WO2001026690A1 - Percutaneous permeability-controlling agents and compositions for electroporation containing the same - Google Patents
Percutaneous permeability-controlling agents and compositions for electroporation containing the same Download PDFInfo
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- WO2001026690A1 WO2001026690A1 PCT/JP2000/002241 JP0002241W WO0126690A1 WO 2001026690 A1 WO2001026690 A1 WO 2001026690A1 JP 0002241 W JP0002241 W JP 0002241W WO 0126690 A1 WO0126690 A1 WO 0126690A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
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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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
Definitions
- the present invention relates to a transdermally permeable control agent, and a composition for election poration containing the same.
- the present invention relates to a transdermally permeable control agent useful for adjusting the transdermally permeating amount of a drug in an electoral poration and a composition for electroporation containing the same.
- the present invention is useful in the field of medicine. Conventional technology
- the percutaneous absorption route is less prone to pain than injections, and has less forgotten administration than oral administration. It is difficult to absorb the skin because of its defensive function, and it has not yet been established as a drug delivery method.
- a so-called electoral poration in which a voltage is applied to create a pore in the skin structure, and a drug is transported through the pore, is exemplified. Improving transdermal permeability is one of the major themes in drug transport in such electroporation, but in addition to this, controlling permeability and controlling drug concentration in the blood are also important.
- One of the major themes is to control the transdermal permeability immediately after the electric field load and to adjust the absorption characteristics of the drug, and the construction of such a control technology has been desired. It has recently become apparent that the behavior of the drug in electoral poration is different from that of normal administration, and a composition for transdermal administration suitable for electroporation, including such de-collection, has been recently developed. Development was desired.
- the present invention has been made under the above circumstances, and has as its object to provide means for controlling a drug permeation rate in an election portion.
- the present inventors have sought to find a means of controlling the drug permeation rate in election poration, and as a result of intensive research efforts, have found such an effect on phospholipids.
- the inventors have found that such control can be performed by appropriately adding this to a composition for election port poisoning, and have completed the invention. That is, the present invention provides a composition for electoral poration containing a phospholipid, and a drug for external use on the skin, which is obtained by combining the composition with an electoral poration device.
- Phospholipid which is an essential component of the composition for electroporation of the present invention
- the composition for electoral port poration of the present invention is characterized by containing a phospholipid.
- lipids that can be contained in the composition for electroporation of the present invention any lipids that are usually used in external preparations for skin and the like can be used without any particular limitation.
- Preferable examples include fatty acid phosphatidic acid and salts thereof.
- difatty acid compounds are preferable, and difatty acid phosphatidylglycerol is particularly preferable.
- constituent fatty acids unsaturated fatty acids are preferred, and oleic acid is particularly preferred. That is, phosphatidylglycerol dioleate is particularly preferred as the phospholipid contained in the composition for electoral poration of the present invention. These may contain only one kind, or may contain two or more kinds in combination. In the composition for election port poration of the present invention, these phospholipids are oriented to the pore portion to adjust the size of the pore formed by the electoportion poration, so that drug permeation occurs at one time, Is considered to have the effect of preventing instantaneous blockage.
- the content of the phospholipid in the composition (1) varies depending on the control pattern of the drug permeability, it is generally about 0.1 to 10% by weight, more preferably 0.5 to 5% by weight. This is because if the control is overkill, the required amount may not be permeated; if the control is not enough, the drug permeation may be biased, resulting in impaired sustainability or transiently increasing drug concentrations, with side effects. This is because they may be expressed.
- composition for electroporation of the present invention may contain, in addition to the essential component, a lipid, an optional component for formulation usually used in a composition for electoral poration.
- optional components include, for example, hydrocarbons such as squalane, petrolatum, and microcrystalline wax, jojoba oil, esters such as carnauba wax, octyldodecyl oleate, olive oil, tallow, coconut oil, and the like.
- Fatty acids such as triglycerides, stearic acid, oleic acid, and ritinoleic acid; higher alcohols such as oleyl alcohol, stearyl alcohol, octyldodecanol; anionic surfactants such as sulfosuccinates and sodium polyoxyethylene alkyl sulfate; alkyls Amphoteric surfactants such as benzoin salt, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, their polyoxyethylene adducts, polyoxetylene alkyl esters Le, nonionic surface active agents such as poly O key Chez Ji Ren fatty acid esters, thickening-gelling agents, antioxidants, ultraviolet absorbers, coloring materials, preservatives, powders and the like can be preferably exemplified.
- the drug to be transdermally administered by such an electroporation can be applied without any particular limitation as long as it is usually used as a pharmaceutical.
