JPH09202728A - Solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new solid preparation having remarkably improved absorbability through digestive tracts by using a specific compound containing nimesulide in combination with an alkaline excipient. SOLUTION: This preparation contains a compound of formula I (X is S or O; R<1> is an alkyl; R<2> , R<3> and R<5> are each H or a halogen; R<4> is H, OH, a halogen or an alkoxy; R<6> is nitro or an alkanoyl; R<7> is H, a halogen or an alkoxy; R<6> and R<7> may together form a group of formula II, etc.; R<8> is H, a halogen or nitro) or its pharmacologically allowable salt in combination with an alkaline excipient. The solid preparation may be incorporated further with a water-soluble excipient or a surfactant. The amount of the alkaline excipient is 0.1-1 pt.wt. based on 1 pt.wt. of the compound of the formula I. The amount of the water-soluble excipient is 1-80wt.% based on the total preparation and that of the surfactant is 0.001-0.2 pt.wt. based on 1 pt.wt. of the compound of the formula I. The compound of the formula I is especially preferably N-(4- nitro-2-phenoxyphenyl)methanesulfonamide of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a solid preparation containing the compound (I) represented by the above general formula or a pharmaceutically acceptable salt thereof as an active ingredient, and in particular, its absorption in the digestive tract is significantly enhanced. The present invention relates to the above-mentioned solid preparation containing an active ingredient.

[0002]

2. Description of the Related Art As a typical example of compound (I) represented by the above general formula, N- (4-nitro-
2-phenoxyphenyl) methanesulfonamide (generic name nimesulide, sometimes abbreviated as nimesulide below)
Is mentioned.

[0003]

Embedded image

This nimesulide is known as an antipyretic and analgesic and anti-inflammatory agent effective for osteoarthritis of the knee, rheumatoid arthritis, etc. However, since it is extremely insoluble in water, if it is formulated by a usual method, it becomes digestive tract. It has a formulation problem of extremely low absorption in.

[0005]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a novel solid preparation in which the absorption of the compound (I) represented by the above general formula containing nimesulide in the digestive tract is remarkably enhanced. .

[0006]

The solid preparation of the present invention has the following general formula:

[0007]

Embedded image

Wherein X is S or O; R ¹ is a lower alkyl group or a lower alkyl group optionally substituted by at least one halogen; R ² , R ³ and R ⁵ are the same or different. H or halogen; R ⁴ is H, hydroxy, halogen or lower alkoxy group; R ⁶ is nitro or lower alkanoyl group, R ⁷ is H, halogen or lower alkoxy group, or R ⁶ and R ⁷ are taken together,

[0009]

Embedded image

R ⁸ has the gist of containing compound (I) represented by H, halogen or nitro) or a pharmaceutically acceptable salt thereof, and an alkaline excipient. In the present invention, those further containing a water-soluble excipient and a surfactant are preferred embodiments of the present invention.

The amount of the alkaline excipient compounded is preferably 0.1 to 1 part by weight relative to 1 part by weight of the compound (I), and the amount of the water-soluble excipient compounded is a solid preparation. It is preferably 1 to 80% by weight based on the total weight, and when a surfactant is added, it is preferably 0.001 to 0.2 parts by weight with respect to 1 part by weight of the compound (I). . Examples of the compound (I) include N- (4-nitro-2
-Phenoxyphenyl) methanesulfonamide (generic name nimesulide) is preferred.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION As described above, the solid preparation of the present invention contains the acidic compound (I) represented by the above general formula or a pharmaceutically acceptable salt thereof as an active ingredient. It has the greatest feature in that it is blended with an alkaline excipient for the purpose of improving absorption in the digestive tract. That is, the formulation of the present invention absorbs a compound from the digestive tract by mixing an alkaline excipient to change the liquidity (acidity) of the compound (I) as an active ingredient from neutral to weakly alkaline. It is intended to improve the activity of the gastrointestinal tract by further adding a water-soluble excipient.

