JP4521492B2 - Microneedle array and manufacturing method thereof - Google Patents
Microneedle array and manufacturing method thereof Download PDFInfo
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- JP4521492B2 JP4521492B2 JP2008335942A JP2008335942A JP4521492B2 JP 4521492 B2 JP4521492 B2 JP 4521492B2 JP 2008335942 A JP2008335942 A JP 2008335942A JP 2008335942 A JP2008335942 A JP 2008335942A JP 4521492 B2 JP4521492 B2 JP 4521492B2
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- microneedle
- water
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- microneedle array
- microneedles
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- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
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- 229960001727 tretinoin Drugs 0.000 description 1
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- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Micromachines (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Media Introduction/Drainage Providing Device (AREA)
Description
本発明は皮膚表層及び/又は皮膚角質層に修飾効果及び/又は機能効果を与えるためのマイクロニードルアレイ及びその製造方法に関する。 The present invention relates to a microneedle array for providing a modification effect and / or functional effect to the skin surface layer and / or the skin stratum corneum, and a method for producing the same.
従来、皮膚表層及び/又は皮膚角質層に修飾効果及び/又は機能効果を与えるためには、薬効成分を含む液状物質、軟膏剤、クリーム製剤、テープ製剤、バッチ製剤、パップ製剤等が使用されており、局部に塗布又は貼付することにより、薬物を皮膚や粘膜を透過して投与している。 Conventionally, liquid substances containing medicinal ingredients, ointments, cream preparations, tape preparations, batch preparations, pup preparations, and the like have been used to give a modification effect and / or functional effect to the skin surface layer and / or skin stratum corneum. The drug is administered through the skin or mucous membrane by applying or sticking it to the local area.
しかし、これらの製剤は皮膚上に塗布又は貼付することにより使用するものなので、使用中に発汗、洗浄、外的圧力等により消失したり脱落するという欠点があった。又、これらの製剤は薬効成分を皮膚に浸透させ体内に拡散することにより薬効を発揮するものであるが、皮膚表層及び/又は皮膚角質層は体内へ異物の侵入を抑止するバリアー機能を有しているので、薬理効果を発揮するのに充分な量の薬効成分を吸収させるのは困難であり、且つ、皮膚表層及び/又は皮膚角質層の特定の場所に薬効成分を確実に供給することは困難であった。 However, since these preparations are used by being applied or pasted onto the skin, there is a drawback that they disappear or fall off due to sweating, washing, external pressure, etc. during use. In addition, these preparations exhibit medicinal effects by penetrating medicinal ingredients into the skin and diffusing into the body, but the skin surface layer and / or skin stratum corneum has a barrier function to prevent the invasion of foreign substances into the body. Therefore, it is difficult to absorb a sufficient amount of a medicinal component to exert a pharmacological effect, and it is difficult to reliably supply a medicinal component to a specific location on the skin surface layer and / or the skin stratum corneum. It was difficult.
最近、これらの問題を解決し、皮膚表層及び/又は皮膚角質層の特定の場所に薬効成分を確実に供給する方法として、マイクロニードルの研究が盛んに行なわれている。例えば、マルトース等の生体内で溶解消失する糖質からなり、一辺又は直径が0.1〜100μmの正方形又は円形の断面形状であり、長さが0.5〜500μmの正方柱状又は円柱状のパイルを基板上に設けた機能性マイクロパイル(特許文献1)や中心部材の周囲にポリ乳酸、マルトース等の生分解性材料を成分として含む複数の針を設けた皮膚用針(特許文献2)が提案されている。また、最近ゼラチン等の樹脂ポリマ−を素材としたマイクロニードルも提案されている(特許文献3,特許文献4)。 Recently, research on microneedles has been actively conducted as a method for solving these problems and reliably supplying a medicinal component to a specific location on the skin surface layer and / or the skin stratum corneum. For example, it is composed of a carbohydrate that dissolves and disappears in a living body such as maltose, and has a square or circular cross-sectional shape with a side or diameter of 0.1 to 100 μm and a length of 0.5 to 500 μm. A functional micropile provided with a pile on a substrate (Patent Document 1) and a skin needle provided with a plurality of needles containing biodegradable materials such as polylactic acid and maltose as components around a central member (Patent Document 2) Has been proposed. Recently, a microneedle made of a resin polymer such as gelatin has also been proposed (
注射針や縫合針の貫通性能や引き抜き性能を向上させるため、水性シリコーン被覆組成物により表面に潤滑性を与えることも提案されている(特許文献5)。 In order to improve the penetration performance and pull-out performance of injection needles and suture needles, it has also been proposed to impart lubricity to the surface with an aqueous silicone coating composition (Patent Document 5).
上記マイクロニードルを使用する際には、マイクロパイル(針)を皮膚表層及び/又は皮膚角質層に刺すと、マイクロパイル(針)は折れて皮膚表層及び/又は皮膚角質層に残留し溶解消失する。従って、皮膚表層及び/又は皮膚角質層の特定の場所に薬効成分を確実に供給することができる。又、マイクロパイル(針)は非常に細いので皮膚表層及び/又は皮膚角質層に刺しても痛みは少ないし出血も少なく且つ穿刺創は速やかに閉鎖されるので、皮膚表層及び/又は皮膚角質層の特定の場所に薬効成分を確実に供給する方法として好適である。 When the microneedle is used, when the micropile (needle) is stabbed into the skin surface and / or skin stratum corneum, the micropile (needle) breaks and remains on the skin surface and / or skin stratum corneum and dissolves and disappears. . Therefore, a medicinal component can be reliably supplied to a specific place on the skin surface layer and / or the skin stratum corneum. In addition, since the micropile (needle) is very thin, there is little pain and no bleeding even when puncturing the skin surface layer and / or skin stratum corneum, and the puncture wound is quickly closed, so the skin surface layer and / or skin stratum corneum It is suitable as a method for reliably supplying a medicinal component to a specific place.
上記マイクロニードルを使用する際に出血せず、患者が痛みを感じないようにするにはマイクロニードルを細くする必要があるが、細くするとマイクロニードルの機械的強度が不足し、マイクロニードルを皮膚に刺す際に均一に刺せず折れてしまうという欠点があった。又、逆にマイクロニードルを皮膚に均一に且つ折れることなく刺すことができるようにするには、マイクロニードルをある程度太くする必要があるが、太くすると刺す際に痛く出血するという欠点があった。 When using the above microneedle, it is necessary to make the microneedle thin so that the patient does not bleed and feel pain. However, if the microneedle is made thin, the mechanical strength of the microneedle is insufficient, and the microneedle is placed on the skin. When stabbed, there was a defect that it would break without being uniformly stabbed. On the other hand, in order to allow the microneedle to puncture the skin uniformly and without breaking, it is necessary to make the microneedle thick to some extent.
本発明の目的は、上記欠点に鑑み、皮膚表層及び/又は皮膚角質層に折れることなく容易且つ均一に刺すことができ、皮膚表層及び/又は皮膚角質層において溶解するマイクロニードルアレイ及びその製造方法を提供することにある。 In view of the above-described drawbacks, an object of the present invention is a microneedle array that can be easily and uniformly inserted into the skin surface layer and / or skin stratum corneum and dissolves in the skin surface layer and / or skin stratum corneum, and a method for producing the same Is to provide.