- examples of such a drug include, but are not limited to, codin, morphine, and Defoam morphone, oxycodone, pethidine, buflenolfin hydrochloride, pentadyne, tramadol hydrochloride, and other analgesic and anti-inflammatory drugs, insulin, calcitonin, elcatonin, corticotropin (ACTH), parathyroid hormone (PTH), selectin, oxotosine, Angiotensin, 5-endorphin, vasopressin, glucagon, somatosustin, luteinizing hormone-releasing hormone (LH_RH), enkephalin, neurotensin, atrial natriuretic peptide (ANP), growth hormone, bradykinin, substance P , Dynolph Thyrin, thyroid stimulating
- the composition for electroporation of the present invention is obtained by treating the above essential components, preferred components, optional components and active ingredients according to a conventional method to adjust the physical properties of the active ingredients, etc. Processed into dosage forms, semi-solid dosage forms, solid dosage forms, etc., and used for electroporation. That is, by using the composition of the present invention, the drug of the active ingredient can be transdermally administered by electroporation. For electroporation, it is used together with a device for electoral poration.
- preferred dosage forms include aqueous dosage forms, and particularly preferred examples include aqueous solution dosage forms, aqueous gel dosage forms, and emulsified dosage forms.
- the drug administration unit for external use on the skin of the present invention is obtained by combining the above-described composition for electroporation of the present invention with the device for election port poration.
- the device for the election port location There are no particular restrictions on the device for the election port location as long as it is normally used for such use.
- Japanese Patent Application Publication No. 11-507341, Japanese Patent Application Publication No. 11-505445 The devices described in JP-A No. 10-502827, JP-A No. 11-503349, JP-A No. 08-51 1680, JP-A No. 03-502416 may be used.
- commercially available devices for such electoral port por- tions include devices such as £ CM-600 manufactured by 8 companies and GENE PULSER manufactured by BI0-RAD, and these devices are used.
- FIG. 1 is a diagram showing an apparatus used in a transmission experiment of Example 2. The present invention will be described in more detail below with reference to examples, but it is needless to say that the present invention is not limited to only these examples.
- a composition for electroporation of the present invention was prepared. That is, the formulation components were stirred and solubilized to obtain a composition for election port poration.
- the transdermal absorption promoting effect of the composition for electroporation of Example 1 was measured by a transdermal permeability test using Franz cells. That is, a skin specimen 2 from the abdomen of a hairless rat, from which the subcutaneous fat was removed, was attached to the Franz cell 1 as a septum with the stratum corneum facing the donor side, and a saline solution was placed on the receiver side. Water 3 was filled, and the donor side was charged with 3 mL of the composition 4 for electroporation of the present invention. The receiver side was stirred with a stirrer 6 at 1200 rpm using a silver head type stirrer 5.
- a composition for electoral port poration of the present invention was prepared according to the following prescription. That is, a prescription component was stirred and solubilized to obtain a composition for electoral port poration.
- a composition for electroporation of the present invention was prepared. That is, the formulation components were stirred and solubilized to obtain a composition for election port poration.
- a composition for electoral port poration of the present invention was prepared according to the following prescription. That is, the ingredients were stirred and solubilized to obtain a composition for electoral port poration.
- composition for electroporation of the present invention was prepared according to the following prescription. That is, the components were stirred and solubilized to obtain a composition for election port poisoning.
- composition for electroporation of the present invention was prepared according to the following formulation (that is, the formulation components were solubilized by stirring to obtain a composition for electoral poration).
- a composition for electroporation of the present invention was prepared. That is, the prescription component A was stirred, dispersed and solubilized, and the mixture was added to the mouth and neutralized to obtain a composition (gel) for elect mouth poration.
- Lithium hydroxide 0.4 parts by weight
- control means of the drug permeation rate in election poration can be provided, and it is useful in the pharmaceutical field.
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Abstract
Description
明細書 経皮透過性コン卜ロール剤及びそれを含有するエレクト口ポーレーシヨン用の組成物 術分 The present invention relates to a transdermally permeable control agent, and a composition for election poration containing the same.
