KR20030050044A - Alprostadil alkyl ester-containing composition for external application - Google Patents

Abstract

PURPOSE: A composition for external use prepared by dissolving alprostadil alkyl ester as a prodrug in a mixture of an oil base, a skin permeation promoter and a skin irritation reducing agent is provided. Therefore, the composition exhibits enhanced effect on penile erection as well as has excellent drug permeability through skin. CONSTITUTION: A composition for external use comprises 0.1 to 5% by weight of alprostadil alkyl ester as a prodrug, 20 to 80% by weight of an oil base, 5 to 70% by weight of a skin permeation promoter and 1 to 30% by weight of a skin irritation reducing agent, based on the total weight of the composition. The alprostadil alkyl ester is characterized in that a C1-5 lower alkyl chain is esterified to alprostadil, and selected from the group consisting of alprostadil methyl ester, alprostadil ethyl ester, alprostadil propyl ester, alprostadil isopropyl ester and alprostadil butyl ester. The oil base is selected from the group consisting of glycerin fatty acid ester, vegetable oils and hard fat thereof, higher fatty acid and ester thereof and higher fatty acid alcohol.

Description

Alprostadil alkyl ester-containing composition for external application

The present invention relates to an external preparation composition comprising alprostadyl alkyl ester.

Erectile dysfunction is when there are not enough erections for men and women to have satisfactory sexual activity due to psychogenicity or temperament, or when more than 25% of the sexual life occurs. In the past, it was caused by mentality, that is, it was caused by lack of confidence or inferior feelings about its performance, but nowadays most of it is caused by temperament, that is, physical cause. Damage to nerves, blood vessels, hormonal system, surgery, and medications are the cause. Methods for treating this include drug therapy and surgical surgery. Drugs used in dual drug therapy include oral and topical agents. Oral yohimbine and trazodone are used, but its clinical effect is small. Recently, sildenafil, a selective phosphodiesterase antagonist, has been developed and used as an oral preparation. There is a disadvantage that causes.

Since erectile dysfunction symptoms are diseases caused by local dysfunction, it is preferable to treat them locally. Topically applied drugs include alprostadil (or prostaglandin E1), papaverine, phentolamine, and the like. Alprostadil is effective by relaxing the cavernous and cavernous artery segments of the urethra and penis of humans, thereby increasing the 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. However, because topical injections have to be injected directly into the penis, patients may exhibit rejection, pain or bleeding may occur at the injection site, and there may be a risk of infection. In addition, the urethral insert is a formulation that eliminates the rejection of the injection, but in this case also may cause discomfort and burning of the urethra, pain in the penis area and the like.

As described above, alprostadil 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 problems in formulating alprostadil into an external preparation.

The first is that when formulated with conventional external preparations containing water, alprostatil is degraded and chemical stability is not guaranteed. That is, dehydration of alprostadil occurs due to water present around the drug in the preparation to cause degradation to prostaglandin A1 or prostaglandin B1. US Patent No. 5,194,670 and US Patent No. 5,681,850 have been disclosed as patents for conventional external preparations. However, since they contain water as mentioned above, a bad effect on stability cannot be ruled out.

Secondly, alprostadil drug itself has a very low skin permeability, which makes it difficult to obtain a desired drug concentration locally when applied as an external preparation for transdermal administration.

In contrast, US Pat. No. 6,046,244 discloses alkyl-2- (N, N-disubstitutedamino) -alkanoate esters or (N, N-disubstitutedamino) -alkanol alkanoates, and US Pat. No. 5,942,545 dioxes. Solan, dioxane, and acetal are used as skin permeation accelerators, but these are new substances and there is no accurate information on the effects other than the skin permeation accelerators. In addition, the present inventors have found and patented the fact that the pyrrolidone derivative, which is an excipient that has already been established as a safety / effectiveness, and not such a new skin permeation promoter, may promote skin penetration of alprostadyl. (Korean Patent Application No. 99-31090). However, alprostadyl skin permeability from this formulation was very good, but the local skin irritation such as skin redness was severe at the site where the formulation was administered. On the other hand, by improving this formulation, a new formulation including a skin irritant has been studied to find a composition that has excellent skin permeability and can reduce local skin irritation and has filed a patent application (Korean Patent Application No. 2000) -26996).

