JPH0276816A - External preparation - Google Patents

Abstract

PURPOSE:To obtain an external preparation useful for treating rheumatism, arthritis, etc., having high percutaneous absorption and rectal absorption without providing patients with irritation by blending a specific amount of lornoxicam with a liquid fatty acid ester, etc., as an absorption promoter. CONSTITUTION:1 pt. wt. lornoxicam is blended with 1-50 pts.wt., preferably 2.5-30 pts.wt. one or more compounds selected from liquid fatty acid ester (e. g., diethyl sebacate or diisopropyl salicylate), a liquid polyethylene glycol and a salicylic ester (e. g., salicylic acid methyl ester). Use of one kind of the absorption promoter raises treating effects of lornoxicam and two or more kinds of the promoters are used to raise the treating effects. Most preferably a mixed solution of a saturated aliphatic dicarboxylic acid ester and the salicylic ester in the ratio of approximately 1:1 is used.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a topical preparation, more specifically for rheumatoid arthritis,
This invention relates to lornoxicam, a topical anti-inflammatory analgesic that can be used to treat muscle cancer, etc.

[Prior art] Indomethacin,
Non-steroidal anti-inflammatory analgesics such as diclofenac sodium are used as transdermal preparations and external preparations such as halved.

Lornoxicam is 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2
H-cheno[2,3-el-1,2-thiazine-3-carboxamide-1,1-dioxide is an excellent non-steroidal anti-inflammatory drug and is used as an oral preparation. However, it has not yet been used as an external preparation because the absorption is extremely poor in transdermal preparations or halved preparations using conventional bases.

[Problems to be Solved by the Invention] As mentioned above, lornoxicam has poor transdermal and rectal absorption even when blended with a regular topical preparation base, and the desired therapeutic effect cannot be obtained. Even if an agent is added to increase the solubility in the base of an external preparation, transdermal absorption or rectal absorption does not necessarily improve, and in fact, it is often unfavorable from a therapeutic point of view because it causes too much irritation to the affected area.

An object of the present invention is to provide an external preparation of lornoxicam that has improved percutaneous absorption and rectal absorption without irritating the affected area.

[Means for Solving the Problems] As a result of intensive research to solve these problems, the present inventors found that by blending a certain amount of liquid fatty acid ester, liquid polyethylene glycol, and salicylic acid ester into an external preparation, succeeded in increasing the transdermal and rectal absorbability of lornoxicam without irritating the affected area, and completed the present invention.

The formulation of the invention comprises 10 lunoxicam, 1 part by weight and 1 part by weight.
This external preparation contains 1 to 50 parts by weight of one or more compounds selected from the group consisting of liquid fatty acid ester, liquid polyethylene glycol, and salicylic acid ester.

In the present invention, external preparations refer to transdermal preparations (e.g., gels, oil ointments, emulsion ointments, lotions, tinctures, patches, poultices, etc.) and halves.

The liquid fatty acid ester refers to an alcohol diester of a saturated aliphatic dicarboxylic acid that is liquid at room temperature, or a medium-chain fatty acid polyhydric alcohol ester that is liquid at room temperature.

For example, examples of the former include diethyl sebacate and diisopropyl adipate, and examples of the latter include propylene glyfur monocaprylate and glycerin monocaprylate.

Liquid polyethylene glycol has an average molecular weight of 200
-700, preferably 200-600, such as macrogol 200-600.

Salicylic acid ester is an ester of salicylic acid and monohydric lower alcohol or ethylene glycol,
Examples include salicylic acid methyl ester, salicylic acid ethyl ester, and salicylic acid ethylene glycol ester.

These compounds promote transdermal absorption and rectal absorption of lornoxicam without irritating the affected area, and the amount of compounding is 1 to 50 times the weight of lornoxicam, preferably 2.5 to 30 times the weight of lornoxicam. If it is less than 1 times the weight, a sufficient therapeutic effect cannot be obtained, and even if it exceeds 50 times the weight, it is difficult to obtain a therapeutic effect greater than that at 50 times the weight.