本発明は、 エレクト口ポーレーシヨンにおいて、 薬物の経皮透過量を調整するのに有用 な経皮透過性コン卜ロール剤及びそれを含有するエレクトロポ一レ一シヨン用の組成物 に関する。 本発明は医薬分野で有用である。 従来の技術 The present invention relates to a transdermally permeable control agent useful for adjusting the transdermally permeating amount of a drug in an electoral poration and a composition for electroporation containing the same. The present invention is useful in the field of medicine. Conventional technology
経皮吸収経路は、 注射などに比して苦痛が少なく、 しかも経口投与に比して投与忘れな どが少ないため、 薬物の投与経路として有望視されているものの、 皮膚が本来的に持って ヽる防御機能に阻まれてなかなか絰皮吸収させることに大きな困難が伴っており、 ドラッ グデリノ リ一手段としては未だ確立されていないのが現状であった。かかる現状の課題を 打破するために考案された方法の 1つとして、 電圧をかけ皮膚構造にポアを作り、 かかる ポアを通して薬物を移送させる、 いわゆるエレクト口ポーレーシヨンが例示できる。 この 様なエレクトロポーレーシヨンにおける、 薬物輸送では、経皮透過性を向上させることも 大きなテーマの一つであるが、 これに加えて、 透過性をコントロールし、 血中の薬物濃度 をコントロールしたり、電界負荷直後に経皮透過性を制御したりして薬物の吸収特性を調 整したりすることも大きなテーマの一つであり、この様な制御技術の構築が望まれていた この様なエレクト口ポーレーシヨンにおいては、薬物の挙動は通常の投与と異なることが 最近明らかになりつつあり、 その様なデ一夕取りも含め、 エレクトロポ一レーシヨンに好 適な経皮投与用の組成物の開発が望まれていた。 The percutaneous absorption route is less prone to pain than injections, and has less forgotten administration than oral administration. It is difficult to absorb the skin because of its defensive function, and it has not yet been established as a drug delivery method. As one of the methods devised to overcome such a current problem, a so-called electoral poration, in which a voltage is applied to create a pore in the skin structure, and a drug is transported through the pore, is exemplified. Improving transdermal permeability is one of the major themes in drug transport in such electroporation, but in addition to this, controlling permeability and controlling drug concentration in the blood are also important. One of the major themes is to control the transdermal permeability immediately after the electric field load and to adjust the absorption characteristics of the drug, and the construction of such a control technology has been desired. It has recently become apparent that the behavior of the drug in electoral poration is different from that of normal administration, and a composition for transdermal administration suitable for electroporation, including such de-collection, has been recently developed. Development was desired.
又、 ホスファチジルコリン等の燐脂質について、 電界をかけない通常の経皮投与製剤に 於いては、 薬物の経皮吸収促進効果があることは既に知られているが、 この様な燐脂質を エレクト口ポーレーシヨンに用いる試みは全く為されておらず、またエレクトロポ一レ一 シヨンにおいて、 この様な燐脂質が経皮透過速度を緩和し、 薬物の透過の制御を行うこと は全く知られていなかった。 又、 現在のところ、 エレクト口ポーレーシヨンにおいて経皮 透過性を制御する物質は現在のところ知られていない。 胡の間示 In addition, it has been known that phospholipids such as phosphatidylcholine have an effect of promoting percutaneous absorption of a drug in a normal transdermal preparation which does not apply an electric field. No attempt has been made to use it in porations, and it has never been known in electroporation that such phospholipids reduce the transdermal permeation rate and control drug permeation. . Also, at the moment, percutaneous No substances that control permeability are currently known. Hu's room
本発明は、 上記の様な状況下為されたものであり、 エレクト口ポーレーシヨンに於ける 薬物透過速度の制御手段を提供することを課題とする。 The present invention has been made under the above circumstances, and has as its object to provide means for controlling a drug permeation rate in an election portion.
本発明者らは、 この様な状況に鑑みて、 エレクト口ポーレーシヨンに於ける薬物透過速 度の制御手段を求めて、 鋭意研究努力を重ねた結果、 燐脂質にその様な作用を見出し、 こ れをエレクト口ポーレーシヨン用の組成物に適宜含有させることにより、この様な制御が 可能であることを見出し、 発明を完成させるに至った。即ち、 本発明は、 燐脂質を含有す るエレクト口ポーレーシヨン用の組成物及び該組成物とエレクト口ポーレーシヨン装置 を組み合わせてなる皮膚外用医薬を提供するものである。 In view of such a situation, the present inventors have sought to find a means of controlling the drug permeation rate in election poration, and as a result of intensive research efforts, have found such an effect on phospholipids. The inventors have found that such control can be performed by appropriately adding this to a composition for election port poisoning, and have completed the invention. That is, the present invention provides a composition for electoral poration containing a phospholipid, and a drug for external use on the skin, which is obtained by combining the composition with an electoral poration device.
