JP6605722B2 - Composition for injection of skin tissue regeneration or volume-enhanced skin tissue containing hollow porous microspheres - Google Patents
Composition for injection of skin tissue regeneration or volume-enhanced skin tissue containing hollow porous microspheres Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/31—Hydrocarbons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
Description
本発明は、皮膚シワ及び陥没部位の改善のための皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物に関する。 The present invention relates to a composition for injecting skin tissue or increasing volume of skin tissue for the improvement of skin wrinkles and depressions.
美容施術を目的として販売されている美容施術用医療機器のうちのフィラー（ｆｉｌｌｅｒ）は、シワや陥没部位の皮膚組織に注入するといった方式で用いられる。 Of the medical devices for cosmetic treatment sold for the purpose of cosmetic treatment, a filler is used in such a manner that it is injected into the skin tissue of wrinkles or depressions.
大半のフィラーは皮膚組織に注入され、該物質自体の体積によって皮膚組織の体積を増大させる方式で皮膚しわや陥没部位を改善する。現在最も多用されるフィラーとしては、ヒアルロン酸とコラーゲンなどのゲル状の無形物質があるが、経時的に皮膚組織内に吸収されることでその美容施術の効果が長期に亘り保持されないという問題がある。 Most fillers are injected into the skin tissue to improve skin wrinkles and depressions in a manner that increases the volume of the skin tissue by the volume of the material itself. Currently, the most frequently used fillers include gel-like intangible substances such as hyaluronic acid and collagen, but the problem is that the effect of the cosmetic treatment is not maintained for a long time by being absorbed into the skin tissue over time. is there.
また、美容施術用医療機器として幅広い使用範囲を有するためには、注射によって伝達しなければならないが、既存開発のフィラー成分である多孔性材料はその大きさが数十ｍｍ以上であったため注射によっては皮膚組織への移植が不可能であり、専ら皮膚組織を切開する手術によって皮膚組織内に移植しなければならないという短所があった。 In addition, in order to have a wide range of use as a medical device for beauty treatment, it must be transmitted by injection, but since the porous material that is an already developed filler component has a size of several tens of mm or more, it can be transmitted by injection. Cannot be transplanted into the skin tissue, and has to be transplanted into the skin tissue exclusively by the operation of incising the skin tissue.
本発明の一目的は、多孔性微小球を注射によって皮膚組織内に注入することができ、且つ前記多孔性微小球内で細胞を増殖させて皮膚組織の体積を増大させることができる皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することにある。 An object of the present invention is to provide a skin tissue that can inject porous microspheres into the skin tissue by injection, and can increase the volume of the skin tissue by growing cells in the porous microsphere. It is to provide a composition for injecting regenerative or volumetric skin tissue.
前記したような目的を解決するために、本発明の一観点は、中央に形成された空洞；及び前記空洞を取り囲む、微細気孔を含む隔壁を含む中空多孔性微小球を含む皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供する。 In order to solve the above-mentioned object, one aspect of the present invention is to regenerate skin tissue including a hollow formed in the center; and hollow porous microspheres including a partition including micropores surrounding the cavity; A composition for injecting volume of skin tissue is provided.
本発明に係る組成物に含まれる中空多孔性微小球は小さい粒子サイズを有することで、既存の多孔性材料は大きい粒子サイズによって皮膚組織を切開して移植しなければならなかったという短所を解決することができる。 The hollow porous microspheres contained in the composition according to the present invention have a small particle size, which solves the disadvantage that the existing porous material had to be incised and transplanted by skin tissue with a large particle size. can do.
前記中空多孔性微小球は、粒子内の中央に形成された巨大空洞と微細気孔を含む隔壁を含む二重構造を有するので、生体内皮膚組織細胞がチャンネルとして前記微細気孔を用いて前記中空多孔性微小球内に容易に移動することができ、前記空洞内で前記移動した皮膚組織細胞が効果的に増殖することができる。さらには、前記本発明に係る中空多孔性微小球は、皮膚組織の再生によって皮膚シワ又は陥没部位の改善だけでなく、骨組織の再生のような医薬の産業にも適用され得る。 Since the hollow porous microsphere has a double structure including a giant cavity formed in the center of the particle and a partition wall including fine pores, skin tissue cells in vivo use the fine pores as channels to form the hollow porous microspheres. Can be easily moved into the microsphere, and the moved skin tissue cells can be effectively proliferated in the cavity. Furthermore, the hollow porous microspheres according to the present invention can be applied not only to the improvement of skin wrinkles or depressions by regeneration of skin tissue, but also to the pharmaceutical industry such as regeneration of bone tissue.
また、本発明によれば、一定期間の経過後に前記中空多孔性微小球が皮膚内で生分解した後で前記新規に増殖した皮膚組織細胞がその体積を保持するので、皮膚組織のボリューム増進効果を増大させるだけでなく、その効果を安全且つ長期に亘り保持することができる。 Further, according to the present invention, since the newly grown skin tissue cells retain their volume after the hollow porous microspheres are biodegraded in the skin after a certain period of time, the volume enhancement effect of the skin tissue is maintained. In addition, the effect can be maintained safely and for a long time.
