JP3059204B2 - Stable prostaglandin I (II)-containing composition for skin application - Google Patents

Description

[Detailed Description of the Invention] Industrial Application Field The present invention relates to a composition for skin application containing a stable prostaglandin _I1 . More specifically, the present invention relates to a composition for treating skin ulcers that is highly stable and comprises prostaglandin _I1 , which has excellent pharmacological effects such as antiulcer activity, platelet aggregation inhibitory activity, and vasodilatory activity, and a water-soluble cellulose lower alkyl ether, and optionally contains a plasticizer.

Prior Art and Problems to be Solved by the Invention Prostaglandins are widely present in the body and are known to have various physiological effects even in small amounts. For example, prostaglandin E ₁ (PGE ₁ ) is used as a therapeutic agent for peripheral circulatory disorders, therapeutic abortion in mid-pregnancy, and peptic ulcers, and PGE ₂ α
is being developed to promote induction of labor in the late stages of pregnancy, and PGI ₂ is being developed as a peripheral circulation improver.

However, prostaglandins are generally unstable compounds, and are known to be very easily decomposed by acids, alkalis, and heat, and are physicochemically unstable. Among them, prostaglandins of groups G to I are extremely unstable, and thus, although they are excellent physiologically active substances, there have been various problems in developing them as pharmaceuticals. Therefore, in order to make stable formulations,
Proposals have been made to add a surfactant to prostaglandin _I2 ( _PGI2 ) (JP Patent Publication No. 15470/1980), to combine cyclodextrin and sugars with _PGI2 (JP Patent Publication No. 18357/1983), and to include _PGI1 and _PGI2 derivatives in cyclodextrin (JP Patent Publication No. 192821/1983).

However, all of these relate to preparations for oral or parenteral administration, and there is no mention of a stable preparation for transdermal absorption that can be applied to skin ulcer sites.

On the other hand, it is known that diseases such as Raynaud's disease, Purger's disease, and bedsores caused by peripheral circulatory insufficiency can cause intractable skin ulcers as they progress. One method of treating these diseases is the transdermal administration of _PGE1 and PGI, which have the effect of improving peripheral circulation, but this has problems such as inactivation due to the physicochemical instability of PGs.

Recently, one of the optical isomers of prostaglandin _I1 derivatives has been
The species 2-[(1S,3R,5S,6R,7R)-7-hydroxy-
Methyl 6[(1E)-(3S,5S)-3-hydroxy-5-methyl-1-nonenyl]bicyclo[3,3,0]oct-3-yl]ethoxyacetate (hereinafter referred to as Compound A)
have been developed (JP-A-59-141536 and JP-A-60-231536).
-156640), which is known to have an excellent effect of improving peripheral circulation.

In order to use such a prostaglandin _I1 derivative having a peripheral circulation improving effect in the treatment of the above-mentioned intractable skin ulcers, the present inventors have investigated the prostaglandin I1 derivatives by various substances in order to obtain a stable preparation that can be applied to the ulcer site.
As a result of investigations into the stabilization of _I1 derivatives, the inventors have found that water-soluble cellulose lower alkyl ethers give prostaglandin _I1 compositions which are excellent in stability and can be applied to ulcer sites, leading to the completion of the present invention.

Means for solving the problems The present invention provides a stable prostaglandin _I1 -containing skin application preparation, which is characterized by blending a water-soluble cellulose lower alkyl ether with a prostaglandin _I1 derivative, particularly the above-mentioned compound A, and further blending a plasticizer, if necessary.

Compound A used in the present invention is a stable prodrug of a prostaglandin _I1 derivative having the following structure. When absorbed percutaneously, the ester group is cleaved by esterase in the tissue to become a pharmacologically active carboxylic acid type, which shows an effect of improving peripheral circulation.