( 1 ) 本発明のエレクトロポーレーシヨン用の組成物の必須成分である燐脂質 (1) Phospholipid which is an essential component of the composition for electroporation of the present invention
本発明のェレクト口ポーレーション用の組成物は、燐脂質を含有することを特徴とする。 本発明のエレクトロポーレーシヨン用の組成物において含有することのできる憐脂質と しては、通常皮膚外用剤などで使用されているものであれば特段の限定無く使用すること ができ、 例えば、 ジ （モノ） 脂肪酸ホスファチジルコリン、 ジ （モノ）脂肪酸ホスファチ ジルグリセロール、 ジ （モノ） 脂肪酸ホスファチジルイノシトール、 ジ （モノ） 脂肪酸ホ スファチジルセリン、 ジ （モノ）脂肪酸ホスファチジルェタノ一ルァミン、 ジ （モノ） 脂 肪酸ホスファチジン酸及びその塩等が好ましく例示でき、 これらの中では、 ジ脂肪酸体が 好ましく、 中でもジ脂肪酸ホスファチジルグリセロールが好ましい。 又、 構成脂肪酸とし ては、 不飽和脂肪酸が好ましく、 ォレイン酸が特に好ましい。即ち、 本発明のエレクト口 ポ—レ―シヨン用の組成物に含有させる燐脂質としては、ジォレイン酸ホスファチジルグ リセロールが特に好ましい。 これらは 1種のみを含有させることもできるし、 2種以上を 組み合わせて含有させることも可能である。本発明のエレクト口ポーレーシヨン用の組成 物において、 これらの燐脂質は、 ポア部に配向して、 エレクト口ポーレーシヨンにより形 成されたポアの大きさを調整し、 薬物透過が一時に起こったり、 ポアが瞬時に閉塞したり するのを防ぐ作用を有しているものと考えられる。本発明のエレクトロポ一レーシヨン用 の組成物に於ける、 該燐脂質の含有量は、 薬物の透過性の制御パターンにより異なるが、 大凡、 0 . 1〜 1 0重量％、 更に好ましくは 0 . 5〜 5重量％が好ましい。 これは制御が 行き過ぎると必要量が透過されない場合があり、 制御が充分でないと、 薬物透過が偏って おこり、 持続性が損なわれたり、 一過的に上昇する薬物濃度に起因して、 副作用が発現し たりする場合があるからである。 The composition for electoral port poration of the present invention is characterized by containing a phospholipid. As the lipids that can be contained in the composition for electroporation of the present invention, any lipids that are usually used in external preparations for skin and the like can be used without any particular limitation. (Mono) fatty acid phosphatidylcholine, di (mono) fatty acid phosphatidylglycerol, di (mono) fatty acid phosphatidylinositol, di (mono) fatty acid phosphatidylserine, di (mono) fatty acid phosphatidylethanolamine, di (mono) fatty acid Preferable examples include fatty acid phosphatidic acid and salts thereof. Among these, difatty acid compounds are preferable, and difatty acid phosphatidylglycerol is particularly preferable. As constituent fatty acids, unsaturated fatty acids are preferred, and oleic acid is particularly preferred. That is, phosphatidylglycerol dioleate is particularly preferred as the phospholipid contained in the composition for electoral poration of the present invention. These may contain only one kind, or may contain two or more kinds in combination. In the composition for election port poration of the present invention, these phospholipids are oriented to the pore portion to adjust the size of the pore formed by the electoportion poration, so that drug permeation occurs at one time, Is considered to have the effect of preventing instantaneous blockage. For electroporation of the present invention Although the content of the phospholipid in the composition (1) varies depending on the control pattern of the drug permeability, it is generally about 0.1 to 10% by weight, more preferably 0.5 to 5% by weight. This is because if the control is overkill, the required amount may not be permeated; if the control is not enough, the drug permeation may be biased, resulting in impaired sustainability or transiently increasing drug concentrations, with side effects. This is because they may be expressed.
( 2 ) 本発明のエレクト口ポーレーシヨン用の組成物 (2) Composition for election port poration of the present invention
本発明のエレクトロポ一レ一シヨン用の組成物は、 上記必須成分である憐脂質以外に、 通常エレク卜口ポーレーシヨン用の組成物で使用される製剤化のための任意成分を含有 することができる。 かかる任意成分としては、 例えば、 スクヮラン、 ワセリン、 マイクロ クリス夕リンワックス等の炭化水素類、 ホホバ油、 カルナゥバワックス， ォレイン酸ォク チルドデシル等のエステル類、 ォリーブ油、 牛脂、 椰子油等のトリグリセライド類、 ステ アリン酸、 ォレイン酸、 リチノレイン酸等の脂肪酸、 ォレイルアルコール、 ステアリルァ ルコール、 ォクチルドデカノ一ル等の高級アルコール、 スルホコハク酸エステルやポリオ キシエチレンアルキル硫酸ナトリゥム等のァニオン界面活性剤類、アルキルべ夕イン塩等 の両性界面活性剤類、 ジアルキルアンモニゥム塩等のカチオン界面活性剤類、 ソルビタン 脂肪酸エステル、 脂肪酸モノグリセライド、 これらのポリオキシエチレン付加物、 ポリオ キシェチレンアルキルエーテル、ポリォキシェチレン脂肪酸エステル等の非イオン界面活 性剤類、 増粘 ·ゲル化剤、 酸化防止剤、 紫外線吸収剤、 色剤、 防腐剤、 粉体等を好ましく 例示できる。 又、 この様なエレクトロポ一レ一シヨンで経皮投与させる薬剤としては、 通 常医薬品として使用されているものであれば特段の限定を受けずに適用できるが、例えば、 コディン、 モルヒネ、 ハイ ド口モルフオン、 ォキシコドン、 ペチジン、 塩酸ブフレノルフ ィン、ペンタヅシン、塩酸トラマドール等の鎮痛解熱消炎剤、ィンスリン、カルシトニン、 エルカトニン、 副腎皮質刺激ホルモン （A C T H ) 、 副甲状腺ホルモン （P T H ) 、 セレ クチン、 ォキシトシン、 アンジォテンシン、 5—エンドルフィン、 バソプレシン、 グルカ ゴン、 ソマトス夕チン、黄体形成ホルモン放出ホルモン（L H _ R H )、エンケファリン、 ニューロテンシン、 心房性ナトリウム利尿ペプチド （A N P ) 、 成長ホルモン、 ブラジキ ニン、 サブスタンス P、 ダイノルフィン、 甲状腺刺激ホルモン、 （T S H ) 、 プロラクチ ン、 G— CS F、グル夕チオンバーオキシダーゼ、スーパーォキサイ ドデイスム夕ーゼ（S OD) 、 デスモブレシン、 ソマトメジン、 メラノサイ ト刺激ホルモン （MSH) 、 カルシ トニン遺伝子関連ペプチド （CGRP)、 ェンドセリン、 チロトロビン放出ホルモン （T RH)等の蛋白系薬物、 インターロイキン、 インターフヱロン類、 抗血小板薬、 血管拡張 薬、 抗動脈硬化薬であるアルガトロパン、 塩酸サルポグレラート、 ベラプロストナロリウ ム、リマブロストアルファデクス、シロシ夕ゾ一ルなどが好ましく例示できる。