本発明のマイクロニードルアレイは、水溶性又は水膨潤性でかつ生体内で溶解しうる樹脂により形成された錐台状又はコニーデ状であり、その先端の1辺又は直径は0.01〜0.08mm、その根元の1辺又は直径は0.15〜1.0mm、高さは0.1〜3.0mmである、複数の微細な針状のマイクロニードルが基板の表面に形成され、少なくともマイクロニードルの表面に流動パラフィン、スクアレン及びスクアランから選ばれた1種以上の炭化水素からなる潤滑成分が被覆されていることを特徴とする。The microneedle array of the present invention has a frustum shape or a conical shape formed of a water-soluble or water-swellable resin that can be dissolved in a living body, and one side or a diameter of the tip thereof is 0.01 to 0.00. A plurality of fine needle-like microneedles having a length of 08 mm, one side or a diameter of the base of 0.15 to 1.0 mm, and a height of 0.1 to 3.0 mm are formed on the surface of the substrate. The surface of the needle is coated with a lubricating component composed of one or more hydrocarbons selected from liquid paraffin, squalene, and squalane .
本発明で使用される水溶性又は水膨潤性樹脂は、生体内で溶解又は膨潤しうる樹脂であればよく、例えば、グリコーゲン、デキストリン、デキストラン、デキストラン硫酸、コンドロイチン硫酸ナトリウム、ヒドロキシプロピルセルロース、キトサン、アルギン酸、アガロース、チキン、キトサン、プルラン、アミロペクチン、澱粉、ヒアルロン酸などの多糖類、コラーゲン、ゼラチン、アルブミンなどの蛋白質、ポリビニルアルコール、カルボキシビニルポリマー、ポリアクリル酸ナトリウム、ポリビニルピロリドン、ポリエチレングリコール等の合成高分子が挙げられ、ヒアルロン酸、コラーゲン、ゼラチン、ポリビニルピロリドン及びポリエチレングリコールから選ばれた高分子物質が好ましい。これら水溶性又は水膨潤性樹脂は単独で用いられてもよいし、2種以上が併用されてもよい。 The water-soluble or water-swellable resin used in the present invention may be any resin that can be dissolved or swelled in a living body. For example, glycogen, dextrin, dextran, dextran sulfate, sodium chondroitin sulfate, hydroxypropylcellulose, chitosan, Synthesis of polysaccharides such as alginic acid, agarose, chicken, chitosan, pullulan, amylopectin, starch, hyaluronic acid, proteins such as collagen, gelatin, albumin, polyvinyl alcohol, carboxyvinyl polymer, sodium polyacrylate, polyvinylpyrrolidone, polyethylene glycol, etc. Examples thereof include polymers, and a polymer substance selected from hyaluronic acid, collagen, gelatin, polyvinyl pyrrolidone and polyethylene glycol is preferable. These water-soluble or water-swellable resins may be used alone or in combination of two or more.
ヒアルロン酸は、グリコサミノグリカン(ムコ多糖)の一種であり、N−アセチルグルコサミンとグルクロン酸の二糖単位が連結した構造を有している。ヒアルロン酸としては、例えば、鶏冠、臍帯等から単離される生物由来のヒアルロン酸、乳酸菌、連鎖球菌等により大量生産される培養由来のヒアルロン酸等が挙げられる。生物由来のヒアルロン酸は、その由来となる生物が有するコラーゲンを完全には除去できず、残存するコラーゲンが悪い影響を与える可能性があるので、コラーゲンを含有しない培養由来のヒアルロン酸が好ましい。従って、ヒアルロン酸は培養由来のヒアルロン酸を50重量%以上含んでいるのが好ましい。 Hyaluronic acid is a kind of glycosaminoglycan (mucopolysaccharide) and has a structure in which disaccharide units of N-acetylglucosamine and glucuronic acid are linked. Examples of hyaluronic acid include hyaluronic acid derived from organisms isolated from chicken crowns, umbilical cords, and the like, hyaluronic acid derived from culture mass-produced by lactic acid bacteria, streptococci, and the like. Biologically-derived hyaluronic acid cannot completely remove the collagen of the organism from which it is derived, and the remaining collagen may adversely affect it, so culture-derived hyaluronic acid that does not contain collagen is preferred. Therefore, the hyaluronic acid preferably contains 50% by weight or more of culture-derived hyaluronic acid.
コラーゲンはゼラチンの加水分解により得られる。ゼラチンは鶏、豚等の組織蛋白質から精製して得られる。ポリビニルピロリドン及びポリエチレングリコールは重合反応によって得られる。 Collagen is obtained by hydrolysis of gelatin. Gelatin is obtained by purifying from tissue proteins such as chicken and pig. Polyvinyl pyrrolidone and polyethylene glycol are obtained by a polymerization reaction.
ヒアルロン酸、コラーゲン、ゼラチン、ポリビニルピロリドン及びポリエチレングリコールから選ばれた高分子物質を成分として用いてマイクロニードルを作成するに当たっては、重量平均分子量が小さくなると硬くなり、大きくなると機械的強度が向上し粘り強くなる。即ち、これら高分子物質から成形されたマイクロニードルは重量平均分子量が小さくなると硬くなり皮膚に刺さりやすくなるが、機械的強度が低下し保存時や皮膚に刺入する際に折れやすくなる。逆に、重量平均分子量が大きくなると機械的強度が向上し粘り強くなるので保存時や皮膚に刺入する際に折れにくくなるが、硬さが低下し皮膚に刺さりにくくなるので重量平均分子量は5千〜200万が好ましい。 When making a microneedle using a polymer substance selected from hyaluronic acid, collagen, gelatin, polyvinyl pyrrolidone and polyethylene glycol as a component, it becomes harder when the weight average molecular weight becomes smaller, and mechanical strength improves and becomes tenacious when it becomes larger. Become. That is, microneedles formed from these polymer substances become harder and easier to pierce the skin when the weight average molecular weight becomes smaller, but the mechanical strength decreases, and the microneedles easily break when stored or inserted into the skin. Conversely, when the weight average molecular weight is increased, the mechanical strength is improved and the tenacity is increased, so that it is difficult to break during storage or penetration into the skin, but the hardness is reduced and the skin is less likely to penetrate, so the weight average molecular weight is 5,000. ~ 2 million is preferred.
又、マイクロニードルを皮膚に刺入する際には刺さりやすく折れにくく、且つ、体内で溶解しやすくするために、重量平均分子量が10万以上の高分子量高分子物質と重量平均分子量が5万以下の低分子量高分子物質の混合物からマイクロニードルを形成してもよい。 In addition, when the microneedle is inserted into the skin, it is easy to puncture and does not break, and in order to be easily dissolved in the body, a high molecular weight polymer substance having a weight average molecular weight of 100,000 or more and a weight average molecular weight of 50,000 or less. A microneedle may be formed from a mixture of the low molecular weight polymer substances.