Conventionally, there is no known formulation example of an acidic drug such as the compound (I) to which an alkaline excipient is added for the purpose of enhancing absorption in the digestive tract. For example, Japanese Patent Publication No. 6-502842 discloses a clathrate compound in which nimesulide is included in cyclodextrin for the purpose of improving gastrointestinal absorption in nimesulide which is an example of the compound (I). Examples include:
A formulation example in which calcium phosphate is added as an excipient is described. However, the above-mentioned publication is intended to enhance the solubility of nimesulide by using an inclusion compound of nimesulide and cyclodextrin, and the formulation of the present invention which does not take the form of the inclusion compound has no formulation mode. different. Furthermore, even if calcium phosphate is described in the examples of the above publications, the purpose of its addition is to improve moldability, and it is not intended to be added for the purpose of improving gastrointestinal absorption as intended in the present invention. . That is, there is no formulation example in which an alkaline excipient is added as in the present invention for the purpose of improving absorption of an acidic drug such as the above-mentioned compound (I) in the digestive tract. is there. Based on such findings, the present invention has found that the intended purpose can be achieved by adding an alkaline excipient and, if necessary, a water-soluble excipient, and completed the present invention. Of.

First, the definition of the substituents of the compound (I) which is the active ingredient of the preparation of the present invention will be explained. “Lower” means a carbon number of 1 to 6 unless otherwise specified. Suitable "lower alkyl group" in "lower alkyl group" or "lower alkyl group optionally substituted by at least one halogen" is methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group. Group, t-
Examples thereof include a butyl group, a pentyl group and a hexyl group.
Suitable "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group and the like.

Suitable "lower alkanoyl group" is
Formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, pivaloyl group and the like can be mentioned.

Suitable "halogen" in "halogen" or "lower alkyl group optionally substituted with at least one halogen" includes chlorine, bromine, iodine and fluorine. Preferred compounds (I) having the above-exemplified groups are as follows.

[0017]

[Chemical 6]

Of the above compounds, nimesulide is particularly preferred. The pharmaceutically acceptable salts of the compound (I) include salts with bases such as inorganic base salts, examples thereof include alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg Calcium salts, magnesium salts, etc.), ammonium salts, etc .; salts with bases such as organic base salts, examples of which are organic amine salts (eg, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine) Salts, N, N′-dibenzylethylenediamine salts, etc.) and the like, which are commonly used non-toxic salts.

Next, the alkaline excipient used in the preparation of the present invention is added for the purpose of enhancing absorption in the digestive tract as described above. As such an example, for example, an inorganic compound ( Anhydrous calcium hydrogen phosphate, calcium phosphate, calcium hydrogen carbonate, calcium carbonate, sodium hydrogen carbonate, sodium carbonate, anhydrous sodium hydrogen phosphate, sodium phosphate, etc .; organic compounds (sodium citrate, sodium aspartate, sodium ascorbate, glycyrrhizin) Acid trisodium, sodium gluconate, etc.). As described above, the alkaline excipient used in the present invention is selected from organic compounds and inorganic compounds as long as it can change the liquidity of the acidic drug from neutral to weakly alkaline and improve the digestive tract absorption. It does not matter whether it is water-soluble or water-insoluble.

These alkaline excipients may be used alone or in admixture of two or more. The amount of the alkaline excipient compounded is preferably in the range of 0.1 to 1 part by weight relative to 1 part by weight of the compound (I).

The water-soluble excipient used in the present invention is added as necessary for the purpose of further promoting the gastrointestinal absorption effect by the addition of the alkaline excipient. In addition, the water-soluble excipient is not particularly limited as long as it is a water-soluble excipient, and it means that the type of liquid depending on pH does not matter. However, as described above, in order to efficiently obtain the promotion of digestive tract absorption by changing the liquidity of the drug of the present invention (acidic drug) to the neutral to weakly alkaline side, the one having strong acidity is not preferable, and the pH is not preferable. It is preferable to use a weakly acidic to weakly alkaline one. Therefore,
The water-soluble excipient used in the present invention may be of a different type from the above-mentioned alkaline excipient, or an excipient that can obtain both properties at once, that is, an alkaline and water-soluble excipient. It is also possible to use an excipient.

