JPH06305969A - Suppository - Google Patents

Abstract

PURPOSE:To provide a suppository exhibiting fast-acting property and good blood concentration transition of almost the same level as an injection, applicable even to a patient apt to vomit and capable of expecting a high bioavailability. CONSTITUTION:The suppository containing 0.1-60mg of (+ or -)-6-chloro-3,4-dihydro-4- methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide mono hydrochloric acid salt as an active component. Releasing speed is controllable by compounding various kinds of base substances.

Description

Detailed Description of the Invention

[0001]

The present invention relates to (±) -as an active ingredient.
6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride (hereinafter sometimes referred to as the present compound) And a suppository containing

[0002]

(±) -6-Chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-
2H-1,4-benzoxazine-8-carboxamide monohydrochloride has a 5-HT ₃ receptor antagonistic effect and is a therapeutic agent for emesis caused by antineoplastic agents, chronic gastritis and irritable bowel syndrome (IBS). It is a compound currently under development for injection and oral administration as a therapeutic agent for digestive system diseases. The dosage form of a drug varies depending on the properties of the active ingredient of the drug, but in general, injection and oral preparations are mainly used because of the ease of administration. By the way, in the field of antiemetic drug, it is difficult to give an oral drug to a vomiting patient, and at present, home treatment of a patient is becoming difficult in chemotherapy for cancer, and home treatment by injection is also difficult. is there. Therefore, a more convenient administration form for patients is needed.

[0003]

As described above, an antiemetic drug that can further satisfy both the dosage form and the fast-acting point is desired. Therefore, an object of the present invention is to provide a suppository containing the present compound as an active ingredient, having a fast-acting effect and being easy to administer.

[0004]

[Means for Solving the Problems] As a result of intensive studies aimed at solving the above problems, the present inventors have shown that the drug exhibits a fast-acting effect and a blood concentration transition that are almost the same as those of injections, and is also administered to patients who are vomiting. The inventors have found possible dosage forms and completed the present invention. That is, the present invention provides (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-
The present invention relates to a suppository containing 2H-1,4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient.

The content of the present compound in the suppository of the present invention may be any amount as long as it exerts its drug effect, and is appropriately selected depending on the age and symptoms of the patient, but usually 0.1 to 60 mg.
Is preferred.

As the base used in the suppository of the present invention, a commonly used base can be used, and animal and vegetable oils and fats such as olive oil, corn oil, castor oil, cottonseed oil, wheat germ oil, cocoa oil, beef tallow and pork. Fat, wool fat, turtle fat,
Squalane, hydrogenated oil, etc. are mineral oils and fats such as petrolatum, white petrolatum, solid paraffin, liquid paraffin,
Dehydrated lanolin, silicone oil and the like, waxes such as jojoba oil, carnauba wax, beeswax, lanolin and the like, partially or totally synthetic glycerin fatty acid ester, for example,
Examples include mono-, di-, or triglycerides of intermediate or higher fatty acids such as linear saturated fatty acids such as lauric acid, myristic acid, palmitic acid and stearic acid, and linear unsaturated fatty acids such as oleic acid, linoleic acid and linolenic acid. . Examples of these commercially available products include Witepsol (manufactured by Dynamit Nobel Co., Ltd .: this has 12 to 12 carbon atoms).
It is a mixture of 18 saturated fatty acid mono-, di-, tri- and glycerides. Specifically, Witepsol H series (for example, Witepsol H5, H12, H15, H1
9, H32, H35, H37, H39, H42, H17
5, H185, etc.), Witepsol W series (for example, Witepsol W25, W31, W35, W45)
Etc.), Witepsol E series (eg Witepsol E75, E76, E79, E85 etc.), Witepsol S series (eg Witepsol S5)
2, S55, S58, etc.). ), Pharmasol (produced by NOF Corporation), Isocaca (produced by Kao Corporation), SB
((Kanebuchi Chemical Co., Ltd.) and (Taiyo Yushi Co., Ltd.): This is a mixture of mono-, di-, tri-glycerides of saturated fatty acids having 12 to 18 carbon atoms. Specifically, SB-H, SB-E, S
B-AM etc. are mentioned. ), Nopata (manufactured by Henkel), and Supoyer (manufactured by Gutfords): This is a mixture of mono-, di-, and tri-glycerides of saturated fatty acids having 10 to 18 carbon atoms. Sapoyer AS, Sapoyer BS, Sapoyer BM, Sapoyer DM, etc.), Masa Estalinum (manufactured by Dynamit Nobel): This is a mixture of mono-, di- and tri-glycerides of saturated fatty acids having 10 to 18 carbon atoms. For more information, see Masa Estorinum A,
AB, B, BB, BC, BCF, C, D, E, BD, and Masa Estarinum 299. ), Miglyol 810 and Miglyol 812 (manufactured by Dynamit Nobel): This is a mixture of triglycerides of saturated fatty acids having 8 to 12 carbon atoms.
If necessary, one or more of these may be mixed and used. ) And the like. Other synthetic products include polyethylene glycol and polyoxyethylene alcohols. The compounding amount of these bases is 25 to 9 of the total amount.
It is 9.9% by weight.