A prodrug is a chemical modification of a drug's structure that allows it to be converted into a drug that is active during or after being absorbed into the body by hydrolysis or enzymatic activity in the body. Usually, prodrugs are made by modifying the physicochemical properties of the drug for the purpose of enhancing the transmembrane of the drug. The synthesis of prodrugs involves the modification of drugs into forms that are susceptible to the action of esterase, which is widely distributed in the body.

Alprostadil has a carboxyl group in the molecule, which can be esterified, and as the chain length of the bonded alkyl group increases, more than 10-fold permeation has been reported (Ho, HO et al., J. Control. Release 1999). ). It is known that the higher the chain length, the higher the fat solubility of the drug and the faster drug distribution to the stratum corneum. In addition, it is known that upon passing through the skin, the prodrug is degraded by esterase present in the skin in large amounts and metabolized to alprostadil.

U.S. Pat. No. 5,219,885 and U.S. Pat.No. 5,380,760 disclose external preparations of alprostadyl alkyl esters. However, US Pat. No. 5,219,885 has a disadvantage in that alprostadyl alkyl esters can be easily hydrolyzed because water is used. In US Pat. No. 5,380,760, the drug is dispersed in a pressure-sensitive adhesive to release the plastic. Since it is manufactured in the form of a star, there is a disadvantage that it is not easy to actually apply to the site.

Accordingly, the present inventors have found that the alprostadyl alkyl ester external preparation prepared by dissolving alprostadyl alkyl ester as a prodrug in a mixture of an oily base, a skin permeation accelerator, and a skin irritant is more alp than a conventional alprostadil preparation. The present invention was completed by discovering that rosadyl has better permeability and shows an excellent increase in the degree of erection.

Accordingly, an object of the present invention is to provide an alprostadyl alkyl ester external preparation which shows little skin irritation, not only ensures chemical stability of the drug in the formulation, but also shows excellent skin permeability and an excellent increase in erection. .

1 is an alprostadyl ethyl ester external preparation of Example 3 ( ) And alprostadyl external preparation of Comparative Example 1 Fig. 1 shows the skin permeability of).

Figure 2 is a diagram showing the degree of erection at the time of applying the alprostadyl ethyl ester external preparation of Example 3 and the alprostadyl external preparation of Comparative Example 1.

The present invention relates to an external preparation composition comprising alprostadyl alkyl ester.

More specifically, the present invention relates to a composition of an alprostatyl alkyl ester external preparation comprising an alprostadyl alkyl ester, an oily base, a skin permeation accelerator, and a skin irritant.

The alprostadyl alkyl ester of the present invention can be used as long as the lower alkyl chain having 1 to 5 carbon atoms is esterified to alprostadil, and preferably alprostadil methyl ester. ), Alprostadil ethyl ester, alprostadil propyl ester, alprostadil isopropyl ester and alprostadil butyl ester One or more components selected from the group consisting of can be used.

Alprostadyl alkyl ester in the present invention is preferably included in 0.1 to 5% by weight as alprostadyl relative to the total weight of the composition. If the content of the alprostadyl alkyl ester is less than 0.1% by weight, it is inconvenient to increase the volume of the formulation to be applied, and if it is more than 5% by weight, a large amount of the main drug becomes permeable to the skin at one time, so that the skin irritation becomes worse.

Alprostadyl alkyl esters have excellent skin permeability, and the ester bond is decomposed during skin permeation to supply alprostadil, an active ingredient, into the skin.

Oily bases that can be used in the compositions of the present invention include, but are not limited to, mono or trifatty acid glycerine esters and polyethylene glycol complexes thereof, polyethylene glycol esters of vegetable oils, fatty acid glycerine esters such as fatty acid propylene glycol esters; Vegetable oils such as sesame oil, soybean oil, castor oil, corn oil, palm oil, peanut oil, cacao oil, cottonseed oil, sunflower seed oil, safflower oil, almond oil, olive oil and hardened oils thereof; Oleic acid, linolenic acid, linoleic acid, palmitic acid, palmitoleic acid, arachidonic acid, myristic acid, capric acid, caprylic acid, lauric acid, stearic acid, ethyl oleate, oleic acid laurate, isopropyl myristate, Higher fatty acids such as isopropyl palmitate, octyldodecyl myristate and cetyl palmitate and esters thereof; And higher fatty acid alcohols such as lauryl alcohol, oleyl alcohol, cetyl alcohol, stearyl alcohol, and the like. At this time, the oily base is preferably included in 20 to 80% by weight relative to the total weight of the composition.

