KR20010011625A - Alprostadil-containing compositions for external use - Google Patents

Abstract

The present invention relates to an alprostadil external preparation composition excellent in stability and skin permeability. The composition of the present invention is a mixed base of alprostadyl and isopropyl esters of higher fatty acids and fatty acids; Mixing bases of isopropyl esters of higher fatty acids with fatty alcohols; And an oily base selected from the group consisting of oleic acid esters and skin permeation accelerators.

Description

Alprostadil-containing compositions for external use

The present invention relates to an alprostadil external preparation composition excellent in stability and skin permeability.

Erectile dysfunction means that due to psychogenicity or temperament, an erection is not sufficient or maintained even if the sex is satisfactory to both sexes. In the past, about 95% were caused by psychogenicity, but nowadays, most of them are caused by organic factors such as vascular disorders, neurological disorders, male hormone secretion disorders, genital lesions, and systemic diseases. Methods for treating this include drug therapy and surgical surgery. Drugs used in dual drug therapy include oral or topical agents. Oral yohimbine and trazodone are used, but they are clinically ineffective. Recently, a selective phosphodiesterase antagonist, sildenafil, has been developed and used for oral preparations. There are disadvantages.

However, because erectile dysfunction is a disease caused by local dysfunction, it is preferable to treat it locally. Topically applied drugs include alprostadil (or prostaglandin E1), papaverine, phentolamine, and the like. Alprostadil is effective in relaxing the cavernous and cavernous artery segments of the urethra and penis of humans and increasing blood flow to the cavernous arteries. As a result of the topical application of the drug, injections and urethra inserts have been developed, and some of them have already been sold at home and abroad. Topical injections must be injected directly into the penis, which may result in patient rejection or pain or bleeding at the injection site, and further risk of infection. Urethral inserts eliminate the rejection of injections, but in this case also cause discomfort, burning of the urethra and pain in the penis.

As described above, alprostadyl has an excellent effect on erectile dysfunction when applied topically, but it can be seen that other formulations other than the most comfortable external preparations are commonly used. This is because there are two major problems in formulating alprostadil into an external preparation.

The first is that when formulated with conventional external preparations containing water, alprostadil is degraded and chemical stability is not guaranteed. That is, dehydration of alprostadil occurs by water present around the drug in the preparation, and decomposition occurs to prostaglandin A1 or prostaglandin B1.

The second is that alprostadil drug itself has a very low skin permeability, making it difficult to obtain a desired drug concentration locally when applied as an external preparation for transdermal administration. For this reason, the injection which shows the most sure effect is used conventionally in spite of problems, such as pain.

US Patent No. 5,194,670 and US Patent No. 5,681,850 have been disclosed as patents for conventional external preparations. However, these are related to emulsions and conventional formulations, respectively, and since these formulations contain water, there is a disadvantage that adversely affects the stability of alprostadil as described above.

Therefore, the present inventors have long researched to develop an alprostatil external preparation having excellent stability and skin permeability, and when the external preparation composition is prepared by dissolving alprostadil in a certain oily base including a skin permeation accelerator. The present invention has been found to be able to effectively overcome the problems of the prior art.

Therefore, an object of this invention is to provide the external preparation composition containing alprostadil.

1 is a view showing the skin permeation test results of the external preparation composition of the present invention.

The present invention is a mixed base of isopropyl ester of alprostadil with higher fatty acids and fatty acids; Mixing bases of isopropyl esters of higher fatty acids with fatty alcohols; And an oily base selected from the group consisting of oleic acid esters and skin permeation accelerators.

In the composition of the present invention, the content of alprostadil, which is a main component, is preferably 0.1 to 5% by weight based on the total weight of the composition.

Mixed bases of isopropyl esters of higher fatty acids with fatty acids as oily bases in the compositions of the present invention; Mixing bases of isopropyl esters of higher fatty acids with fatty alcohols; Or oleic acid esters.

Isopropyl esters of higher fatty acids may be used isopropyl myristate or isopropyl palmitate, and fatty acids may include linolenic acid, linoleic acid, oleic acid, palmitoleic acid, arachidonic acid, capric acid or lauric acid. The fatty acid alcohol may be lauryl alcohol or oleyl alcohol and the like.

In the oily base, when a mixed base of isopropyl ester of higher fatty acid and fatty acid or isopropyl ester of higher fatty acid and fatty alcohol is used, the content of fatty acid or fatty alcohol is preferably 1 to 20% by weight based on the total weight of the composition. .

