JP2005320282A - Skin care preparation for external use for local anaesthesis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To enhance immediate effectiveness and durability of local-anaesthetic effect by enhancing skin permeability of an amide type local anaesthetic agent in a skin care preparation for external use containing the amide type local anaesthetic agent. <P>SOLUTION: This skin care preparation for external use is prepared by adding one or more kinds of nonionic surfactants, semisolid or liquid at room temperature, selected from the group consisting of fatty acid esters of glycerol, fatty acid esters of sorbitan, fatty acid esters of a polyglycerol, fatty acid esters of a polyoxyethylene glycerol and fatty acid esters of a polyethylene glycol with the amide type local anaesthetic agent, and bringing the same to an oil-based formulation. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an external preparation for skin containing a local anesthetic. More specifically, the present invention relates to a topical anesthetic-containing oily skin external preparation having a high skin permeability of a local anesthetic and excellent immediate effect and sustainability of the local anesthetic effect.

  Conventionally, injections of amide type local anesthetics such as lidocaine have been performed for local anesthesia in dermatological and dental surgery. Also, particularly in recent years, in various clinical settings, subcutaneous or intradermal injection of an amide type local anesthetic has been actively performed in order to relieve patients from pain. Amide-type local anesthetics can block nerve transmission at the site of application and relieve pain locally, and are expected to make a significant contribution to improving the quality of treatment for patients and facilitating medical treatment. Has been. However, since amide type local anesthetic injection is painful at the time of injection, improvement has been strongly demanded particularly in infants and the elderly.

  Therefore, as an alternative to conventional injections, various external preparations for local anesthesia such as creams, ointments, gels containing amide type local anesthetics have been proposed (for example, Patent Documents 1 to 3, And non-patent document 1). However, amide type local anesthetics have low skin permeability, and conventional topical anesthetic preparations have a problem that the local anesthetic effect disappears in a short time. Since amide type local anesthetics pass through the stratum corneum, which is a permeation barrier, and immediately enter the circulating blood, a high skin permeation rate is required to maintain the anesthetic effect in the skin region. Since the skin penetration rate of drugs generally depends on the concentration of the drug contained in the base, the skin permeation rate is very low, especially when the compounding concentration in the base of amide type local anesthetics is low, and application to the skin Due to this, a continuous anesthetic effect could not be obtained.

On the other hand, a patch containing a high concentration of local anesthetic is provided, and a certain level of anesthetic effect is obtained, but there are problems such as skin irritation and itching, and the treatment site is small or uneven. In some cases, it has been complicated to use in clinical settings, such as cutting off the patch according to the site, and requiring some ingenuity for application.
JP-A-8-259464 Japanese Patent Laid-Open No. 10-1441 Japanese Patent Application No. 2002-243722 Hospital Pharmacy Formulation, 2003, 5th edition, pages 186-188

   The present invention has been made in view of the above circumstances, and in an external preparation for skin containing an amide type local anesthetic, the skin permeability of the amide type local anesthetic is increased, and the immediate effect and sustainability of the local anesthetic effect is excellent. An object of the present invention is to provide an external preparation for skin.

  As a result of further intensive studies to solve the above problems, the present inventors have found that together with an amide type local anesthetic, glycerin fatty acid ester, sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkyl ether and When applied to the skin by blending a semi-solid or liquid nonionic surfactant selected from the group consisting of polyethylene glycol fatty acid esters at room temperature with a semi-solid or liquid nonionic surfactant, and further forming an oily preparation The inventors have found that the skin permeability of amide type local anesthetics is remarkably enhanced, and have completed the present invention.

  The external preparation for skin of the present invention is selected from the group consisting of an amide type local anesthetic and glycerin fatty acid ester, sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkyl ether and polyethylene glycol fatty acid ester It is an oil-based preparation containing one or more kinds of nonionic surfactants that are semi-solid or liquid at room temperature.

  The above-mentioned specific nonionic surfactants enhance the skin permeability of amide type local anesthetics when an oily topical preparation containing amide type local anesthetics is applied to the skin, as well as the usability and stability of oily formulations. Can be improved. Preferably, the nonionic surfactant is a polyoxyethylene alkyl ether having an alkyl group having 12 to 18 carbon atoms and an ethylene oxide addition mole number of 2 to 10.

  It is preferable that the compounding quantity of a nonionic surfactant is 0.5-20 mass% with respect to the total mass of a skin external preparation.

  Moreover, it is preferable that the compounding quantity of an amide type local anesthetic is 10-60 mass% with respect to the total mass of a skin external preparation.

