JPH09323933A - Suppository having improved stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a suppository containing a benzimidazole derivative and sodium hydrogensulfite, excellent in preservation stability and absorptivity in the rectum and used as a serotonin3 receptor antagonist. SOLUTION: This suppository contains both 6-amino-5-chloro-1-isopropyl-2-(4- methyl-1-pyperadinyl)benzimidazole of the formula and sodium hydrogen sulfite as active ingredients. The components are dissolved or dispersed in a suppository base and formed into the suppository with an optionally added additive such as a surfactant by the conventional method. The sodium hydrogensulfite is blended in 1-300 pts.wt. and the suppository base is blended in 10-20,000 pts.wt. based on 1 pt.wt. compound of the formula. The divided does of the compound of the formula is 0.1-100mg and the dairy dose is 1-3 times of the divided dose. The suppository can be dosed to a patient impossible to swallow down a medicine because of vomiting and impossible to be dosed by injection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 6-amino-5-chloro-1-isopropyl-, which has improved storage stability.
It relates to a suppository containing 2- (4-methyl-1-piperazinyl) benzimidazole (I). The suppository of the present invention,
Used as a serotonin ₃ receptor antagonist.

[0002]

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[0003]

2. Description of the Related Art Suppositories are capable of administering a relatively large amount of drugs as compared with orally administered preparations and injections, can avoid gastrointestinal disorders, and are safer than injections.
Easier to avoid drug degradation or metabolism than oral administration, irrelevant to dietary intake, expected to have a good effect by administration before bedtime or during sleep, incapable of ingestible patient or injection It has the advantages of being suitable for pediatric and geriatric fields, such as being able to be administered to various patients, and being suitable for home treatment without having to be carried out by a doctor or a nurse like injections (suppository-formulation From clinical application-, Shozo Muranishi, 1985, published by Nanzando). For this reason, in recent years, many suppositories for various diseases with systemic action and local action have been clinically used.

6-amino-5 used in the suppository of the present invention
-Chloro-1-isopropyl-2- (4-methyl-1-)
Piperazinyl) benzimidazole [hereinafter referred to as benzimidazole derivative (I)] is an excellent serotonin ₃
It is known that the compound has a receptor antagonistic action and is useful as an antiemetic agent against vomiting associated with cancer chemotherapy such as cisplatin (see JP-A-5-17449).
It is also known that the above-mentioned benzimidazole derivative (I) is a compound useful for irritable bowel syndrome on the basis of serotonin ₃ receptor antagonistic action (JP-A-6-145).
No. 152).

Based on the above-mentioned usefulness, Japanese Unexamined Patent Publication No. 7-4825
No. 8 discloses a preparation for transdermal administration such as a patch or an ointment, which is used as a serotonin ₃ receptor antagonist characterized by containing the above-mentioned benzimidazole derivative (I). There is no disclosure of suppositories containing the benzimidazole derivative (I) as an active ingredient.

[0006]

The present inventor has conducted various studies on suppositories containing a benzimidazole derivative (I) as an active ingredient, and as a result, by administering the suppositories rectally,
It was found that the benzimidazole derivative (I) has excellent rectal absorbability (Japanese Patent Application No. 6-329476).

However, although the above suppositories have excellent rectal absorbability regardless of which suppository base is used,
It was found that there is room for improvement in storage stability.

An object of the present invention is to provide a suppository containing a benzimidazole derivative (I) having improved storage stability.

[0009]

Means for Solving the Problems The present inventor has conducted various studies to improve the storage stability of suppositories containing the benzimidazole derivative (I). As a result, (i) the benzimidazole derivative (I), and (B) It was found that suppositories containing sodium bisulfite have excellent storage stability, and that such suppositories also have good rectal absorbability of the benzimidazole derivative (I). Was completed.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The benzimidazole derivative (I) used in the present invention can be obtained by the production method described in JP-A-5-17449.

