WO2005107733A1 - Dermatological external preparation for local anesthesia - Google Patents
Dermatological external preparation for local anesthesia Download PDFInfo
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- WO2005107733A1 WO2005107733A1 PCT/JP2005/008383 JP2005008383W WO2005107733A1 WO 2005107733 A1 WO2005107733 A1 WO 2005107733A1 JP 2005008383 W JP2005008383 W JP 2005008383W WO 2005107733 A1 WO2005107733 A1 WO 2005107733A1
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- skin
- fatty acid
- external preparation
- acid ester
- local anesthetic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Definitions
- the present invention relates to an external preparation for skin containing a local anesthetic. More specifically, the present invention relates to an oil-based external preparation containing a local anesthetic, which has a high skin permeability of a local anesthetic, and is excellent in immediate effect and sustainability of a local anesthetic effect.
- amide-type local anesthetic such as lidocaine
- injection of an amide-type local anesthetic has been performed for local anesthesia.
- subcutaneous or intradermal injections of amide-type local anesthetics have been actively performed to relieve patients of pain.
- Amide-type local anesthetics can block nerve transmission at the application site and locally relieve pain, and are expected to make a significant contribution to improving the quality of life for patients and facilitating medical treatment.
- injection of an amide-type local anesthetic is painful at the time of injection, and there has been a strong demand for improvement, especially in infants and the elderly.
- the amide-type local anesthetic passes into the stratum corneum, which is a barrier for permeation, it is immediately transferred to the circulating blood. Therefore, a high skin penetration rate is required to maintain the anesthetic effect at the local skin.
- the penetration rate of a drug into the skin depends on the concentration of the drug contained in the base.Therefore, especially when the concentration of the amide type local anesthetic in the base is low, the skin penetration rate is extremely low, and Is it possible to obtain a persistent anesthetic effect by application? I got it.
- a patch containing a high concentration of a local anesthetic is provided, and the power to obtain an anesthesia effect of a certain cereal ⁇ If there is a problem such as skin irritation or itching, or if the treatment site is small When there is unevenness or unevenness, the patch has to be cut off according to the site, and the patch needs to be devised.
- the present invention has been made in view of the above circumstances, and in a skin external preparation containing an amide-type local anesthetic, the skin sensitivity of the amide-type local anesthetic is enhanced, thereby improving the immediate effect of the local anesthetic effect. It is intended to provide an excellent preparation for external use on the skin. Disclosure of the invention
- glycerin fatty acid ester sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxetylene glycerin fatty acid ester, and polyoxyethylene were used together with the amide type local anesthetic.
- Apply to skin by blending one or more nonionic surfactants at room temperature, which are semi-solid or liquid, selected from the group consisting of alkyl ethers and polyethylene glycol fatty acid esters In doing so, they found that the skin permeability of the amide-type local anesthetic was significantly increased, and completed the present invention.
- the external preparation for skin of the present invention comprises a amide type local anesthetic and a group consisting of glycerin fatty acid ester, sonolebitan fatty acid ester, polyglycerin fatty acid ester, polyoxetylene glycerin fatty acid ester, polyoxyethylene alkyl ether and polyethylene dalicol fatty acid ester. It is characterized by being an oily preparation containing one or two or more selected non-ionic surfactants which are semi-solid or liquid at normal temperature.
- the specific nonionic surfactant mentioned above enhances the skin permeability of the amide-type local anesthetic when applied to the skin with an oil-based external preparation containing the amide-type local anesthetic, and improves the usability of the oil-based preparation.
- the stability can be improved.
- the nonionic surfactant has 12 to 18 carbon atoms in the alkyl group and has a calorie with ethylene oxide. It is a polyoxyethylene alkyl ether having a monole number of 2 to 10.
- the compounding amount of the nonionic surfactant is 0.5 to 20 mass based on the total mass of the external preparation for skin. / 0 is preferred.
- the amount of the amide-type local anesthetics is preferably 1 0-6 0 weight 0/0 relative to the total weight of the external skin preparation.
- the oily topical skin preparation of the present invention is preferably semi-solid or solid from the viewpoint of its usability and stability.
- the external preparation for skin of the present invention can provide higher skin permeability of an amide-type local anesthetic 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.
- FIG. 1 is a graph showing the skin permeation rate of lidocaine in an external preparation containing various nonionic surfactants.
- FIG. 2 is a graph showing the skin permeation rate of lidocaine in an external preparation containing POE (2) oleyl ether at each blending amount.
- FIG. 3 is a graph showing the skin permeation rate of lidocaine in an external preparation containing lidocaine at each blending amount.
- the external preparation for skin of the present invention contains an amide type local anesthetic and a specific nonionic surfactant as essential components.
- amide-type local anesthetic used in the present invention examples include, for example, lidocaine, jib force-in, prilocaine, bupiva force-in, oral viva force-in, etide force-in, propitocaine, mepipa force-in, oxesasein, piberidinoacetyla. Ethyl minobenzoate and the like.
- these amide-type local anesthetics can be used alone or in combination of two or more.
- the amount of the amide-type local anesthetic in the external preparation for skin of the present invention is not particularly limited.
- 1 0-6 is preferably 0 mass 0/0 relative to the total weight, more preferably 2 0-4 0 wt% Dearu. If the amount is less than 10% by mass, sufficient local anesthetic effect may not be obtained when applied to the skin, and if the amount exceeds 60% by mass, the stability of the preparation may be deteriorated.
- the nonionic surfactant used in the present invention may be selected from glycerin fatty acid ester, sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkynoleether, and polyethylene glycol fatty acid ester. Selected from the group consisting of
- non-ionic surfactants which are semisolid or liquid at normal temperature and which can be used in the external preparation for skin of the present invention are exemplified below.
- glycerin fatty acid ester examples include glyceryl monooleate and glyceryl monodistearate.
- sorbitan fatty acid ester examples include sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sonorebitan monoisostearate, and sorbitan sesquiisostearate.
- polyglycerin fatty acid ester examples include diglyceryl monooleate, diglyceryl dioleate, diglyceryl monoisostearate, tetraglyceryl monooleate, hexaglyceryl monooleate, decaglyceryl disostearate, deglyceryl trioleate, Examples include depot glycerinol pentaisostearate, decaglyceryl pentaoleate, decaglyceryl monooleate, and decaglyceryl monoisostearate.
- Polyoxyethylene (hereinafter, POE) glycerin fatty acid esters include, for example, POE hydrogenated castor oil, POE castor oil, POE glyceryl monooleate, and the like.
- polyoxyethylene alkyl ether examples include POE lauryl ether, POE cetino ole ether, POE stealin ole ether, POE olein ole ether, and the like.
