine powder. That is, the average particle size is 50 μm.
m or less is preferable, and more preferably the average particle size is 10 μm.
It is the following.

The alkaline substances used in the present invention include sodium hydrogen carbonate, magnesium oxide, magnesium hydroxide, calcium carbonate, magnesium carbonate, dried aluminum hydroxide gel, synthetic hydrotalcite, disodium phosphate, calcium hydrogen phosphate, Glycinal, cumulite, magnesium aluminometasilicate, magnesium silicate, synthetic aluminum silicate, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitate and the like, but preferably sodium hydrogen carbonate, magnesium oxide, magnesium hydroxide, Calcium carbonate and magnesium carbonate.

The amount of the alkaline substance used in the present invention does not necessarily have to increase the pH in the stomach. That is, it varies depending on the type of sulfonamide anti-inflammatory agent and the type of alkaline substance to be blended, but generally 0.1 to 1 per 1 part by weight of the sulfonamide anti-inflammatory agent.
0 parts by weight is preferable, and 0.5 to 5 parts by weight is more preferable.

The composition for oral solid preparation of the present invention can be produced by a general method such as stirring granulation, fluidized bed granulation, tumbling granulation,
It can be manufactured by centrifugal tumbling granulation, extrusion granulation, vacuum granulation and the like. For example, it can be manufactured as follows.

That is, a sulfonamide anti-inflammatory agent, an alkaline substance, an excipient, a disintegrating agent, and a binder are mixed and pulverized, and purified water, ethanol or a mixed solution thereof is used as a solvent, and the mixture is stirred and granulated to obtain a fluidized bed. It is obtained by pulverizing after drying in order to obtain an appropriate particle size. Further, a surfactant and the like can be blended if necessary.

The composition thus obtained may be used as it is or, if necessary, further with additives such as excipients, disintegrating agents, binders, lubricants, antioxidants, coating agents, coloring agents, Mix flavors, surfactants, etc.,
It may be an oral solid preparation such as powder, fine granules, granules, tablets and capsules.

Examples of the excipient used include mannitol, sucrose, lactose, crystalline cellulose, starch, light anhydrous silicic acid, titanium oxide, polyethylene glycol and the like.

As the disintegrant, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, croscarmellose sodium.
Type A (actisol), starch, crystalline cellulose, hydroxypropyl starch, partially pregelatinized starch and the like can be mentioned.

Examples of the binder include hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, gelatin, gum arabic,
Ethyl cellulose, polyvinyl alcohol, pullulan,
And the like.

Examples of the surfactant include glyceryl monostearate, polysorbates, sodium lauryl sulfate, lauromacrogol, sucrose fatty acid ester and the like.

As the lubricant, for example, stearic acid,
Magnesium stearate, calcium stearate,
Examples include talc, hydrogenated oil, sucrose fatty acid ester, and the like.

Examples of the antioxidant include dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), α-tocopherol and citric acid.

Examples of the coating agent include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, cellulose. Examples thereof include acetate trimellitate (CAT) and polyvinyl acetate phthalate.

Examples of colorants include tar dyes and titanium oxide.

Examples of the corrigent include citric acid, adipic acid, ascorbic acid, menthol and the like.

[0021]

INDUSTRIAL APPLICABILITY According to the present invention, the elution properties of sulfonamide anti-inflammatory agents in water and acidic solutions are remarkably improved,
Furthermore, in vivo, a solid oral preparation having not only immediate effect but also significantly improved absorption rate was obtained.

[0022]

EXAMPLES The pharmaceutical composition of the present invention can be produced by the usual granulation method as described above. The present invention will be described in detail below with reference to Examples.

Example 1 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm)
After mixing 2.5 g, sodium hydrogencarbonate 1.25 g, magnesium oxide 1.25 g, crystalline cellulose 2.75 g, corn starch 1.5 g, anhydrous light silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g, 30 M
Sift through and mix thoroughly, then dissolve 0.5 g of hydroxypropylmethylcellulose (HPMC) and 0.25 g of polysorbate 80 in water as a binder, granulate in a mortar, dry, and then sift at 24M. To obtain a composition.