上記高分子量高分子物質の重量平均分子量は10万以上であればよく、200万以下が好ましい。又、低分子量高分子物質の重量平均分子量は5万以下であればよく、1000以上が好ましい。尚、本発明において、重量平均分子量はゲルパーミェーションクロマトグラフィー(GPC)によって測定された値である。 The high molecular weight polymer substance may have a weight average molecular weight of 100,000 or more, preferably 2 million or less. The weight average molecular weight of the low molecular weight polymer substance may be 50,000 or less, preferably 1000 or more. In the present invention, the weight average molecular weight is a value measured by gel permeation chromatography (GPC).
又、高分子量高分子物質と低分子量高分子物質を混合する際の比率は、各高分子物質の種類及び重量平均分子量によっても異なるので、好ましい機械的強度及び硬さになるように適宜決定されればよいが、一般に、高分子量高分子物質60〜95重量%と低分子量高分子物質40〜5重量%よりなるのが好ましい。 In addition, the mixing ratio of the high molecular weight polymer substance and the low molecular weight polymer substance varies depending on the type and weight average molecular weight of each polymer substance, so that it is appropriately determined so as to obtain a preferable mechanical strength and hardness. In general, however, it preferably comprises 60 to 95% by weight of a high molecular weight polymer substance and 40 to 5% by weight of a low molecular weight polymer substance.
更に、上記水溶性又は水膨潤性樹脂に薬効成分が添加されていてもよい。薬効成分としては、従来から経皮吸収製剤として使用されている薬物及び化粧品の原料であれば特に限定されず、例えば、解熱鎮痛消炎剤、ステロイド系抗炎症剤、血管拡張剤、不整脈用剤、血圧降下剤、局所麻酔剤、ホルモン剤、抗ヒスタミン剤、全身麻酔剤、睡眠鎮痛剤、抗癲癇剤、精神神経用剤、骨格筋弛緩剤、自立神経用剤、抗パーキンソン剤、利尿剤、血管収縮剤、呼吸促進剤、麻薬等が挙げられる。 Furthermore, a medicinal component may be added to the water-soluble or water-swellable resin. The medicinal component is not particularly limited as long as it is a drug and a cosmetic raw material conventionally used as a percutaneous absorption preparation. For example, antipyretic analgesic / antiinflammatory agent, steroidal anti-inflammatory agent, vasodilator, arrhythmia agent, Antihypertensive agent, local anesthetic agent, hormonal agent, antihistamine agent, general anesthetic agent, sleep analgesic agent, antiepileptic agent, neuropsychiatric agent, skeletal muscle relaxant agent, independent nerve agent, antiparkinsonian agent, diuretic agent, vasoconstrictor agent , Respiratory stimulants, narcotics and the like.
上記解熱鎮痛消炎剤としては、例えば、イブプロフェン、フルルピプロフェン、ケトプロフェン等が挙げられ、上記ステロイド系抗炎症剤としては、例えば、ヒドロコルチゾン、トリアムシノロン、プレドニゾロン等が挙げられる。上記血管拡張剤としては、例えば、塩酸ジルチアゼム、硝酸イソソルビド等が挙げられる。上記不整脈用剤としては、例えば、塩酸プロカインアミド、塩酸メキシレチン等が挙げられる。 Examples of the antipyretic analgesic and anti-inflammatory agent include ibuprofen, flurpiprofen, ketoprofen and the like, and examples of the steroidal anti-inflammatory agent include hydrocortisone, triamcinolone and prednisolone. Examples of the vasodilator include diltiazem hydrochloride and isosorbide nitrate. Examples of the arrhythmia agent include procainamide hydrochloride, mexiletine hydrochloride and the like.
上記血圧降下剤としては、例えば、塩酸クロニジン、塩酸ブニトロロール、カプトプリル等が挙げられる。上記局所麻酔剤としては、例えば、塩酸テトラカイン、塩酸プロピトカイン等が挙げられる。上記ホルモン剤としては、例えば、プロピルチオウラシル、エストラジオール、エストリオール、プロゲステロン等が挙げられる。上記抗ヒスタミン剤としては、例えば、塩酸ジフェンヒドラミン、マレイン酸クロルフェニラミン等が挙げられる。 Examples of the antihypertensive agent include clonidine hydrochloride, bunitrolol hydrochloride, captopril and the like. Examples of the local anesthetic include tetracaine hydrochloride and propitocaine hydrochloride. Examples of the hormone agent include propylthiouracil, estradiol, estriol, progesterone and the like. Examples of the antihistamine include diphenhydramine hydrochloride and chlorpheniramine maleate.
上記全身麻酔剤としては、例えば、ペントバルビタールナトリウム等が挙げられる。上記睡眠・鎮痛剤としては、例えば、アモバルビタール、フェノバルビタール等が挙げられる。上記抗癲癇剤としては、例えば、フェニトインナトリウム等が例示される。上記精神神経用剤としては、例えば、塩酸クロルプロマジン、塩酸イミプラミン、クロルジアゼポキシド、ジアゼパム等が挙げられる。上記骨格筋弛緩剤としては、例えば、塩酸スキサメトニウム、塩酸エペリゾン等が挙げられる。 Examples of the general anesthetic include pentobarbital sodium. Examples of the sleep / analgesic agent include amobarbital and phenobarbital. Examples of the anti-epileptic agent include phenytoin sodium. Examples of the neuropsychiatric agent include chlorpromazine hydrochloride, imipramine hydrochloride, chlordiazepoxide, diazepam and the like. Examples of the skeletal muscle relaxant include sisamethonium hydrochloride, eperisone hydrochloride, and the like.
上記自立神経用剤としては、例えば、臭化ネオスチグミン、塩化ベタネコール等が挙げられる。上記抗パーキンソン剤としては、例えば、塩酸アマンタジン等が挙げられる。上記利尿剤としては、例えば、ヒドロフルメチアジド、イソソルビド、フロセミド等が挙げられる。上記血管収縮剤としては、例えば、塩酸フェニレフリン等が挙げられる。上記呼吸促進剤としては、例えば、塩酸ロベリン、ジモルホラミン、塩酸ナロキソン等が挙げられる。上記麻薬としては、例えば、塩酸モルヒネ、塩酸コカイン、塩酸ペチジン等が挙げられる。 Examples of the above-mentioned autonomic nerve agent include neostigmine bromide and betanecol chloride. Examples of the anti-Parkinson agent include amantadine hydrochloride and the like. Examples of the diuretic include hydroflumethiazide, isosorbide, furosemide and the like. Examples of the vasoconstrictor include phenylephrine hydrochloride. Examples of the respiratory accelerator include lobeline hydrochloride, dimorphoamine, naloxone hydrochloride and the like. Examples of the narcotic include morphine hydrochloride, cocaine hydrochloride, pethidine hydrochloride and the like.
上記化粧品の原料としては、例えば、パルミチン酸アスコルビル、コウジ酸、ルシノール、トラネキサム酸、油用性甘草エキス、ビタミンA誘導体等の美白成分;レチノール、レチノイン酸、酢酸レチノール、パルミチン酸レチノール等の抗しわ成分;酢酸トコフェロール、カプサイン、ノリル酸バニリルアミド等の血行促進成分;ラズベリーケトン、月見草エキス、海草エキス等のダイエット成分:イソプロピルメチルフェノール、感光素、酸化亜鉛等の抗菌成分;ビタミンD2、ビタミンD3、ビタミンK等のビタミン類などが挙げられる。Examples of the cosmetic material include whitening ingredients such as ascorbyl palmitate, kojic acid, lucinol, tranexamic acid, oily licorice extract, vitamin A derivatives; anti-wrinkles such as retinol, retinoic acid, retinol acetate, retinol palmitate, etc. Ingredients; blood circulation promoting ingredients such as tocopherol acetate, capsine, and vanillylamide; diet ingredients such as raspberry ketone, evening primrose extract and seaweed extract: antibacterial ingredients such as isopropylmethylphenol, photosensitizer and zinc oxide; vitamin D 2 , vitamin D 3 , Vitamins such as vitamin K are listed.