本明細書において「皮膚」とは、生物の外部を覆っている器官を意味するものであって、表皮、真皮及び皮下脂肪層から構成されており、顔またはからだ全体の外部を覆う組織だけでなく、頭皮と毛髪を含む最広義の概念である。 In this specification, “skin” means an organ that covers the outside of a living organism, and is composed of the epidermis, dermis, and subcutaneous fat layer. It is the broadest concept including scalp and hair.
本明細書において「フィラー（ｆｉｌｌｅｒ）」とは、体内に注入される充填剤、補強剤などを意味するものであって、皮膚の表皮、真皮、または皮下脂肪層や関節などに美容、整形、機能強化のために注入される物質がいずれも含まれる最広義の意味である。 As used herein, the term “filler” refers to a filler, a reinforcing agent, or the like that is injected into the body, and is used for cosmetics, shaping, skin epidermis, dermis, subcutaneous fat layer, joints, and the like. This means in the broadest sense that any substance that is injected for functional enhancement is included.
本明細書において「平均径」とは、対象の横断面の両端を結ぶ線分である径を平均した値を意味し、例えば、本発明の空洞の場合、中空多孔性微小球内に形成される空洞が真球状ではないときに前記空洞自体が持つ径の平均値を意味していてよい。または、複数の微小球内に存在する各空洞の径の平均値を意味していてもよい。微細気孔の場合、微細気孔自体が真球状ではないときに前記微細気孔自体が持つ径の平均値または複数の微細気孔の径の平均値を意味していてよい。 In the present specification, the “average diameter” means a value obtained by averaging the diameters that are line segments connecting both ends of the cross section of the object. For example, in the case of the cavity of the present invention, the average diameter is formed in the hollow porous microsphere. It may mean an average value of the diameters of the cavities themselves when the cavities are not spherical. Or you may mean the average value of the diameter of each cavity which exists in a some microsphere. In the case of fine pores, it may mean the average value of the diameters of the fine pores themselves or the average value of the diameters of a plurality of fine pores when the fine pores themselves are not spherical.
以下、本発明を詳しく説明する。 The present invention will be described in detail below.
本発明の一実施例は、中央に形成された空洞；及び前記空洞を取り囲む、微細気孔を含む隔壁を含む中空多孔性微小球を含む、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供する。 One embodiment of the present invention is a composition for injecting skin tissue or increasing volume of skin tissue, comprising a hollow formed in the center; and hollow porous microspheres comprising a partition wall containing micropores surrounding the cavity. I will provide a.
本発明の他の一実施例は、皮膚組織の再生又は皮膚組織のボリューム増進のための注射方法であって、当該方法は、中空多孔性微小球を含む組成物を必要対象に有効量で投与する段階を含み、前記中空多孔性微小球が、前記中央に形成された空洞及び前記空洞を取り囲む微細気孔を含む隔壁を含むものを提供することができる。 Another embodiment of the present invention is an injection method for skin tissue regeneration or skin tissue volume increase comprising administering an effective amount of a composition comprising hollow porous microspheres to a subject. The hollow porous microsphere may include a partition including a cavity formed in the center and a micropore surrounding the cavity.
本発明の他の一実施例は、中空多孔性微小球の皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物の製造のための使用であって、前記中空多孔性微小球が、前記中央に形成された空洞及び前記空洞を取り囲む微細気孔を含む隔壁を含むものを提供することができる。 Another embodiment of the present invention is the use of hollow porous microspheres for the production of skin tissue regeneration or skin tissue volume-enhancing composition, wherein the hollow porous microspheres And a partition including a fine pore surrounding the cavity.
本発明の他の一実施例は、皮膚組織の再生又は皮膚組織のボリューム増進注射に用いるための中空多孔性微小球であって、当該中空多孔性微小球が、前記中央に形成された空洞及び前記空洞を取り囲む微細気孔を含む隔壁を含むものを提供することができる。 Another embodiment of the present invention is a hollow porous microsphere for use in skin tissue regeneration or skin tissue volume enhancement injection, wherein the hollow porous microsphere comprises a cavity formed in the center and It is possible to provide one including a partition wall including fine pores surrounding the cavity.