The water-soluble cellulose lower alkyl ethers used in the present invention include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose,
Hydroxyethyl cellulose, etc. are preferred, and hydroxypropyl cellulose and hydroxypropyl methyl cellulose are particularly preferred. The viscosity range of these water-soluble cellulose lower alkyl ethers is 5 to 50,000 cps (2%
Aqueous solution at 20°C, Brookfield viscometer) is preferred.

The amount of the water-soluble cellulose lower alkyl ether to be blended is within the range of 10 to 10,000,000 parts by weight, and more preferably within the range of 2,000 to 200,000 parts by weight, per part by weight of compound A.

It is also used as a plasticizer to improve the flexibility of formulations.
Polyethylene glycol, propylene glycol, 1,3
-butanediol, etc. can be added, the amount of which is preferably in the range of 5 to 40% by weight.

The stabilized prostaglandin _I1 derivative composition of the present invention can be prepared as follows.

A solvent capable of dissolving both Compound A and the water-soluble cellulose lower alkyl ether, such as methanol, ethanol,
The composition of the present invention is obtained by mixing the mixture of water and ethanol with a plasticizer added as required for about 1 hour, and then spreading and drying.

The present invention will be described below with reference to examples, but the present invention is not limited to these.

Example 1: 10 g of hydroxypropyl cellulose and 100 ml of ethanol
Add the solution, stir to dissolve, degas, spread and dry to obtain a film with a thickness of about 100 μm. Place about 100 mg of this film in a test tube, drop 10 μl of Compound A solution (10 mg/ml Compound A in methanol) into the tube, dry and store at 100°C for 16 hours. Repeat the procedure for hydroxypropylmethylcellulose. For comparison, repeat the procedure for other water-soluble polymers. The remaining percentage of Compound A in these samples was measured using the HP
The results of measurement by the LC method are shown in Table 1. As a result, excellent stabilizing effects were observed for hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and hydroxyethyl cellulose, and among these, particularly excellent stabilizing effects were observed for hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

Example 2: 20 g of hydroxypropyl cellulose (viscosity 150-400 centipoise) was mixed with ethanol to make 200 g, and the mixture was stirred to dissolve. 20 mg of compound A was added to the mixture and thoroughly stirred. After degassing, the mixture was spread and dried to obtain a film having a thickness of about 100 μm.
The film is placed in an aluminum bag, sealed, and stored at 40°C. The same procedure is performed for hydroxypropylmethylcellulose. Also, 170 g of water is added to 30 g of polyvinyl alcohol (fully saponified type, polymerization degree 1500 or more), and dissolved by stirring while heating. Next, about 25 mg of compound A is added and thoroughly stirred. After degassing, the mixture is spread and dried, placed in an aluminum bag, sealed, and stored at 40°C. These samples are taken over time, and the remaining rate of compound A is measured by HPLC.
The results are shown in Table 2.

Example 3 10 mg of compound A was dissolved in 100 ml of ethanol to obtain a solution. 50 ml of this solution was taken and further ethanol was added to obtain a solution of 14 ml.
0g. Add 10g of hydroxypropyl cellulose to this solution.
Gradually add with stirring and continue to dissolve until uniform. After degassing, spread to a thickness of 500 μm and dry to obtain the desired composition.

Example 4 1g of propylene glycol and 1ml of an ethanol solution of compound A (10mg/ml) are added to 100g of ethanol, and the mixture is thoroughly stirred and dissolved in advance. Next, 9g of hydroxypropyl cellulose (viscosity 150-400 centipoise) is gradually added while stirring the liquid, and stirring is continued until the particles are completely dispersed and dissolved. After degassing, the mixture is spread and dried to obtain a film with a thickness of about 50μm, and the film is stored at 100℃ for 16 hours. The residual rate of compound A in this sample was measured by HPLC, and the results are shown in Table 3.