上記薬効成分はいずれも分子量600以下の低分子化合物であるが、高分子の薬効成分であってもよく、好ましい高分子薬効成分としては、例えば、生理活性ペプチド類とその誘導体、核酸、オリゴヌクレオチド、各種の抗原蛋白質、バクテリア、ウイルスの断片等が挙げられる。 The above-mentioned medicinal ingredients are all low molecular compounds having a molecular weight of 600 or less, but may be polymeric medicinal ingredients. Preferred polymer medicinal ingredients include, for example, physiologically active peptides and derivatives thereof, nucleic acids, oligonucleotides And various antigen proteins, bacteria, virus fragments and the like.
上記生理活性ペプチド類とその誘導体としては、例えば、カルシトニン、副腎皮質刺激ホルモン、副甲状腺ホルモン(PTH)、hPTH(1→34)、インスリン、セクレチン、オキシトシン、アンギオテンシン、β−エンドルフィン、グルカゴン、バソプレッシン、ソマトスタチン、ガストリン、黄体形成ホルモン放出ホルモン、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、成長ホルモン、成長ホルモン放出ホルモン、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、プロラクチン、インターフェロン、インターロイキン、G−CSF、グルタチオンパーオキシダーゼ、スーパーオキシドディスムターゼ、デスモプレシン、ソマトメジン、エンドセリン、及びこれらの塩等が挙げられる。抗原蛋白質としては、ジフテリアトキソイド、破傷風トキソイド、HBs表面抗原、HBe抗原等が挙げられる。 Examples of the physiologically active peptides and derivatives thereof include calcitonin, adrenocorticotropic hormone, parathyroid hormone (PTH), hPTH (1 → 34), insulin, secretin, oxytocin, angiotensin, β-endorphin, glucagon, vasopressin, Somatostatin, gastrin, luteinizing hormone releasing hormone, enkephalin, neurotensin, atrial natriuretic peptide, growth hormone, growth hormone releasing hormone, bradykinin, substance P, dynorphin, thyroid stimulating hormone, prolactin, interferon, interleukin, G- Examples include CSF, glutathione peroxidase, superoxide dismutase, desmopressin, somatomedin, endothelin, and salts thereof.Examples of the antigen protein include diphtheria toxoid, tetanus toxoid, HBs surface antigen, HBe antigen and the like.
本発明のマイクロニードルアレイのマイクロニードルの形状は錘状、錐台状又はコニーデ状であり、その根元の1辺又は直径は0.15〜1.0mm、高さは0.1〜3.0mmである。 The shape of the microneedle of the microneedle array of the present invention is a pyramid shape, a frustum shape, or a cone shape, one side or diameter of the root is 0.15 to 1.0 mm, and the height is 0.1 to 3.0 mm. It is.
錘状のマイクロニードルとしては、例えば、円錐状、楕円錘状、三角錐状、四角錘状、六角錘状等のマイクロニードルが挙げられ、その根元の1辺又は直径は0.15〜1.0mm、高さは0.1〜3.0mmであり、マイクロニードルとマイクロニードルのピッチは、短くなると皮膚に刺しにくくなり、長くなると面積あたりのマイクロニードルの数が少なくなり、所定の狭い部位に多量のマイクロニードルを供給できなくなるので、0.4〜1.0mmが好ましい。 Examples of the spindle-shaped microneedle include a microneedle having a conical shape, an elliptical cone shape, a triangular pyramid shape, a quadrangular pyramid shape, a hexagonal pyramid shape, and one side or a diameter of the root is 0.15 to 1. 0 mm, height is 0.1 to 3.0 mm, and the pitch between microneedles and microneedles is less likely to pierce the skin, and when longer, the number of microneedles per area decreases, and a predetermined narrow area is formed. Since a large amount of microneedles cannot be supplied, 0.4 to 1.0 mm is preferable.
錐台状のマイクロニードルとしては、例えば、三角錐台状、四角錘台状、六角錘台状などの角錐台状、円錐台状、楕円錘台状等のマイクロニードルが挙げられ、マイクロニードルとマイクロニードルのピッチは、短くなると皮膚に刺しにくくなり、長くなると面積あたりのマイクロニードルの数が少なくなり、所定の狭い部位に多量のマイクロニードルを供給できなくなるので、0.4〜1.0mmが好ましい。 Examples of the frustum-shaped microneedles include a triangular frustum shape, a quadrangular frustum shape, a hexagonal frustum shape, and other microneedles such as a truncated cone shape, a truncated cone shape, and an elliptic frustum shape. When the pitch of the microneedles becomes shorter, it becomes difficult to pierce the skin, and when the pitch becomes longer, the number of microneedles per area decreases, and a large amount of microneedles cannot be supplied to a predetermined narrow portion. preferable.
錐台状のマイクロニードルの根元の1辺又は直径は、細くなると皮膚に刺した際に折れて皮膚内に残るマイクロニードルの量が減少すると共に皮膚に刺す際に折れやすくなり、太くなると皮膚に刺す際に苦痛を伴うので0.15〜1.0mmであり、好ましくは、0.2〜0.5mmである。先端の1辺又は直径は、細くなると(尖っていると)皮膚に刺す際に折れやすくなり、太くなると皮膚に刺しにくくなり苦痛を伴うので0.01〜0.08mmが好ましい。 When the side or diameter of the base of the frustum-shaped microneedle is thin, it breaks when it is stabbed into the skin, and the amount of microneedles remaining in the skin decreases, and it becomes easy to break when stabbed into the skin. It is 0.15 to 1.0 mm because it causes pain when stabbed, and preferably 0.2 to 0.5 mm. One side or the diameter of the tip is preferably 0.01 to 0.08 mm because it is easy to break when it is stabbed into the skin when it is thin (pointed), and it is difficult to stab into the skin when it becomes thick and painful.
錐台状のマイクロニードルの高さは、低くなるとマイクロニードルを皮膚表層及び/又は皮膚角質層の所定位置に供給しにくくなり、高くなると皮膚に刺す際に折れやすくなるので0.1〜3.0mmであり、好ましくは0.2〜1.2mmである。 When the height of the frustum-shaped microneedle is low, it becomes difficult to supply the microneedle to a predetermined position of the skin surface layer and / or the skin stratum corneum, and when the height is high, the microneedle is easily broken when piercing the skin. 0 mm, preferably 0.2 to 1.2 mm.