一実施例として、前記中空多孔性微小球の中央に形成された空洞は５〜１５０μｍの平均径を有していてよい。前記空洞の径が５μｍ未満であると細胞の成長が困難となり、また１５０μｍを超えると微小球の強度が弱すぎて生体内注入の際に破壊され得る。具体的に、前記空洞の平均径は、５μｍ以上、１０μｍ以上、１３μｍ以上、１５μｍ以上、１７μｍ以上、２０μｍ以上、２３μｍ以上、２５μｍ以上、２７μｍ以上、３０μｍ以上、３３μｍ以上、３５μｍ以上、３７μｍ以上、４０μｍ以上、４３μｍ以上、４５μｍ以上、４８μｍ以上、５０μｍ以上、６０μｍ以上、７０μｍ以上、８０μｍ以上、９０μｍ以上、１００μｍ以上、１１０μｍ以上、１２０μｍ以上、１３０μｍ以上、１４０μｍ以上または１５０μｍであってよい。また、前記空洞の平均径は、１５０μｍ以下、１４０μｍ以下、１３０μｍ以下、１２０μｍ以下、１１０μｍ以下、１００μｍ以下、９０μｍ以下、８０μｍ以下、７０μｍ以下、６０μｍ以下、５０μｍ以下、４７μｍ以下、４５μｍ以下、４３μｍ以下、４０μｍ以下、３７μｍ以下、３５μｍ以下、３３μｍ以下、３０μｍ以下、２８μｍ以下、２５μｍ以下、２３μｍ以下、２０μｍ以下、１８μｍ以下、１５μｍ以下、１３μｍ以下、１０μｍ以下または５μｍであってよいが、皮膚組織細胞の増殖が可能な大きさであれば必ずしも前記した大きさに制限されるものではない。 As an example, the cavity formed in the center of the hollow porous microsphere may have an average diameter of 5 to 150 μm. If the diameter of the cavity is less than 5 μm, cell growth becomes difficult, and if it exceeds 150 μm, the strength of the microsphere is too weak and can be destroyed during in vivo injection. Specifically, the average diameter of the cavity is 5 μm or more, 10 μm or more, 13 μm or more, 15 μm or more, 17 μm or more, 20 μm or more, 23 μm or more, 25 μm or more, 27 μm or more, 30 μm or more, 33 μm or more, 35 μm or more, 37 μm or more, It may be 40 μm or more, 43 μm or more, 45 μm or more, 48 μm or more, 50 μm or more, 60 μm or more, 70 μm or more, 80 μm or more, 90 μm or more, 100 μm or more, 110 μm or more, 120 μm or more, 130 μm or more, 140 μm or more. The average diameter of the cavity is 150 μm or less, 140 μm or less, 130 μm or less, 120 μm or less, 110 μm or less, 100 μm or less, 90 μm or less, 80 μm or less, 70 μm or less, 60 μm or less, 50 μm or less, 47 μm or less, 45 μm or less, 43 μm or less. 40 μm or less, 37 μm or less, 35 μm or less, 33 μm or less, 30 μm or less, 28 μm or less, 25 μm or less, 23 μm or less, 20 μm or less, 18 μm or less, 15 μm or less, 13 μm or less, 10 μm or less, or 5 μm The size is not necessarily limited to the above-described size as long as it can grow.
一実施例として、本発明に係る組成物に含まれる前記中空多孔性微小球の粒子は、５０〜２００μｍの平均径を有していてよいが、注射によって皮膚組織内注入が可能であり、且つ皮膚組織細胞の増殖が可能であれば必ずしも前記範囲に制限されるものではない。前記中空多孔性微小球は、前記したような範囲の小さい粒子サイズを有することで、皮膚組織内に３００μｍ以下の内径を有する注射針を介して投与することができ、既存の多孔性材料は大きい粒子サイズによって皮膚組織を切開して移植する必要があったという短所を解決することができる。前記中空多孔性微小球の径が５０μｍ未満であると皮膚組織細胞の増殖が困難となり、また２００μｍを超えると皮膚組織内への注射針を用いた多孔性微小球の移植が容易ではない。具体的に、前記中空多孔性微小球粒子の平均径は、５０μｍ以上、６０μｍ以上、７０μｍ以上、８０μｍ以上、９０μｍ以上、１００μｍ以上、１１０μｍ以上、１２０μｍ以上、１３０μｍ以上、１４０μｍ以上、１５０μｍ以上、１６０μｍ以上、１７０μｍ以上、１８０μｍ以上、１９０μｍ以上または２００μｍであってよい。また、前記中空多孔性微小球粒子の平均径は、２００μｍ以下、１９０μｍ以下、１８０μｍ以下、１７０μｍ以下、１６０μｍ以下、１５０μｍ以下、１４０μｍ以下、１３０μｍ以下、１２０μｍ以下、１１０μｍ以下、１００μｍ以下、９０μｍ以下、８０μｍ以下、７０μｍ以下、６０μｍ以下または５０μｍであってよい。 As an example, the hollow porous microsphere particles contained in the composition according to the present invention may have an average diameter of 50 to 200 μm, but can be injected into skin tissue by injection, and If the proliferation of skin tissue cells is possible, it is not necessarily limited to the above range. Since the hollow porous microspheres have a small particle size in the above-described range, they can be administered into the skin tissue via an injection needle having an inner diameter of 300 μm or less, and existing porous materials are large. The disadvantage of having to cut and transplant skin tissue according to the particle size can be solved. When the diameter of the hollow porous microsphere is less than 50 μm, the proliferation of skin tissue cells becomes difficult, and when it exceeds 200 μm, the implantation of the porous microsphere using an injection needle into the skin tissue is not easy. Specifically, the average diameter of the hollow porous microsphere particles is 50 μm or more, 60 μm or more, 70 μm or more, 80 μm or more, 90 μm or more, 100 μm or more, 110 μm or more, 120 μm or more, 130 μm or more, 140 μm or more, 150 μm or more, 160 μm. As described above, it may be 170 μm or more, 180 μm or more, 190 μm or more, or 200 μm. The average diameter of the hollow porous microsphere particles is 200 μm or less, 190 μm or less, 180 μm or less, 170 μm or less, 160 μm or less, 150 μm or less, 140 μm or less, 130 μm or less, 120 μm or less, 110 μm or less, 100 μm or less, 90 μm or less, It may be 80 μm or less, 70 μm or less, 60 μm or less, or 50 μm.