- Polyethylene glycol (hereinafter, PEG) fatty acid esters include, for example, PEG monostearate, PEG monooleate, PEG diisostearate, PEG monolaurate, and the like.
- the above-mentioned nonionic surfactants can be used alone or in combination of two or more.
- the compounding 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 1% by mass, based on the total mass of the external preparation for skin. 0 mass. / 0 . If the amount is less than 0.5% by mass, a sufficient effect of enhancing the permeability of the amide-type local anesthetic may not be obtained, and if the amount exceeds 20% by mass, the permeability is enhanced by increasing the amount of the compounding agent. No increase in effect is obtained, and it is not preferable in terms of safety on the skin.
- the external preparation for skin of the present invention is an oily preparation.
- oil-based preparation or "oil-based external preparation for skin” means a preparation containing an oil-based component as a main base and basically does not contain water. Some moisture may be contained as long as the object of the present invention can be achieved, such as moisture absorbed in the process.
- the water content is preferably 10% by mass or less, more preferably 5% by mass or less, based on the total mass of the external preparation. Yes, more preferably 2% by 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 blended with an external preparation such as cosmetics, pharmaceuticals, and quasi-drugs.
- an external preparation such as cosmetics, pharmaceuticals, and quasi-drugs.
- Kisir Millis Synthetic ester oils such as phosphate myristyl, dimethylpolysiloxane, methylol Roh reflex Eni Honoré polysiloxane, Jifue - Honoré polysiloxane of sheet Liquid fats and oils such as corn oil, olive oil and rapeseed oil can be used in the external preparation for skin of the present invention.
- Synthetic ester oils such as phosphate myristyl, dimethylpolysiloxane, methylol Roh reflex Eni Honoré polysiloxane, Jifue - Honoré polysiloxane of sheet Liquid fats and oils such as corn oil, olive oil and rapeseed oil can be used 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 amount of these oily base components in the external preparation for skin of the present invention is appropriately determined depending on the desired dosage form, the feeling of use when applied to the skin, and the like, and is not particularly limited. It is 20 to 80% by mass relative to the total mass of the preparation.
- the formulation for external use on the skin of the present invention is not particularly limited as long as it is an oily formulation, and includes any formulation such as an oil-liquid system, a paste system, and an ointment system. It is preferably in the form or a solid.
- a semi-solid or solid external preparation for skin can be prepared.
- the compounding amount of the liquid oily base component in the external preparation for skin of the present invention is preferably 15 to 70% by mass, more preferably 30 to 70% by mass, based on the total mass of the external preparation for skin. 6 0 mass 0/0.
- the amount is less than 15% by mass, it may be difficult to appropriately dissolve or disperse the topical anesthetic in a topical skin preparation. If the amount exceeds 70% by mass, the hardness may be too low, May drop when applied to skin, causing poor usability.
- the external preparation for skin of the present invention may contain, in addition to the above specific nonionic surfactant, any surfactant usually used in external preparations for skin, as long as the effects of the present invention are not impaired.
- the external preparation for skin of the present invention may contain, in addition to the amide-type local anesthetic, other optional components having a local anesthetic effect.
- the method for preparing the external preparation for skin of the present invention is not particularly limited.
- an amide-type local anesthetic and a nonionic surfactant are added to a heat-soluble oily base component, and the mixture is dissolved or dispersed by a stirring mixer. And cooled.
- the topical skin preparation of the present invention may be used as a topical preparation for local anesthesia such as, for example, laser treatment, blood sampling, intravenous power injection, pain relief at the time of injection, post-herpetic neuralgia, trigeminal neuralgia, etc. It can be used for any purpose such as relieving causal pain, relieving pain and itch at skin wound sites such as soreness, rash, cuts and abrasions.
- lidocaine was used as an amide-type local anesthetic.
- all the compounding amounts are represented by mass% with respect to the total amount of the preparation.
- the skin permeability of lidocaine in each preparation was measured by a skin permeability test using an abdominal depilated and excised skin of inVitro rats.
- the method is as follows: (Method)
- the receptor solution was stirred with a magnetic stirrer, and sampled in lmL every 2 hours until 10 hours later.
- FIG. 1 shows the results.
- the preparations of Examples 1 to 18 of the present invention containing a specific nonionic surfactant which is semisolid or liquid at normal temperature together with lidocaine are the same as the preparation of Comparative Example 1 containing no nonionic surfactant. In comparison, it resulted in significantly higher lidocaine skin penetration rates.
- Examples 9 to 14 containing a polyoxyethylene alkynoleether having an alkyl group having 12 to 18 carbon atoms and an ethylene oxide addition mole number of 2 to 10 lidocaine skin The transmission speed was high.
- Comparative Examples 2 to 4 containing nonionic surfactants (glyceryl monostearate, sorbitan monostearate, and POE (5) behe-leatenole) which are solid at room temperature showed that lidocaine permeated the skin through lidocaine.
- the rates were comparable or rather low as in Comparative Example 1, which contained no nonionic surfactant.
- POE Polyoxyethylene (The number in the box is the number of monocles with ethylene oxide.) The result is shown in figure 2. Compared with the formulation containing no nonionic surfactant, the skin permeation rate of lidocaine was significantly higher in the formulation containing 0.5 to 20% by mass of POE (2) oleyl ether. Was. In particular, in formulations containing 1% by mass or more of POE (2) oleyl ether, the skin permeation rate of lidocaine was remarkably high.
- lidocaine as an amide-type local anesthetic, the effect of the compounding amount on its skin permeability was examined.
- POE (2) oleinole ether was used as the nonionic surfactant
- glycerinole monostearate was used as the nonionic surfactant.
- Formulations containing the respective amounts of lidocaine were prepared according to the formulation shown in Table 3 below, and the skin permeation rate of lidocaine in each formulation was measured by the skin permeability test described above.