Example 5 3 g of polyethylene glycol 400 and 1 ml of an ethanol solution of compound A (10 mg/ml) are added to 50 g of ethanol, and the mixture is thoroughly stirred and dissolved in advance. Next, 7 g of hydroxypropyl cellulose (viscosity about 6 centistokes) is gradually added to the mixture while stirring, and stirring is continued until the particles are completely dispersed and dissolved. After degassing, the mixture is spread and dried to about 100 g.
A film having a thickness of 1 μm was obtained, and the film was heated at 100° C. for 1
The sample was stored for 6 hours. The remaining percentage of compound A in this sample was
The results of measurement by the PLC method are shown in Table 3.

Example 6 2g of 1,3-butanediol and 1ml of an ethanol solution of compound A (10mg/ml) are added to 55g of ethanol, and the mixture is thoroughly stirred and dissolved in advance. Next, 8g of hydroxypropylcellulose (viscosity about 6 centistokes) is gradually added while stirring the liquid, and stirring is continued until the particles are completely dispersed and dissolved. After degassing, the mixture is spread and dried to obtain a film with a thickness of about 100μm, and the film is stored at 100℃ for 16 hours. The residual rate of compound A in this sample was measured by HPLC, and the results are shown in Table 3.

Example 7 1 g of propylene glycol and 1 ml of an ethanol solution of Compound A (10 mg/ml) were added to 250 g of water, and the mixture was thoroughly stirred to dissolve. Next, hydroxyethyl cellulose (viscosity 4000 to 5500 centipoise) was added to the solution while stirring.
Add 9 g of the mixture little by little and continue stirring until the particles are completely dispersed and dissolved. After degassing, spread and dry to obtain a film with a thickness of about 40 μm, and store this film at 100° C. for 16 hours.
The residual rate of compound A in this sample was measured by HPLC, and the results are shown in Table 3.

Comparative Example 1 1 g of glycerin and 1 ml of an ethanol solution of Compound A (10 mg/ml) were added to 100 g of ethanol, and the mixture was thoroughly stirred to dissolve. Next, 9 g of hydroxypropyl cellulose (viscosity 150 to 400 centipoise) was added to the mixture while stirring.
Gradually add and continue stirring until the particles are completely dispersed and dissolved. After degassing, spread and dry to obtain a film with a thickness of about 50 μm, and store this film at 100° C. for 16 hours. The residual rate of compound A in this sample was measured by HPLC, and the results are shown in Table 3.

Comparative Example 2 5g of glycerin and 1ml of an ethanol solution of compound A (10mg/ml) are added to 60g of water, and the mixture is thoroughly stirred and dissolved in advance. Next, 5g of methylcellulose (viscosity 3500-5600 centipoise) is gradually added while stirring the liquid, and stirring is continued until the particles are completely dispersed and dissolved. After degassing, the mixture is spread and dried to obtain a film with a thickness of about 150μm, and the film is stored at 100℃ for 16 hours. The residual rate of compound A in this sample was measured by HPLC, and the results are shown in Table 3.

Effect of the Invention As described above, the present invention makes it possible to formulate a composition that can be applied directly to ulcerative sites with excellent physicochemical stability by combining Compound A, which is a PGI ₁ class compound that has a peripheral circulation improving effect and is difficult to formulate into a transdermal formulation due to its physicochemical instability, with a water-soluble cellulose lower alkyl ether and, if necessary, a specific plasticizer.

Continued from the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K 31/5578 A61K 9/70 A61K 47/38 A61P 17/02 CAPLUS (STN) MEDLINE (STN) EMBASE (STN)

Claims (4)

(57) [Claims] 1. A composition for application to skin, comprising a prostaglandin _I1 derivative and a water-soluble cellulose lower alkyl ether. Claim 2: The water-soluble cellulose lower alkyl ether is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, and hydroxyethyl cellulose, and the amount of the water-soluble cellulose lower alkyl ether is in the range of 10 to 10,000,000 parts by weight per part by weight of the prostaglandin _I1 derivative.
The composition described in 3. The composition according to claim 1, further comprising a plasticizer. 4. The composition according to claim 3, wherein the plasticizer is one or more selected from propylene glycol, polyethylene glycol, and 1,3-butanediol, and the amount thereof is in the range of 5 to 40% by weight of the composition.