コニーデ状とは、いわゆる火山型と呼ばれる形状であり、図5に示したように円錐台状の側面が内側方向に湾曲した形状であり、コニーデ状のマイクロニードルは、その先端直径は細くなると(尖っていると)皮膚に刺す際に曲がったり折れやすくなり、太くなると皮膚に刺しにくくなり苦痛を伴うので0.01〜0.05mmが好ましい。 The coneide shape is a so-called volcano shape, and the shape of the truncated cone-shaped side surface is curved inward as shown in FIG. 5. When the tip diameter of a coneide microneedle becomes thin ( When the skin is pierced, it becomes easier to bend and break, and when it gets thicker, it is difficult to pierce the skin and causes pain.
コニーデ状のマイクロニードルの高さは、低くなると皮膚に刺さりにくくなってマイクロニードルを皮膚表層及び/又は皮膚角質層の所定位置に供給しにくくなり、高くなると皮膚に刺す際に折れやすくなると共に深く刺さって苦痛を伴うようになるので0.1〜3.0mmであり、好ましくは0.15〜1.2mmである。 When the height of the conical microneedle is low, it is difficult to pierce the skin, and it is difficult to supply the microneedle to a predetermined position of the skin surface layer and / or the horny layer of the skin. The thickness is 0.1 to 3.0 mm, preferably 0.15 to 1.2 mm, because it becomes stabbed and painful.
コニーデ状のマイクロニードルの根元直径は細くなると、マイクロニードル円錐台型の側面が内側方向に湾曲する度合いが小さくなり、全体的に細くする必要があるので皮膚内に刺す際に折れやすくなり、太くなると一定面積中に立設されるマイクロニードルの数が少なくなるので、0.15〜1.0mmであり、マイクロニードルの高さの0.5〜1.2倍が好ましい。 If the root diameter of a cone needle-shaped microneedle becomes thinner, the degree of side curvature of the microneedle frustoconical shape will become smaller, and it will be necessary to make it thinner overall. In this case, the number of microneedles standing in a certain area is reduced, so that it is 0.15 to 1.0 mm, preferably 0.5 to 1.2 times the height of the microneedle.
又、コニーデ状のマイクロニードルとマイクロニードルのピッチは、短くなると皮膚に刺しにくくなり、長くなると面積あたりのマイクロニードルの数が少なくなり、所定の狭い部位に多量のマイクロニードルを供給できなくなるので、0.4〜1.0mmが好ましい。 In addition, if the pitch between the conical microneedles and the microneedles is shortened, it becomes difficult to pierce the skin, and if the pitch is increased, the number of microneedles per area decreases, and a large amount of microneedles cannot be supplied to a predetermined narrow portion. 0.4 to 1.0 mm is preferable.
本発明のマイクロニードルアレイは、上記微細な針状のマイクロニードルが基板の表面に形成されてなるが、基板はその表面にマイクロニードルを形成しうるものであれば、特に限定されないが、マイクロニードルと親和性を有する物質であることが必要である。例えば、エチルセルロース、ウレタン樹脂、アルミニウム等のフィルム又はシートが挙げられる。又、基板は、マイクロニードルを構成する水溶性又は水膨潤性樹脂よりなるフィルム又はシートであってもよい。 The microneedle array of the present invention has the fine needle-like microneedles formed on the surface of the substrate, but the substrate is not particularly limited as long as it can form microneedles on the surface. It is necessary that the substance has an affinity for. For example, a film or sheet of ethyl cellulose, urethane resin, aluminum, or the like can be given. The substrate may be a film or sheet made of a water-soluble or water-swellable resin that constitutes the microneedle.
本発明のマイクロニードルアレイは、マイクロニードルの皮膚への貫通性能を向上させるため、マイクロニードルの表面に潤滑成分が被覆されている。潤滑成分は、マイクロニードルの滑り性を向上させ、マイクロニードルが苦痛を伴うことなく皮膚に容易に刺さりやすくするためのものである。潤滑成分としては、常圧で200℃以上の沸点を有し、常温で液体又は半固体であり、水溶性又は水膨潤性樹脂と相溶性を有さない炭化水素又はエステルが好ましい。マイクロニードルを構成する水溶性又は水膨潤性樹脂は皮膚内で溶解し、酵素が関与する代謝により消失するが、これら潤滑成分もまた、皮膚内で溶解し酵素が関与する代謝により消失すると考えられる。
なお、潤滑成分は基板をも被覆していても良い。In the microneedle array of the present invention, the surface of the microneedle is coated with a lubricating component in order to improve the penetration performance of the microneedle into the skin. The lubricating component improves the slipperiness of the microneedles and makes the microneedles easily pierce the skin without causing pain. The lubricating component is preferably a hydrocarbon or ester that has a boiling point of 200 ° C. or higher at normal pressure, is liquid or semi-solid at room temperature, and is not compatible with water-soluble or water-swellable resins. The water-soluble or water-swellable resin that constitutes the microneedle dissolves in the skin and disappears due to metabolism involving the enzyme, but these lubricating components also dissolve in the skin and are thought to disappear due to metabolism involving the enzyme. .
The lubricating component may also cover the substrate.
潤滑成分の常圧での沸点が200℃未満であると加工中や保存中に揮散しやすく、水溶性又は水膨潤性樹脂と相溶性を有していると水溶性又は水膨潤性樹脂と相溶性して潤滑成分の層がなくなり滑り性が向上しなくなる。 If the boiling point at normal pressure of the lubricating component is less than 200 ° C., it will easily evaporate during processing or storage, and if it is compatible with the water-soluble or water-swellable resin, it will be compatible with the water-soluble or water-swellable resin. It becomes soluble and the lubricating component layer disappears, and the slipperiness is not improved.
上記潤滑成分としては、例えば、流動パラフィン、シリコンオイル、スクアレン、スクアラン、ラノリン、ホホバ油、ミリスチン酸イソプロピル、パルミチン酸エチル、パルミチン酸イソプロピル、ビタミンCパルミテート、ビタミンAオイル、ビタミンEオイル、サフラワー油等が挙げられる。 Examples of the lubricating component include liquid paraffin, silicone oil, squalene, squalane, lanolin, jojoba oil, isopropyl myristate, ethyl palmitate, isopropyl palmitate, vitamin C palmitate, vitamin A oil, vitamin E oil, safflower oil. Etc.
これらの中でも、流動パラフィンが特に好ましい。パラフィンは活性の置換基を有していないため化学的に非活性であり、マイクロニードル中の薬効成分と反応して薬効成分を分解あるいは変質させる可能性が殆どないためである。 Among these, liquid paraffin is particularly preferable. This is because paraffin is chemically inactive because it does not have an active substituent, and it hardly reacts with the medicinal component in the microneedle to decompose or alter the medicinal component.
マイクロニードルに好ましい潤滑成分と注射針に好ましい潤滑成分とは異なる。マイクロニードルでは潤滑成分は体内で代謝により消失する必要があるが、注射針では針と共に再び体外に取り出されるからむしろ体内に残らない成分が好ましい。従って、注射針でよく用いられるシリコーン系の被覆用組成物は、体内で酵素による代謝を受けにくく、マイクロニードルには不適当である。 The lubricating component preferred for microneedles is different from the preferred lubricating component for injection needles. In the microneedle, the lubricating component needs to be eliminated by metabolism in the body. However, in the injection needle, a component that does not remain in the body is preferable because it is taken out together with the needle. Accordingly, silicone-based coating compositions often used for injection needles are not easily metabolized by enzymes in the body and are not suitable for microneedles.