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Abstract
Description
m 糸田 局所麻酔用皮膚外用製剤 技術分野 m Itoda Skin preparation for local anesthesia Technical field
本発明は、 局所麻酔薬を含有する皮膚外用製剤に関する。 より詳細には、 局所 麻酔薬の皮膚透過性が高く、 局所麻酔効果の即効性および持続性に優れた、 局所 麻酔薬含有油性皮膚外用製剤に関する。 背景技術 The present invention relates to an external preparation for skin containing a local anesthetic. More specifically, the present invention relates to an oil-based external preparation containing a local anesthetic, which has a high skin permeability of a local anesthetic, and is excellent in immediate effect and sustainability of a local anesthetic effect. Background art
従来から、 皮膚科や歯科での手術において、 局所麻酔のためにリドカイン等の アミド型局所麻酔薬の注射が行われている。 また、 特に近年、 様々な臨床現場に おいて、 患者を痛みから解放するために、 アミド型局所麻酔薬の皮下または皮内 注射が積極的に行われるようになってきた。 アミド型局所麻酔薬は、 適用部位で 神経伝達を遮断して、 局所的に疼痛を緩和させることができ、 患者の治療生活の 質の改善や、 医療処置の円滑化に大きな貢献をもたらすと期待されている。 しか しながら、 アミド型局所麻酔薬の注射は、 注射時に痛みを伴うため、 特に幼児や 高齢者においてその改善が強く求められていた。 Conventionally, in dermatology and dental operations, injection of an amide-type local anesthetic such as lidocaine has been performed for local anesthesia. In recent years, especially in various clinical settings, subcutaneous or intradermal injections of amide-type local anesthetics have been actively performed to relieve patients of pain. Amide-type local anesthetics can block nerve transmission at the application site and locally relieve pain, and are expected to make a significant contribution to improving the quality of life for patients and facilitating medical treatment. Have been. However, injection of an amide-type local anesthetic is painful at the time of injection, and there has been a strong demand for improvement, especially in infants and the elderly.
そこで、 従来の注射剤に代わるものとして、 アミド型局所麻酔薬を含有するク リーム剤、 軟膏剤、 ゲル剤等の様々な局所麻酔用外用製剤が提案されている （例 えば、 特開平 8 _ 2 5 9 4 6 4号公報、 特開平 1 0— 1 4 4 1号公報、 特開 2 0 0 4— 8 3 4 3 7号公報、 および病院薬局製剤、 2 0 0 3年、 第 5版、 1 8 6— 1 8 8頁を参照)。 しかしながら、アミド型局所麻酔薬は皮膚透過性が低く、従来 の局所麻酔用外用製剤では、 局所麻酔効果が短時間で消失するという問題があつ た。 アミド型局所麻酔薬は透過の障壁である角質層を通過後、 直ちに循環血中に 移行するため、 皮膚局所における麻酔効果の持続のためには高レヽ皮膚透過速度が 必要とされる。 一般に薬剤の皮膚透過速度は基剤中に含まれる薬剤の濃度に依存 するため、 特にアミド型局所麻酔薬の基剤中の配合濃度が低い場合に皮膚透過速 度が非常に低く、 皮膚への適用によって持続的な麻酔効果を得ることができなか つた。 Therefore, various external preparations for local anesthesia, such as creams, ointments, and gels, containing amide-type local anesthetics have been proposed as alternatives to conventional injections (for example, see JP-A-8_ Japanese Patent Application Laid-Open No. 2005-6464, Japanese Patent Laid-Open No. Hei 10-1441, Japanese Patent Laid-open No. 2004-834337, and Hospital Pharmacy Preparations, 2003, 5th edition 186-188). However, the amide type local anesthetic has low skin permeability, and the conventional topical preparation for local anesthesia has a problem that the local anesthetic effect disappears in a short time. Since the amide-type local anesthetic passes into the stratum corneum, which is a barrier for permeation, it is immediately transferred to the circulating blood. Therefore, a high skin penetration rate is required to maintain the anesthetic effect at the local skin. In general, the penetration rate of a drug into the skin depends on the concentration of the drug contained in the base.Therefore, especially when the concentration of the amide type local anesthetic in the base is low, the skin penetration rate is extremely low, and Is it possible to obtain a persistent anesthetic effect by application? I got it.
一方、 高濃度の局所麻酔薬を含有した貼付剤が提供されており、 ある禾^^の麻 酔効果が得られている力 皮膚のかぶれや痒み等の問題があり、 また治療部位が 小さい場合や凹凸がある場合に、 貼付剤を部位にあわせて切取ったり、 また貼付 けに工夫を要する等、 臨床現場での使用時の煩雑さがあった。 On the other hand, a patch containing a high concentration of a local anesthetic is provided, and the power to obtain an anesthesia effect of a certain cereal ^^ If there is a problem such as skin irritation or itching, or if the treatment site is small When there is unevenness or unevenness, the patch has to be cut off according to the site, and the patch needs to be devised.
本発明は上記事情に鑑みなされたものであり、 アミド型局所麻酔薬を含有する 皮膚外用製剤においてアミド型局所麻酔薬の皮膚 過性を高めて、 局所麻酔効果 の即効性おょぴ持続性に優れた皮膚外用製剤を提供することを目的とするもので ある。 発明の開示 The present invention has been made in view of the above circumstances, and in a skin external preparation containing an amide-type local anesthetic, the skin sensitivity of the amide-type local anesthetic is enhanced, thereby improving the immediate effect of the local anesthetic effect. It is intended to provide an excellent preparation for external use on the skin. Disclosure of the invention
本発明者らは上記課題を解決するためさらに鋭意検討した結果、 アミド型局所 麻酔薬と共に、 グリセリン脂肪酸エステル、 ソルビタン脂肪酸エステル、 ポリグ リセリン脂肪酸エステル、 ポリォキシェチレングリセリン脂肪酸エステル、 ポリ ォキシエチレンアルキルエーテルおよびポリエチレングリコール脂肪酸エステル より成る群から選択される 1種または 2種以上の常温で半固形状または液状の非 イオン性界面活性剤を配合し、 さらに油性製剤にすることによって、 皮膚に適用 した際にアミド型局所麻酔薬の皮膚透過性が顕著に高められることを見出し、 本 発明を完成するに至った。 The present inventors have conducted further intensive studies to solve the above-mentioned problems. As a result, glycerin fatty acid ester, sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxetylene glycerin fatty acid ester, and polyoxyethylene were used together with the amide type local anesthetic. Apply to skin by blending one or more nonionic surfactants at room temperature, which are semi-solid or liquid, selected from the group consisting of alkyl ethers and polyethylene glycol fatty acid esters In doing so, they found that the skin permeability of the amide-type local anesthetic was significantly increased, and completed the present invention.
本発明の皮膚外用製剤は、アミド型局所麻酔薬と、グリセリン脂肪酸エステル、 ソノレビタン脂肪酸エステル、 ポリグリセリン脂肪酸エステル、 ポリォキシェチレ ングリセリン脂肪酸エステル、 ポリオキシエチレンアルキルエーテルおよびポリ エチレンダリコール脂肪酸エステルより成る群から選択される 1種または 2種以 上の常温で半固形状または液状の非ィオン性界面活性剤とを含有する油性製剤で あることを特徴とする。 The external preparation for skin of the present invention comprises a amide type local anesthetic and a group consisting of glycerin fatty acid ester, sonolebitan fatty acid ester, polyglycerin fatty acid ester, polyoxetylene glycerin fatty acid ester, polyoxyethylene alkyl ether and polyethylene dalicol fatty acid ester. It is characterized by being an oily preparation containing one or two or more selected non-ionic surfactants which are semi-solid or liquid at normal temperature.