The therapeutic effect of lornoxicam can be enhanced even if only one type of these absorption enhancers is used, but in order to enhance the therapeutic effect, it is preferable to use two or more types, most preferably a saturated aliphatic dicarboxylic acid diester and a saturated aliphatic dicarboxylic acid diester. A mixture with the salicylic acid ester in a ratio of approximately 1:1 is used.

As the base, use the base commonly used for transdermal preparations and halved products, and add other drugs, coolants (such as peppermint oil, menthol, camphor, limonene, etc.), surfactants (anionic surfactants, etc.) as necessary. (nonionic surfactants, etc.) can be used.

The preparation of the present invention can be manufactured by a normal manufacturing method for transdermal preparations or halved preparations.

[Effects of the Invention] The formulation of the present invention significantly increases percutaneous or rectal absorption of lornoxicam without irritating the affected area.
It can be used in the treatment of rheumatism, arthritis, osteoarthritis, shoulder periarthritis, muscle pain, etc. in the field of orthopedics.

[Example] Hereinafter, the present invention will be specifically explained with reference to Examples and Test Examples.

Example 1 Carboxyvinyl polymer 1. to purified water go, o g.
Dissolve 0g of lornoxicam, 1.0g of diethyl sebacate, and sorbitan monocaprylate L.
, Og, 5.0 g of propylene glycol, and 5.0 g of ethanol were added and stirred to form a solution.

To this, 0.5 g of diisopropanolamine and the remaining amount of purified water were added to make the total amount 100.0 g, and the mixture was sufficiently stirred to prepare a gel.

Example 2 (Prescription) Lornoxicam 1.0g Diisopropyl adipate 5.0g Macrogol 400 15. Og ethanol
5.0g carboxyvinyl polymer 1.0g diisopropazuramine 1.0gtoo, g According to Example 1, a gel was prepared according to the above formulation.

Example 3 (Formulation) Lornoxicam 0.5 g Methyl salicylate 10.0 g Diisopropyl sebacate 3.0 g Propylene glycol to, o g Carboxyvinyl polymer 1.0 g Diisopropazuramine 1.0 g Ethanol
30.0 gtoo, o g According to Example 1, a gel was prepared according to the above formulation.

Example 4 0 lunoxicam 1. Og, diisopropyl adipate 5
．． 0g, oleyl alcohol S, Og, glyceryl monostearate 8.0g, polyoxyethylene (20) sorbitan monostearate 5.0g, sorbitan monostearate 3.0g, butyl roseoxybenzoate 0.1
g, butylated hydroxytoluene 0.05g 75-85
The mixture was heated to ℃ and dissolved, and this was used as Solution A.

Separately, 0.1 g of ethylenediaminetetraacetic acid disodium salt,
Macrogol 20010. Og, purified water 60.7 g
was heated and dissolved at 75 to 85°C, and this was used as liquid B.

Solution B was added to solution A while stirring, and cooled after 20 minutes to prepare an emulsion ointment.

Example 5 (Formulation) Lornoxicam 0.5g Methyl salicylate 2.0g Liquid paraffin 5.0g Diisopropyl adipate 2.0 and polyoxyethylene (20
) Sorbitan monostearate 6.0g
Sorbitan Monostearate 3.0g Glyceryl Monostearate 8. Og Butyl oxybenzoate 0.1g Butylated hydroxytoluene 0.1g Ethylenedicyantetraacetic acid disodium salt 0.1g Propylene glycol 12: According to Og Example 4, an emulsion ointment was prepared according to the above formulation.

Example 6 0 lunoxicam 1.0 g, diisopropyl sebacate 1
．． 0 g, ethylene glycol salicylate 2.0 g 1 propylene glycol 2. 1.0 g of a polyoxyethylene hydrogenated castor oil derivative was heated to 60 to 70°C and dissolved, and this was used as a liquid A.

Separately paraffin wax 2. Og, liquid paraffin 20.0
g1 72.9 g of white vaseline was heated to 60 to 70°C and dissolved, and this was used as liquid B.

Solution B was added to solution A while stirring, and stirring was continued and cooled to prepare an oily ointment.

Example 7 0.2 g of lunoxicam, 5.0 g of propylene glycol monocaprylate, and 4004.5 g of macrogol.

60.0 g of ethanol was stirred and dissolved at 60 to 70°C.