一実施例として、前記中空多孔性微小球の空洞の体積は、前記中空多孔性微小球の全体積に対し２０〜８０体積％であってよい。前記２０体積％未満であると皮膚組織細胞が増殖する空間が十分ではなく、また８０体積％を超えると、隔壁の厚みが薄すぎるようになるため微小球の形態が保持できずに崩れ得る。一実施例として、前記隔壁の厚みは、前記中空多孔性微小球の全径の１／５〜１／２であってよい。 As an example, the volume of the hollow of the hollow porous microsphere may be 20 to 80% by volume with respect to the total volume of the hollow porous microsphere. If the volume is less than 20% by volume, the space in which the skin tissue cells grow is not sufficient, and if it exceeds 80% by volume, the thickness of the partition wall becomes too thin and the shape of the microspheres cannot be maintained and may collapse. As an example, the thickness of the partition may be 1/5 to 1/2 of the total diameter of the hollow porous microsphere.
具体的に、前記中空多孔性微小球の隔壁に含まれる微細気孔は、一実施例として、５〜５０μｍの平均径を有していてよい。前記平均径が５μｍ未満であると前記中空多孔性微小球を皮下組織に注入したときに皮膚組織細胞が微小球内部に移動することができず、また前記平均径が５０μｍを超えると隔壁内気孔の占める体積が増加して微小球の形態が保持され難くなる。 Specifically, the fine pores included in the partition walls of the hollow porous microspheres may have an average diameter of 5 to 50 μm as an example. When the average diameter is less than 5 μm, skin tissue cells cannot move into the microsphere when the hollow porous microspheres are injected into the subcutaneous tissue, and when the average diameter exceeds 50 μm, the pores in the partition walls Increases the volume occupied by the microspheres, making it difficult to maintain the shape of the microspheres.
例えば、前記中空多孔性微小球の好ましい孔隙率は、平均２０〜８０％であってよい。
本発明の一実施例に係る前記中空多孔性微小球は、一実施例として、疎水性の生分解性高分子を含んでいてよい。具体的に、前記疎水性の生分解性高分子としては、ポリ乳酸（Ｐｏｌｙ−Ｌ−Ｌａｃｔｉｃ Ａｃｉｄ、ＰＬＬＡ）、ポリグリコール酸（ｐｏｌｙｇｌｙｃｏｌｉｃ ａｃｉｄ、ＰＧＡ）、ポリ乳酸−グリコール酸共重合体（ｐｏｌｙ（ｌａｃｔｉｃ−ｃｏ−ｇｌｙｃｏｌｉｃ ａｃｉｄ）、ＰＬＧＡ）、ポリ−ε−（カプロラクトン）（Ｐｏｌｙｃａｐｒｏｌａｃｔｏｎｅ、ＰＣＬ）、ポリ無水物（ｐｏｌｙａｎｈｙｄｒｉｄｅｓ）、ポリオルトエステル（ｐｏｌｙｏｒｔｈｏｅｓｔｅｒ）、ポリビニルアルコール（ｐｏｌｙｖｉｎｉｙａｌｃｏｈｏｌ）、ポリエチレングリコール（ｐｏｌｙｅｔｈｙｌｅｎｅｇｌｙｃｏｌ）、ポリウレタン（ｐｏｌｙｕｒｅｔｈａｎｅ）、ポリアクリル酸（ｐｏｌｙａｃｒｙｌｉｃ ａｃｉｄ）、ポリ−Ｎ−イソプロピルアクリルアミド（Ｐｏｌｙ−Ｎ−ｉｓｏｐｒｏｐｙｌ ａｃｒｙｌａｍｉｄｅ）、ポリ（エチレンオキサイド）−ポリ（プロピレンオキサイド）−ポリ（エチレンオキサイド）共重合体（ｐｏｌｙ ｅｔｈｙｌｅｎｅ ｏｘｉｄｅ）−ｐｏｌｙ ｐｒｏｐｙｌｅｎｅ ｏｘｉｄｅ−ｐｏｌｙ ｅｔｈｙｌｅｎｅ ｏｘｉｄｅ ｃｏｐｏｌｙｍｅｒ）、これらの共重合体、及びこれらの混合物からなる群より選択された一つ以上を含んでいてよいが、皮膚組織内に注入されたときに安全且つ分解可能なものであれば必ずしもこれらに制限されものではない。
For example, the average porosity of the hollow porous microspheres may be 20 to 80%.