これらは、 必要量を経時的に投与する必要があり、 それが経皮投与の特性と合致するからである。本 発明のエレクトロポーレーシヨン用の組成物は、 上記の必須成分、 好ましい成分、 任意成 分及び有効成分を常法に従って処理して、 有効成分の物性等に適合させた、 溶液剤形、 乳 化剤形、半固形剤形、固形剤形などの剤形に加工し、エレクトロポーレーシヨンに用いる。 すなわち、 本発明の組成物を用いて、 エレクトロポ一レ一シヨンにより、 有効成分の薬剤 を絰皮投与させることができる。エレクトロポーレーシヨンに際しては、 エレクト口ポー レーシヨン用のデバイスと共に用いる。前記剤形のうち、 好ましい剤形としては、 水性剤 形が例示でき、 水性溶液剤形や水性ゲル剤形や乳化剤形などが特に好ましく例示できる。 The composition for electroporation of the present invention may contain, in addition to the essential component, a lipid, an optional component for formulation usually used in a composition for electoral poration. it can. Such optional components include, for example, hydrocarbons such as squalane, petrolatum, and microcrystalline wax, jojoba oil, esters such as carnauba wax, octyldodecyl oleate, olive oil, tallow, coconut oil, and the like. Fatty acids such as triglycerides, stearic acid, oleic acid, and ritinoleic acid; higher alcohols such as oleyl alcohol, stearyl alcohol, octyldodecanol; anionic surfactants such as sulfosuccinates and sodium polyoxyethylene alkyl sulfate; alkyls Amphoteric surfactants such as benzoin salt, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, their polyoxyethylene adducts, polyoxetylene alkyl esters Le, nonionic surface active agents such as poly O key Chez Ji Ren fatty acid esters, thickening-gelling agents, antioxidants, ultraviolet absorbers, coloring materials, preservatives, powders and the like can be preferably exemplified. The drug to be transdermally administered by such an electroporation can be applied without any particular limitation as long as it is usually used as a pharmaceutical. Examples of such a drug include, but are not limited to, codin, morphine, and Defoam morphone, oxycodone, pethidine, buflenolfin hydrochloride, pentadyne, tramadol hydrochloride, and other analgesic and anti-inflammatory drugs, insulin, calcitonin, elcatonin, corticotropin (ACTH), parathyroid hormone (PTH), selectin, oxotosine, Angiotensin, 5-endorphin, vasopressin, glucagon, somatosustin, luteinizing hormone-releasing hormone (LH_RH), enkephalin, neurotensin, atrial natriuretic peptide (ANP), growth hormone, bradykinin, substance P , Dynolph Thyrin, thyroid stimulating hormone, (TSH), prolacti G-CSF, glutamate thiombar oxidase, superoxide dismutase (SOD), desmobresin, somatomedin, melanosite-stimulating hormone (MSH), calcitonin gene-related peptide (CGRP), endocerin, thyrotrobin release Hormones (THR) and other protein drugs, interleukins, interferons, antiplatelet drugs, vasodilators, anti-atherosclerotic drugs argatropane, sarpogrelate hydrochloride, beraprostonalolium, limabrost alfadex, shiroshi evening A preferred example is zole. They need to be administered in the required amount over time, which is consistent with the characteristics of transdermal administration. The composition for electroporation of the present invention is obtained by treating the above essential components, preferred components, optional components and active ingredients according to a conventional method to adjust the physical properties of the active ingredients, etc. Processed into dosage forms, semi-solid dosage forms, solid dosage forms, etc., and used for electroporation. That is, by using the composition of the present invention, the drug of the active ingredient can be transdermally administered by electroporation. For electroporation, it is used together with a device for electoral poration. Among the above-mentioned dosage forms, preferred dosage forms include aqueous dosage forms, and particularly preferred examples include aqueous solution dosage forms, aqueous gel dosage forms, and emulsified dosage forms.