The most recommended water-soluble excipients are those around neutrality that do not adversely affect the liquidity (near neutrality) obtained by the addition of alkaline excipients. Such examples include sugars (lactose, sucrose, glucose, mannitol, fructose, sorbitol, etc.), starch (corn starch, potato starch, wheat starch, etc.), polymer compounds (hydroxypropyl cellulose, gum arabic, gelatin, Sodium alginate, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, sodium carboxymethyl cellulose, etc.). These water-soluble excipients may be used alone or in combination of two or more. The compounding amount of the water-soluble excipient is preferably 1 to 80% by weight, more preferably 1 to 50% by weight, based on the total weight of the preparation.

The preparation of the present invention contains the above-mentioned components as essential components, but it is recommended to further contain a surfactant for the purpose of further promoting absorption. As the surfactant used in the present invention, a nonionic surfactant [for example, polyoxyethylene-based surfactant (for example, polysorbate 80, polyoxyl 40 stearate,
Lauromacrogol, polyoxyethylene hydrogenated hydrogenated castor oil (HCO-50); sucrose fatty acid ester etc.], ionic surfactant [anionic surfactant (eg sodium lauryl sulfate etc.), cationic surfactant (eg Benzalkonium chloride, etc.), amphoteric surfactants (lecithin, etc.)] and the like. These surfactants may be used alone or in combination of two or more. The amount of the surfactant blended is 0.001 to 0.2 with respect to 1 part by weight of the compound (I) as an active ingredient.
It is preferable to set it as a weight part, More preferably, it is 0.0.
1 to 0.1 part by weight. In formulating the preparation of the present invention, a pharmaceutically acceptable carrier may be added, if necessary, according to a conventional method, and further coating may be performed.

As an example of the formulation example, after adding a water-soluble excipient and an alkaline excipient to nimesulide and mixing, a solution in which a binder and a surfactant which are water-soluble excipients are further dissolved is prepared. In addition, knead, powder according to the usual method,
Formulated into various solid preparations such as fine granules, granules, pills, tablets, soft / hard capsules, and powders.

As the above-mentioned pharmaceutically acceptable carriers, excipients (disintegrants, lubricants, extenders, etc.), colorants, flavors, preservatives, stabilizers, and other commonly used carriers are appropriately used. be able to. Specific examples include crystalline cellulose, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, magnesium stearate, talc, light anhydrous silicic acid, food coloring, aromatic essential oils, and the like.

The dosage of the preparation of the present invention is determined in consideration of the type of compound (I) to be used, the type of dosage form, the administration method, the age and weight of the patient, the type and site of the patient's symptoms, and the degree of progression. Although it is finally determined appropriately by the doctor's judgment, in general, for adults, for example, 25-600 mg of nimesulide is preferably orally administered in 1 to several times a day. More preferably 25-400 mg /
Day, even more preferably 50-200 mg / day.

The present invention will be described in detail below based on examples.
However, the following examples do not limit the present invention,
Modifications and implementations without departing from the spirit of the above and below are all included in the technical scope of the present invention.

[0028]

EXAMPLES The following formulation examples and test examples show the results using nimesulide as an example of the above-mentioned compound (I) and furothulide represented by the following structural formula. The results show representative examples of the present invention. Yes, but not limited to this.

[0029]

Embedded image

Formulation Example 1: Tablets (1) Nimesulide (100 g) was mixed with lactose (10 g), anhydrous calcium hydrogen phosphate (57 g) and crystalline cellulose (13 g), and the mixture was mixed with purified water to prepare hydroxypropylcellulose.2.
What melt | dissolved 6g was added, it kneaded with the mixer, and it dried. After sizing the dried product thus obtained,
Tablets (190 mg / tablet) were obtained by adding and mixing carmellose calcium 5.6 g and magnesium stearate 1.8 g.

