JPH0383926A - Ointment composition - Google Patents

Abstract

PURPOSE:To obtain an ointment composition excellent in stability, percutaneous absorbability and drug effects by including PGE1 in etherified cyclodextrins(ECD) and blending the resultant clathrate with a specific ointment base. CONSTITUTION:An ointment composition obtained by blending an ointment base composed of 15-45wt.% saturated fatty alcohols, preferably 16-24C saturated monohydric alcohol (e.g. cetyl alcohol or stearyl alcohol), 50-85wt.% glycols, especially 1,3-butylene glycol and 0.01-8wt.% absorbefacient, preferably 1-[2-(decylthio)ethyl]azabicyclopent-2-one with 0.001-10wt.%, preferably 0.05-5wt.% PGE1-ECD. The PGE1-ECD is preferably prepared by including 0.0001-1wt.%, especially 0.001-1wt.% PGE1 in ECD (optimally carboxymethylethyl-beta- cyclodextrin) in an amount of 1-300 times, preferably 3-30 times based on the PGE1.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is directed to a compound (hereinafter referred to as
The present invention relates to an ointment composition containing PGE (abbreviated as -ECD) and having excellent stability, transdermal absorbability, and medicinal efficacy.

[Conventional technology]

Prostaglandin E+ (hereinafter abbreviated as PGE)
is known to have various specific pharmacological activities (eg, platelet aggregation, concentration production, peripheral vasodilation, etc.). Among these, the peripheral vasodilator effect is particularly remarkable, and preparations associated with this effect have been widely studied. However, PGE is a compound that is unstable in terms of aggregation and is easily decomposed by acids, alkalis, heat, light, etc., and dehydration occurs especially under acidic conditions or heating, resulting in prostaglandin A.
It is converted to I. It is also known that isomerization occurs under alkaline conditions and is converted to prostaglandin B.

Therefore, when formulating PGE as a pharmaceutical product, it is strongly desired to particularly improve its stability over time. Therefore, such an unstable compound P G E l
Various attempts are being considered to stabilize the Among them, in JP-A No. 59-10525, PG
It has been described that the stability of PGE is significantly improved by including E with an etherified cyclodextrin. It is also stated that it can be used as an injection, an aerosol, a suppository, and an oral preparation.
There is no mention of ointment formulations or formulations thereof intended for transdermal administration, much less any mention of such formulations.

[Problem that the invention seeks to solve]

Therefore, unstable P G E I exhibiting useful pharmacological activity
Although it is necessary to particularly consider the stability of the formulation when formulating it as a drug, there have been few studies on ointment formulations for transdermal application, and the stability, At present, there are almost no ointment preparations that are satisfactory in transdermal absorption and medicinal efficacy.

[Means to solve the problem]

Therefore, the present inventors have developed a PGEI that can satisfy the above problems.
Stability over time of ointment formulations containing PGE and PGE
The most suitable formulation is an ointment-based formulation that has better stability under GEI-containing conditions, or an ointment formulation that has good transdermal absorption from the human skin, and is also suitable for use as an ointment formulation for diseases to be treated. After intensive research and numerous experiments to develop the formulation, we found that PGEI was found in a specific ointment base.
By incorporating ECD, the decomposition of P G Er is significantly suppressed, and an ointment preparation that has favorable results in all of the above-mentioned problems has been discovered and the present invention has been completed.

That is, the present invention combines PGE, -EC into a base consisting of saturated fatty alcohols, glycols and/or absorption enhancers.
By blending D, the desired ointment composition containing P G E + can be provided.

To explain the present invention in more detail, the saturated fatty alcohols in the present invention are: saturated fatty alcohols having 16 to 24 carbon atoms or mixtures thereof, preferably saturated-hydrogen primary alcohols. Among these, particularly preferred are cetyl alcohol, stearyl alcohol, and behenyl alcohol. Further, these saturated fatty alcohols are contained in an amount of 15 to 45% by weight, preferably 20 to 30% by weight of the total amount. Glycols include propylene glycol or butylene glycol (preferably 1
．． 3-butylene glycol), which are used singly or in combination of two or more, and are contained in an amount of 50 to 85% by weight, preferably 60 to 75% by weight of the total amount.