  The oily skin external preparation of the present invention is preferably semi-solid or solid from the viewpoints of its usability and stability.

  The external preparation for skin of the present invention can provide higher amide-type local anesthetic skin permeability when applied to the skin, and is excellent in immediate effect and sustainability of the local anesthetic effect. It is also excellent in usability and stability.

  Hereinafter, the best mode for carrying out the present invention will be described in detail.

  The external preparation for skin of the present invention contains an amide type local anesthetic and a specific nonionic surfactant as essential components.

  Examples of the amide type local anesthetic used in the present invention include lidocaine, dibucaine, prilocaine, bupivacaine, ropivacaine, etidocaine, propitocaine, mepivacaine, oxesasein, ethyl piperidinoacetylaminobenzoate and the like. In the present invention, these amide type local anesthetics can be used alone or in combination of two or more. The blending amount of the amide type local anesthetic in the external preparation for skin of the present invention is not particularly limited, but is preferably 10 to 60% by mass, more preferably 20 to 40% by mass with respect to the total mass of the external preparation for skin. %. If it is less than 10% by mass, a sufficient local anesthetic effect may not be obtained when applied to the skin, and if it exceeds 60% by mass, the stability of the preparation may be deteriorated.

  The nonionic surfactant used in the present invention is selected from the group consisting of glycerin fatty acid ester, sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkyl ether and polyethylene glycol fatty acid ester, And it is semi-solid or liquid at room temperature (25 ° C.). Although not particularly limited, non-ionic surfactants that are semi-solid or liquid at room temperature that can be used in the external preparation for skin of the present invention are exemplified below.

  Examples of the glycerin fatty acid ester include glyceryl monooleate and glyceryl monoisostearate.

  Examples of the sorbitan fatty acid ester include sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monoisostearate, sorbitan sesquiisostearate, and the like.

  Examples of polyglycerol fatty acid esters include diglyceryl monooleate, diglyceryl dioleate, diglyceryl monoisostearate, tetraglyceryl monooleate, hexaglyceryl monooleate, decaglyceryl diisostearate, decaglyceryl trioleate, pentaisostearate Examples include decaglyceryl acid, decaglyceryl pentaoleate, decaglyceryl monooleate, decaglyceryl monoisostearate, and the like.

  Examples of the polyoxyethylene (hereinafter referred to as POE) glycerin fatty acid ester include POE hydrogenated castor oil, POE castor oil, POE glyceryl monooleate, and the like.

  Examples of the polyoxyethylene alkyl ether include POE lauryl ether, POE cetyl ether, POE stearyl ether, and POE oleyl ether.

  Examples of the polyethylene glycol (hereinafter referred to as PEG) fatty acid ester include PEG monostearate, PEG monooleate, PEG diisostearate, PEG monolaurate, and the like.

  In the external preparation for skin of the present invention, the above nonionic surfactants can be used alone or in combination of two or more. The blending amount of these nonionic surfactants in the external preparation for skin of the present invention is preferably 0.5 to 20% by mass, more preferably 1 to 10% by mass with respect to the total mass of the external preparation for skin. is there. If the amount is less than 0.5% by mass, sufficient amide-type local anesthetic permeability promoting effect may not be obtained, and even if the amount exceeds 20% by mass, the permeability promoting effect due to the increase in the amount of blended An increase cannot be obtained, and it is not preferable in terms of safety to the skin.

  The external preparation for skin of the present invention is an oily preparation. In the present specification, the term “oil-based preparation” or “oil-based external preparation for skin” means a preparation mainly composed of an oily component, and basically does not contain water. As long as the object of the present invention can be achieved, such as moisture that absorbs moisture, it may contain some moisture. However, from the viewpoint of the purpose of the present invention and the stability of the preparation, the water content is preferably 10% by mass or less, more preferably 5% by mass or less, more preferably 5% by mass or less, based on the total mass of the external preparation. Preferably it is 2 mass% or less.

  The oily base component used in the external preparation for skin of the present invention is not particularly limited as long as it can be incorporated into external preparations such as cosmetics, pharmaceuticals, and quasi drugs. For example, liquid oils such as liquid paraffin, squalane, solid paraffin, ceresin, squalene, petrolatum, microcrystalline wax, solid fats such as cacao butter, coconut oil, palm oil, hardened oil, beeswax, candelilla wax, cotton wax, carnauba wax, etc. Waxes, higher fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, higher alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, isopropyl myristate , Synthetic ester oils such as cetyl octoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, dimethylpolysiloxane Sun, methylphenyl polysiloxane, silicone oils such as diphenyl polysiloxane, olive oil, or the like can be used liquid oil rapeseed oil and the like in the skin external preparations of the present invention.