As an example, the hollow porous microsphere according to an embodiment of the present invention may include a hydrophobic biodegradable polymer. Specifically, examples of the hydrophobic biodegradable polymer include polylactic acid (Poly-L-Lactic Acid, PLLA), polyglycolic acid (PGA), and polylactic acid-glycolic acid copolymer (poly (poly (L)). (lactic-co-glycolic acid), PLGA), poly-ε- (caprolactone) (Polycaprotone, PCL), polyanhydrides, polyorthoester, polyvinyl alcohol (polyol), polyethylene glycol (polyvinyleol) Polyurethane, polyacrylic acid, poly-N-I Copolymers of propyl acrylamide (Poly-N-isopropyl acrylate), poly (ethylene oxide) -poly (propylene oxide) -poly (ethylene oxide) -polypropylene oxide-poly ethylene oxide, and polypropylene oxide-poly ethylene oxide It may contain one or more selected from the group consisting of polymers and mixtures thereof, but is not necessarily limited to these as long as it is safe and degradable when injected into the skin tissue. .
また、本発明の一実施例によれば、前記中空多孔性微小球の空洞及び微細気孔は気孔形成誘導物質、すなわちポロゲン（ｐｏｒｏｇｅｎ）により形成されたものであり、前記ポロゲンは、疎水性の生分解性高分子と相溶性がなく、且つ密度が水よりも低い疎水性流体であればその種類は特に制限されない。具体的に、前記空洞及び微細気孔形成誘導物質は、１ａｔｍ、２５０℃以下で沸点を有する物質であればよく、１ａｔｍ、３０〜１５０℃で液状の物質であればよい。例えば、前記空洞及び微細気孔形成誘導物質は、アルカン（ａｌｋａｎｅ）類、植物性油及びこれらの混合物からなる群より選択された一つ以上であってよい。一実施例として、前記アルカン類は、オクタン（Ｏｃｔａｎｅ）、ウンデカン（Ｕｎｄｅｃａｎｅ）、トリデカン（Ｔｒｉｄｅｃａｎｅ）、ペンタデカン（Ｐｅｎｔａｄｅｃａｎｅ）及びこれらの混合物からなる群より選択された一つ以上であり、前記植物性油は、大豆油、とうもろこし油、綿実油、オリーブ油、ブドウ種子油、クルミ油、ゴマ油、エゴマ油及びこれらの混合物からなる群より選択された一つ以上を含んでいてよい。本発明は、前記具体的な物質以外に他の物質を適用して気孔を形成することもでき、一実施例として、本発明は、前記中空多孔性微小球の製造の際に気孔を形成するポロゲンの濃度及び種類によって中空及び微細気孔の大きさや形態を調節することができ、且つ気孔均一度も増加させることができる。 In addition, according to an embodiment of the present invention, the cavities and micropores of the hollow porous microspheres are formed by a pore formation inducer, that is, porogen, and the porogen is hydrophobic. The type of the fluid is not particularly limited as long as it is not compatible with the degradable polymer and has a density lower than that of water. Specifically, the cavity and the micropore formation inducing substance may be any substance having a boiling point at 1 atm and 250 ° C. or lower, and may be a liquid substance at 1 atm and 30 to 150 ° C. For example, the cavity and micropore formation inducer may be at least one selected from the group consisting of alkanes, vegetable oils, and mixtures thereof. In one embodiment, the alkane is one or more selected from the group consisting of octane, undecane, tridecane, pentadecane, and mixtures thereof, and the vegetable oil May include one or more selected from the group consisting of soybean oil, corn oil, cottonseed oil, olive oil, grape seed oil, walnut oil, sesame oil, sesame oil, and mixtures thereof. In the present invention, pores can be formed by applying other substances in addition to the specific substance. As an example, the present invention forms pores during the production of the hollow porous microspheres. Depending on the concentration and type of porogen, the size and shape of the hollow and fine pores can be adjusted, and the pore uniformity can be increased.
一実施例によれば、前記したような本発明の組成物に係る前記皮膚組織の再生又は皮膚組織のボリューム増進は、一実施例として、生体内皮膚組織細胞が前記微細気孔を通じて前記中空多孔性微小球内に移動し、中央の空洞で前記移動した皮膚組織細胞が増殖して皮膚組織を再生させ又はボリュームを増進させることを含んでいてよい。すなわち、生体組織内に存在する細胞が前記中空多孔性微小球内に浸透し、成長***して新規生体組織を形成することができる。本発明の一実施例によれば、前記気孔形成誘導物質と疎水性の生分解性高分子の混合比を調節することで、微小球の中央に形成される空洞の及び隔壁の微細気孔の大きさや形態を調節自在とすることができ、前記中空多孔性微小球の外部に存在する線維芽細胞、脂肪細胞などが多孔性微小球内に浸透した後、成長し***することができる空間を与えることができる。 According to one embodiment, the regeneration of the skin tissue or the volume enhancement of the skin tissue according to the composition of the present invention as described above may be performed as follows. It may involve migrating into the microsphere and allowing the migrated skin tissue cells to proliferate and regenerate skin tissue or increase volume in a central cavity. That is, a cell existing in a living tissue can penetrate into the hollow porous microsphere, and can grow and divide to form a new living tissue. According to one embodiment of the present invention, by adjusting the mixing ratio of the pore formation inducing substance and the hydrophobic biodegradable polymer, the size of the micropores of the cavity and the partition formed in the center of the microsphere The shape of the sheath can be adjusted to provide a space in which fibroblasts, adipocytes, etc. existing outside the hollow porous microsphere have penetrated into the porous microsphere and can then grow and divide. be able to.