In order to promote skin permeation of alprostadyl alkyl esters, it is preferable to use pyrrolidone derivatives, and more preferably N-methyl-2-pyrroli, as skin permeation promoters that can be used in the composition of the present invention. Don, 2-pyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1-caprylpyrrolidone, 1-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 and 1-lauryl-4-methyloxy One or more components selected from the group consisting of carbonyl-2-pyrrolidone can be used. Skin permeation promoter is preferably included in 5 to 70% by weight based on the total weight of the composition, outside this range does not exhibit a sufficient skin permeation effect.

In addition, in order to further promote the skin permeation of the alprostadyl alkyl ester together with the pyrrolidone derivative, the composition of the present invention may further comprise an auxiliary skin penetration enhancer. As an auxiliary skin permeation promoter that can be used in the present invention, it is preferable to use at least one component selected from nonionic surfactants such as polyoxyethylene sorbitan fatty acid ester, sorbitan ester, and polyoxyethylene alkyl ether. Auxiliary skin permeation promoter is preferably included in 1 to 30% by weight based on the total weight of the composition.

When the alprostadyl alkyl ester external preparation is administered to the glans of the application site, redness may occur at the site of administration due to the drug, excipient, or a mixture thereof, and may cause skin irritation, which is accompanied by pain. Skin irritation is used to reduce these side effects, such as squalene, squalane, avocado oil, tocopherol, polyvinylpyrrolidone, chamomile extract, ginkgo biloba extract, elder tree extract, portuguese extract, centella extract, arnica Extract, green tea extract, polysaccharide extracted from honey, hyaluronic acid, aloe vera gel, cola fruit extract, spinocin, beta glucan, rose mario oil, allantoin, camphor, free fatty oil, various kinds of polypeptides, hydrated protein, legumes It is possible to use one or more components selected from the group consisting of amino acids and acetamides. In this case, the skin irritant may be included in an amount of 1 to 30% by weight based on the total weight of the composition. When the amount of the skin irritant is less than 1% by weight, the skin irritation may not be alleviated. If exceeded, it may interfere with skin penetration of alprostadyl alkyl ester or reverse irritation by these substances may occur.

The external preparation of alprostadyl alkyl ester can be prepared by dissolving alprostadyl alkyl ester as an active ingredient of the present invention in a mixture of an oily base, a skin permeation accelerator, and a skin irritant. The external preparation of the alprostadyl alkyl ester prepared as described above is a viscous liquid formulation, but may be used as it is, but by increasing the viscosity of the formulation, it may be easy to carry and convenient to use. To this end, the external preparation of the alprostadyl alkyl ester of the present invention may further include a thickener.

Examples of the thickener include waxes such as carnauba wax, beeswax, beeswax, braze, paraffin, petrolatum, lanolin, and PEG-8 beeswax; Metal stearates such as aluminum stearate, calcium stearate, magnesium stearate and zinc stearate; One or more components selected from the group consisting of polyethylene, polyethylene glycol (high molecular weight) and polyethylene oxide can be used. The thickener is preferably included in an amount of 1 to 50% by weight based on the total weight of the composition. When the thickener is included in an amount of more than 50% by weight, the viscosity is too high to make it uncomfortable to use.

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

Example 1

Alprostadil Methyl Ester 1.04

Isopropyl Myristate

N-methyl-2-pyrrolidone20

Oleic acid 4

Avocado Oil 15

1.04 g of alprostadyl methyl ester (1 g as alprostadyl) was added to a mixture of 59.96 g of isopropyl myristate, 20 g of N-methyl-2-pyrrolidone, 4 g of oleic acid and 15 g of avocado oil, and dissolved completely. I was.

Example 2

Alprostadil ethyl ester 0.43

Octyldodecyl Myristate

Beeswax 10

N-methyl-2-pyrrolidone40

Tocopherol 20

After heating 10 g of beeswax at 70 degreeC and melt | dissolving, 29.57 g of octyl dodecyl myristate were added, it mixed until it became a homogeneous liquid, and it cooled to room temperature. 40 g of N-methyl-2-pyrrolidone and 20 g of tocopherol were mixed with this solution, and 0.43 g of alprostadyl ethyl ester (0.4 g as alprostadyl) was further dissolved in the mixed solution.