( 3 ) 本発明の皮膚外用医薬投薬ュニット (3) The external skin drug administration unit of the present invention
本発明の皮膚外用医薬投薬ュニットは、上記本発明のエレクトロポーレーシヨン用の組 成物とエレクト口ポーレーシヨン用のデバイスとを組み合わせてなる。エレクト口ポ一レ ーシヨン用のデバイスとしては、通常この様な使用に用いられるもののであれば特段の限 定は受けず、 例えば、 特表平 1 1一 507341号、 特表平 1 1— 505445号、 特表 平 10— 502827号、 特表平 1 1一 503349号、 特表平 08— 51 1680号、 特表平 03— 502416号などに記載のデバイスを用いればよい。又、 この様なエレク ト口ポーレーシヨン用のデバイスとして市販されているものとしては、 8丁 社製の£ C M— 600や B I 0— RAD社製の GENE P U L S E R等の装置が存在し、これらを 使用することも可能である。エレクト口ポーレーシヨンの条件としては、 電圧を 300 V 程度に、 コンデンサー容量を 25〃F程度に設定し、 30秒程度の通電を行うのが好まし い。本発明の皮膚外用医薬は、 エレクトロポーレーシヨンにより、 薬物の経皮透過性は向 上させながら、長時間の薬物放出維持性や血中薬物濃度の急激な上昇の抑制作用に優れる 1^1而の簡 ίϋな説昍 図 1は、 実施例 2の透過実験に用いた装置を示す図である。 nfl»^施する めの 自の开熊 以下に、 実施例を挙げて、 本発明について更に詳細に説明を加えるが、 本発明がこれら 実施例にのみ限定を受けないことは言うまでもない。 The drug administration unit for external use on the skin of the present invention is obtained by combining the above-described composition for electroporation of the present invention with the device for election port poration. There are no particular restrictions on the device for the election port location as long as it is normally used for such use. For example, Japanese Patent Application Publication No. 11-507341, Japanese Patent Application Publication No. 11-505445 The devices described in JP-A No. 10-502827, JP-A No. 11-503349, JP-A No. 08-51 1680, JP-A No. 03-502416 may be used. In addition, commercially available devices for such electoral port por- tions include devices such as £ CM-600 manufactured by 8 companies and GENE PULSER manufactured by BI0-RAD, and these devices are used. It is also possible. As the conditions for election port por- tion, it is preferable to set the voltage to about 300 V, set the capacitor capacity to about 25〃F, and energize for about 30 seconds. The drug for external use on the skin of the present invention is excellent in sustaining drug release for a long time and suppressing a rapid increase in drug concentration in blood while improving transdermal permeability of the drug by electroporation. FIG. 1 is a diagram showing an apparatus used in a transmission experiment of Example 2. The present invention will be described in more detail below with reference to examples, but it is needless to say that the present invention is not limited to only these examples.
<実施例 1 > <Example 1>
下記に示す処方に従って、 本発明のエレクトロポーレーシヨン用の組成物を作製した。 即ち、 処方成分を攪拌可溶化し、 エレクト口ポーレーシヨン用の組成物を得た。 According to the following formulation, a composition for electroporation of the present invention was prepared. That is, the formulation components were stirred and solubilized to obtain a composition for election port poration.