The sodium bisulfite used in the present invention is the 13th edition of the Japanese Pharmacopoeia (published by Dai-ichi Law,
Sodium bisulfite described on page 1088 of 1996) is preferably used.

In the suppository of the present invention, the benzimidazole derivative (I) and sodium bisulfite are dissolved or suspended in a suppository base, and an additive such as a surfactant is appropriately added if necessary, and a conventional suppository is added. It can be manufactured by a method.
For example, the suppository of the present invention can be manufactured by the melting method as follows.

That is, a suppository base is melted by heating, and the benzimidazole derivative (I), sodium bisulfite and, if necessary, an additive such as a surfactant are uniformly mixed therein, and then a predetermined amount of each is added. Is poured into a mold and cooled and solidified to manufacture.

As the suppository base, an oily base or a water-soluble base can be used.

Examples of the oily base include hard fat. Hard fat is a mixture of glycerides in which each constituent fatty acid is a straight chain saturated fatty acid having 8 to 18 carbon atoms, and for example, this is, for example, Martindale the Extra Pharmacopia (Martinda).
le The Extra Pharmacopei
a, 28th edition, p. 1067, The Pharmaceu
Technical Press, issued in 1982) and (Supervised by the Examination Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Pharmaceutical Additives Standard, 199
3 years, page 243, June 28, 1993, published by Yakuji Nipposha). This is, for example, Witepsol ^TM H-5, Witepsol ^TM H-15, Witepsol ^TM H-35, Witepsol ^TM W-25, Witepsol ^TM W-35, Witepsol ^TM S-. 5
5, Witepsol ^TM S-58 [above, manufactured by Huls AG], Nissan Pharmasol ^TM B
-115, Nissan Pharmasol ^TM N-145 (manufactured by NOF CORPORATION) and the like are commercially available.

These hard fats can be used as a mixture of two or more, if necessary.

Examples of the water-soluble base include macrogol which is solid at room temperature. Macrogol is an addition polymer of ethylene oxide and water, and there are Macrogol 1000, Macrogol 1500, Macrogol 1540, Macrogol 4000, and Macrogol 6000, etc., depending on the difference in average molecular weight. These may be used alone or in two types. The above can be mixed and used.

Further, the suppository of the present invention comprises a benzimidazole derivative (I) and a sulfurous acid based on an oily suppository which is liquid at room temperature, a water-soluble base which is liquid at room temperature, or an emulsion base which is a combination thereof with an emulsifier. It can also be produced by filling or molding a solution or suspension of sodium hydrogen into a soft capsule for rectal administration.

Examples of the oily base that is liquid at room temperature include liquid paraffin and vegetable oil.

Examples of water-soluble bases which are liquid at room temperature include Macrogol 200, Macrogol 300, Macrogol 400 and Macrogol 600.

Examples of the emulsifier include sorbitan monostearate, sorbitan monopalmitate, polysorbate 60, polysorbate 80, sodium lauryl sulfate and lecithin.

Among the above suppository bases, an oily base, particularly hard fat, is preferable, and among the hard fats,
A hard fat having a hydroxyl value of 50 or less is more preferable, and a hard fat having a hydroxyl value of 15 or less is more preferable.

Examples of the hard fat having a hydroxyl value of 15 or less include Witepsol ^™ H-5, Witepsol ^™ H-15, Witepsol ^™ H-35 [above,
Huls AG], Nissan Pharmasol ^TM B-115 (Nippon Oil & Fats Co., Ltd.), and the like. Examples of the hard fat having a hydroxyl value of 50 or less include, for example, Witepsol. ^TM W-2
5, Witepsol ^TM W-35 [above, manufactured by Huls AG], Nissan Pharmasol ^TM N
-145 (manufactured by NOF CORPORATION) and the like.

The benzimidazole derivative (I) and sodium bisulfite have an average particle size of 3 to 150.
It is preferably used as a fine powder of μm.

The amount of sodium bisulfite used is benz
It is usually 1 to 3 parts by weight with respect to 1 part by weight of the imidazole derivative (I).
It is 00 parts by weight.