In addition to the above-mentioned base, it is desirable to incorporate an absorption enhancer for the purpose of further promoting percutaneous absorption.As absorption enhancers, 1-dodecyl azacyclohebutan-2-one, 1-(2-(decylthio)ethyl]azacyclopentan-2-one, dimethyl sulfoxide,
Aliphatic alcohols such as lauryl alcohol or oleyl alcohol, crotamiton, fatty acids such as lauric acid or oleic acid, or terpene compounds such as l-menthol are preferred, especially 1-(2-(decylthio)ethyl)azacyclopenk -2-one is the most preferred, and the amount of these absorption enhancers used is 0% of the total amount.
．． It is contained in an amount of 0.1 to 8% by weight, preferably 0.1 to 5% by weight.

PGE and -ECD, which are active ingredients, are prepared by including PGE1 in the following etherified cyclodextrin. For example, dimethyl-(α, β or γ) cyclodextrin, hydroxypropyl-(α,
β or γ)-cyclodextrin, diethyl-(α,
β or r) -cyclodextrin, triethyl-
(α, β or T>-cyclodextrin, carboxymethylethyl-(α, β or γ)-cyclodextrin, etc., among which β-type cyclodextrin is most preferred in the pharmaceutical formulation. Carboxymethylethyl-β-cyclodextrin is optimal.

In addition, the etherified cyclodextrin that includes PGE + is used in an amount of 1 to 300 times, preferably 3 to 30 times, the amount of PGE + used to prepare pGE,
By inclusion of 0.0001 to 1% by weight, preferably 0.001 to 1% by weight, the stability of PGEI is further maintained. PGEI thus obtained -
The amount of ECD used is 0.001 to 10% by weight, preferably 0.05 to 5% by weight.

By blending each ointment base and active ingredient as described above and preparing the specified formulation, P.
It is possible to make an ointment preparation for transdermal application that satisfies all of the stability, transdermal absorbability, and medicinal efficacy of GE1. In addition, the ointment formulation of the present invention may contain other additives, such as organic acids (
citric acid, succinic acid, tartaric acid, lactic acid, etc.), auxiliary solvents (e.g. polyethylene glycol with molecules tioo~800, glycerol, diethylene glycol monoethyl ether, propylene glycol monomethyl ether, dipropylene glycol monoethyl ether, 2,2-dimethyl- 1,3-dioxolane-4-methanol, etc.) to 2
5% by weight or less, plasticizer (e.g., molecular weight 800-200
00 polyethylene glycol, l.

2.6-hexanetriol, sorbitol, etc.) at 15
% by weight or less, campling agents (e.g. stearic acid,
Saturated fatty acids having 16 to 24 carbon atoms such as palmitic acid and behenic acid, fatty acid amides such as oleic acid amide, balmitic acid amide, stearic acid amide, and behenic acid amide, sorbitol, nostearate, polyethylene glycol monostearate , aliphatic esters having 16 to 24 carbon atoms such as propylene glycol monostearate, or other fatty acid esters such as oleic acid and palmitic acid corresponding thereto) in an amount of 15% by weight or less. In addition, it is desirable for the blending amount of the auxiliary solvent and plasticizer in the above formulation to be 20% by weight or more.

In addition to the above-mentioned bases, the formulation may be stabilized by incorporating antioxidants (e.g., ethylenediaminetetraacetic acid, ether chelating agents, propyl gallate, -butylated oxyanisole, etc.), surfactants, etc. This is desirable for promotion.