一実施例として、前記中空多孔性微小球の大きさと中央に形成される空洞と隔壁の微細気孔は、微細流体デバイスまたは膜乳化装置を利用して調節及び製造されていてよい。前記微細流体デバイスの場合、連続相を移送する導管内に微細導管を介して不連続相を注入する速度を調節して微小球の大きさを一定に制御することができる。膜乳化の場合は、微細流体デバイスで用いる微細導管の代わりに孔隙の大きさが一定の膜（ｍｅｍｂｒａｎｅ）を通じて不連続相を連続相が流れる導管に移送させて制御することができる。 As an example, the size of the hollow porous microspheres and the fine pores of the cavity and partition formed in the center may be adjusted and manufactured using a microfluidic device or a membrane emulsifying device. In the case of the microfluidic device, the size of the microsphere can be controlled to be constant by adjusting the rate at which the discontinuous phase is injected through the microconduit into the conduit transporting the continuous phase. In the case of membrane emulsification, the discontinuous phase can be transferred to a conduit through which a continuous phase flows through a membrane having a constant pore size instead of a fine conduit used in a microfluidic device.
本発明の一実施例によれば、前記組成物は、皮膚シワ又は皮膚陥没部位の改善用であってよい。より具体的に、前記組成物は、皮膚シワを含む老化の改善、皮膚色調の改善、又は皮膚弾力の改善用フィラー（ｆｉｌｌｅｒ）又はリフティングなどを目的にして用いられてよいが、皮膚の組織再生のためであれば必ずしもこれらに制限されるものではない。例えば、人工皮膚、人工軟骨、骨充填剤、整形補型物などに用いられていてよい。または、前記本発明に係る組成物は、一実施例として、薬学又は化粧料組成物としても提供されていてよい。 According to one embodiment of the present invention, the composition may be for improving skin wrinkles or skin depressions. More specifically, the composition may be used for the purpose of improving aging including skin wrinkles, improving skin tone, or a filler or lifting for improving skin elasticity. For this reason, it is not necessarily limited to these. For example, it may be used for artificial skin, artificial cartilage, bone filler, orthopedic prosthesis and the like. Alternatively, the composition according to the present invention may be provided as a pharmaceutical or cosmetic composition as an example.
また、本発明に係る皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物は、前記中空多孔性微小球を組成物の総質量に対し１〜５０質量％で含んでいてよい。前記１質量％未満であると中空多孔性微小球の含有量が少なすぎて皮膚組織内への注入時に目的とする効果を期待し難く、また５０質量％を超えると注射によって皮膚組織内への注入を円滑に行い難い。より具体的に、本発明に係る皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物は、一実施例として、前記中空多孔性微小球を組成物の総質量に対し５〜２０質量％で含んでいてよい。 Moreover, the composition for regenerating skin tissue or volume-injecting skin tissue according to the present invention may contain the hollow porous microspheres in an amount of 1 to 50% by mass based on the total mass of the composition. If the content is less than 1% by mass, the content of the hollow porous microspheres is too small, and it is difficult to expect the intended effect at the time of injection into the skin tissue. It is difficult to perform injection smoothly. More specifically, the composition for skin tissue regeneration or skin tissue volume enhancement injection according to the present invention includes, as an example, 5 to 20% by mass of the hollow porous microspheres based on the total mass of the composition. May contain.
一実施例として、前記組成物は、中空多孔性微小球の他、多孔性微小球を含む組成物の粘性と安定性を向上するために水溶性高分子が含まれていてよい。一実施例として、前記水溶性高分子は、アルギン酸（ａｌｇｉｎｉｃ ａｃｉｄ）、ヒアルロン酸（ｈｙａｌｕｒｏｎｉｃ ａｃｉｄ）、カルボキシメチルセルロース（ｃａｒｂｏｘｙｍｅｔｈｙｌ ｃｅｌｌｕｌｏｓｅ）、デキストラン（ｄｅｘｔｒａｎ）、コラーゲン（ｃｏｌｌａｇｅｎ）及びこれらの分解物であるゼラチン（ｇｅｌａｔｉｎ）、エラスチン（ｅｌａｓｔｉｎ）からなる群より選択される１種以上の化合物をさらに含んでいてよい。 As an example, the composition may include a water-soluble polymer in order to improve the viscosity and stability of the composition including the porous microspheres in addition to the hollow porous microspheres. For example, the water-soluble polymer may include alginic acid, hyaluronic acid, carboxymethyl cellulose, dextran, collagen, and a degradation product thereof, gelatin ( It may further contain one or more compounds selected from the group consisting of gelatin and elastin.