潤滑成分は少なくともマイクロニードルの表面に被覆されていればよいが、基板の表面にも被覆されてもよい。潤滑成分の被覆層の厚さは、特に限定されず、一般に0.1μm〜10μmである。 The lubricating component only needs to be coated on at least the surface of the microneedle, but may also be coated on the surface of the substrate. The thickness of the coating layer of the lubricating component is not particularly limited, and is generally 0.1 μm to 10 μm.
本発明のマイクロニードルアレイの製造方法は、特に限定されず、従来公知の任意の方法で製造されればよいが、例えば、マイクロニードルの形状が穿設された型に、上記水溶性又は水膨潤性樹脂及び必要に応じて薬効成分の水溶液を流延し、乾燥した後剥離する方法が挙げられ、潤滑成分を被覆する方法としては、例えば、剥離後、マイクロニードル上に潤滑成分を塗布する、吹き付ける等の方法が挙げられる。又、異なる製造方法として、マイクロニードルの形状が穿設された型に、潤滑成分を塗布した後、上記水溶性又は水膨潤性樹脂及び必要に応じて薬効成分の水溶液を流延し、乾燥した後剥離する方法が挙げられる。更に、異なる製造方法として、マイクロニードル形成用組成物水溶液中に微量の潤滑成分を分散させておき水を揮散させることにより潤滑成分がマイクロニードル表面にブリードすることを利用してもよい。この製造方法は、本発明におけるマイクロニードルを構成する成分は全て水溶性高分子又は水膨潤性であり潤滑成分とはきわめて相溶性が悪いことを利用した製法である。 The manufacturing method of the microneedle array of the present invention is not particularly limited, and may be manufactured by any conventionally known method. For example, the above-described water-soluble or water-swelling type is formed in a mold having a microneedle shape. A method of casting a water-soluble resin and, if necessary, an aqueous solution of a medicinal component, drying and then peeling off is exemplified. As a method of coating the lubricating component, for example, after peeling, a lubricating component is applied on the microneedle, The method of spraying etc. is mentioned. As another manufacturing method, after applying a lubricating component to a mold having a microneedle shape, the water-soluble or water-swellable resin and, if necessary, an aqueous solution of a medicinal component are cast and dried. The method of exfoliating is mentioned. Furthermore, as a different production method, it may be utilized that a lubricating component is bleed on the surface of the microneedle by dispersing a small amount of the lubricating component in the aqueous microneedle forming composition solution and volatilizing water. This manufacturing method is a manufacturing method that utilizes the fact that all the components constituting the microneedle in the present invention are water-soluble polymers or water-swellable and are extremely incompatible with the lubricating component.
本発明のマイクロニードルアレイの構成は上述の通りであり、水溶性又は水膨潤性樹脂により形成された錘状、錐台状又はコニーデ状であり、その根元の1辺又は直径は0.15〜1.0mm、高さは0.1〜3.0mmである、複数の微細な針状のマイクロニードルが基板の表面に形成され、少なくともマイクロニードルの表面に潤滑成分が被覆されているから、皮膚表層及び/又は皮膚角質層に折れることなく容易に刺すことができ、皮膚内で溶解又は膨潤したマイクロニードルを皮膚表層及び/又は皮膚角質層の特定の場所に確実に供給することができる。又、マイクロニードルに薬効成分が添加されていると、皮膚表層及び/又は皮膚角質層の特定の場所に薬効成分を確実に供給することができる。 The configuration of the microneedle array of the present invention is as described above, and is a weight, frustum, or coneide shape formed of a water-soluble or water-swellable resin, and one side or diameter of the root is 0.15 to 0.15. Since a plurality of fine needle-like microneedles having a thickness of 1.0 mm and a height of 0.1 to 3.0 mm are formed on the surface of the substrate, and at least the surface of the microneedles is coated with a lubricating component, the skin It can be easily stabbed into the surface layer and / or the skin stratum corneum without breaking, and microneedles dissolved or swollen in the skin can be reliably supplied to a specific location on the skin surface layer and / or the skin stratum corneum. Further, when a medicinal component is added to the microneedle, the medicinal component can be reliably supplied to a specific location on the skin surface layer and / or the skin stratum corneum.
次に、本発明を図面を参照して詳細に説明するが、本発明は実施例に限定されるものではない。 Next, the present invention will be described in detail with reference to the drawings, but the present invention is not limited to the examples.
(実施例1)
図1は本発明のマイクロニードルアレイの製造方法の一例を示す断面図である。図中1は、感光性樹脂に光照射するリソグラフィ法により所定形状のマイクロニードルパターンを形成した後、電鋳加工することにより所定形状のマイクロニードルパターンを転写したマイクロニードル形成用凹部11が形成された鋳型である。Example 1
FIG. 1 is a cross-sectional view showing an example of a method for producing a microneedle array of the present invention. In FIG. 1, a
マイクロニードル形成用凹部11は根元の直径が0.2mm、先端直径が0.04mm、深さ0.8mの円錐台状であり、0.8mm間隔に格子状に配列されており、1cm2あたり144個形成されている。又、マイクロニードル形成用凹部11は1辺が1.0cmの正方形内に形成されている。
図中2はヒアルロン酸水溶液層であり、重量平均分子量10万の高分子量ヒアルロン酸(紀文フードケミカル社製、商品名「FUH−SU」)、培養由来)13.5重量部と重量平均分子量1万の低分子量ヒアルロン酸(キューピー社製、商品名「ヒアルオリゴ」、培養由来)1.5重量部を水85重量部に溶解して得られたヒアルロン酸水溶液を鋳型1上に流延して形成した。 In the figure, 2 is a hyaluronic acid aqueous solution layer, high molecular weight hyaluronic acid having a weight average molecular weight of 100,000 (manufactured by Kibun Food Chemical Co., Ltd., trade name “FUH-SU”), 13.5 parts by weight and weight average molecular weight 1 Formed by casting on a mold 1 an aqueous solution of hyaluronic acid obtained by dissolving 1.5 parts by weight of 10,000 low molecular weight hyaluronic acid (trade name “Hyal-oligo”, culture origin) by 85 parts by weight of water. did.