Next, in producing the ointment formulation containing PGE and -ECD in the present invention, saturated fatty alcohol (15 to 45
(% by weight), glycols (50-85% by weight), absorption enhancers (0.01-8!1 fft%), or other additives if necessary, and while heating and dissolving at 80-95°C. Stir and mix in the presence or absence of nitrogen gas. The mixture is further cooled at room temperature with stirring. Next, the active ingredient P G E , (0,0
001-1% by weight) and etherified-(α, β or γ)-cyclodextrin (0,001-10% by weight)
is dissolved in an organic solvent (e.g., ethanol, methylene chloride, ethyl acetate, etc.), and then the organic solvent is distilled off, and the resulting clathrate compound (PGE, -ECD) is added to the base component in the presence of nitrogen gas. Alternatively, the ointment preparation targeted by the present invention can be obtained by blending in their absence and stirring and mixing.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 Stearyl alcohol was used as the saturated fatty alcohol.
95g, cetyl alcohol 0.8g, behenyl alcohol 0.9g, glycols propylene glycol 7.024g, absorption enhancer 1-(2-
Add 0.3 g of (decylthio)ethyl]azacyclopenkun-2-one, dissolve and stir on an oil bath at 95°C, then seal and cool at room temperature with stirring. PGE in this base
, 1■ and carboxymethylethyl-β-cyclodextrin 25■ were dissolved in ethanol, and then the ethanol was distilled off.

- Ruboxymethylethyl-β-cyclodextrin clathrate compound was added and stirred and mixed to obtain the desired ointment preparation.

Example 2 Stearyl alcohol was used as the saturated fatty alcohol.
95g, cetyl alcohol 0.8g, behenyl alcohol 0.9g, glycols such as propylene glycol 0.689g, 1.3-butylene gel! J
-2-/LzG 6.335 g and 0.3 g of lauryl alcohol as an absorption enhancer were added, dissolved and stirred on an oil bath at 95°C, then sealed and cooled at room temperature with stirring.

In this base, PGE, 1■ and carboxymethylethyl-β
-After dissolving 25μ of cyclodextrin in ethanol,
The PGEI-carboxymethylethyl-β-cyclodextrin clathrate compound from which ethanol had been distilled off was added and mixed with stirring to obtain the desired ointment preparation.

Example 3 Stearyl alcohol was used as the saturated fatty alcohol.
8g, cetyl alcohol 0.6g, behenyl alcohol 0.6g, glycols such as propylene glycol 2.145g, 1.3-butylene glycol 5g
．． 005 g and 0.8 g of 1-dodecyl azacyclohebutan-2-one as an absorption enhancer were added, dissolved and stirred on an oil bath at 95°C, then sealed and cooled at room temperature with stirring. Into this base, 1 inch of PGE1 and 49 inch of carboxymethylethyl-β-cyclodextrin were dissolved in ethyl acetate, and then the ethyl acetate was distilled off.
A carboxymethylethyl-β-cyclodextrin clathrate compound was added and mixed with stirring to obtain a composition.

Example 4 1 stearyl alcohol as saturated fatty alcohol
．． 0g, cetyl alcohol 0.5g, propylene glycol as glycols 1.398g, 1゜3-
5.592 g of butylene glycol, 0.5 g of PEG-6000 as a plasticizer, 1,2.6-
Add 0.3 g of hexanetriol, 0.2 g of sorbitan monostearate as a camping agent, and 0.01 g of oleic acid as an absorption enhancer, dissolve and stir on an oil bath at 95°C, then seal and leave at room temperature. Cool while stirring.

After dissolving PGE, Q, Ig and 0.4 g of dimethyl-β-cyclodextrin in methylene chloride, add the PGEI-dimethyl-β-cyclodextrin clathrate compound from which the methylene chloride has been distilled off, and mix with stirring. By doing so, the desired ointment formulation was obtained.