If desired, the suppository of the present invention may contain a preservative, a stabilizer, a surfactant, a fragrance, a colorant, a pH adjuster, purified water and the like.

The dosage form used in the present suppository is a rectal suppository which is solid at room temperature and melts at body temperature, an ointment or an enema liquid dissolved or dispersed in a liquid base, for example, a rectal soft capsule. A dosage form using a rectal administration injector or the like is used.

[0009]

The suppository of the present invention containing the present compound as an active ingredient and prepared by blending each base and additive exhibits a fast-acting and blood concentration transition almost equivalent to that of an injection. , To act as a vomiting therapeutic agent. Moreover, unlike oral agents, administration is easy even for vomiting persons. The above can be said to be great merits for home-treatment patients.

[0010]

EXAMPLES The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited thereto.

Example 1 12.67 g of Witepsol H15 was melted at about 40 ° C., 30 mg of the raw material of the present compound was added, and the mixture was stirred and dispersed. The uniformly mixed mixture was filled in a suppository mold having a diameter of 4 mm to give a suppository containing 0.3 mg of the present compound in 127 mg. This product was stored in a cool and dark place at about 4 ° C.

Example 2 35.7 g of Witepsol H15 was melted at about 40 ° C., 0.3 g of the raw material of this compound was added, and the mixture was stirred and dispersed. A suppository type was prepared by uniformly mixing the suppository molds so that the weight of the suppository was 1.2 g each, to give suppositories containing 10 mg of the present compound per 1.2 g. This product was stored in a cool and dark place at about 4 ° C.

Test Example 1 With respect to the suppository obtained in Example 2, a rotatory cell method (900 ml, 37 ° C.) using a PTSW type suppository release tester (manufactured by Japan Machinery) with a pH 7.2 phosphate buffer solution was used. 100
The dissolution test was carried out with a drug amount of 10 mg. The result is shown in FIG.

Test Example 2 The suppository obtained in Example 1 (0.3 mg drug in 127 mg)
SD male male rat having a body weight of 250 g to 350 g
Rectal administration was performed so that 1 mg / kg was given to 5 animals. The compound aqueous solution (0.1%) was intravenously administered,
The blood drug concentration of this compound was quantified using high performance liquid chromatography. Fig. 2 shows changes in blood concentration of each preparation.

[0015]

INDUSTRIAL APPLICABILITY According to the present invention, the suppository of the present invention exhibits almost the same rapid-acting and blood concentration transition as an injection, and can be administered to a vomiting patient or a patient who cannot administer an injection. , High bioavailability can be expected. In addition, the release rate can be controlled by combining various bases.

[Brief description of drawings]

1 shows the dissolution rate of suppositories obtained in Example 2.

FIG. 2 shows changes in blood concentration of the suppository obtained in Example 1.

Continuation of the front page (72) Inventor Yuko Nagamatsu Yoshiwari, Chikomi-gun, Fukuoka 955, Ozai Shoji, Yoshitomi Pharmaceutical Co., Ltd.

Claims (2)

[Claims] 1. (±) -6-Chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-
A suppository comprising 2H-1,4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient. 2. (±) -6-Chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-
A suppository containing 0.1 to 60 mg of 2H-1,4-benzoxazine-8-carboxamide monohydrochloride.