生理食塩水 4 7 重量部 Physiological saline 4 7 parts by weight
力ルセインナトリウム 1 mM Sodium lucein 1 mM
プロピレングリコール 5 0 重量部 Propylene glycol 50 parts by weight
ジォレオイルフォスファチジルグリセロール 3 重量部 Giore oil phosphatidyl glycerol 3 parts by weight
<実施例 2 > <Example 2>
上記実施例 1のエレクトロポ一レ一シヨン用の組成物について、フランツセルを用いた 経皮透過性試験により、 その経皮吸収促進作用を測定した。即ち、 フランツセル 1にはへ アレスラッ卜の腹部より採取し、 皮下脂肪を取り除いた皮膚標本 2を、 角層をドナ一サイ ドに向けて、 隔壁として装着し、 レシ一バーサイ ドには生理食塩水 3を満たし、 ドナーサ ィ ドには上記本発明のエレクトロポ一レーシヨン用の組成物 4を 3 m L充填した。レシ一 バ一サイ ドはス夕一へッド型攪拌子 5を用いて、スターラー 6で 1 2 0 0 r p mで攪拌し た。 経時的に 0 . 3 m Lを採取し、 同量の生理食塩水を加え経皮透過性を調べた。 力ルセ インナトリゥム量は、 蛍光光度計により測定した。対照としては実施例 1のジォレオイル ホスファチジルグリセロールを生理食塩水に置換したものを用いた。又、 エレクト口ポー レ一シヨンの条件は、 ノ レス電圧発生装置 7として、 B I 0— RAD社製の GENE P ULSERを用い、 300 Vでコンデンサー容量 25〃Fにし、 60分の内の最初の 5分 に、 1パルス （0. 5分間） をかけ、 残りの 55分は電圧をオフした。結果を 1時間毎の 累積透過量 （nmo l/cm2) として表 1に示す。 これより、 本発明のエレクトロポー レーシヨン用の組成物は、 絰皮吸収促進効果しめしつつも、 一時に薬物が透過するのを抑 制し、透過速度をコントロールする作用を有することがわかる。尚、この装置については、 図 1に示す。 表 1 The transdermal absorption promoting effect of the composition for electroporation of Example 1 was measured by a transdermal permeability test using Franz cells. That is, a skin specimen 2 from the abdomen of a hairless rat, from which the subcutaneous fat was removed, was attached to the Franz cell 1 as a septum with the stratum corneum facing the donor side, and a saline solution was placed on the receiver side. Water 3 was filled, and the donor side was charged with 3 mL of the composition 4 for electroporation of the present invention. The receiver side was stirred with a stirrer 6 at 1200 rpm using a silver head type stirrer 5. Over time, 0.3 mL was collected, and the same volume of physiological saline was added to examine the transdermal permeability. The amount of sodium phosphate was measured with a fluorometer. As a control, the one obtained by substituting the physiological saline for the dioleoyl phosphatidylglycerol of Example 1 was used. Also, elect opening port The conditions of the condition were as follows: BI 0—RAD's GENE PULSER was used as the noise voltage generator 7; the capacitor capacity was 25 V at 300 V; A pulse (0.5 minutes) was applied and the voltage was turned off for the remaining 55 minutes. The results are shown in Table 1 as the cumulative amount of permeation per hour (nmol / cm2). This indicates that the composition for electroporation of the present invention has an effect of suppressing permeation of a drug at one time and controlling a permeation rate while having an effect of promoting percutaneous absorption. This device is shown in Fig. 1. table 1
<実施例 3> <Example 3>
下記に示す処方に従って、 本発明のエレクト口ポーレーシヨン用の組成物を作製した < 即ち、 処方成分を攪拌可溶化し、 エレクト口ポーレーシヨン用の組成物を得た。 A composition for electoral port poration of the present invention was prepared according to the following prescription. That is, a prescription component was stirred and solubilized to obtain a composition for electoral port poration.
生理食塩水 46 重量部 46 parts by weight of physiological saline
塩酸ブフノレフィン 1 重量部 Bufnorefine hydrochloride 1 part by weight
プロピレングリコール 50 重量部 Propylene glycol 50 parts by weight
ジォレオイルフォスファチジルグリセロール 3 重量部 Giore oil phosphatidyl glycerol 3 parts by weight
<実施例 4 > <Example 4>
下記に示す処方に従って、 本発明のエレクトロポ一レーシヨン用の組成物を作製した。 即ち、 処方成分を攪拌可溶化し、 エレクト口ポーレーシヨン用の組成物を得た。 According to the following formulation, a composition for electroporation of the present invention was prepared. That is, the formulation components were stirred and solubilized to obtain a composition for election port poration.
生理食塩水 46 重量部 インシュリン 1 重量部 46 parts by weight of physiological saline Insulin 1 part by weight
プロピレングリコール 5 0 重量部 Propylene glycol 50 parts by weight
ジォレオイルフォスファチジルグリセロール 3 重量部 Giore oil phosphatidyl glycerol 3 parts by weight
<実施例 5 > <Example 5>
下記に示す処方に従って、 本発明のエレクト口ポーレーシヨン用の組成物を作製した 即ち、 処方成分を攪拌可溶化し、 エレクト口ポーレーシヨン用の組成物を得た。 A composition for electoral port poration of the present invention was prepared according to the following prescription. That is, the ingredients were stirred and solubilized to obtain a composition for electoral port poration.
生理食塩水 4 6 重量部 Saline 4 6 parts by weight
塩酸ブフノレフィン 1 重量部 Bufnorefine hydrochloride 1 part by weight
プロピレングリコール 5 0 重量部 Propylene glycol 50 parts by weight
ジォレオイルフォスファチジルコリン 3 重量部 Giore oil phosphatidylcholine 3 parts by weight
<実施例 6 > <Example 6>
下記に示す処方に従って、 本発明のエレクトロポーレーシヨン用の組成物を作製した 即ち、 処方成分を攪拌可溶化し、 エレクト口ポーレーシヨン用の組成物を得た。 The composition for electroporation of the present invention was prepared according to the following prescription. That is, the components were stirred and solubilized to obtain a composition for election port poisoning.