以下、実施例を通じて本発明をより詳しく説明することにする。これらの実施例は単に本発明を例示するためのものに過ぎず、本発明の範囲がこれらの実施例によって制限されるものではないと解釈されることは当業界における通常の知識を有する者にとって自明であろう。 Hereinafter, the present invention will be described in more detail through examples. These examples are merely to illustrate the present invention, and it is understood by those skilled in the art that the scope of the present invention should not be construed as being limited by these examples. It will be self-evident.
［実施例１］中空多孔性微小球の製造１
本発明の一実施例に係る中空多孔性微小球を下記の方法で製造した。
[Example 1] Production 1 of hollow porous microspheres
Hollow porous microspheres according to an example of the present invention were manufactured by the following method.
段階１：微細流体デバイス（ｓｉｍｐｌｅ ｆｌｕｉｄｉｃ ｄｅｖｉｃｅ）の製作
ＰＶＣチューブに９０°で折り曲げた３０ゲージ注射針を入れ、注射針とＰＶＣチューブとの間に微細ガラス管を挿入して微細流体デバイスを製作した。製作された微細流体デバイスはエポキシ接着剤を用いて微細な隙間を埋め込んだ。
Step 1: Fabrication of a microfluidic device A microfluidic device was fabricated by inserting a 30-gauge needle bent at 90 ° into a PVC tube and inserting a fine glass tube between the needle and the PVC tube. . The manufactured microfluidic device was embedded with fine gaps using epoxy adhesive.
段階２：アルカン類が含まれたＰＬＬＡ溶液の製造
疎水性の生分解性高分子としてＰＬＬＡ（ＲＥＳＯＭＥＲ ＬＲ ７０４Ｓ、Ｅｖｏｎｉｋ Ｉｎｄｕｓｔｒｉｅｓ ＡＧ）０．１ｇ、Ｄｉｃｈｌｏｒｏｍｅｔｈａｎｅ (３４３５５−０３５０、Ｊｕｎｓｅｉ）１０ｇ、気孔形成誘導物質としてアルカン類物質、具体的にオクタン（Ｏｃｔａｎｅ、４１２２３６、Ｓｉｇｍａ−ａｌｄｒｉｃｈ）またはウンデカン（Ｕｎｄｅｃａｎｅ、U４０７、Ｓｉｇｍａ−ａｌｄｒｉｃｈ）またはトリデカン（Ｔｒｉｄｅｃａｎｅ、T５７４０１、Ｓｉｇｍａ−ａｌｄｒｉｃｈ）またはペンタデカン（Ｐｅｎｔａｄｅｃａｎｅ、７６５１０、Ｓｉｇｍａ−ａｌｄｒｉｃｈ）をそれぞれ０．１、０．３ｇ及び０．６ｇ混ぜ合わせて（１、３、６質量％）疎水性の生分解性高分子（ＰＬＬＡ）溶液を製造した。
Step 2: Production of PLLA solution containing alkanes PLLA (RESOMER LR 704S, Evonik Industries AG) 0.1 g as hydrophobic biodegradable polymer, Dichloromethane (34355-0350, Junsei) 10 g, pore formation inducer As alkanes, specifically octane (Octane, 41236, Sigma-aldrich) or undecane (Undecane, U407, Sigma-aldrich) or tridecane (Tridecane, T57401, Sigma-aldrich) or pentadecane ) 0.1, 0.3 g and 0.6 g respectively (1, 3, 6% by mass) Solution polymer (PLLA) solution was prepared.
段階３：均一なＰＬＬＡエマルジョンの製造
微細流体デバイスに、２％ ＰＶＡ溶液を流速が分当たり１．５ｍｌの連続相（ｃｏｎｔｉｎｕｏｕｓ ｐｈａｓｅ）で供給し、且つ前記ＰＶＡ溶液に、前記段階２で得たアルカン類が含まれたＰＬＬＡ溶液を３０ゲージ注射器針を用いて流速が分当たり０．１ｍｌの不連続相（ｄｉｓｃｏｎｔｉｎｕｏｕｓ ｐｈａｓｅ）で供給して、一定の大きさを有するエマルジョンが形成されるようにした。
Step 3: Production of a homogeneous PLLA emulsion A microfluidic device is fed with 2% PVA solution in a continuous phase with a flow rate of 1.5 ml per minute, and the PVA solution is fed with the alkane obtained in step 2 above. The PLLA solution containing the species was fed in a discontinuous phase with a flow rate of 0.1 ml per minute using a 30 gauge syringe needle to form an emulsion with a constant size.