Example 2 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle diameter: 5 μm) 2.
5 g, sodium hydrogencarbonate 1.25 g, magnesium oxide 1.25 g, crystalline cellulose 2.75 g, corn starch 1.5 g, anhydrous light silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g were mixed and sieved at 30 M. After further thorough mixing, 0.5 g of hydroxypropylmethyl cellulose (HPMC) and 0.25 g of polysorbate 80 dissolved in water were granulated as a binder in a mortar, dried and sieved at 24 M to form a composition. I got a thing.

Example 3 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm)
After mixing 2.5 g, sodium hydrogencarbonate 1.25 g, magnesium oxide 1.25 g, crystalline cellulose 2.75 g, corn starch 1.5 g, anhydrous light silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g, 30 M
And then thoroughly mixed, and then 0.5 g of hydroxypropylmethyl cellulose (HPMC) dissolved in water is granulated as a binder in a mortar, dried, and then sieved at 24 M to obtain a composition. It was

Example 4 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm)
2.5 g, sodium hydrogen carbonate 2.5 g, crystalline cellulose 2.75 g, corn starch 1.5 g, anhydrous light silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g were mixed and sieved at 30 M, and more sufficiently After mixing with water, add hydroxypropyl methylcellulose (HPM
C) 0.5 g of polysorbate 80 and 0.25 g of polysorbate 80 were used as a binder to granulate in a mortar, and after drying, 2
The composition was obtained by sieving with 4M.

Example 5 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm)
2.5 g, magnesium oxide 2.5 g, crystalline cellulose 2.75 g, corn starch 1.5 g, light anhydrous silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g were mixed and sieved at 30 M, and further thoroughly. After mixing, add hydroxypropyl methylcellulose (HPM
C) 0.5 g of polysorbate 80 and 0.25 g of polysorbate 80 were used as a binder to granulate in a mortar, and after drying, 2
The composition was obtained by sieving with 4M.

Example 6 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm)
2.5 g, magnesium hydroxide 2.5 g, crystalline cellulose 2.75 g, corn starch 1.5 g, light anhydrous silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g were mixed and sieved at 30 M, and more sufficiently After mixing with water, add hydroxypropyl methylcellulose (HPM
C) 0.5 g of polysorbate 80 and 0.25 g of polysorbate 80 were used as a binder to granulate in a mortar, and after drying, 2
The composition was obtained by sieving with 4M.

Example 7 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm)
2.5 g, calcium carbonate 2.5 g, crystalline cellulose 2.75 g, corn starch 1.5 g, light anhydrous silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g were mixed and sieved at 30 M, and further thoroughly. After mixing, add hydroxypropyl methylcellulose (HPM
C) 0.5 g of polysorbate 80 and 0.25 g of polysorbate 80 were used as a binder to granulate in a mortar, and after drying, 2
The composition was obtained by sieving with 4M.

Example 8 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm)
2.5 g, magnesium carbonate 2.5 g, crystalline cellulose 2.75 g, corn starch 1.5 g, light anhydrous silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g were mixed and sieved at 30 M, and further thoroughly. After mixing, add hydroxypropyl methylcellulose (HPM
C) 0.5 g of polysorbate 80 and 0.25 g of polysorbate 80 were used as a binder to granulate in a mortar, and after drying, 2
The composition was obtained by sieving with 4M.

Example 9 Nimeslide (average particle size: 50 μm) 2.5 g, sodium hydrogen carbonate 1.25 g, magnesium oxide 1.25
g, crystalline cellulose 2.75 g, corn starch 1.5
g, anhydrous light silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g were mixed, sieved at 30 M, further thoroughly mixed, and then dissolved in water with 0.5 g of hydroxypropyl methyl cellulose (HPMC). As a binder, the mixture was granulated in a mortar, dried, and sieved at 24 M to obtain a composition.

