JPS6024764B2 - Topical drugs containing indomethacin - Google Patents

Description

[Detailed description of the invention] This invention relates to topical drugs containing indomethacin.

Indomethacin (1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid) has been used for many years as a drug for a wide range of purposes due to its excellent anti-inflammatory, antipyretic, and analgesic properties. .

In particular, indomethacin is used orally, preferably in the form of capsules or in the form of suppositories, not only for the relief of rheumatism and gout, but also for analgesia, antipyretics and relief of congestion. When administered orally or intravenously,
Indomethacin enters the bloodstream and is distributed throughout the body. Particularly in the case of rheumatism, since rheumatism drugs must be taken for a long period of time, in severe cases for a lifetime, continuous patient monitoring and blood cell counts are necessary when taking indomethacin.

Compared to other drugs with similar efficacy, such as salicylates, corticosteroids, or phenylptazone compounds, indomethacin has fewer side effects as a result of its oral administration. However, if taken for a long period of time, it may damage the gastric mucosa depending on the patient's constitution, and the formation of gastric ulcer cannot be avoided. Since rheumatoid arthritis of the joints and muscles, bruises, or sports injuries are generally localized, it is best to apply indomethacin topically to the inflamed skin. Furthermore, it would be advantageous if the patient himself could apply indomethacin topically to the skin, and indomethacin was formulated to be absorbed by the skin and applied topically through the skin to the affected area. West German Patent No. 2,103,833 relates to an anti-inflammatory agent for external use, which is characterized in that it contains an effective amount of indomethacin in a methyl salicylate carrier.

According to this patent specification, methyl salicylate has been adopted and used as a carrier for many adhesives for many years because of its anti-inflammatory properties. Especially if the patient's skin is sensitive, the inflammatory stimulating effect of methyl salicylate may be harmful, or because of this inflammatory stimulating effect, West German Patent No. 21
It may even become impossible to use indomethacin topically in methyl salicylate according to the teachings of No. 03833. West German Patent No. 16176
No. 53 relates to indomethacin, in which indomethacin is dissolved in a base consisting of at least one gester of the general formula ROOC-(C ratio)n-COOR.

However, R is an aliphatic alkyl group having 1 to 4 carbon atoms, and n is 1 to 8. Such indomethacin formulations containing a gester with this general formula are only stable to a limited extent in storage due to the transesterification reaction that occurs between the acetic acid residue and indomethacin and the ester group of the gester. However, the regulations for official approval of drugs require that the active substances in the drug remain unchanged for at least three years. Furthermore, an analgesic ointment containing indomethacin is known from DE 28 27 018, in which indomethacin is neutralized with a glycol, such as polyethylene glycol, and in addition to this, cellulose and/or an amine. The carboxyvinyl polymer is contained in a medium containing a sufficient amount of water. However, the sorption capacity of this drug, ie the absorption of active substances through the skin, is still not completely satisfactory. Therefore,
There is a need for a topical drug containing indomethacin that does not contain methyl salicylate, is stable on storage, and has good absorption through the skin.

The present invention provides a topical drug containing an effective amount of indomethacin in a carrier comprising a mixture of at least one polyalkylene glycol and a smaller amount of polyethylene glycol alkyl (10 to 14 carbon atoms) ether. .

Polyethylene glycol and polypropylene glycol are examples of polyalkylene glycols.

A preferred polyalkylene glycol is polyethylene glycol represented by the formula HOH-(C ratio 101C ratio)n-C ratio OH.

However, n is 3 and 200. Polyethylene glycols with a molecular weight of about 600 or less are liquid at room temperature, and those with a molecular weight of about 1,000 to 11,000 have a viscosity ranging from a soft wax to a hard wax as the molecular weight increases.