  In the external preparation for skin of the present invention, these oily base components can be used alone or in combination of two or more. The blending amount of these oily base components in the external preparation for skin of the present invention is appropriately determined according to the desired dosage form and the feeling of use when applied to the skin, and is not particularly limited, but preferably the external preparation for skin It is 20-80 mass% with respect to the total mass of.

  The external preparation for skin of the present invention is not particularly limited as long as it is an oily preparation, and includes any dosage form such as an oil liquid system, a paste system, an ointment system, etc. A shape or a solid form is preferred. A semi-solid or solid external preparation for skin can be prepared by appropriately adjusting the blending amount of the liquid oily base component. Although not particularly limited, the amount of the liquid oil base component in the external preparation for skin of the present invention is preferably 15 to 70% by mass, more preferably 30 to 60% by mass, based on the total mass of the external preparation for skin. It is. If it is less than 15% by mass, it may be difficult to appropriately dissolve or disperse the amide type local anesthetic in the external preparation for skin, and if it exceeds 70% by mass, the hardness becomes too low to be applied to the skin. It may fall down and become unusable.

  Furthermore, in addition to the above essential components, other optional components that are usually used in external preparations for skin such as cosmetics and pharmaceuticals can be added to the external preparation for skin according to the present invention as long as the effects of the present invention are not impaired. It can mix | blend suitably. For example, refreshing agents, antioxidants, chelating agents, powders, preservatives, thickeners, colorants, fragrances and the like can be appropriately blended in the external preparation for skin of the present invention. Further, the external preparation for skin of the present invention further contains, in addition to the specific nonionic surfactant described above, any surfactant that is usually used in external preparations for skin unless the effects of the present invention are impaired. Good. Furthermore, the external preparation for skin of the present invention may contain any other component having a local anesthetic effect in addition to the amide type local anesthetic.

  The method for producing the external preparation for skin of the present invention is not particularly limited. For example, an amide-type local anesthetic and a nonionic surfactant are added to a heat-dissolved oily base component and mixed and dissolved or dispersed by a stirring mixer. It can be prepared by cooling.

  The external preparation for skin of the present invention is an external preparation for local anesthesia, for example, pain relief during laser treatment, blood collection, vein cannulation, injection, neuropathic pain such as postherpetic neuralgia, trigeminal neuralgia, etc. It can be used in any application such as relief of pain, soreness, rash, cuts, abrasions, etc., and pain relief and itching.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to the following Example. Lidocaine was used as an amide type local anesthetic. In addition, all compounding quantities are represented by the mass% with respect to the formulation whole quantity.

Skin permeability test The skin permeability of lidocaine in each preparation was measured by a skin permeability test using in vitro rat abdominal hair removal skin. The method is as follows:
(Method)
Six- to seven-week-old male rats (SPF) (CD (SD) IGS system, Nippon Charles River Co., Ltd.) were euthanized by ether anesthesia, and then the abdomen was shaved with an electric clipper and the skin was removed. This was attached to a ^two -chamber type Franz type diffusion cell (effective transmission area 3.14 cm ² , receptor side volume 17 mL) so that the stratum corneum is on the upper surface. Apply 50 mg of the test preparation uniformly on the donor side (keratin layer side), use phosphate buffer (pH 7.4) as the receptor side (dermis side) solution, and perfuse 37 ° C water into the diffusion cell chamber. By doing so, the skin surface temperature was kept at 30 ° C. The receptor solution was stirred with a magnetic stirrer, and 1 mL was sampled every 2 hours until the 10th hour. The lidocaine concentration in the sampled receptor solution was measured using high performance liquid chromatography. The cumulative value of lidocaine permeation from the lidocaine concentration to the receptor was calculated, the cumulative value was plotted against time, and the steady-state permeation rate (μg / cm ² / hr) was calculated from the slope of the straight line portion. . The results were expressed as mean ± SD (n = 3).