上記の特定の非イオン性界面活性剤は、 アミド型局所麻酔薬を含有する油性外 用製剤を皮膚に適用したときにアミド型局所麻酔薬の皮膚透過性を高めると共に、 油性製剤の使用性おょぴ安定性を向上させることができる。 好ましくは、 非ィォ ン性界面活性剤は、 アルキル基の炭素数が 1 2〜 1 8で、 エチレンォキシド付カロ モノレ数が 2〜 1 0のポリオキシエチレンアルキルエーテルである。 The specific nonionic surfactant mentioned above enhances the skin permeability of the amide-type local anesthetic when applied to the skin with an oil-based external preparation containing the amide-type local anesthetic, and improves the usability of the oil-based preparation. The stability can be improved. Preferably, the nonionic surfactant has 12 to 18 carbon atoms in the alkyl group and has a calorie with ethylene oxide. It is a polyoxyethylene alkyl ether having a monole number of 2 to 10.
非イオン性界面活性剤の配合量は、 皮膚外用製剤の全質量に対して 0 . 5〜2 0質量。 /0であることが好ましい。 The compounding amount of the nonionic surfactant is 0.5 to 20 mass based on the total mass of the external preparation for skin. / 0 is preferred.
また、 アミド型局所麻酔薬の配合量は、 皮膚外用製剤の全質量に対して 1 0〜 6 0質量0 /0であることが好ましい。 The amount of the amide-type local anesthetics is preferably 1 0-6 0 weight 0/0 relative to the total weight of the external skin preparation.
本発明の油性皮膚外用製剤は、 その使用性および安定性の観点から、 半固形状 または固形状であることが好ましい。 The oily topical skin preparation of the present invention is preferably semi-solid or solid from the viewpoint of its usability and stability.
本発明の皮膚外用製剤は、 皮膚に適用した際により高いアミド型局所麻酔薬の 皮膚透過性をもたらすことができ、 局所麻酔効果の即効性および持続性に優れて いる。 また、 使用性および安定性にも優れている。 図面の簡単な説明 The external preparation for skin of the present invention can provide higher skin permeability of an amide-type local anesthetic 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. Brief Description of Drawings
図 1は、 各種非イオン性界面活性剤を含有する外用製剤におけるリドカインの 皮膚透過速度を示すグラフである。 FIG. 1 is a graph showing the skin permeation rate of lidocaine in an external preparation containing various nonionic surfactants.
図 2は、 各配合量で P O E ( 2 ) ォレイルエーテルを含有する外用製剤におけ るリ ドカインの皮膚透過速度を示すグラフである。 FIG. 2 is a graph showing the skin permeation rate of lidocaine in an external preparation containing POE (2) oleyl ether at each blending amount.
図 3は、 各配合量でリドカインを含有する外用製剤におけるリドカインの皮膚 透過速度を示すグラフである。 発明を実施するための最良の形態 FIG. 3 is a graph showing the skin permeation rate of lidocaine in an external preparation containing lidocaine at each blending amount. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 本発明を実施するための最良の形態について詳述する。 Hereinafter, the best mode for carrying out the present invention will be described in detail.
本発明の皮膚外用製剤は、 アミド型局所麻酔薬と、 特定の非イオン性界面活性 剤とを必須成分として含有する。 The external preparation for skin of the present invention contains an amide type local anesthetic and a specific nonionic surfactant as essential components.
本発明において用いられるアミド型局所麻酔薬としては、例えば、リドカイン、 ジブ力イン、 プリロカイン、 ブピバ力イン、 口ビバ力イン、 ェチド力イン、 プロ ピトカイン、 メピパ力イン、 ォキセサゼイン、 ピベリジノアセチルァミノ安息香 酸ェチル等が挙げられる。 本究明において、 それらアミド型局所麻酔薬を 1種単 独で、 または 2種以上を組合せて用いることができる。 本発明の皮膚外用製剤に おけるアミド型局所麻酔薬の配合量は、 特に限定はされないが、 皮膚外用製剤の 全質量に対して 1 0〜6 0質量0 /0であることが好ましく、 より好ましくは 2 0〜 4 0質量％でぁる。 1 0質量％未満では、 皮膚に適用した際に十分な局所麻酔効 果が得られない場合があり、 また 6 0質量％を超えて配合すると、 製剤の安定性 が悪くなる場合がある。 Examples of the amide-type local anesthetic used in the present invention include, for example, lidocaine, jib force-in, prilocaine, bupiva force-in, oral viva force-in, etide force-in, propitocaine, mepipa force-in, oxesasein, piberidinoacetyla. Ethyl minobenzoate and the like. In this study, these amide-type local anesthetics can be used alone or in combination of two or more. The amount of the amide-type local anesthetic in the external preparation for skin of the present invention is not particularly limited. 1 0-6 is preferably 0 mass 0/0 relative to the total weight, more preferably 2 0-4 0 wt% Dearu. If the amount is less than 10% by mass, sufficient local anesthetic effect may not be obtained when applied to the skin, and if the amount exceeds 60% by mass, the stability of the preparation may be deteriorated.
本発明において用いられる非イオン性界面活性剤は、 グリセリン脂肪酸エステ ル、 ソルビタン脂肪酸エステル、 ポリグリセリン脂肪酸エステル、 ポリオキシェ チレングリセリン脂肪酸エステル、 ポリォキシエチレンアルキノレエ一テルおょぴ ポリエチレングリコール脂肪酸エステルより成る群から選択され、 かつ常温 ( 2 The nonionic surfactant used in the present invention may be selected from glycerin fatty acid ester, sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkynoleether, and polyethylene glycol fatty acid ester. Selected from the group consisting of
5 °C) で半固形状または液状のものである。 特に限定はされないが、 本発明の皮 膚外用製剤において用いることができる常温で半固形状または液状の非イオン性 界面活性剤を以下に例示する。 It is semisolid or liquid at 5 ° C). Although not particularly limited, non-ionic surfactants which are semisolid or liquid at normal temperature and which can be used in the external preparation for skin of the present invention are exemplified below.
グリセリン脂肪酸エステルとして、 例えば、 モノォレイン酸グリセリル、 モノ ィソステアリン酸グリセリル等が挙げられる。 Examples of the glycerin fatty acid ester include glyceryl monooleate and glyceryl monodistearate.
ソルビタン脂肪酸エステルとして、 例えば、 モノラウリン酸ソルビタン、 モノ ォレイン酸ソルビタン、 セスキォレイン酸ソルビタン、 トリオレイン酸ソルビタ ン、 モノイソステアリン酸ソノレビタン、 セスキイソステアリン酸ソルビタン等が 挙げられる。 Examples of the sorbitan fatty acid ester include sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sonorebitan monoisostearate, and sorbitan sesquiisostearate.