Example 5 Stearyl alcohol was used as the saturated fatty alcohol.
5 g, 1.0 g of cetyl alcohol, 1.0 g of behenyl alcohol, 3.735 g of propylene glycol as glycols, 1.265 g of 1.3-phthylene gelicol, 1,2.6-hexanetriol as a plasticizer. and 0.10 g of polyethylene glycol monostearate as a camping agent.

Add 0.27 g of l-menthol as an absorption enhancer, dissolve and stir on an oil bath at 95°C, then seal and cool at room temperature with stirring. P G E t 100q to this base
After dissolving 0.03 g of triethyl-β-cyclodextrin in ethanol, the ethanol was distilled off.
E + ) riethyl-β-cyclodextrin clathrate compound was added, and the desired ointment preparation was obtained by stirring and mixing.

Example 6 Stearyl alcohol was used as the saturated fatty alcohol in 1.
5g, propylene glycol as glycols 0.
84 g, 1.3-butylene glycol 7.56
g. Add 0.05 g of 1-(2-(decylthio)ethyl)azacyclopentan-2-one as an absorption enhancer, dissolve and stir in an oil bath at 95°C, then seal and stir at room temperature. Cool. Into this base, dissolve 10 μg of PGE and 40 μg of diethyl-β-cyclodextrin in ethyl acetate, and then distill off the ethyl acetate to obtain the PGE, -diethyl-
A β-cyclodextrin clathrate compound was added and mixed with stirring to obtain the desired ointment preparation.

Example 7 Stearyl alcohol was used as the saturated fatty alcohol in 1.
0 g, 0.8 g of cetyl alcohol, 6.4 g of 1.3-butylene glycol as glycols, 0.2 g of sorbitan monostearate as a camping agent.
, 0.5g of PEG-6000 was added as a plasticizer,
After dissolving and stirring on an oil bath at 95°C, the mixture is sealed and cooled at room temperature with stirring. After dissolving PGEI100■ and hydroxypropyl-β-cyclodextrin Ig in ethanol, the PGE-hydroxypropyl-β-cyclodextrin clathrate compound obtained by distilling off the ethanol was added to this base, and mixed with stirring. An ointment preparation was obtained.

Example 8 Stearyl alcohol was used as the saturated fatty alcohol.
95 g, cetyl alcohol 0.8 g, behenyl alcohol 0.9 g, glycols propylene glycol 6.924 g, absorption enhancer 1-
0.3 g of (2-(decylthio)ethyl)azacyclobencune-2-one and 0.1 g of lactic acid as a stabilizer.
After dissolving and stirring on an oil bath at 95°C, the mixture was sealed and cooled at room temperature with stirring. In this base, PGE1 1■ and carboxymethylethyl-β-cyclodextrin 25
After dissolving ■ in ethanol, the ethanol was distilled off.
G E I -carboxymethylethyl-β-cyclodextrin clathrate compound was added, and the desired ointment preparation was obtained by stirring and mixing.

Example 9 Stearyl alcohol was used as the saturated fatty alcohol in 1.
0 g, 0.5 g of cetyl alcohol, 1.398 g of propylene glycol as glycols, 1゜3
-5.592 g of butylene glycol, 0.5 g of PEG-6000 as a plasticizer, 1,2.6
- Added 0.3 g of hexanetriol, 0.1 g of sorbitan monostearate as a coupling agent, 0.01 g of oleic acid as an absorption enhancer, and 0.1 g of lactic acid as a stabilizer, and heated on an oil bath at 95°C. After dissolving and stirring at room temperature, the mixture is sealed and cooled at room temperature while stirring. PG in this base
E.

0.1g and dimethyl-β-cyclodextrin 0.4g
After dissolving P in methylene chloride, the methylene chloride was distilled off.
GE, -dimethyl-β-cyclodextrin inclusion compound was added and stirred and mixed to obtain the desired ointment preparation.