生理食塩水 4 6 重量部 Saline 4 6 parts by weight
塩酸ブフノレフィン 1 重量部 Bufnorefine hydrochloride 1 part by weight
プロピレングリコール 5 0 重量部 Propylene glycol 50 parts by weight
ジォレオイルフォスファチジルセリン 3 重量部 Giore oil phosphatidylserine 3 parts by weight
<実施例 7 > <Example 7>
下記に示す処方に従って、 本発明のエレクトロポーレーシヨン用の組成物を作製した ( 即ち、 処方成分を攪拌可溶化し、 エレクト口ポーレーシヨン用の組成物を得た。 The composition for electroporation of the present invention was prepared according to the following formulation (that is, the formulation components were solubilized by stirring to obtain a composition for electoral poration).
生理食塩水 4 6 重量部 Saline 4 6 parts by weight
塩酸ブフノレフィン 1 重量部 Bufnorefine hydrochloride 1 part by weight
プロピレングリコール 5 0 重量部 Propylene glycol 50 parts by weight
ジォレオイルフォスファチジルイノシトール 3 重量部 <実施例 8 > Giore oil phosphatidylinositol 3 parts by weight <Example 8>
下記に示す処方に従って、 本発明のエレクトロポーレーシヨン用の組成物を作製した。 即ち、 処方成分ィを攪拌、 分散 '可溶化し、 口を加え中和してエレクト口ポーレーシヨン 用の組成物 （ゲル） を得た。 According to the following formulation, a composition for electroporation of the present invention was prepared. That is, the prescription component A was stirred, dispersed and solubilized, and the mixture was added to the mouth and neutralized to obtain a composition (gel) for elect mouth poration.
生理食塩水 4 6 Saline 4 6
カルボキシビ二ルポリマー 0 . 6重量部 0.6 parts by weight of carboxyvinyl polymer
塩酸ブフレノルフィン 1 Bufrenorphin hydrochloride 1
プロピレングリコール 3 0 Propylene glycol 30
ホスファチジルコリン （リポソ一ム） 3 Phosphatidylcholine (Liposom) 3
D D
生理食塩水 1 9 Saline 1 9
水酸化力リウム 0 . 4重量部 纏卜の禾 ilffl ?T能桦 Lithium hydroxide 0.4 parts by weight
本発明によれば、エレクト口ポーレーシヨンに於ける薬物透過速度の制御手段を提供す ることができ、 医薬分野で有用である。 ADVANTAGE OF THE INVENTION According to this invention, the control means of the drug permeation rate in election poration can be provided, and it is useful in the pharmaceutical field.
Claims
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001529751A JP4801863B2 (en) | 1999-10-13 | 2000-04-06 | Transdermal permeability control agent and electroporation composition containing the same |
| AU36718/00A AU3671800A (en) | 1999-10-13 | 2000-04-06 | Percutaneous permeability-controlling agents and compositions for electroporation containing the same |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11/290534 | 1999-10-13 | ||
| JP29053499 | 1999-10-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001026690A1 true WO2001026690A1 (en) | 2001-04-19 |
Family
ID=17757280
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2000/002241 Ceased WO2001026690A1 (en) | 1999-10-13 | 2000-04-06 | Percutaneous permeability-controlling agents and compositions for electroporation containing the same |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP4801863B2 (en) |
| AU (1) | AU3671800A (en) |
| WO (1) | WO2001026690A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989006555A1 (en) * | 1988-01-21 | 1989-07-27 | Massachusetts Institute Of Technology | Transport of molecules across tissue using electroporation |
| WO1996033771A2 (en) * | 1995-04-28 | 1996-10-31 | Alza Corporation | Composition and method of enhancing electrotransport agent delivery |
| JPH09255561A (en) * | 1996-03-26 | 1997-09-30 | Hisamitsu Pharmaceut Co Inc | Microemulsion preparation for elecroporation |
-
2000
- 2000-04-06 AU AU36718/00A patent/AU3671800A/en not_active Abandoned
- 2000-04-06 WO PCT/JP2000/002241 patent/WO2001026690A1/en not_active Ceased
- 2000-04-06 JP JP2001529751A patent/JP4801863B2/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989006555A1 (en) * | 1988-01-21 | 1989-07-27 | Massachusetts Institute Of Technology | Transport of molecules across tissue using electroporation |
| WO1996033771A2 (en) * | 1995-04-28 | 1996-10-31 | Alza Corporation | Composition and method of enhancing electrotransport agent delivery |
| JPH09255561A (en) * | 1996-03-26 | 1997-09-30 | Hisamitsu Pharmaceut Co Inc | Microemulsion preparation for elecroporation |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3671800A (en) | 2001-04-23 |
| JP4801863B2 (en) | 2011-10-26 |
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