Formulation Example 2: Tablet (2) To 100 g of nimesulide, 17 g of lactose, 40 g of anhydrous calcium hydrogen phosphate and 21.2 g of crystalline cellulose were added and mixed, and then 2.6 g of hydroxypropyl cellulose and sodium lauryl sulfate were added to purified water. What melt | dissolved 1.8g was added, it kneaded with the mixer, and it dried.
The dried product thus obtained was sized, and then tablets (190 mg) were prepared by adding and mixing carmellose calcium 5.6 g and magnesium stearate 1.8 g.
/ Tablet) was obtained.

Formulation Example 3: Film Coated Tablets To 100 g of Nimesulide, 86 g of crystalline cellulose and 55 g of anhydrous calcium hydrogen phosphate were added and mixed, and then 4 g of hydroxypropyl cellulose dissolved in purified water was added and kneaded with a mixer. And then dried. The dried product thus obtained was sized, and then added with 12 g of carmellose calcium and 3 g of magnesium stearate.
A tablet (130 mg / tablet) was obtained by mixing.

Next, 7.8 g of hydroxypropylmethyl cellulose, 0.6 g of triethyl citrate, 1.0 g of titanium oxide, and 0.02 g of yellow ferric sesquioxide were dissolved and dispersed in purified water. The obtained dispersion was film-coated on the above tablets by a conventional method to obtain film-coated tablets (134.7 mg / tablet).

Formulation Example 4: Tablet (3) 24 g of lactose, 55 g of anhydrous calcium hydrogen phosphate and 270 g of crystalline cellulose were added to 100 g of frothuride and mixed, and then hydroxypropyl cellulose 1 was added to purified water.
What melt | dissolved 0 g was added, it kneaded with the mixer, and it dried. After sizing the dried product thus obtained,
Tablets were prepared by adding and mixing 16 g of carmellose calcium and 5 g of magnesium stearate.
mg / tablet) was obtained.

Formulation Example 5: Capsules To 100 g of nimesulide, 21 g of mannitol, 57 g of anhydrous calcium hydrogen phosphate, 10 g of crystalline cellulose and 2 g of magnesium stearate were added and mixed, and then 190 mg of the mixture was filled into No. 3 capsules. A capsule was obtained.

Formulation Example 6: Fine Granules To 100 g of Nimesulide, 25 g of sucrose, 50 g of anhydrous calcium hydrogen phosphate and 13 g of crystalline cellulose were added and mixed, and then 2 g of hydroxypropyl cellulose was added to purified water.
What was melt | dissolved was added, and after kneading with a mixer, wet sizing was immediately performed. The obtained sized product was dried and then sieved to obtain a fine granule.

Control Formulation Example 1: Tablet (1) To 100 g of Nimesulide, 34.4 g of lactose and 46 g of crystalline cellulose were added and mixed, and then 2.4 g of hydroxypropyl cellulose dissolved in purified water was added.
It was kneaded in a mixer and then dried. The dried product thus obtained was sized, and then carmellose calcium 5.4
g and 1.8 g of magnesium stearate were added and mixed to obtain tablets (1 containing no alkaline excipient).
90 mg / tablet) was obtained.

Control Preparation Example 2: Tablet (2) 80 g of crystalline cellulose was added to 100 g of nimesulide and mixed, and then purified water was added and kneaded. Next, this kneaded product was dried and then sized. To the obtained sized product, 8 g of carmellose calcium and 2 g of magnesium stearate were added and mixed to obtain tablets (190 mg / tablet) containing no alkaline excipient.