Example 3

Alprostadil Ethyl Ester 1.08

Capryl / Capric Acid Propylene Glycol

Safflower oil 5

Carnauba Nap15

N-methyl-2-pyrrolidone30

Sorbate oleate 5

Squalene 3

15 g of carnauba lead was previously melted by heating to 70 ° C., and then a mixed solution of 40.92 g of capryl / capric propylene glycol and 5 g of safflower oil was added, mixed until a homogeneous liquid, and cooled to room temperature. To this solution, 30 g of N-methyl-2-pyrrolidone, 5 g of sorbitan oleate and 3 g of squalene were mixed, and 1.08 g of alprostadyl ethyl ester (1 g as alprostadil) was completely dissolved in the mixed solution. .

Example 4

Alprostadil Ethyl Ester 2.16

Isopropyl Palmitate

Safflower oil 10

1-dodecylpyrrolidone10

Polyoxyethylene 20 sorbitan oleic acid 3

Squalane 15

59.84 g of isopropyl palmitate with 2.16 g of alprostadyl ethyl ester (2 g as alprostadyl), 10 g of safflower oil, 10 g of 1-dodecylpyrrolidone, 3 g of polyoxyethylene 20 sorbitanoleic acid and 15 g of squalene It was added to the mixed solution and dissolved completely.

Example 5

Alprostadil Isopropyl Ester 0.11

PEG-8 Capryl / Capric Acid Triglycerides

Glycerin Stearate 30

N-methyl-2-pyrrolidone15

Sorbitan sorbate 9.9

Squalane 25

19.99 g of PEG-8 caprylic / capric acid triglyceride, 0.1 g of alprostadyl isopropyl ester (0.1 g as alprostadyl) and 30 g of stearic acid, 15 g of N-methyl-2-pyrrolidone, It was added to a mixed solution of 9.9 g of sorbitan sorbate and 25 g of squalane and completely dissolved.

Example 6

Alprostadil Ethyl Ester 1.08

Ethyl Oleate 14.92

Olive oil PEG-6 ester 10

N-ethyl-2-pyrrolidone40

Polyoxyethylene Lauryl Ether 30

Tocopherol 4

14.08 g of ethyl oleate, 10 g of olive oil PEG-6 ester, 40 g of N-ethyl-2-pyrrolidone, 30 g of polyoxyethylene lauryl ether mixed with 1.08 g of alprostadyl ethyl ester (1 g as alprostadyl) in advance And 4 g of tocopherol and completely dissolved.

Comparative Example 1

Alprostadil 1

Capryl / Capric Acid Propylene Glycol 41

Safflower oil 5

Carnauba Nap15

N-methyl-2-pyrrolidone30

Sorbate oleate 5

Squalene 3

15 g of carnauba lead was previously melted by heating to 70 ° C., and then a mixed solution of 41 g of capryl / caprylic acid propylene glycol and 5 g of safflower oil was added, mixed until a homogeneous liquid, and cooled to room temperature. To this solution, 30 g of N-methyl-2-pyrrolidone, 5 g of sorbitan oleate and 3 g of squalene were mixed, and 1 g of alprostatil was further added to the mixed solution to completely dissolve it.

Experimental Example 1

The alprostadil ethyl ester external preparation prepared in Example 3 was subjected to a skin permeation test using a Franz diffusion cell equipped with extracted guinea pig skin. As a control agent, the formulation of Comparative Example 1, which is an alprostadil external preparation prepared according to Example 3 of Korean Patent Application No. 2000-26996, was used. 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. It can be seen that the alprostadyl ethyl ester external preparation of the present invention exhibits about 5 times higher skin permeability than Comparative Example 1.

Experimental Example 2

An erectile force test was performed on live cats using the alprostadyl ethyl ester external preparation prepared in Example 3. As a control agent, the formulation of Comparative Example 1, which is an alprostadil external preparation prepared according to Example 3 of Korean Patent Application No. 2000-26996, was used. Cats were anesthetized with pentobarbital, the penile skin was excised, and corpus cavernous was connected to a Grass model 7 polygraph and a statum pressure transducer to measure intracavernosal pressure. Expression time was the time when intracavernosal pressure increased and erection was the maximum penile size, and duration was evaluated as the duration of maximum cavernosal pressure.

The resulting erection is shown in Figure 2, it was confirmed that the alprostadyl ethyl ester external preparation increased the erection compared to the alprostadyl external preparation.