Purified water was added to this to make the total amount too much, and a lotion was prepared.

Example 8 0 Lunoxicam 0.5 g 1 Glycerin monocaprylate 5
．． 0g, diethyl sebacate 5.0g, macrogol 1
54050.5g, macrogol 400089.0g
was heated to 70 to 80°C, stirred, and dissolved.

This was cooled to 50° C., filled in 1.5 g portions into crude drug containers, and cooled to prepare half-open containers.

Example 9 (Formulation) Lornoxicam 0.5 g Ethylene glycol monocaprylate 2.0 g Diisopropyl adipate 2.0 g 150.0 g Planing according to the above recipe according to Example 8 (weight 15 g)
was prepared.

Example 10 Lornoxicam 5.0g 1 glycerin monocaprylate 1
0.0 g, diisopropyl adipate lO, og.

1475 g of sesame oil was heated and dissolved at 70 to 80°C.

This is made into soft capsules (
(Content capacity 1.0 g, for raw cloth) was prepared.

Example 11 Styrene-isobrene-styrene block copolymer 7
g, Alfun P-100 [trade name, aromatic hydrocarbon resin manufactured by Arayo Kagaku Co., Ltd.] 37 g, liquid paraffin 21 g,
Titanium oxide 1g 5 Magnesium aluminate metasilicate 3
g was heated to 90° C. and mixed uniformly.

To this were added 0.035 g of lornoxicam, 1.5 g of ethylene glyfur salicylate, and 0.35 g of peppermint oil and mixed uniformly under heating to obtain a paste.

This plaster was maintained at 90° C. and applied to a thickness of about 0.2 mm on a nonwoven fabric to prepare a hard lHf1 (plaster).

Test Example 1 Carrageenin Edema Suppression Test (1) A gel-type test agent was prepared according to Example 1 based on the formulation shown in Table 1.

(2) Body weight 1 with pre-breeding for more than 3 days and hair removed from the left hind leg
One group consisted of 5 male Wistar rats weighing 30 g, and the number of groups of animals corresponding to the number of test agents were prepared.

0) Each test drug (for preparations containing lornoxicam, the equivalent amount is 2 mg of lornoxicam, and for preparations containing no lornoxicam, 0.4 g)
) was applied to the hair-removed area of the left hind paw of each group of animals, and 4 hours later, 0.1 - of a 1% carrageenan solution was subcutaneously administered to the left hind paw of the animals.

4 hours after administration of carrageenan, the volume of the foot kick was measured as pleth-y.
Measurements were made using a smometer (manufactured by Vnikon), and Table 1 shows the average value of the edema rate using the following formula and the edema suppression rate (%) determined from that value.

Table 1 Note) Wealth: p<0.05 Kurumamoto: pku0, OI Test Example 2 Rectal absorption test (1) Formula shown in Table 2 (per 1 flattened piece, unit: mg)
A test planing was prepared according to Example 8 based on the following.

Table 2 (Prescription) Test sample 1 piece 1.5g (2) Weight 2
A group of five male Wistar rats weighing 20 to 250 g was prepared, and the number of animals in the group corresponded to the number of test specimens.

(3) Animals in each group were treated with bendoparbital (40 mg/k)
g) The animals in each group were fixed under anesthesia and each test specimen equivalent to 2 mg of lornoxicam was administered at a position 1.5 cm from the anus of each group of animals.

After administration, blood was collected over time from the inclined artery, centrifuged to collect plasma, and the concentration of lornoxicam in the plasma was measured by HPL.
Measured by method C.

In addition, as a control, a carboxymethyl cellulose suspension of lornoxicam was orally administered in an amount equivalent to the lornoxicam in the test cutting to another group of animals, and the concentration of lornoxicam in plasma was measured over time in the same manner as in the test cutting. did.

The results are shown in FIG.

[Brief explanation of the drawing]

FIG. 1 is a graph showing changes over time in the blood concentration of lornoxicam when administered rectally and orally.

Claims (1)

[Claims] (1) An external preparation containing 1 part by weight of "lornoxicam" and 1 to 50 parts by weight of "one or more compounds selected from the group consisting of liquid fatty acid ester, liquid polyethylene glycol, and salicylic acid ester."