Example 1O fi! As Japanese fatty alcohol, 2.5 g of stearyl alcohol, 0.99 g of cetyl alcohol, 1.0 g of behenyl alcohol, propylene glycol @ 3.735 g Sl as glycol, 1.265 g of 3-butylene glycol, 1 as plasticizer. ,2.6
-0.10 g of hexanetriol, o of polyethylene glycol monostearate as a camping agent,
i.

0.27 g of l-menthol as g1 absorption enhancer
.

Add 0.01 g of lactic acid as a stabilizer and heat on an oil bath at 95°C.
After dissolving and stirring at room temperature, the mixture is sealed and cooled at room temperature while stirring. After dissolving 100q of PGE and 0.03 g of triethyl-β-cyclodextrin in this base in ethanol, the PGE,-triethyl-β-cyclodextrin clathrate compound from which ethanol had been distilled off was added, and the mixture was stirred. By mixing, the desired ointment formulation was obtained.

Example 11 Stearyl alcohol was used as the saturated fatty alcohol in 1.
5 g, 0 propylene glycol as glycols
．． 83 g Sl, 7.4 3-butylene glycol
7g, 0.05g of 1-(2-<decylthio)ethyl]azacyclopentan-2-one as an absorption enhancer, and 0.1g of lactic acid as a stabilizer, dissolved and stirred on an oil bath at 95°C, Seal and cool at room temperature with stirring. After dissolving 10 cm of PGE and 40 cm of diethyl-β-cyclodextrin in this base with ethyl acetate, the ethyl acetate was distilled off to obtain PGE.

Add diethyl-β-cyclodextrin clathrate,
The desired ointment formulation was obtained by stirring and mixing.

Example 12 Stearyl alcohol was used as the saturated fatty alcohol in 1.
0 g, 0.8 g of cetyl alcohol, 6.0 g of 1.3-butylene glycol as glycols, 0.5 g of PEG-6000 as a plasticizer, 0.2 g of sorbitan monostearate as a cambling agent, Add 0.5 g of lactic acid as a stabilizer, dissolve and stir on an oil bath at 95°C, then seal and cool at room temperature with stirring. After dissolving 100 μg of P G E 1 and 0.9 g of hydroxypropyl-β-cyclodextrin in ethanol, the PGEI-hydroxypropyl-β-cyclodextrin clathrate compound obtained by distilling off the ethanol was added.
The desired ointment formulation was obtained by stirring and mixing.

Comparative Example 1 Stearyl alcohol was used as the saturated fatty alcohol.
95 g, 0.8 g of cetyl alcohol, 0.9 g of behenyl alcohol, 0.704 g of propylene glycol as glycols, 6.345 g of 1.3-butylene glycol, 1-[2(
Decylthio)ethyl]azacyclopentan 2-one is 0
．． Add 3 g, dissolve and stir on an oil bath at 95°C, then seal and cool at room temperature. One inch of PGE was added to this base and mixed with stirring to obtain an ointment preparation.

Comparative Example 2 Stearyl alcohol was used as saturated fatty alcohol at 0.0%.
95 g, cetyl alcohol 0.8 g, behenyl alcohol 0.9 g, glycols propylene glycol 0.704 g, 1,3-butylene glycol 6.320 g, absorption enhancer 1-[
2-decylthio)ethyl]azacyclopenkun-2-
Add 0.3 g of On, dissolve and stir on an oil bath at 95°C, then seal and cool at room temperature with stirring. PG in this base
After dissolving 1+v of E and β-cyclodextrin in 25 μm of ethanol, the ethanol was distilled off to obtain P G
The E + -β-cyclodextrin clathrate compound was stirred and mixed to obtain an ointment preparation.

Comparative Example 3 8.299 g of white petrolatum, 0 g of Sarasimillow
．． 8 g 1 stearyl alcohol 0.3 g 1 cholesterol 0.3 g 1-(2-(decylthio)ethyl)azacyclopentan-2-one as an absorption enhancer 0.
Add 3 g, heat on a water bath, dissolve and stir, then seal and cool at room temperature while stirring. One inch of PGE was added to this base and mixed with stirring to obtain an ointment preparation.