ポリグリセリン脂肪酸エステルとして、例えば、モノォレイン酸ジグリセリル、 ジォレイン酸ジグリセリル、 モノイソステアリン酸ジグリセリル、 モノォレイン 酸テトラグリセリル、 モノォレイン酸へキサグリセリル、 ジィソステアリン酸デ カグリセリル、 トリオレイン酸デ力グリセリル、 ペンタイソステアリン酸デ力グ リセリノレ、 ペンタォレイン酸デカグリセリル、 モノォレイン酸デカグリセリル、 モノイソステアリン酸デカグリセリル等が挙げられる。 Examples of the polyglycerin fatty acid ester include diglyceryl monooleate, diglyceryl dioleate, diglyceryl monoisostearate, tetraglyceryl monooleate, hexaglyceryl monooleate, decaglyceryl disostearate, deglyceryl trioleate, Examples include depot glycerinol pentaisostearate, decaglyceryl pentaoleate, decaglyceryl monooleate, and decaglyceryl monoisostearate.
ポリオキシエチレン （以下、 P O E) グリセリン脂肪酸エステルとして、 例え ば、 P O E硬化ヒマシ油、 P O Eヒマシ油、 モノォレイン酸 P O Eグリセリル等 が挙げられる。 Polyoxyethylene (hereinafter, POE) glycerin fatty acid esters include, for example, POE hydrogenated castor oil, POE castor oil, POE glyceryl monooleate, and the like.
ポリオキシエチレンアルキルエーテルとして、 例えば、 P O Eラウリルエーテ ノレ、 P O Eセチノレエーテノレ、 P O Eステアリノレエーテノレ、 P O Eォレイノレエーテ ル等が挙げられる。 ポリエチレングリコール （以下、 P E G) 脂肪酸エステルとして、 例えば、 モ ノステアリン酸 P E G、 モノォレイン酸 P E G、 ジイソステアリン酸 P E G、 モ ノラウリン酸 P E G等が挙げられる。 Examples of the polyoxyethylene alkyl ether include POE lauryl ether, POE cetino ole ether, POE stealin ole ether, POE olein ole ether, and the like. Polyethylene glycol (hereinafter, PEG) fatty acid esters include, for example, PEG monostearate, PEG monooleate, PEG diisostearate, PEG monolaurate, and the like.
本発明の皮膚外用製剤において、 上記のような非イオン性界面活性剤を 1種単 独で、 または 2種以上を組合せて用いることができる。 本発明の皮膚外用製剤に おけるこれら非ィォン性界面活性剤の配合量は、皮膚外用製剤の全質量に対して、 好ましくは 0 . 5〜2 0質量％でぁり、 より好ましくは 1〜1 0質量。 /0である。 0 . 5質量％未満では、 十分なアミド型局所麻酔薬の透過性促進効果が得られな い場合があり、 また 2 0質量％を超えて配合しても、 配合量の増加による透過性 促進効果の上昇は得られず、 また皮膚に対する安全性の面で好ましくない。 In the external preparation for skin of the present invention, the above-mentioned nonionic surfactants can be used alone or in combination of two or more. The compounding 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 1% by mass, based on the total mass of the external preparation for skin. 0 mass. / 0 . If the amount is less than 0.5% by mass, a sufficient effect of enhancing the permeability of the amide-type local anesthetic may not be obtained, and if the amount exceeds 20% by mass, the permeability is enhanced by increasing the amount of the compounding agent. No increase in effect is obtained, and it is not preferable in terms of safety on the skin.
本発明の皮膚外用製剤は油性製剤である。本明細書において、 「油性製剤」また は 「油性皮膚外用製剤」 とは、 油性成分を主基剤とする製剤を意味し、 基本的に 水を配合しないが、 例えば原料に含まれる水分や製造過程で吸湿する水分等、 本 発明の目的を達成できる限り、 多少の水分を含んでいて差し支えない。 伹し、 本 願発明の目的および製剤の安定性の観点から、 水分含有量は、 外用製剤の全質量 に対して、 1 0質量％以下であることが好ましく、 より好ましくは 5質量％以下 であり、 さらに好ましくは 2質量％以下である。 The external preparation for skin of the present invention is an oily preparation. In this specification, the term "oil-based preparation" or "oil-based external preparation for skin" means a preparation containing an oil-based component as a main base and basically does not contain water. Some moisture may be contained as long as the object of the present invention can be achieved, such as moisture absorbed in the process. However, from the viewpoint of the object 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, based on the total mass of the external preparation. Yes, more preferably 2% by mass or less.
本発明の皮膚外用製剤で用いられる油性基剤成分は、 化粧品、 医薬品、 医薬部 外品等の外用製剤に配合可能なものであれば特に限定されない。 例えば、 流動パ ラフィン、 スクヮラン、 固形パラフィン、 セレシン、 スクヮレン、 ワセリン、 マ イク口クリスタリンワックス等の炭化水素油、 カカオ脂、 ヤシ油、 パーム油、 硬 化油等の固体油脂、 ミツロウ、 カンデリラロゥ、 綿ロウ、 カルナゥバロウ等の口 ゥ類、 ラウリン酸、 ミリスチン酸、 パルミチン酸、 ステアリン酸、 ベへニン酸、 ォレイン酸等の高級脂肪酸、 ラウリルアルコール、 セチルアルコール、 ステアリ ノレアノレコーノレ、 ベへニノレアノレコーノレ、 ミ リスチノレアノレコースレ、 ォレイノレアノレコー ル等の高級アルコール、 ミ リスチン酸イソプロピル、 オクタン酸セチル、 ミ リス チン酸オタチルドデシル、 パルミチン酸イソプロピル、 ステアリン酸プチル、 ラ ゥリン酸へキシル、 ミリスチン酸ミリスチル等の合成エステル油、 ジメチルポリ シロキサン、 メチノレフエニノレポリシロキサン、 ジフエ-ノレポリシロキサン等のシ リコーン油、 ォリーブ油、 ナタネ油等の液体油脂などを本発明の皮膚外用製剤で 用いることができる。 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 blended with an external preparation such as cosmetics, pharmaceuticals, and quasi-drugs. For example, liquid paraffin, squalane, solid paraffin, hydrocarbon oils such as ceresin, squalene, petrolatum, crystallin wax, cocoa butter, coconut oil, palm oil, solid oils such as palm oil, hardened oil, beeswax, candelillarole, cotton Oral products such as wax and carnauba wax, higher fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, and oleic acid, lauryl alcohol, cetyl alcohol, stearyl alcohol, and behenino alcohol To higher alcohols such as oleoresin, myristinoleanolesolecole, and oleinoleanolechol, isopropyl myristate, cetyl octanoate, otatyl dodecyl myristate, isopropyl palmitate, butyl stearate, and radiric acid. Kisir, Millis Synthetic ester oils such as phosphate myristyl, dimethylpolysiloxane, methylol Roh reflex Eni Honoré polysiloxane, Jifue - Honoré polysiloxane of sheet Liquid fats and oils such as corn oil, olive oil and rapeseed oil can be used in the external preparation for skin of the present invention.