The amount of suppository base used is benz Imidazole
Usually 10 to 20,000 weight per 1 part by weight of the derivative (I)
Parts by weight, preferably 50 to 2000 parts by weight.

The dosage of the suppository of the present invention varies depending on the age, body weight, symptom, etc. of the patient, but it is usually administered 1 to 3 times per day, and the dosage of the benzimidazole derivative (I) per administration is , 0.1 to 100 mg.

[0028]

INDUSTRIAL APPLICABILITY The suppository of the present invention is excellent not only in the storage stability of the benzimidazole derivative (I) but also in the rectal absorbability (see Test Example 1 and Test Example 2 below). Further, the suppository of the present invention can be administered to patients who cannot swallow due to vomiting or the like and patients who cannot administer injections.

Therefore, the suppository of the present invention can be expected to have a medicinal effect based on the serotonin ₃ receptor antagonistic action of the benzimidazole derivative (I) by rectal administration. More specifically, the suppository of the present invention is an antiemetic agent or serotonin ₃ for vomiting associated with cancer chemotherapy such as cisplatin.
It is useful as a therapeutic agent for irritable bowel syndrome based on receptor antagonism.

The usefulness of the suppository of the present invention will be described in detail below with reference to test examples. [Test Example 1] Storage stability test The content of the benzimidazole derivative (I) in the test example is p
-Using propyl aminobenzoate as internal standard,
It was quantified by liquid chromatography under the following conditions (hereinafter abbreviated as HPLC method). HPLC condition / column: L-column ODS [4.6 mm × 2
50 mm, manufactured by Japan Chemicals Inspection Association] ・ Mobile phase: 8.7 g of dipotassium hydrogen phosphate in purified water 10
A mixed solution of 4 volumes of a solution dissolved in 00 ml and adjusted to pH 7.4 by adding phosphoric acid and 6 volumes of methanol-Column temperature: 30 ° C-Flow rate: 1.0 ml / min-Detection method: Absorbance at UV254 nm Measurement

1. Specimens Suppositories of Example 1 and suppositories of Comparative Example 1

2. Test method The sample was stored in a thermostat at 60 ° C., and after a certain period of time (1 month), they were sampled and the content of the benzimidazole derivative (I) in the sample was measured by the HPLC method. The test was performed three times for one sample.
The average value was obtained, and the residual ratio with respect to the content immediately after preparation (average value of 3 cases) was calculated.

3. Test results Table 1 shows the results of residual rate (%) ± standard deviation (SD).

[0034]

[Table 1] As is clear from Table 1, the suppository of the present invention was excellent in storage stability.

Test Example 2 Rectal Absorption Test The plasma concentration of the benzimidazole derivative (I) in the test example was 6-amino-5-chloro-1-propyl-2- (4
-Methyl-1-piperazinyl) benzimidazole (see JP-A-5-17449) was used as an internal standard substance, and quantified by the HPLC method under the following conditions. Conditions of HPLC method / column: Inertsil ODS-2 [4.6 mm
× 150 mm, manufactured by GL Sciences Inc.] ・ Mobile phase: mixed solution of 30 volumes of acetonitrile, 70 volumes of water and 0.05 volumes of triethylamine ・ Column temperature: 35 ° C ・ Flow rate: 1.0 ml / min ・ Detection method: UV at 315 nm Absorbance measurement