In the composition of the present invention, the skin permeation promoter is preferably a pyrrolidone derivative, specifically N-methyl-2-pyrrolidone, 2-pyrrolidone, caprylylpyrrolidone, laurylpyrrolidone, N -Ethyl-2-pyrrolidone, N-cyclohexyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-hexyl 2-pyrrolidone, 1-hexyl-4-methyloxycarbonyl-2-pyrrolidone, 1- (2-hydroxyethyl) pyrrolidone, 3-hydroxy-N-methyl-2-pyrroli Money, or 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone, and the like, and the content of the skin permeation accelerator is preferably 5 to 70% based on the total weight of the composition, and is outside this range. If not enough skin penetration effect.

In addition, the composition of the present invention is prepared by dissolving a solid dispersion prepared by dispersing alprostadil in a copolymer of polyoxyethylene and polyoxypropylene in a mixture of the oily base and the skin permeation accelerator to stabilize the external composition. And it is preferable because it can further enhance the skin permeation effect.

The solid dispersion in the composition of the present invention uses a copolymer of polyoxyethylene and polyoxypropylene, and among the copolymers of polyoxyethylene and polyoxypropylene, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, and the like. It is preferable that at least one is selected from.

In the preparation of the solid dispersion, it is preferable that the copolymer of polyoxyethylene and polyoxypropylene is melted at 90 to 150 ° C., and then melted by addition of alprostadil, followed by cooling to room temperature to prepare a solid dispersion. At this time, if the above temperature range is less than 90 ℃ alprostadil may not be completely dissolved in the copolymer of polyoxyethylene and polyoxypropylene, and if it is higher than 150 ℃ there is a risk of drug decomposition by high temperature.

It is preferable that the usage-amount of the copolymer of the polyoxyethylene and polyoxypropylene is 1-100 weight part with respect to 1 weight part of alprostadyl. If the weight ratio of the copolymer of polyoxyethylene and polyoxypropylene in the solid dispersion is less than 1 part by weight with respect to 1 part by weight of alprostadyl, there is a problem in that a complete solid dispersion is not formed, and more than 100 parts by weight. This is because a copolymer of polyoxyethylene and polyoxypropylene of more than necessary amount is used, which is not preferable, and further, the effect of promoting the skin permeation of alprostadil by the copolymer of polyoxyethylene and polyoxypropylene is reduced.

If the content of alprostadil to be contained in the formulation is higher than the drug's solubility in the base used, solubilizers can be added to dissolve it completely, including ethanol, isopropanol, dimethyl isosorbide, and propylene. Propylene carbonate, propylene glycol monocaprirate, and the like. The amount of these used is preferably less than 10% of the formulation, because more than this reduces the skin permeability of alprostadil.

The external preparation composition of the present invention may have a conventional pharmaceutical external preparation formulation, of which the liquid or semi-solid form is more preferred. More preferred are semi-solid formulations comprising gels which are more portable and easier to use.

In preparing the external preparation composition of the present invention in gel form, a thickener such as colloidal silicon dioxide is usually added. The colloidal silicon dioxide can be used, such as Aerosil sold by Degussa, Cab-O-Sil sold by Carbot carbon, etc. The amount of these used is preferably 1 to 10% by weight based on the total weight of the composition. If less than this range it may not be able to maintain the semi-solid state, in many cases too high viscosity may be inconvenient to use.

The external preparation composition of the present invention can effectively enhance skin permeation promoting effect and stability by dissolving alprostadil in a specific oily base as shown in the following Examples and Experimental Examples to prepare the external preparation composition, By preparing a solid dispersion together with a copolymer of polyoxyethylene and polyoxypropylene, it is possible to further enhance the skin penetration promoting effect and stability of alprostadil.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the present invention is not limited by these Examples and Experimental Examples.

Example 1

Alprostadil 0.4

Poloxamer 407 4

Isopropyl myristate 55.6

N-methyl-2-pyrrolidone 30

Oleic acid 10

4 g of poloxamer 407 was heated and melted at about 100 ° C., 0.4 g of alprostadyl was added thereto to completely melt, and then cooled to room temperature. This was added to a mixed solution of 55.6 g of isopropyl myristate, 30 g of N-methyl-2-pyrrolidone, and 10 g of oleic acid, which were mixed in advance, and stirred until completely dissolved to prepare an external solution.

Example 2

Alprostadil 0.2

Ethyl oleate 49.8

N-methyl-2-pyrrolidone 50

0.2 g of alprostadyl was added to a mixed solution of 49.8 g of ethyl oleate and 50 g of N-methyl-2-pyrrolidone mixed in advance and stirred until completely dissolved to prepare an external solution.