They are colorless, odorless and harmless and are already widely used in cosmetic production as a replacement for glycerin and also as an ingredient in ointments and creams. Polyethylene glycols have also been used as binders in tablet formulations. A preferred polyethylene glycol alkyl (10-14 carbon) ether is polyethylene glycol decyl ether, which has local and internal anesthetic effects.

The molecular weight of this ether is preferably between 580 and 700. The concentration of indomethacin in the body, which consists of a mixture of polyalkylene glycol and polyethylene glycol alkyl (10 to 14 carbon atoms) ether, is not important, as is the type and severity of the disease, and the degree of topical use. and other factors. Preferred formulations contain about 1 to 12 doses of indomethacin in 100 doses of ointment, more preferably 2 to 6 doses. A carrier made of polyalkylene glycol and polyethylene glycol alkyl (10 carbon atoms, 14 carbon atoms) ether contains more polyalkylene glycol than polyethylene glycol alkyl (10 carbon atoms, 14 carbon atoms) ether.

The weight ratio of polyalkylene glycol to polyethylene glycol alkyl (10 to 14 carbon atoms) ether is preferably from 20:0.5 to 10:1. Topical formulations according to the invention may also contain additives such as surfactants, water and perfumes. A typical formulation of an ointment according to this invention is as follows. indomethacin
Polyethylene glycol decyl ether with a molecular weight of 0 and 5.0
Polyethylene glycol with a molecular weight of 300 - 6
Polyethylene glycol with a molecular weight of 5.0 and 1000
Polyethylene glycol with a molecular weight of 1500
Mixture of 95% by weight of stearic acid monoglyceride and 5% by weight of polyethylene glycol alkyl ether 7.5% by weight Pure water
7.4 Yuka oil
0.1 evening 100-0
The polyethylene glycol is preferably a mixture of polyethylene glycols having different chain lengths.

In the above formulation, polyethylene glycol (n=4) with a molecular weight of 300 is the main component, while polyethylene glycol with a molecular weight of 1000 and 1
500 polyethylene glycol (n is 13 and 20 respectively) gives the ointment a harder consistency. Ointment can be made in the usual way. For example, formulation can be carried out to produce the final product of lk9. Formulation 1 50 mg of indomethacin and 50 mg of polyethylene glycol decyl ether at room temperature of 650 mg of molecular weight 300
Dissolve in polyethylene glycol while stirring.

Formulation 295% by weight stearic acid monoglyceride and 5
Mixture with polyethylene glycol alkyl ether containing 75% polyethylene glycol, 50% polyethylene glycol with a molecular weight of 1000, 50% polyethylene glycol with a molecular weight 1500
Boil the mixture at 60°C in a water bath until a clear solution is obtained.

Add the resultant of Formulation 1 to the resultant of Formulation 2 while stirring uniformly, and then add 74 hours of pure water at 40°C. The resulting formulation is stirred until gel formation begins, then perfumed oil is added overnight.

The formulation is agitated for a final time at room temperature until filling.
Indomethacin is soluble in a mixture of polyethylene glycol and polyethylene glycol alkyl (10 carbon atoms L.Shi14) ether.

In order to keep the structural viscosity and plasticity of the ointment unchanged under the temperature of the skin, topical formulations are preferably formulated to have a disseminated property (chickentropy). Topical formulations according to the invention are particularly suitable for non-invasive bruises, bruises and similar sports injuries.

Claims (1)

[Claims] 1. At least one type of polyalkylene glycol;
A mixture of polyethylene glycol C_1_0 to C_1_4 alkyl ether, the polyalkylene glycol and the polyethylene glycol C_1_0 to C_1_
Weight ratio with 4 alkyl ether is 20:0.5 to 1
A topical drug comprising an effective amount of indomethacin in a carrier comprising: 0:1. 2. The topical drug according to claim 1, wherein the polyethylene glycol C_1_0 to C_1_4 alkyl ether is polyethylene glycol decyl ether. 3. The topical drug according to claim 1 or 2, wherein the topical drug is in the form of a thixotropic ointment.