次に、加熱してヒアルロン酸水溶液層2の水分を蒸発させた後、鋳型1から剥離した。次いで、マイクロニードルに1%流動パラフィン/エチルアルコール溶液を吹き付けてその後エチルアルコールを蒸発させて図2に示した本発明のマイクロニードルアレイを得た。図3は図2におけるA部の拡大図である。マイクロニードルアレイは基板3の表面にマイクロニードル形成用凹部11の形状が転写された微細な円錐状の多数のマイクロニードル4が立錐されており、基板3とマイクロニードル4の両方共上記高分子量ヒアルロン酸と低分子量ヒアルロン酸から形成されていた。 Next, after heating to evaporate the moisture in the hyaluronic acid
マイクロニードル4は高さaが0.8mm、根元の直径bが0.2mm、先端直径cが0.04mmである円錐台状であり、マイクロニードル4とマイクロニードル4の間隔dは0.8mmで格子状に配列されており、1cm2あたり144個形成されていた。マイクロニードル4の表面には約1μmの厚さの流動パラフィン層5が被覆されていた。又、基板3の厚さeは0.2mmであり、1辺が1.0cmの正方形であった。The
得られたマイクロニードルアレイを被験者の額に軽く押し当てると、マイクロニードル4は皮膚に容易に刺入され且つ60分後には皮膚内刺入部は皮膚内で溶解して形をとどめなかった。この際、被験者は痛みを感じなかった。又、剥離後の基板2を顕微鏡で観察したところマイクロニードル4は100%溶けており全く残存していなかった。 When the obtained microneedle array was lightly pressed against the subject's forehead, the
(実施例2)
重量平均分子量50万の高分子量ゼラチン(ニッピ社製、商品名「ニッピゼラチン」、豚皮由来)13.5重量部と重量平均分子量1万の低分子量ヒアルロン酸(キューピー社製、商品名「ヒアルオリゴ」、培養由来)1.5重量部を水85重量部に溶解して混合物水溶液を得た。(Example 2)
High molecular weight gelatin with a weight average molecular weight of 500,000 (Nippi, trade name “Nippi Gelatin”, derived from pork skin) 13.5 parts by weight and low molecular weight hyaluronic acid with a weight average molecular weight of 10,000 (trade name “Hyaluoligo”, produced by Kewpie) ", Derived from culture) 1.5 parts by weight was dissolved in 85 parts by weight of water to obtain a mixed aqueous solution.
実施例1で用いた鋳型のマイクロニードル形成用凹部11に1%流動パラフィン/エチルアルコール溶液を吹き付けてその後エチルアルコールを蒸発させ、次いで得られた混合物水溶液を鋳型1上に流延し加熱してマイクロニードルを形成し、更に、その上に10重量%ポリビニルアルコール(クラレ社製、商品名「PVA203」)水溶液を流延し加熱して水分を蒸発させて基板を形成した後、鋳型1から剥離してマイクロニードルアレイを作成した。マイクロニードル4の表面には約1μmの厚さの流動パラフィン層が被覆されていた。得られたマイクロニードルアレイはマイクロニードルが上記高分子量ゼラチンと低分子量ヒアルロン酸から形成され、基板はポリビニルアルコールから構成されていた。 A 1% liquid paraffin / ethyl alcohol solution is sprayed on the
得られたマイクロニードルアレイを被験者の額に軽く押し当てると、マイクロニードル4は皮膚に容易に刺入された。この際、被験者は痛みを感じなかった。180分後に剥離後の基板2を顕微鏡で観察したところマイクロニードル4は先端部皮膚内に全て残留して基板には全く残存していなかった。 When the obtained microneedle array was lightly pressed against the subject's forehead, the
(実施例3)
図4は本発明のマイクロニードルアレイの製造方法の異なる例を示す断面図である。図中1’は、感光性樹脂に光照射するリソグラフィ法によりコニーデ型のマイクロニードルパターンを形成した後、電鋳加工することによりコニーデ型のマイクロニードルパターンを転写したコニーデ型のマイクロニードル形成用凹部11’が形成された鋳型である。(Example 3)
FIG. 4 is a cross-sectional view showing a different example of the manufacturing method of the microneedle array of the present invention. In the figure, 1 ′ represents a concave portion for forming a coneide type microneedle, in which a coneide type microneedle pattern is formed by electroforming after forming a coneide type microneedle pattern by a lithography method in which a photosensitive resin is irradiated with light. 11 ′ is a template formed.
マイクロニードル形成用凹部11’は根元の直径が0.6mm、先端直径が0.02mm、深さ0.4mのコニーデ型であり、0.8mm間隔に格子状に配列されており、1cm2あたり144個形成されている。又、マイクロニードル形成用凹部11は1辺が1.0cmの正方形内に形成されていた。Microneedle forming recess 11 'is 0.6mm is the root diameter, the tip diameter 0.02 mm, a volcano-type depth 0.4 m, are arranged in a lattice pattern on 0.8mm interval, per 1 cm 2 144 are formed. In addition, the
図中2’は、室温で水100重量部にコラーゲン(株式会社ニッピ製、商品名「リヤスシャーク」、重量平均分子量5,000)20重量部を溶解した水溶液24重量部と水溶性コラーゲン1重量%水溶液(高研社製、商品名「ブタアテコラーゲン」)100重量部を混合した水溶液を鋳型1’上に流延して形成した水溶液層である。 In the figure, 2 ′ represents 24 parts by weight of an aqueous solution obtained by dissolving 20 parts by weight of collagen (trade name “Rias Shark”, weight average molecular weight 5,000, manufactured by Nippi Corporation) in 100 parts by weight of water at room temperature and 1 part by weight of water-soluble collagen. It is an aqueous solution layer formed by casting an aqueous solution mixed with 100 parts by weight of a 100% aqueous solution (trade name “Butaate Collagen”, manufactured by Koken Co., Ltd.) on the mold 1 ′.
次に、加熱して混合水溶液層2’の水分を蒸発させた後、鋳型1’から剥離した。次いで、マイクロニードルに1重量%流動パラフィン/エチルアルコール溶液を吹き付けた後、エチルアルコールを蒸発させて、図5に示した本発明のマイクロニードルアレイを得た。マイクロニードルアレイは基板3’の表面にマイクロニードル形成用凹部11’の形状が転写された微細なコニーデ型の多数のマイクロニードル4’が立錐されており、基板3’とマイクロニードル4’の両方共上記コラーゲンから形成されていた。 Next, the mixture was heated to evaporate moisture from the mixed
マイクロニードル4’は高さa’が0.4mm、根元の直径b’が0.6mm、先端直径c’が0.02mmであるコニーデ型であり、マイクロニードル4’とマイクロニードル4’の間隔d’は0.8mmで格子状に配列されており、1cm2あたり144個形成されていた。マイクロニードル4’の表面には約1μmの厚さの流動パラフィン層が被覆されていた。又、基板3’の厚さe’は0.2mmであり、1辺が1.0cmの正方形であった。The
得られたマイクロニードルアレイを被験者の額に軽く押し当てると、マイクロニードル4’は皮膚に容易に刺入され且つ60分後には皮膚内刺入部は皮膚内で溶解して形をとどめなかった。この際、被験者は痛みを感じなかった。又、剥離後の基板2’を顕微鏡で観察したところマイクロニードル4’は上部の30%(0.12mm)が溶けており、下部の70%(0.28mm)は残存していた。 When the obtained microneedle array was lightly pressed against the subject's forehead, the microneedle 4 'was easily inserted into the skin, and after 60 minutes, the intradermal insertion portion dissolved in the skin and did not retain its shape. . At this time, the subject felt no pain. Further, when the peeled substrate 2 'was observed with a microscope, the upper part 30% (0.12mm) of the microneedle 4' was melted, and the lower part 70% (0.28mm) remained.