Example 3

Alprostadil 1

Ethyl oleate 82

N-methyl-2-pyrrolidone 10

Dimethylisosorbide 5

Aerosil 2

1 g of alprostadil was added to a mixed solution of 82 g of ethyl oleate, 10 g of N-methyl-2-pyrrolidone, and 5 g of dimethylisosorbide, which had been mixed beforehand, and stirred until completely dissolved. While stirring this solution, 2 g of aerosil was slowly added to prepare a gel.

Example 4

Alprostadil 0.5

Isopropyl Palmitate 77.5

N-ethyl-2-pyrrolidone 20

Oleic acid 2

An external solution was prepared by adding 0.5 g of alprostadil to a mixed solution of 77.5 g of isopropyl palmitate, 20 g of N-ethyl-2-pyrrolidone, and 2 g of oleic acid, and stirring until completely dissolved.

Example 5

Alprostadil 0.5

Poloxamer 407 25

Isopropyl myristate 54.5

N-ethyl-2-pyrrolidone 10

Lauryl Alcohol 10

25 g of poloxamer 407 was heated and melted at about 100 ° C., and 0.5 g of alprostadyl was added thereto to completely melt and cooled to room temperature. This was added to a mixed solution of 54.5 g of isopropyl myristate, 10 g of N-ethyl-2-pyrrolidone, and 10 g of lauryl alcohol, which were mixed in advance, and stirred until completely dissolved to prepare an external solution.

Example 6

Alprostadil 0.1

Poloxamer 407 10

Ethyl oleate 19.9

N-methyl-2-pyrrolidone 70

10 g of poloxamer 407 was heated and melted at about 100 ° C., and 0.1 g of alprostadyl was added thereto to completely melt and cooled to room temperature. This was added to a mixed solution of 19.9 g of ethyl oleate and 70 g of N-methyl-2-pyrrolidone mixed in advance, and stirred until completely dissolved to prepare an external solution.

Example 7

Alprostadil 1

Isopropyl myristate 57

N-methyl-2-pyrrolidone 30

Lauryl Alcohol 5

Aerosil 7

1 g of alprostadil was added to a mixed solution of 57 g of isopropyl myristate, 30 g of N-methyl-2-pyrrolidone, and 5 g of lauryl alcohol, and stirred until completely dissolved. While stirring the solution, 7 g of aerosil was slowly added to prepare a gel.

Example 8

Alprostadil 1

Isopropyl myristate 69

N-ethyl-2-pyrrolidone 5

Oleic acid 20

Propylene Carbonate 5

1 g of alprostadil was added to a mixed solution of 69 g of isopropyl myristate, 5 g of N-ethyl-2-pyrrolidone, 20 g of oleic acid and 5 g of propylene carbonate and stirred until completely dissolved to prepare an external solution.

Example 9

Alprostadil 1

Poloxamer 407 10

Isopropyl myristate 74

N-methyl-2-pyrrolidone 10

Oleic acid 5

10 g of poloxamer 407 was heated and melted at about 100 ° C., and 1 g of alprostadyl was added thereto to completely melt and cooled to room temperature. This was added to a mixed solution of 74 g of isopropyl myristate, 10 g of N-methyl-2-pyrrolidone, and 5 g of oleic acid, which were mixed in advance, and stirred until completely dissolved, thereby preparing an external solution.

Example 10

Alprostadil 5

Poloxamer 407 25

Ethyl oleate 40

N-methyl-2-pyrrolidone 20

Ethanol 10

25 g of poloxamer 407 was heated and melted at about 100 ° C., and 5 g of alprostadyl was added thereto to completely melt and cooled to room temperature. This was added to a mixture of 40 g of ethyl oleate, 20 g of N-methyl-2-pyrrolidone, and 10 g of ethanol, which were mixed in advance, and stirred until completely dissolved to prepare an external solution.

Example 11

Alprostadil 0.4

Isopropyl myristate 55.6

N-methyl-2-pyrrolidone 30

Oleic acid 14

0.4 g of alprostadil was added to a mixed solution of 55.6 g of isopropyl myristate, 30 g of N-methyl-2-pyrrolidone, and 14 g of oleic acid, which were stirred until completely dissolved to prepare an external solution.

Comparative Example 1

Alprostadil 0.4

Hydrophilic Ointment 100

0.4 g of alprostadyl was mixed until 100 g of the hydrophilic ointment was completely dissolved to prepare an ointment.

