JPWO2005082334A1 - Sustained release cream - Google Patents

Abstract

It contains 10 to 25% by mass of the oil phase based on the total amount of the formulation, and the content of the liquid fatty acid ester contained in the oil phase is 25 to 60% by mass based on the whole oil phase. The sustained-release cream is excellent in use feeling and can release the active ingredient continuously for a long time.

Description

  The present invention relates to a sustained release cream.

  Drug administration methods include intravenous injection, oral administration, and transdermal administration. Among these, transdermal administration has the characteristics that the first-pass effect of the liver can be avoided and administration is simple. Examples of dosage forms for transdermal administration include patches, ointments and lotions.

  Ointments and lotions have a problem that the drug duration is short because the drug is released more quickly than the patch. In order to solve this problem, for example, an external preparation comprising a non-porous polymer fine particle containing a drug and a spreadable base, and the non-porous polymer fine particle is dispersed in the spreadable base. Has been proposed (Patent Document 1).

JP 2003-096331 A

  However, although the above external preparation can release the active ingredient continuously for a long time, the feeling of use such as stickiness and extensibility is not always excellent.

  Accordingly, an object of the present invention is to provide a sustained-release cream that improves stickiness and extensibility and has an excellent feeling of use, and that can release an active ingredient continuously for a long time.

  In order to achieve the above object, the present invention contains 10 to 25% by mass of an oil phase based on the total amount of the preparation, and the content of the liquid fatty acid ester contained in the oil phase is 25 based on the whole oil phase. Provided is a sustained-release cream characterized by being ˜60 mass%.

  The cream having the above composition is excellent in use feeling (for example, stickiness, spread, dryness, and dripping) when applied to the skin and the like, and can release the active ingredient continuously for a long time.

  Such an effect becomes more prominent when the liquid fatty acid ester is a saturated fatty acid monoester having 17 to 32 carbon atoms and / or a saturated dicarboxylic acid diester having 12 to 16 carbon atoms. The liquid fatty acid ester is at least one compound selected from the group consisting of isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl 2-ethylhexanoate, diisopropyl adipate and diethyl sebacate. Particularly preferred.

  The sustained-release cream of the present invention preferably contains an antifungal agent as an active ingredient, and the antifungal agent is preferably a benzylamine compound, an imidazole compound or an allylamine compound. Particularly preferred antifungal agents are butenafine hydrochloride, a benzylamine compound, neticonazole hydrochloride, an imidazole compound, and terbinafine hydrochloride, an allylamine compound. When the active ingredient is these drugs, the effect of sustained release becomes even more remarkable.

  Moreover, it is preferable that the sustained-release cream of the present invention contains an acne vulgaris therapeutic agent, particularly ibuprofen piconol as an active ingredient. When the active ingredient is these drugs, the effect of sustained release becomes even more remarkable.

  According to the present invention, it is possible to provide a sustained-release cream that is improved in stickiness and extensibility and has excellent usability and capable of releasing an active ingredient continuously for a long time.

It is the graph showing the relationship between elapsed time and the cumulative release rate (%) of butenafine hydrochloride, (a) shows Comparative Example 1, (b) shows Example 1, and (c) shows Example 2. It is the graph showing the relationship between elapsed time and the amount (mg) of butenafine hydrochloride released per unit time, (a) shows Comparative Example 1 and (b) shows Example 1.

  Hereinafter, preferred embodiments of the present invention will be described in detail.

  The sustained-release cream of the present invention contains a liquid fatty acid ester, an oily base, a surfactant, water, and a drug (active ingredient). The sustained-release cream of the present invention contains 10 to 25% by mass of the oil phase based on the total amount of the formulation, and the content of the liquid fatty acid ester contained in the oil phase is based on the whole oil phase. It is 25-60 mass%.

  With such a composition, the sustained-release cream of the present invention is excellent in use feeling and can release the active ingredient continuously for a long time.

  The oil phase contains a liquid fatty acid ester and an oily base. Moreover, when the sustained release cream of the present invention contains a higher alcohol, a fatty acid ester, a silicone oil, a gelling agent, etc., these are also included in the oil phase.

  When the content of the oil phase in the cream is lowered, generally, stickiness and the like are improved, and it is expected that the feeling of use of the cream is improved. On the other hand, when the drug (active ingredient) contained in the cream is fat-soluble, generally, the drug is rapidly released (percutaneously absorbed) when the oil phase content in the cream is lowered. it is conceivable that.