Control Formulation Example 3: Film Coated Tablets 141 g of crystalline cellulose was added to 100 g of Nimesulide and mixed, and then hydroxypropyl cellulose 4 was added to purified water.
What melt | dissolved g was added, it kneaded with the mixer, and it dried. The dried product thus obtained was sized, and then 12 g of carmellose calcium and 3 g of magnesium stearate were added and mixed to obtain tablets (130 mg / tablet) containing no alkaline excipient. Next, a film-coated tablet (134.7 mg /
Tablets).

Test Example: Gastrointestinal Absorption Test of Nimesulide-containing Solid Preparation Using Beagle dogs, Preparation Examples 1 and 2 (both tablets),
Formulation Example 3 (Film-coated tablets), Control Formulation Example 1,
Gastrointestinal absorption tests of 2 (all tablets) and Control formulation example 3 (film-coated tablets) were conducted in the following manner.

The test was carried out with 5 animals per group, and nimesulide 100 was used.
mg / tablet / animal was orally administered by gavage. However, in the case of administering the film-coated tablets of Formulation Example 3 and Control Formulation Example 3, two 130 mg tablets (containing 50 mg of nimesulide) were administered to obtain 100 mg / nimesulide.
Tablets / animal were administered.

After administration, blood was collected from the vein every predetermined time (10 ml / time), and the nimesulide content in plasma was analyzed by liquid chromatography. The average value of the nimesulide concentration in plasma analyzed in this way was calculated, and the results are shown in Table 1 and FIG. 1, and the kinetic parameters [AUC (concentration in blood) calculated based on these measurement results were calculated. The results of the area under the time curve), Cmax (maximum blood concentration) and Tmax (time to reach Cmax)] are shown in Table 2.

[0043]

[Table 1]

[0044]

[Table 2]

From these results, the preparation of the present invention (Formulation Example 1)
It can be seen that the compounds (3) to (3) significantly improve the absorption of nimesulide into the digestive tract, as compared with the control preparations (Control Examples 1 to 3).

[0046]

EFFECTS OF THE INVENTION The solid preparation of the present invention is constituted as described above, and its absorption into the digestive tract can be remarkably enhanced as compared with the conventional preparations.

[Brief description of drawings]

FIG. 1 is a graph showing the relationship between the elapsed time after administration and the concentration of nimesulide in plasma.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 9/50 A61K 31/35 ABG 31/35 ABG 31/63 AAG 31/63 AAG 47/02 B 47/02 9/14 L (72) Inventor Yoshikazu Tada 1-3-3, Tomobuchi-cho, Miyakojima-ku, Osaka-shi, Osaka 25-505 (72) Inventor Masayuki Yamada 2--11, Yamato-nishi, Kawanishi-shi, Hyogo

Claims (7)

[Claims] 1. A compound of the general formula (In the formula, X is S or O; R ¹ is a lower alkyl group or a lower alkyl group optionally substituted with at least one halogen; R ² , R ³ and R ⁵ are the same or different and are H or halogen; R ⁴ is H, hydroxy, halogen or lower alkoxy group; R ⁶ is nitro or lower alkanoyl group, R ⁷ is H, halogen or lower alkoxy group, or R ⁶ and R ⁷ are taken together, ] R ⁸ represents H, halogen or nitro respectively) or a pharmaceutically acceptable salt thereof, and an alkaline excipient. 2. The solid preparation according to claim 1, which further contains a water-soluble excipient. 3. The solid preparation according to claim 1 or 2, which further contains a surfactant. 4. The solid preparation according to claim 1, wherein the amount of the alkaline excipient compounded is 0.1 to 1 part by weight relative to 1 part by weight of the compound. 5. The solid preparation according to claim 2, wherein the content of the water-soluble excipient is 1 to 80% by weight based on the total weight of the solid preparation. 6. The solid preparation according to claim 3, wherein the content of the surfactant is 0.001 to 0.2 part by weight relative to 1 part by weight of the compound. 7. The solid preparation according to claim 1, wherein the compound is N- (4-nitro-2-phenoxyphenyl) methanesulfonamide.