Example 10 N- (2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (average particle size: 50 μm)
After mixing 2.5 g, sodium hydrogencarbonate 1.25 g, magnesium oxide 1.25 g, crystalline cellulose 2.75 g, corn starch 1.5 g, anhydrous light silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g, 30 M
And then thoroughly mixed, and then 0.5 g of hydroxypropylmethyl cellulose (HPMC) dissolved in water is granulated as a binder in a mortar, dried, and then sieved at 24 M to obtain a composition. It was

Example 11 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle diameter: 50 μm) 2
50 g, sodium hydrogencarbonate 125 g, magnesium oxide 125 g, mannitol 200 g, crystalline cellulose 21
0g, Constarch 202.5g, Light anhydrous silicic acid 10
After thoroughly mixing 0 g, 130 g of hydroxypropylcellulose and 250 g of carboxymethylcellulose calcium, the mixture was stirred and granulated with water as a binder solvent, dried in a fluidized bed, and sieved at 24 M to obtain a composition.

Example 12 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 5 μm) 25
0 g, sodium hydrogencarbonate 125 g, magnesium oxide 125 g, mannitol 200 g, crystalline cellulose 210
g, corn starch 200 g, anhydrous light silicic acid 100 g,
After thoroughly mixing 130 g of hydroxypropyl cellulose and 250 g of carboxymethyl cellulose calcium,
A solution in which 25 g of polysorbate 80 was dissolved in water was granulated with stirring as a binding solvent, dried in a fluidized bed, and sieved at 24 M to obtain a composition.

Example 13 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm) 2
50 g, sodium hydrogencarbonate 125 g, magnesium oxide 125 g, mannitol 200 g, crystalline cellulose 21
0g, Constarch 202.5g, Light anhydrous silicic acid 10
After thoroughly mixing 0 g, 130 g of hydroxypropyl cellulose and 250 g of carboxymethyl cellulose calcium, the mixture was stirred and granulated with ethanol as a binder solvent, dried in a fluidized bed, and sieved at 24 M to obtain a composition.

Example 14 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 5 μm) 25
0 g, sodium hydrogencarbonate 125 g, magnesium oxide 125 g, mannitol 200 g, crystalline cellulose 210
g, corn starch 200 g, anhydrous light silicic acid 100 g,
After thoroughly mixing 130 g of hydroxypropyl cellulose and 250 g of carboxymethyl cellulose calcium,
25 g of polysorbate 80 in 50% aqueous ethanol solution
Was dissolved and granulated with stirring as a binding solvent, dried in a fluidized bed, and sieved at 24 M to obtain a composition.

Example 15 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 5 μm) 25
0 g, sodium hydrogencarbonate 125 g, magnesium oxide 125 g, mannitol 200 g, crystalline cellulose 210
g, corn starch 200 g, anhydrous light silicic acid 100 g,
And 250 g of carboxymethyl cellulose calcium are thoroughly mixed, and then hydroxypropyl cellulose 13 is added to water.
The composition was obtained by fluidized bed granulation using 0 g and a solution of 25 g of polysorbate 80 as a binding solvent.

Control Example 1 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle size: 50 μm)
2.5 g, lactose 2.0 g, crystalline cellulose 2.75 g,
1.5 g of corn starch, 0.4 g of light anhydrous silicic acid and 3.0 g of low-substituted hydroxypropyl cellulose were mixed, sieved at 30 M, and further thoroughly mixed, and then 0.5 g of hydroxypropylmethyl cellulose (HPMC) and polysorbate. 80 0.25 g was used as a binder and granulated in a mortar, dried, and sieved at 24 M to obtain a composition.

Control Example 2 N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (average particle diameter: 5 μm) 2.
After mixing 5 g, lactose 2.0 g, crystalline cellulose 2.75 g, corn starch 1.5 g, anhydrous light silicic acid 0.4 g and low-substituted hydroxypropyl cellulose 3.0 g, 30
After sieving with M, and further thoroughly mixing, 0.5 g of hydroxypropylmethylcellulose (HPMC) and 0.25 g of polysorbate 80 dissolved in water are granulated as a binder in a mortar, dried, and then sieved at 24 M. To obtain a composition.