本発明の皮膚外用製剤において、 これら油性基剤成分を 1種単独で、 または 2 種以上を組合せて用いることができる。 本発明の皮膚外用製剤におけるこれら油 性基剤成分の配合量は、 所望の剤形や皮膚に適用した際の使用感等に応じて適宜 決められ、特に限定はされないが、好ましくは、皮膚外用製剤の全質量に対して、 2 0〜8 0質量％である。 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 amount of these oily base components in the external preparation for skin of the present invention is appropriately determined depending on the desired dosage form, the feeling of use when applied to the skin, and the like, and is not particularly limited. It is 20 to 80% by mass relative to the total mass of the preparation.
本発明の皮膚外用製剤は、 油性製剤であれば、 その剤形は特に限定されず、 油 液系、 ペースト系、 軟膏系等任意の剤形を含むが、 その使用性の観点から、 半固 形状または固形状であることが好ましい。 液状油性基剤成分の配合量を適切に調 整することによって、 半固形状または固形状の皮膚外用製剤を作成することがで きる。 特に限定はされないが、 本発明の皮膚外用製剤における液状油性基剤成分 の配合量は、皮膚外用製剤の全質量に対して、好ましく 1 5〜7 0質量％であり、 より好ましくは 3 0〜 6 0質量0 /0である。 1 5質量％未満では、 了ミド型局所麻 酔薬を皮膚外用製剤に適切に溶解または分散させることが困難な場合があり、 ま た 7 0質量％を超えると、 硬度が低くなりすぎて、 皮膚に適用した際にたれ落ち て、 使用性が悪くなる場合がある。 The formulation for external use on the skin of the present invention is not particularly limited as long as it is an oily formulation, and includes any formulation such as an oil-liquid system, a paste system, and an ointment system. It is preferably in the form or a solid. By appropriately adjusting the amount of the liquid oily base component, a semi-solid or solid external preparation for skin can be prepared. Although not particularly limited, the compounding amount of the liquid oily base component in the external preparation for skin of the present invention is preferably 15 to 70% by mass, more preferably 30 to 70% by mass, based on the total mass of the external preparation for skin. 6 0 mass 0/0. If the amount is less than 15% by mass, it may be difficult to appropriately dissolve or disperse the topical anesthetic in a topical skin preparation. If the amount exceeds 70% by mass, the hardness may be too low, May drop when applied to skin, causing poor usability.
さらに、 上記の必須成分の他に、 通常化粧品や医薬品等の皮膚外用製剤に用い られる他の任意の成分を、 本発明の効果を損なわない範囲で、 必要に応じて本発 明の皮膚外用製剤に適宜配合することができる。 例えば、 清涼剤、 抗酸化剤、 キ レート剤、 粉末類、 防腐剤、 増粘剤、 色剤、 香料等を、 本発明の皮膚外用製剤中 に適宜配合することができる。 また、 本発明の皮膚外用製剤は、 上記の特定の非 イオン性界面活性剤の他に、通常皮膚外用製剤で用いられる任意の界面活性剤を、 本発明の効果を損なわない限りさらに含んでいてよい。 さらに、 本発明の皮膚外 用製剤は、 アミド型局所麻酔薬の他に、 局所麻酔効果を有する他の任意の成分を 含んでいてもよい。 Furthermore, in addition to the above essential components, other optional components usually used for external preparations for skin such as cosmetics and pharmaceuticals may be added to the external preparation for skin of the present invention, if necessary, as long as the effects of the present invention are not impaired. Can be appropriately blended. For example, a cooling agent, an antioxidant, a chelating agent, powders, a preservative, a thickener, a coloring agent, a fragrance, and the like can be appropriately compounded in the external preparation for skin of the present invention. In addition, the external preparation for skin of the present invention further contains, in addition to the above specific nonionic surfactant, any surfactant usually used in external preparations for skin, as long as the effects of the present invention are not impaired. Good. Further, the external preparation for skin of the present invention may contain, in addition to the amide-type local anesthetic, other optional components having a local anesthetic effect.
本発明の皮膚外用製剤の製法は特に限定されないが、 例えば、 加熱溶解した油 性基剤成分に、 アミド型局所麻酔薬および非イオン性界面活性剤を添加し、 攪拌 混合機により混合溶解もしくは分散させ、 冷却することにより調製できる。 本発明の皮膚外用製剤は、 局所麻酔用の外用製剤として、 例えば、 レーザー治 療時や、 採血、 静脈力二ユレーシヨン、 注射時等の痛みの緩解、 帯状疱疹後神経 痛、 三叉神経痛等の神経原因性疼痛の緩和、 ただれ、 かぶれ、 切り傷、 擦り傷等 の皮膚創傷部位の痛みや痒みの緩解等、任意の用途において用いることができる。 以下、 実施例を挙げて本発明を具体的に説明する力 本発明は下記の実施例に 限定されるものではない。 以下の実施例ではアミド型局所麻酔薬としてリドカイ ンを用いた。 尚、 配合量は全て製剤全量に対する質量％で表す。 The method for preparing 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-soluble oily base component, and the mixture is dissolved or dispersed by a stirring mixer. And cooled. The topical skin preparation of the present invention may be used as a topical preparation for local anesthesia such as, for example, laser treatment, blood sampling, intravenous power injection, pain relief at the time of injection, post-herpetic neuralgia, trigeminal neuralgia, etc. It can be used for any purpose such as relieving causal pain, relieving pain and itch at skin wound sites such as soreness, rash, cuts and abrasions. Hereinafter, the ability to specifically describe the present invention with reference to examples The present invention is not limited to the following examples. In the following examples, lidocaine was used as an amide-type local anesthetic. In addition, all the compounding amounts are represented by mass% with respect to the total amount of the preparation.