Experimental Example 1: Skin Permeation Test

Skin permeation tests were performed on the alprostadil external preparations prepared in Examples 1 and 11 using Franz diffusion cells equipped with extracted hairless skin. As a receptor solution, 0.01 M phosphate buffer (pH 7.4) was used. The recepta solution was taken at a fixed time up to 180 minutes, and the content of alprostadil in this solution was quantified by high performance liquid chromatography. The experiment was repeated three times. The resulting skin penetration of alprostadil is shown in FIG. 1.

Skin permeability (mean ± standard deviation) calculated from the results of FIG. 1 is 11.8 ± 0.5 μg / cm 2 / min in Example 1, and 9.8 ± 1.7 μg / cm 2 / min in Example 11 It can be seen that the high skin permeability.

Experimental Example 2: Stability Test

The stability of alprostadil in the formulations of the external preparations prepared in Examples 1 and 11 and the ointment prepared in Comparative Example 1 were measured. In the stability measurement method, the samples were sealed and stored at 40 ° C., and collected at 2, 4, and 8 weeks to quantify the content of alprostadil in the sample by high performance liquid chromatography. The results are shown in Table 1 below.

Long-term storage of alprostadil external preparation (mean ± standard deviation, n = 3, unit:%) Elapsed days Example 1 Example 11 Comparative Example 1 Right after manufacturing 100.0 (± 1.0) 100.0 (± 1.1) 100.0 (± 1.5) 2 weeks 101.9 (± 1.5) 98.6 (± 2.8) 69.5 (± 0.6) 4 Weeks 98.8 (± 1.6) 92.9 (± 0.6) 48.3 (± 0.6) 8 Weeks 96.3 (± 1.3) 89.4 (± 1.1) 19.3 (± 0.3)

As can be seen in Table 1, it can be seen that the alprostadyl external preparation according to the present invention exhibits much better stability than the conventional ointment of Comparative Example 1, and the alprostadyl polyoxyethylene and polyoxy It can be seen that the external preparation prepared from the solid dispersion prepared by dispersing in the copolymer of propylene shows more excellent stability.

Alprostatil-containing external preparation prepared according to the production method according to the present invention can be seen that not only the stability of the drug in the formulation is very good, but also excellent skin permeability.

Claims (11)

Mixing bases of alprostadil with isopropyl esters of higher fatty acids and fatty acids; Mixing bases of isopropyl esters of higher fatty acids with fatty alcohols; And an oil-based base selected from the group consisting of oleic acid esters and a skin permeation accelerator. The external preparation composition according to claim 1, wherein the content of alprostadil is 0.1 to 5% by weight based on the total weight of the composition. The external preparation according to claim 1, wherein the content of fatty acid or fatty alcohol in the mixed base of isopropyl ester of higher fatty acid and fatty acid or isopropyl ester of higher fatty acid and fatty alcohol is 1 to 20% by weight based on the total weight of the composition. Composition. The method of claim 1, wherein the isopropyl ester of the higher fatty acid is isopropyl myristate or isopropyl palmitate; Fatty acids are linolenic acid, linoleic acid, oleic acid, palmitoleic acid, arachidonic acid, capric acid or lauric acid; The external preparation composition characterized in that the fatty acid alcohol is lauryl alcohol or oleyl alcohol. The skin permeation promoter of claim 1 is N-methyl-2-pyrrolidone, 2-pyrrolidone, caprylylpyrrolidone, laurylpyrrolidone, N-ethyl-2-pyrrolidone, N- Cyclohexyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1-hexyl- 4-methyloxycarbonyl-2-pyrrolidone, 1- (2-hydroxyethyl) pyrrolidone, 3-hydroxy-N-methyl-2-pyrrolidone or 1-lauryl-4-methyloxy Carbonyl-2-pyrrolidone The external preparation composition characterized by the above-mentioned. The external preparation composition according to claim 1, wherein the content of the skin permeation promoter is 5 to 70% by weight based on the total weight of the composition. The external preparation composition according to claim 1, wherein the solid dispersion prepared by dispersing alprostadil in a copolymer of polyoxyethylene and polyoxypropylene is dissolved in a mixture of the oily base and the skin permeation accelerator. 8. The external preparation composition according to claim 7, wherein the copolymer of polyoxyethylene and polyoxypropylene is at least one selected from the group consisting of poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407. The external preparation composition according to claim 7, wherein the copolymer of polyoxyethylene and polyoxypropylene is 1 to 100 parts by weight based on 1 part by weight of alprostadyl. The external preparation composition according to claim 1, comprising colloidal silicon dioxide as a solubilizer or thickener selected from the group consisting of ethanol, isopropanol, dimethylisosorbide, propylene carbonate and propylene glycol monocaprirate. 11. The external preparation composition according to claim 10, wherein the formulation is a liquid or semisolid.