Alprostadyl alkyl ester external preparations according to the present invention, compared to the alprostadil external preparations, not only the skin permeability of the drug is very excellent but also shows an increased effect on the erection degree.

Claims (19)

An external preparation composition comprising an alprostadil alkyl ester, an oily base, a skin permeation accelerator, and a skin irritant. The external preparation composition according to claim 1, wherein the alprostadyl alkyl ester is esterified with a lower alkyl chain having 1 to 5 carbon atoms to alprostadyl. 3. The alprostadyl alkyl ester according to claim 2, wherein the alprostadil alkyl ester consists of alprostadil methyl ester, alprostadil ethyl ester, alprostadil propyl ester, alprostadil isopropyl ester and alprostadil butyl ester An external preparation composition, characterized in that at least one component selected from the group. The composition of claim 1, wherein the alprostadyl alkyl ester is contained in an amount of 0.1 to 5% by weight as alprostadyl relative to the total weight of the composition. The external preparation composition according to claim 1, wherein the oily base is at least one component selected from the group consisting of fatty acid glycerin esters, vegetable oils and hardened oils thereof, higher fatty acids and esters thereof, and higher fatty acid alcohols. 6. The oily base according to claim 5, wherein the oily base is mono or trifatty acid glycerin esters and polyethylene glycol complexes thereof, polyethylene glycol esters and fatty acid propylene glycol esters of vegetable oils; Sesame oil, soybean oil, castor oil, corn oil, palm oil, peanut oil, cacao oil, cottonseed oil, sunflower seed oil, safflower oil, almond oil, olive oil and their cured oils; Oleic acid, linolenic acid, linoleic acid, palmitic acid, palmitoleic acid, arachidonic acid, myristic acid, capric acid, caprylic acid, lauric acid, stearic acid, ethyl oleate, oleic acid laurate, isopropyl myristate, Isopropyl palmitate, octyldodecyl myristate and cetyl palmitate; And at least one component selected from the group consisting of lauryl alcohol, oleyl alcohol, cetyl alcohol and stearyl alcohol. The external preparation composition according to claim 1, wherein the oily base is included in an amount of 20 to 80 wt% based on the total weight of the composition. The external preparation composition according to claim 1, wherein the skin penetration promoter is a pyrrolidone derivative. The method of claim 8, wherein the skin permeation promoter is N-methyl-2-pyrrolidone, 2-pyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1-caprylpyrrolidone, 1- 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 A composition for external preparation, characterized in that at least one component selected from the group consisting of -methyl-2-pyrrolidone and 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone. The external preparation composition according to claim 1, wherein the skin permeation accelerator is included in an amount of 5 to 70 wt% based on the total weight of the composition. The method of claim 1, wherein the skin irritant is extracted from squalene, squalane, avocado oil, tocopherol, polyvinylpyrrolidone, chamomile extract, ginkgo biloba extract, elderberry extract, portulaca extract, centella extract, arnica extract, green tea extract, honey extract Group consisting of polysaccharides, hyaluronic acid, aloe vera gel, cola fruit extract, spinocin, betaglucan, rosemary oil, allantoin, camphor, free fatty oil, various kinds of polypeptides, hydrated proteins, amino acids and acetamides in legumes Exterior composition, characterized in that at least one component selected from. The external preparation composition according to claim 1, wherein the skin irritant is contained in an amount of 1 to 30% by weight based on the total weight of the composition. The composition for external preparation according to claim 1, further comprising an auxiliary skin permeation accelerator. The external preparation composition according to claim 13, wherein the auxiliary skin permeation promoter is a nonionic surfactant. 15. The external preparation composition according to claim 14, wherein the auxiliary skin permeation accelerator is at least one component selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, sorbitan ester, and polyoxyethylene alkyl ether. The external preparation composition according to claim 13, wherein the auxiliary skin permeation accelerator is included in an amount of 1 to 30% by weight based on the total weight of the composition. The external preparation composition according to claim 1, further comprising a thickener. 18. The external preparation composition according to claim 17, wherein the thickener is at least one component selected from the group consisting of waxes and derivatives thereof, metal stearates, polyethylene, polyethylene glycol (high molecular weight) and polyethylene oxide. 18. The external preparation composition according to claim 17, wherein the thickener is contained in an amount of 1 to 50% by weight based on the total weight of the composition.