Experimental Example 1 Stability Test In order to examine the stability of P G E + in the ointment formulations of the present invention, 2 g each of the ointment formulations obtained in Examples 1 to 12 and Comparative Examples 1 to 3 were coated on the inside with phenol resin. The mixture was filled into an aluminum tube and stored in a constant temperature bath at 40° C. for 40 days, and the remaining amount of prostaglandin was quantified using liquid chromatography. Liquid chromatography uses an octadecylsilylated silica gel column with a mobile phase of 0. OIM Kll□P
Detection was performed at 201 nm using an O4-acetonitrile mixture. The results are shown in Table 1.

Table 1 From the test results, it was found that in the ointment formulation of the present invention, the decomposition of PGE was significantly suppressed by inclusion of PGE with etherified cyclodextrin, compared to Comparative Examples 1, 2, and 3. .

Experimental Example 2 Skin Blood Flow Test In order to confirm the local efficacy of the ointment formulation of the present invention,
Skin blood flow was measured.

Hairless mouse dorsal skin IXIc anesthetized with urethane using the compositions obtained in Example 1 and Comparative Example 1.2, respectively.
10 μm each were applied in a non-sealed manner to J. Before application and after application of the ointment, skin blood flow was measured at 5 minute intervals for up to 2 hours using a laser Doppler blood flow meter.

The results are the difference before and after applying the ointment (all/sin/100
g) was calculated. The results are shown in Figure 1.

The test results show that the ointment formulation of the present invention significantly increases skin blood flow compared to Comparative Example 1, in which PGE is not encapsulated with etherified cyclodextrin, and Comparative Example 2, in which PGE is encapsulated with β-cyclodextrin. It was found that the ointment formulation of the present invention was sufficiently absorbed through the skin and had sufficient medicinal efficacy.

[Action/effect of the invention]

The ointment formulation of the present invention is an ointment composition that can be obtained for the first time by combining PGE and -ECD with a specific ointment base.

Moreover, as is clear from the above stability test, since PGE clathrated with etherified cyclodextrin is formulated with an ointment base, the decomposition of PGE is significantly suppressed, which is very preferable for formulation. In addition, since the formulation is extremely stable, it can be stored for a long period of time, which is convenient for quality control and is optimal for commercialization.

In addition, in the skin blood flow test, a remarkable increase in skin blood flow was observed, and it was revealed that this effect was maintained for several hours, but this was because the ointment formulation of the present invention was absorbed more quickly than through the skin. , which sufficiently supports the development of medicinal efficacy, and is preferable in terms of drug formulation.

As described above, the ointment preparation of the present invention is excellent in terms of PGEI stability, pharmacological action development, and transdermal absorption, and can be used as an ointment preparation for topical application to treat Raynaud's disease, bedsores, skin ulcers, etc. It is expected to be used in the treatment of dryness, arteriosclerosis, etc., or as a hair growth agent.

In particular, the problem of stabilizing PGE, which is the most essential condition for ointment formulations, has been solved, which is unique in pharmaceutical formulations and is very useful in the pharmaceutical industry.

[Brief explanation of drawings]

Figure 1 shows the test results for skin blood flow when the formulation of the present invention is applied topically. The vertical axis shows the difference in blood flow before and after applying the composition, and the horizontal axis shows the time elapsed after applying the composition. is expressed in time.

Claims (1)

[Scope of Claims] 1. An ointment composition comprising an active ingredient in which prostaglandin E_1 is encapsulated with etherified cyclodextrins. 2. An ointment composition comprising an active ingredient in which prostaglandin E_1 is encapsulated with etherified cyclodextrins, saturated fatty alcohols, glycols, and/or an absorption enhancer.