1. Sample Suppository A, Suppository X

2. Preparation of Specimen Suppository A Hard Fat [Witepsol ^™ H-15, hydroxyl value 9.8, manufactured by Huls AG] 9.38
g in a stainless steel beaker, heated to 40 to 45 ° C. to melt, and added to the benzimidazole derivative (I)
0.22 g and 0.40 g of sodium hydrogen sulfite (manufactured by Wako Pure Chemical Industries, Ltd.) were added and stirred to be mixed uniformly. While keeping this mixture at 37 to 45 ° C., it was filled in a cylindrical mold and then cooled, and a diameter of 3 mg containing 1.1 mg of the benzimidazole derivative (I) per 50 mg of this mixture.
A suppository A having a cylindrical shape of mm was obtained. Suppository X Hard Fat [Witepsol ^™ H-15, hydroxyl value 9.8, manufactured by Huls AG] 9.78
g in a stainless steel beaker, heated to 40 to 45 ° C. to melt, and added to the benzimidazole derivative (I)
0.22 g was added and stirred to uniformly mix. While keeping this mixture at 37 to 45 ° C., it was filled in a cylindrical mold and then cooled to obtain a column-shaped suppository X having a diameter of 3 mm and containing 1.1 mg of the benzimidazole derivative (I) per 50 mg of this mixture. It was

3. Test method Wistar rats (body weight 190-90) fasted for 24 hours
240 g) was intrarectally administered with a sample corresponding to 5.7 mg of benzimidazole derivative (I) per 1 kg of body weight, and then cyanoacrylate adhesive (Aron Alpha ^TM ,
Toa Synthetic Chemical Industry Co., Ltd.) was used to adhere the anus to prevent drug leakage. 0.25, 0.5, 1, 2, 4, 6, after administration,
At 8 hours, blood was collected from the jugular vein cannula with a heparin-treated syringe, centrifuged (12000 rpm, 5 minutes), and the concentration of benzimidazole derivative (I) in the obtained plasma was quantified by the HPLC method. The test was performed twice for one sample.

4. Test results 0.25, 0.5, 1, 2, 4, 6 after administration for each administration group
And maximum plasma concentration (C _max ) and plasma concentration-determined from the amount of plasma benzimidazole derivative (I) at 8 hours (average value of 2 cases per group, unit: ng / ml)-
The area under the time curve (AUC _0-8h ) is shown in Table 2.

[0040]

[Table 2] As shown in Table 2, the rectal absorptivity of the benzimidazole derivative (I) when the suppository of the present invention was administered rectally was superior to that when the comparative suppository was administered rectally.

[0041]

EXAMPLES The present invention will be described below with reference to examples and comparative examples. Example 1 Hardfat [Witepsol ^™ H-15, hydroxyl value 9.8, manufactured by Huls AG] 9.88
9 g was placed in a stainless beaker and heated to 40 to 45 ° C. to melt, and 0.011 g of the benzimidazole derivative (I) and 0.1 g of sodium hydrogen sulfite (manufactured by Wako Pure Chemical Industries, Ltd.) were added and stirred. And mix evenly. While maintaining this mixture at 37 to 45 ° C., 1 g of each was charged in a spindle mold and then cooled to obtain a suppository of Example 1 containing 1.1 mg of each benzimidazole derivative (I).

Comparative Example 1 Hardfat [Witepsol ^™ H-15, hydroxyl value 9.8, manufactured by Huls AG] 9.98
9 g is put into a stainless beaker and heated to 40 to 45 ° C. to be melted, 0.011 g of the benzimidazole derivative (I) is added thereto, and the mixture is stirred and uniformly mixed.
While maintaining this mixture at 37 to 45 ° C, 1 g of each was charged into a spindle mold and then cooled to obtain a suppository of Comparative Example 1 containing 1.1 mg of the benzimidazole derivative (I) per one.

Claims (4)

[Claims] 1. A suppository containing (a) 6-amino-5-chloro-1-isopropyl-2- (4-methyl-1-piperazinyl) benzimidazole and (b) sodium bisulfite. Agent. 2. (a) Consisting of 6-amino-5-chloro-1-isopropyl-2- (4-methyl-1-piperazinyl) benzimidazole, (b) sodium bisulfite, and (c) hard fat. Suppository characterized by. 3. The suppository according to claim 1, wherein the hard fat is a hard fat having a hydroxyl value of 50 or less. 4. The suppository according to claim 1, wherein the hard fat is a hard fat having a hydroxyl value of 15 or less.