皮膚透過†生試験 Skin penetration test
各製剤におけるリドカインの皮膚透過性は、 i n V i t r oラット腹部除毛 摘出皮膚を用いた皮膚透過性試験によって測定した。 方法は以下の通りである： (方法） The skin permeability of lidocaine in each preparation was measured by a skin permeability test using an abdominal depilated and excised skin of inVitro rats. The method is as follows: (Method)
6〜 7週令の雄性ラット （SPF) (CD (SD) I GS系、 日本チヤ一ルスリ パー株式会社） をエーテル麻酔により安楽死させた後、 腹部を電気バリ力ンで剪 毛し、 皮膚を摘出した。 これを 2—チャンバ一型の F r a 11 z型拡散セル （有効 透過面積 3. 14 cm2, レセプター側容¾ 17 m L) に角質層が上面になるよ うに装着した。 ドナー側 （角質層側） には試験製剤 5 Omgを均一に塗布し、 レ セプター側 （真皮側） 溶液にはリン酸緩衝液 (pH7. 4) を用い、 拡散セルの チャンバ一に 37°Cの水を灌流することにより皮膚表面温度を 30°Cに保った。 レセプター溶液をマグネティックスターラーにて攪拌し、 2時間ごとに 10時間 後まで lmLずつサンプリングした。 高速液体クロマトグラフィーを用いて、 サ ンプリングしたレセプター溶液中のリ ドカイン濃度を測定した。 リドカイン濃度 からレセプター側へのリドカインの透過量の累積値を計算し、 その累積値を時間 に対してプロットし、 直線部分の傾きから定常状態の透過速度
非ィオン性界面活性剤の検討 Examination of nonionic surfactant
以下の表 1一 1および表 1一 2に示す配合組成で、 実施例 1力 ら 18および比 較例 2力 ら 4の各種非イオン性界面活性剤を含有する外用製剤、 ならびに非ィォ ン性界面活性剤を含有しない比較例 1の外用製剤をそれぞれ調製し、 上述した皮 膚透過性試験によって、 各製剤におけるリ ドカインの皮膚透過速度を測定した。 難例 難例 雞例 雞例 難例 難例 難例 成分 An external preparation containing the various nonionic surfactants of Examples 1 to 18 and Comparative Examples 2 to 4 having the composition shown in Tables 11 and 12 below, and a nonionic preparation Each of the external preparations of Comparative Example 1 containing no surfactant was prepared, and the skin permeation rate of lidocaine in each preparation was measured by the skin permeability test described above. Difficult case Difficult case Example 雞 Example Difficult case Difficult case Difficult example Component
1 2 3 4 5 6 7 8 9 10 11 ジドカイン 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 マイクロクリスタリンワックス 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 白色ワセリン 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 固 ラフィン 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 1 2 3 4 5 6 7 8 9 10 11 Zidocaine 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 Microcrystalline wax 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 White petrolatum 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Solid raffin 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0
^ラフィン 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 モノォレイン齢、、リセリル 5.0 ^ Raffin 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 Monolein age, Lyceryl 5.0
モノォレイン ルビタン 5.0 Monolein Lubitan 5.0
セスキォレイン || ルビタン 5.0 Sesquiolein || Rubitan 5.0
トリオレイン ¾ ルビタン 5.0 Trio Rain ¾ Rubitan 5.0
モノォレイン酸ジグリセリル 5.0 Diglyceryl monooleate 5.0
モノ才レイン！^キサグリセリル 5.0 One-year-old rain! ^ Oxaglyceryl 5.0
POE(3)ヒマシ油 5.0 POE (3) Castor oil 5.0
モノォレイン^ POE(5)グリセリル 5.0 Monoolein ^ POE (5) glyceryl 5.0
POE(2)ラウリノレエ一テル 5.0 POE (2) Lauri Norrete 5.0
POE(2)セチルエーテル 5.0 POE (2) cetyl ether 5.0
POE(2)ステアリルエーテル 5.0 POE (2) stearyl ether 5.0
POE(2)ォレイノレエ一テル POE (2) Oleino Reiter
POE(7)ォレィルエーテル POE (7) oleyl ether
POE(IO)ォレイル工ーテル POE (IO)
モノステアリン^ PEG(2EO) Monostearin ^ PEG (2EO)
モノォレイン PEG(2EO) Monoolein PEG (2EO)
モノォレイン膨 EG(6EO) Monolein expansion EG (6EO)
モノォレイン膨 EG(IOEO) Monolein dilation EG (IOEO)
モノステアリン 、'リセリル Monostearin, 'Lyseryl'
モノステアリン^ ルビタン Monostearin ^ rubitan
P〇E(5)ベへ-ルェーテル P〇E (5) Behe-Luther
P OE：ポリオキシエチレン （カツコ內はエチレンォキシドィ Pモ Λ¾) P OE: Polyoxyethylene (Katsuko is ethylene oxide P model)
P EG：ポリエチレングリコール P EG: polyethylene glycol
難例 難例 難例 難例 雞例 雞例 ]：賴 ]：麵 ]：瞧 1；咖 成分 Difficult Difficult Difficult Difficult Difficult Difficult 雞 Example 雞 Example]: 賴]: 麵]: 瞧 1; 咖 Ingredient
12 13 14 15 16 17 18 1 2 3 4 ジドカイン 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 マイクロクリスタリンワックス 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 白色ワセリン 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 固形パラフィン 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 !κラフィン 25.0 25.0 25.0 25.0 25.0 25.0 25.0 30.0 25.0 25.0 25.0 モノォレイン リセリル 12 13 14 15 16 17 18 1 2 3 4 Zidocaine 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 Microcrystalline wax 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 White petrolatum 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Solid paraffin 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0! Κ raffin 25.0 25.0 25.0 25.0 25.0 25.0 25.0 30.0 25.0 25.0 25.0 Monoolein lyseryl
モノォレイン^ルビタン Monolein ^ Rubitan
セスキォレイン^ ルビタン Sesquilein ^ Rubitan
トリオレイン ¾ ルビタン Trio Rain ¾ Rubitan
モノォレイン麼ジグリセリル Monoglycine or diglyceryl
モノォレイン キサクリセリル Monoolein Kisacceryl
POE(3)ヒマ、ン由 POE (3) Hima, N
モノォレイン^ POE(5)グリセリル Monoolein ^ POE (5) glyceryl
POE(2)ラウリノレエ一テル POE (2) Laurinolete Teru
POE(2)セチルエーテル POE (2) cetyl ether
POE(2)ステアリルエーテル POE (2) stearyl ether
POE(2)ォレイルェーテル 5.0 POE (2) Olerjötel 5.0
POE(7)ォレィルエーテル 5.0 POE (7) oleyl ether 5.0
POE(IO)ォレイノレエ一テル 5.0 POE (IO) Oreino Reiter 5.0
モノステアリン EG(2EO) 5.0 Monostearin EG (2EO) 5.0
モノォレイン PEG(2EO) 5.0 Monoolein PEG (2EO) 5.0
モノォレイン膨 EG(6EO) 5.0 Monolein expansion EG (6EO) 5.0
モノォレイン PEG(IOEO) 5.0 Monoolein PEG (IOEO) 5.0
モノステアリン リセリル 5.0 Monostearin Lyseryl 5.0
モノステアリン レビタン 5.0 Monostearin Levitan 5.0
POE(5)ベへ-ルェーテル 5.0 POE (5) Behe-Louther 5.0
POE：ポリ^ンエチレン (カツコ内はェチレ ^シド^) ル数: POE ： Polyethylene (Echile ^ Side ^ in Katsuko)
PEG:ポリエチレンダリコール PEG: polyethylene dali call
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 1 8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 1 2〜 1 8で、 エチレン ォキシド付加モル数が 2〜 1 0のポリォキシエチレンアルキノレエ一テルを含有す る実施例 9から 1 4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、 P O E ( 5 ) ベへ-ルエーテノレ） 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つた。 Figure 1 shows the results. The preparations of Examples 1 to 18 of the present invention containing a specific nonionic surfactant which is semisolid or liquid at normal temperature together with lidocaine are the same as the preparation of Comparative Example 1 containing no nonionic surfactant. In comparison, it resulted in significantly higher lidocaine skin penetration rates. In particular, in Examples 9 to 14 containing a polyoxyethylene alkynoleether having an alkyl group having 12 to 18 carbon atoms and an ethylene oxide addition mole number of 2 to 10, lidocaine skin The transmission speed was high. On the other hand, the formulations of Comparative Examples 2 to 4 containing nonionic surfactants (glyceryl monostearate, sorbitan monostearate, and POE (5) behe-leatenole) which are solid at room temperature showed that lidocaine permeated the skin through lidocaine. The rates were comparable or rather low as in Comparative Example 1, which contained no nonionic surfactant.