  However, the sustained-release cream of the present invention can release the contained drug continuously for a long time, regardless of whether the contained drug is water-soluble or fat-soluble, and also has an excellent feeling of use. Yes. This effect occurs because the sustained-release cream of the present invention is not only adjusted in the content of the oil phase, but also adjusted in the content of the liquid fatty acid ester that is a component contained in the oil phase. It is thought that this is because The role played by liquid fatty acid esters is not always clear, but liquid fatty acid esters have a polar part (ester bond) and a nonpolar part (alkyl group). It is thought that it tends to stay in the lowered cream. If the content of the liquid fatty acid ester is too low, the drug will be released quickly, and if the content is too high, a sufficient amount of drug will not be released to exert its medicinal effects. In any case, it is not a sustained release cream. Therefore, in the sustained release cream of the present invention, the content of the liquid fatty acid ester must be 25 to 60% based on the whole oil phase.

  The liquid fatty acid ester refers to a fatty acid ester that is liquid at normal temperature and pressure, and is a saturated fatty acid monoester having 17 to 32 carbon atoms, a saturated dicarboxylic acid diester having 12 to 16 carbon atoms, or a mixture thereof. preferable. Here, the carbon number refers to the total number of carbon number of fatty acid and carbon number of alcohol. Specific examples include isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl 2-ethylhexanoate, diisopropyl adipate, diethyl sebacate, diisopropyl adipate, medium chain fatty acid triglyceride, triisooctanoic acid glyceride and the like. It is done. And from the viewpoint of good balance between the polar part and the non-polar part and excellent sustained release effect, the liquid fatty acid ester is isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl 2-ethylhexanoate. And at least one compound selected from the group consisting of diisopropyl adipate and diethyl sebacate.

  Examples of the oily base include liquid paraffin, petrolatum, paraffin wax, squalane and the like.

  The surfactant may be any of an anionic surfactant, a nonionic surfactant, a cationic surfactant, or an amphoteric surfactant. Examples of the anionic surfactant include polyoxyethylene alkyl phosphate ester and sodium alkyl sulfate. Nonionic surfactants include, for example, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate, sorbitan fatty acid esters such as polyoxyethylene stearic acid sorbitan, and polyoxyethylene nonyl ether, Examples thereof include polyoxyethylene ethers such as monooxyethylene cetyl ether and monooxyethylene lauryl ether. Examples of the cationic surfactant include benzethonium chloride and benzalkonium chloride.

  The drug contained in the sustained-release cream of the present invention may be fat-soluble or water-soluble. Regardless of the drug having any property, the sustained-release cream of the present invention can release the drug continuously for a long time.

  The drug contained in the sustained release cream of the present invention is preferably an antifungal agent. In this case, the sustained-release cream of the present invention is effective as a therapeutic agent for athlete's foot, and the effect can be sustained for two days or more by one application. As the antifungal agent, a benzylamine compound is preferable, and butenafine hydrochloride is particularly preferable. This is because when the drug contains butenafine hydrochloride, the sustained-release effect of the sustained-release cream becomes significant. Butenafine hydrochloride is a fat-soluble compound, and its physicochemical properties are shown in Table 1.

  The content of butenafine hydrochloride is usually 0.1 to 10% by mass, preferably 1 to 5% by mass, based on the whole preparation, from the viewpoint of efficacy as an antifungal agent.

  As antifungal agents, neticonazole hydrochloride, which is an imidazole compound, and terbinafine hydrochloride, which is an allylamine compound, are also preferable. This is because the sustained-release cream of the present invention containing these drugs has a remarkable sustained-release effect. The content of neticonazole hydrochloride and terbinafine hydrochloride is usually 0.1 to 10% by mass, preferably 1 to 5% by mass, based on the whole preparation, from the viewpoint of efficacy as an antifungal agent.

  It is preferable that the drug contained in the sustained-release cream of the present invention is a therapeutic agent for acne vulgaris (acne), particularly ibuprofen piconol. In this case, the sustained-release cream of the present invention is effective as a therapeutic agent for acne vulgaris, and the effect can be sustained for 2 days or more by one application.

  The sustained-release cream of the present invention may contain, in addition to the above components, higher alcohols, fatty acid esters, silicone oils, polyhydric alcohols or derivatives thereof, gelling agents, and the like.

  The higher alcohol is an alcohol having 10 to 22 carbon atoms, and is preferably cetyl alcohol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol, or behenyl alcohol.

  The fatty acid ester is an ester of a higher fatty acid, and examples thereof include esters of higher fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, caprylic acid, capric acid and alcohols having 1 to 18 carbon atoms.

  Examples of the polyhydric alcohol or derivative thereof include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, dipropylene glycol, polyethylene glycol and polypropylene glycol, and esters or ethers thereof.

  Examples of the gelling agent include carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like.