(実施例4)
室温で水100重量部にゼラチン(株式会社ニッピ製、商品名「ニッピハイグレートゼラチンAPAT」、重量平均分子量60,000)15重量部を溶解して、ゼラチン水溶液を得た。得られた水溶液を用いて実施例3で行ったと同様にして、表面に約1μmの厚さの流動パラフィン層が被覆されているコニーデ型のマイクロニードルを有するマイクロニードルアレイを得た。得られたマイクロニードルアレイを直径2cmの円形の保護絆創膏上に置き、保護絆創膏と共に、被験者の額の皺の部分の皮膚内に挿入し1時間後に取り除いた。投与直後から皺の部分がふっくらと膨れ皺が目立たなくなり、その効果は投与後約1ヵ月持続した。Example 4
15 parts by weight of gelatin (manufactured by Nippi Corporation, trade name “Nippi High Great Gelatin APAT”, weight average molecular weight 60,000) was dissolved in 100 parts by weight of water at room temperature to obtain a gelatin aqueous solution. In the same manner as in Example 3 using the obtained aqueous solution, a microneedle array having a Conide type microneedle having a surface coated with a liquid paraffin layer having a thickness of about 1 μm was obtained. The obtained microneedle array was placed on a circular protective bandage having a diameter of 2 cm, and inserted into the skin of the subject's forehead together with the protective bandage, and removed after 1 hour. Immediately after administration, the wrinkles swelled and the wrinkles became inconspicuous, and the effect persisted for about 1 month after administration.
(実施例5)
室温で水1gにゼラチン(ニッピ社製、商品名「ニッピゼラチン」、重量平均分子量10万)0.15g及びヒアルロン酸ナトリウム(紀文フードケミカル社製、商品名「FCH−SU」、培養由来、重量平均分子量10万)0.05gを溶解して、ゼラチン−ヒアルロン酸ナトリウム混合水溶液を得た。別途、牛インスリン(ナカライテスク社製)をpH2.5の塩酸水溶液に溶解して0.003g/mlの水溶液を得た。得られた水溶液の1mlを上記混合液に添加しインスリン−ゼラチン−ヒアルロン酸ナトリウム水溶液を得た。更に、ステアリン酸メチルの1mgを0.1mlのエタノールに溶解した溶液を得られたインスリン−ゼラチン−ヒアルロン酸ナトリウム水溶液に添加し、よく攪拌してインスリン水溶液を得た。得られたインスリン水溶液を用いて実施例3で行ったと同様にして、コニーデ型のマイクロニードルを有するマイクロニードルアレイを得た。尚、マイクロニードルに1重量%流動パラフィン/エチルアルコール溶液を吹き付けなかった。
得られたマイクロニードルアレイのマイクロニードル表面にステアリン酸メチルがブリードして約1μmの厚さのステアリン酸メチル層が形成されていた。得られたマイクロニードルアレイを直径2cmの円形の保護絆創膏上に置き、保護絆創膏と共に、下記の血糖降下試験に供した。(Example 5)
0.15 g of gelatin (Nippi, trade name “Nippi Gelatin”, weight average molecular weight 100,000) and sodium hyaluronate (trade name “FCH-SU”, trade name “FCH-SU”, manufactured by Kibun Food Chemical Co., Ltd.) An average molecular weight of 100,000) 0.05 g was dissolved to obtain a gelatin-sodium hyaluronate mixed aqueous solution. Separately, bovine insulin (manufactured by Nacalai Tesque) was dissolved in a hydrochloric acid aqueous solution having a pH of 2.5 to obtain a 0.003 g / ml aqueous solution. 1 ml of the obtained aqueous solution was added to the above mixture to obtain an insulin-gelatin-sodium hyaluronate aqueous solution. Further, a solution obtained by dissolving 1 mg of methyl stearate in 0.1 ml of ethanol was added to the obtained insulin-gelatin-sodium hyaluronate aqueous solution, and stirred well to obtain an insulin aqueous solution. A microneedle array having a coneide type microneedle was obtained in the same manner as in Example 3 using the obtained aqueous insulin solution. In addition, the 1 wt% liquid paraffin / ethyl alcohol solution was not sprayed on the microneedle.
On the surface of the microneedle of the obtained microneedle array, methyl stearate was bleeded to form a methyl stearate layer having a thickness of about 1 μm. The obtained microneedle array was placed on a circular protective bandage having a diameter of 2 cm, and subjected to the following blood glucose lowering test together with the protective bandage.
糖尿病ラットモデルの作成
ストレプトゾトシン(STZ)をクエン酸緩衝液(pH4.4)に溶解しSTZ溶液を作成した。ラット尾静脈から50mg/1kgのSTZ溶液を投与し、2週目及び3週目に血糖値を測定し空腹時血糖が250mg/dl以上のラットを糖尿病モデルラットして以下の血糖降下試験に供した。 Preparation of diabetic rat model Streptozotocin (STZ) was dissolved in citrate buffer (pH 4.4) to prepare an STZ solution. A 50 mg / 1 kg STZ solution was administered from the rat tail vein, blood glucose levels were measured at 2 and 3 weeks, and rats with fasting blood glucose of 250 mg / dl or more were diabetic model rats and used in the following hypoglycemic test. did.
血糖降下試験
試験前日から糖尿病モデルラットを14時間絶食させた。ラットをネンブタール(30mg/kg)で麻酔後,腹部皮膚を剃毛し、上記のインスリンマイクロニードルを1枚の保護絆創膏で裏打ちして投与した。投与時間は1時間であった。3時間後、5時間後、7時間後及び9時間後に採血し血糖測定して結果を表1に示した。Diabetic model rats were fasted for 14 hours from the day before the hypoglycemic test . The rat was anesthetized with Nembutal (30 mg / kg), the abdominal skin was shaved, and the insulin microneedle was lined with one protective bandage and administered. The administration time was 1 hour. Blood was collected after 3 hours, 5 hours, 7 hours and 9 hours, and blood glucose was measured. The results are shown in Table 1.
(比較例1)
マイクロニードル4に流動パラフィンを被覆しない以外は実施例1で行なったと同様にしてマイクロニードルアレイを得た。得られたマイクロニードルアレイを被験者の額に押し当てると皮膚内へ刺さりにくく、力をいれて押すと刺さるが、被験者は強い痛みを感じ、又、出血も見られた。(Comparative Example 1)
A microneedle array was obtained in the same manner as in Example 1 except that the
(比較例2)
マイクロニードル4の高さaを3.5mmとした以外は実施例1で行なったと同様にしてマイクロニードルアレイを得た。得られたマイクロニードルアレイを被験者の額に押し当てると皮膚内へ刺さるが、被験者は強い痛みを感じ、又、出血も見られた。又、剥離後の基板2を顕微鏡で観察したところマイクロニードル4は約15%が折れ曲がって残存していた。(Comparative Example 2)
A microneedle array was obtained in the same manner as in Example 1 except that the height a of the
(比較例3)
マイクロニードル4の根元直径bを1.5mmとした以外は実施例1で行なったと同様にしてマイクロニードルアレイを得た。得られたマイクロニードルアレイを被験者の手の甲に強く押し当て刺針したところ被験者は痛みを感じた。1時間後針を取り出し基板2を顕微鏡で観察したところマイクロニードル4は先端部の0.2mmが溶けていた。(Comparative Example 3)
A microneedle array was obtained in the same manner as in Example 1 except that the root diameter b of the
1 鋳型
11 マイクロニードル形成用凹部
2 ヒアルロン酸水溶液層
3 基板
4 マイクロニードル
5 流動パラフィン層DESCRIPTION OF SYMBOLS 1
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