非ィオン性界面活性剤の配合量の検討 Examination of blending amount of nonionic surfactant
非イオン性界面活性剤として P O E ( 2 ) ォレイルエーテルを用いて、 リドカ ィンの皮膚透過性に対するその配合量の影響について検討した。 以下の表 2に示 す配合組成で、 各配合量の P O E ( 2 ) ォレイルエーテルを含有する製剤を調製 し、 上述した皮膚透過性試験によって、 各製剤におけるリ ドカインの皮膚透過速 度を測定した。 Using POE (2) oleyl ether as a nonionic surfactant, the effect of the amount of lidocaine on the skin permeability of lidocaine was examined. Formulations containing POE (2) oleyl ether of each formulation amount were prepared with the formulation shown in Table 2 below, and the skin permeation rate of lidocaine in each formulation was measured by the skin permeability test described above. did.
【表 2】 [Table 2]
P O E：ポリォキシエチレン （力ッコ内はエチレンォキシド付カ卩モノレ数) 結果を図 2に示す。 非イオン性界面活性剤を含有しない製剤と比較して、 PO E (2) ォレイルエーテルを 0. 5〜 20質量％の配合量で含有する製剤におい て、 リドカインの皮膚透過速度が有意に高かった。 特に、 POE (2) ォレイル エーテルを 1質量％以上含有する製剤において、 リドカインの皮膚透過速度が顕 著に高かった。 POE: Polyoxyethylene (The number in the box is the number of monocles with ethylene oxide.) The result is shown in figure 2. Compared with the formulation containing no nonionic surfactant, the skin permeation rate of lidocaine was significantly higher in the formulation containing 0.5 to 20% by mass of POE (2) oleyl ether. Was. In particular, in formulations containing 1% by mass or more of POE (2) oleyl ether, the skin permeation rate of lidocaine was remarkably high.
ァミド型局所麻酔薬の配合量の検討 On the amount of amide-type local anesthetic
アミド型局所麻酔薬としてリドカインを用いて、 その皮膚透過性に対する配合 量の影響について検討した。 実施例 22から 29では非イオン性界面活性剤とし て POE (2) ォレイノレエーテルを用い、 また比較例 5から 9では非イオン性界 面活性剤としてモノステアリン酸グリセリノレを用いた。 以下の表 3に示す配合組 成で、 各配合量のリドカインを含有する製剤を調製し、 上述した皮膚透過性試験 によって、 各製剤におけるリドカインの皮膚透過速度を測定した。 Using lidocaine as an amide-type local anesthetic, the effect of the compounding amount on its skin permeability was examined. In Examples 22 to 29, POE (2) oleinole ether was used as the nonionic surfactant, and in Comparative Examples 5 to 9, glycerinole monostearate was used as the nonionic surfactant. Formulations containing the respective amounts of lidocaine were prepared according to the formulation shown in Table 3 below, and the skin permeation rate of lidocaine in each formulation was measured by the skin permeability test described above.
【表 3】 [Table 3]
ΡΟΕ：ポリ; ンェチレン (カツコ内はエチレン^シド働 ノ^ ：) ΡΟΕ ： Poly; Nethylene (The inside of kazuko is ethylene ^ side function ^^)
結果を図 3に示す。 非イオン性界面活性剤として P O E ( 2 ) ォレイルエーテ ルを含有する実施例 2 2から 2 9では、 2 0〜 6 0質量％のリ ドカィンの配合量 で高いリドカインの皮膚透過速度が認められた。 一方、 非イオン性界面活性剤と して固形状のモノステアリン酸グリセリルを含有する比較例 5力、ら 9では、 測定 したいずれのリドカイン配合量でもリドカインの皮膚透過速度は低かった。 The results are shown in Figure 3. In Examples 22 to 29 containing POE (2) oleyl ether as a nonionic surfactant, a high lidocaine skin permeation rate was observed at a compounding amount of lidocaine of 20 to 60% by mass. On the other hand, in Comparative Examples 5 and 9 containing solid glyceryl monostearate as a nonionic surfactant, the skin permeation rate of lidocaine was low with any of the measured lidocaine content.
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| WO2011121034A3 (en) * | 2010-04-01 | 2012-05-31 | Pharmanest Ab | Water-free pharmaceutical compositions suitable for local anaesthetics |
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| ES2385737T3 (en) * | 2004-11-10 | 2012-07-31 | Hisamitsu Pharmaceutical Co., Inc. | Drug for external use and adhesive patch |
| ES2389630T3 (en) * | 2004-11-10 | 2012-10-29 | Hisamitsu Pharmaceutical Co., Inc. | Drugs for external use and adhesive patch |
| JP2023027715A (en) * | 2021-08-17 | 2023-03-02 | 株式会社カネカ | Pharmaceutical composition, and patch |
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| CN102892408A (en) * | 2010-04-01 | 2013-01-23 | 帕玛内斯特公司 | Water-free pharmaceutical compositions suitable for local anaesthetics |
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