Reference Example 1 1 part by weight to 1.5 parts by weight of magnesium stearate, based on 156.5 parts by weight of the compositions of Examples 12 to 15,
After adding 2 parts by weight of hardened oil, sieving at 30 M and thoroughly mixing, compression molding was carried out by a rotary tableting machine to contain 25 mg of N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide. Tablet diameter 7 mm, 1 tablet 160
A mg tablet was obtained.

Reference Example 2 The tablets of Reference Example 1 were sprayed with a solution in which Opadry (trade name) was suspended by a coating machine to give 10 mg as a base material per tablet to give film-coated tablets.

Reference Example 3 1 part by weight of magnesium stearate was added to 129 parts by weight of the compositions of Examples 1 to 11, sieved at 30 M and thoroughly mixed, and then filled into No. 3 capsules.

Test Example 1 The compositions of Example 1, Example 2, Control Example 1 and Control Example 2 were
0.1 g of magnesium stearate was added and the mixture was compression molded to 130 mg of 1 tablet of N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide.
A tablet having a tablet diameter of 7 mm and containing 5 mg was obtained. These tablets were subjected to an absorption test using a beagle dog.
The control examples 1 and 2 were samples in which no alkaline substance was blended.

The absorbability test was carried out by administering one tablet of each sample in 4 cases per group by the crossover method and measuring the drug concentration in plasma. Table 1 shows the results.

[0045]

[Table 1]

From these results, it can be seen that the tablets using the composition of the Example are completely absorbed, while the Control Example is not completely absorbed.

Test Example 2 Magnesium stearate (0.1 g) was added to the compositions of Examples 1, 3, 4, 5, 6, 7, 8 and Comparative Example 1 and the mixture was compression-molded to give a tablet of 130 mg. N- (5-amino-4
A tablet having a diameter of 7 mm and containing 25 mg of -nitro-2-phenoxyphenyl) methanesulfonamide was obtained. With respect to these tablets, using a liquid prepared by adding 2% sodium lauryl sulfate to water, the Japanese Pharmacopoeia dissolution test No. 2 method (paddle method), paddle rotation speed 100 rpm, test liquid 9
It was performed with 00 ml. The results of comparison of elution properties are shown in FIG. The elution of N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide from the tablet using the composition of Example was superior to that of the tablet of Control Example 1. It was

Test Example 3 To the compositions of Examples 1 and 2 and Control Example 1, 0.1 g of magnesium stearate was added and compression-molded to give 1 tablet 13
A tablet having a diameter of 7 mm and containing 25 mg of N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide in 0 mg was obtained. For these tablets, a solution obtained by adding 2% sodium lauryl sulfate to the Japanese Pharmacopoeia disintegration test No. 1 liquid was used according to the Japanese Pharmacopoeia dissolution test No. 2 method (paddle method) with a paddle rotation speed of 100 rpm and a test liquid 9
It was performed with 00 ml. The results of comparison of elution properties are shown in FIG. The elution of N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide from the tablets using the composition of Example is superior to that of the tablet of Control Example 1. It was Further, the pH of the eluate after the test did not change from that before the test.

[Brief description of drawings]

FIG. 1 shows the results of a dissolution test in Test Example 2.

FIG. 2 shows the results of a dissolution test in Test Example 3.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI technical display location // C07C 311/08 7419-4H (72) Inventor Masami Nemoto 3-24 Takada, Toshima-ku, Tokyo No. 1 within Taisho Pharmaceutical Co., Ltd.

Claims (3)

[Claims] 1. A composition for internal solid preparation, which comprises a sulfonamide anti-inflammatory agent and one or more alkaline substances. 2. A sulfonamide anti-inflammatory agent is N- (5
The composition for oral solid preparation according to claim 1, which is -amino-4-nitro-2-phenoxyphenyl) methanesulfonamide or N- (2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide. 3. The alkaline substance is sodium hydrogen carbonate,
The composition for oral solid preparation according to claim 1, which is one or more selected from the group consisting of magnesium oxide, magnesium hydroxide, calcium carbonate and magnesium carbonate.