  The external skin cream of the present invention may contain a pH adjuster, antioxidant, preservative, preservative, moisturizer, chelating agent, fragrance, and other additives usually blended in the external skin cream. Good.

  The external skin cream of the present invention can be produced by mixing and emulsifying each component according to a conventional method.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, this invention is not limited to these Examples.

(Examples 1-4 and Comparative Examples 1-2)
A cream preparation containing butenafine hydrochloride as an active ingredient was produced by a conventional method according to the formulation of Table 2 (numerical values in Table 2 represent mass% based on the whole preparation unless otherwise specified). More specifically, the water phase and the oil phase were each heated to 80 ° C., and both were mixed and emulsified with sufficient stirring. Then, the cream agent was obtained by cooling to room temperature, stirring.

(Test Example 1)
By the method according to the dissolution test “paddle method” described in the Japanese Pharmacopoeia (14th revision), the dissolution test of butenafine hydrochloride from the creams of Comparative Example 1 and Examples 1-2 was performed. More specifically, it is as follows. The cell coated with the cream was immersed in the test solution, and the test solution above the cell was stirred with a paddle at a constant rotational speed. The test solution was collected at regular intervals, and the amount of butenafine hydrochloride contained therein was quantified by HPLC method (high performance liquid chromatography method) to calculate the release rate of butenafine hydrochloride from the cream.

  The obtained results are shown in Table 3 and FIGS. Table 3 shows the cumulative release rate (%) of butenafine hydrochloride at each elapsed time (hour). FIG. 1 is a graph showing the relationship between the elapsed time and the cumulative release rate (%) of butenafine hydrochloride. (A) is Comparative Example 1, (b) is Example 1, and (c) is Example 2. Show. FIG. 2 is a graph showing the relationship between the elapsed time and the amount of butenafine hydrochloride released per unit time (mg), where (a) shows Comparative Example 1 and (b) shows Example 1.

  In the cream of Comparative Example 1, 80% or more of butenafine hydrochloride in the formulation was released 2 hours after the start of the test, whereas in the cream of Example 1, only 40%, which is less than half of that, was released. (See Table 3). Moreover, in the cream of Example 1, drug release was confirmed even 6 hours after the start of the test (see FIG. 2).

  From this, it is considered that the sustained-release cream of the present invention can control the release of the drug from the preparation and has the characteristics as a sustained-release preparation.

  Moreover, since the cream of Comparative Example 1 is a preparation that is administered once a day, the cream of Example 1 is expected to be a preparation that exhibits a sufficient therapeutic effect once every two days. is there.

(Test Example 2)
By using a sensory test, the feelings of use of the cream of Example 3 and the cream of Comparative Example 2 were compared. Appropriate amounts of both creams were applied to the back of the hands of 20 subjects, and the usability was evaluated. There are five evaluation items: good spread, good burnishing, quick drying, low stickiness and overall taste. Answer which cream is preferred or comparable. I got it. The results are shown in Table 4.

  As is apparent from the results shown in Table 4, the cream of Example 3 is superior in use feeling compared to the cream of Comparative Example 2.

  As described above, it was confirmed that the sustained-release cream of the present invention has improved stickiness and extensibility, is excellent in feeling of use, and can release the active ingredient continuously for a long time.

  ADVANTAGE OF THE INVENTION According to this invention, stickiness and extensibility are improved, it is excellent in a usability | use_condition, and the sustained release cream which can release an active ingredient continuously for a long time is provided.

Claims (8)

  It contains 10 to 25% by mass of an oil phase based on the total amount of the formulation, and the content of the liquid fatty acid ester contained in the oil phase is 25 to 60% by mass based on the entire oil phase. Sustained release cream.   The sustained-release cream according to claim 1, wherein the liquid fatty acid ester is a saturated fatty acid monoester having 17 to 32 carbon atoms and / or a saturated dicarboxylic acid diester having 12 to 16 carbon atoms. Sustained release cream.   The sustained-release cream according to claim 1, wherein the liquid fatty acid ester is composed of isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl 2-ethylhexanoate, diisopropyl adipate and diethyl sebacate. A sustained-release cream comprising at least one compound selected from the group consisting of:   The sustained-release cream according to any one of claims 1 to 3, comprising an antifungal agent.   5. The sustained release cream according to claim 4, wherein the antifungal agent is a benzylamine compound, an imidazole compound or an allylamine compound.   5. The sustained-release cream according to claim 4, wherein the antifungal agent is butenafine hydrochloride.   The sustained-release cream according to claim 4, wherein the antifungal agent is neticonazole hydrochloride.   5. The sustained-release cream according to claim 4, wherein the antifungal agent is terbinafine hydrochloride.

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