図１に結果を示す。本発明の、常温で半固形状または液状の特定の非イオン性界面活性剤をリドカインと共に含有する実施例１から１８の製剤は、非イオン性界面活性剤を含有しない比較例１の製剤と比較して、顕著に高いリドカインの皮膚透過速度をもたらした。特に、アルキル基の炭素数が１２〜１８で、エチレンオキシド付加モル数が２〜１０のポリオキシエチレンアルキルエーテルを含有する実施例９から１４において、リドカインの皮膚透過速度が高かった。一方、常温で固形状の非イオン性界面活性剤（モノステアリン酸グリセリル、モノステアリン酸ソルビタン、ＰＯＥ（５）ベヘニルエーテル）を含有する比較例２から４の製剤では、リドカインの皮膚透過速度は、非イオン性界面活性剤を含有しない比較例１と同程度かむしろ低かった。 Examination of nonionic surfactants External preparations containing various nonionic surfactants of Examples 1 to 18 and Comparative Examples 2 to 4 having the composition shown in Table 1-1 and Table 1-2, and The external preparation of Comparative Example 1 containing no ionic surfactant was prepared, and the skin permeation rate of lidocaine in each preparation was measured by the skin permeability test described above.

The results are shown in FIG. The preparations of Examples 1 to 18 containing a specific nonionic surfactant that is semi-solid or liquid at room temperature together with lidocaine of the present invention are compared with the preparation of Comparative Example 1 that does not contain a nonionic surfactant. Resulted in a significantly higher lidocaine skin permeation rate. In particular, in Examples 9 to 14 containing polyoxyethylene alkyl ether having an alkyl group having 12 to 18 carbon atoms and 2 to 10 ethylene oxide addition moles, the skin permeation rate of lidocaine was high. On the other hand, in the preparations of Comparative Examples 2 to 4 containing a solid nonionic surfactant (glyceryl monostearate, sorbitan monostearate, POE (5) behenyl ether) at room temperature, the skin permeation rate of lidocaine is It was comparable or rather low as in Comparative Example 1 containing no nonionic surfactant.

Examination of blending amount of nonionic surfactant Using POE (2) oleyl ether as a nonionic surfactant, the influence of the blending amount on the skin permeability of lidocaine was examined. Each formulation containing each amount of POE (2) oleyl ether was prepared with the formulation shown in Table 2, and the skin permeation rate of lidocaine in each formulation was measured by the skin permeability test described above.

  The results are shown in FIG. In Examples 19, 20, 12 and 21 containing POE (2) oleyl ether in a blending amount of 0.5 to 20% by mass, compared with Comparative Example 1 containing no nonionic surfactant, Skin penetration rate was high. In particular, in Examples 20, 12, and 21 containing 1% by mass or more of POE (2) oleyl ether, the skin permeation rate of lidocaine was remarkably high.

Examination of the amount of amide type local anesthetic compounded Lidocaine was used as an amide type local anesthetic agent, and the effect of the compounded amount on the skin permeability was examined. In Examples 22 to 29, POE (2) oleyl ether was used as a nonionic surfactant, and in Comparative Examples 5 to 9, glyceryl monostearate was used as a nonionic surfactant. Each formulation containing each amount of lidocaine with the formulation shown in Table 3 was prepared, and the skin permeation rate of lidocaine in each formulation was measured by the skin permeability test described above.

  The results are shown in FIG. In Examples 22 to 29 containing POE (2) oleyl ether as a nonionic surfactant, a high lidocaine skin permeation rate was observed at a blending amount of 20-60 mass% lidocaine. On the other hand, in Comparative Examples 5 to 9 containing solid glyceryl monostearate as a nonionic surfactant, the skin permeation rate of lidocaine was low at any measured lidocaine content.

Graph showing the skin permeation rate of lidocaine in external preparations containing various nonionic surfactants The graph which shows the skin permeation | transmission speed | rate of lidocaine in the external preparation containing POE (2) oleyl ether of each compounding quantity. Graph showing the skin permeation rate of lidocaine in an external preparation containing each amount of lidocaine

Claims (5)

Amide type local anesthetic and one or more selected from the group consisting of glycerin fatty acid ester, sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkyl ether and polyethylene glycol fatty acid ester An oily external preparation for skin containing a non-solid surfactant that is semi-solid or liquid at room temperature. The oily skin external application according to claim 1, wherein the nonionic surfactant is a polyoxyethylene alkyl ether having 12 to 18 carbon atoms in the alkyl group and 2 to 10 moles of ethylene oxide added. Formulation. The oily external preparation for skin according to claim 1 or 2, wherein the blending amount of the nonionic surfactant is 0.5 to 20% by mass with respect to the total mass of the external preparation for skin. The oily skin external preparation according to any one of claims 1 to 3, wherein the amount of the amide type local anesthetic is 10 to 60% by mass based on the total mass of the external preparation for skin. The oily skin external preparation according to any one of claims 1 to 4, which is semi-solid or solid.

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