段階４：均一な中空多孔性微小球の製造
前記段階３で得たエマルジョンを２％ ＰＶＡ収集相（ｃｏｌｌｅｃｔｉｏｎ ｐｈａｓｅ）に分散させて１５０ｒｐｍで攪拌させた後、ジクロロメタンを十分に揮発させた。
Step 4: Preparation of uniform hollow porous microspheres The emulsion obtained in Step 3 above was dispersed in 2% PVA collection phase and stirred at 150 rpm, and then dichloromethane was sufficiently volatilized.
段階５：気孔形成誘導物質を除去して多孔性付与
前記段階４で得たＰＬＬＡビード蒸溜水（Ｄ．Ｗ．）で数回洗浄した後、凍結乾燥器を利用してアルカン類を昇華させて均一な大きさの中空多孔性微小球の多孔性ＰＬＬＡビードを製造した。
Step 5: Removal of pore formation inducing substances and imparting porosity After washing several times with PLLA bead distilled water (DW) obtained in Step 4, alkanes are sublimated using a freeze dryer. Uniformly sized hollow porous microsphere porous PLLA beads were prepared.
前記製造された各中空多孔性微小球を図１に示した。気孔形成誘導物質の含有量が増加するにつれて、または炭化水素鎖の長さが長くなるにつれて、微小球の中央に空洞がより効果的に製造されることを確認することができる。 The produced hollow porous microspheres are shown in FIG. It can be seen that the cavity is more effectively produced in the center of the microsphere as the content of the pore formation inducing substance increases or as the length of the hydrocarbon chain increases.
［実施例２］中空多孔性微小球の製造２
本発明の一実施例に係る中空多孔性微小球を下記の方法で製造した。
[Example 2] Production of hollow porous microspheres 2
Hollow porous microspheres according to an example of the present invention were manufactured by the following method.
段階１：微細流体デバイス（ｓｉｍｐｌｅ ｆｌｕｉｄｉｃ ｄｅｖｉｃｅ）の製作
ＰＶＣチューブに９０°で折り曲げた３０ゲージ注射針を入れ、注射針とＰＶＣチューブとの間に微細ガラス管を挿入して微細流体デバイスを製作した。製作された微細流体デバイスはエポキシ接着剤を利用して微細な隙間を埋め込んだ。
Step 1: Fabrication of a microfluidic device A microfluidic device was fabricated by inserting a 30-gauge needle bent at 90 ° into a PVC tube and inserting a fine glass tube between the needle and the PVC tube. . The fabricated microfluidic device filled in the fine gaps using epoxy adhesive.
段階２：植物性油が含まれたＰＬＬＡ溶液の製造
疎水性の生分解性高分子としてＰＬＬＡ（ＲＥＳＯＭＥＲ ＬＲ ７０４Ｓ、Ｅｖｏｎｉｋ Ｉｎｄｕｓｔｒｉｅｓ ＡＧ）０．１ｇ、Ｄｉｃｈｌｏｒｏｍｅｔｈａｎｅ (３４３５５−０３５０、Ｊｕｎｓｅｉ）１０ｇ、気孔形成誘導物質として綿実油または大豆油をそれぞれ０．５ｇに混ぜ合わせて疎水性の生分解性高分子（ＰＬＬＡ）溶液を製造した。
Step 2: Production of PLLA solution containing vegetable oil PLLA (RESOMER LR 704S, Evonik Industries AG) 0.1 g as hydrophobic biodegradable polymer, Dichloromethane (34355-0350, Junsei) 10 g, pore formation induction A hydrophobic biodegradable polymer (PLLA) solution was prepared by mixing 0.5 g of cottonseed oil or soybean oil as a substance.
段階３：均一なＰＬＬＡエマルジョンの製造
微細流体デバイスに、２％ ＰＶＡ溶液を流速が分当たり１．５ｍｌの連続相（ｃｏｎｔｉｎｕｏｕｓ ｐｈａｓｅ）で供給し、且つ前記ＰＶＡ溶液に、前記段階２で得た植物性油が含まれたＰＬＬＡ溶液を、３０ゲージ注射器針を用いて流速が分当たり０．１ｍｌの不連続相（ｄｉｓｃｏｎｔｉｎｕｏｕｓ ｐｈａｓｅ）で供給して、一定の大きさを有するエマルジョンが形成されるようにした。
Step 3: Production of a uniform PLLA emulsion A microfluidic device is fed with a 2% PVA solution in a continuous phase with a flow rate of 1.5 ml per minute and the PVA solution is fed to the plant obtained in Step 2 above. The PLLA solution containing the essential oil is supplied in a discontinuous phase with a flow rate of 0.1 ml per minute using a 30 gauge syringe needle so that an emulsion of a certain size is formed. did.
段階４：均一なＰＬＬＡビードの製造
前記段階３で得たエマルジョンを２％ ＰＶＡ収集相（ｃｏｌｌｅｃｔｉｏｎ ｐｈａｓｅ）に分散させて１５０ｒｐｍで攪拌させた後、ジクロロメタンを十分に揮発させた。
Step 4: Preparation of uniform PLLA beads The emulsion obtained in Step 3 above was dispersed in 2% PVA collection phase and stirred at 150 rpm, and then dichloromethane was sufficiently volatilized.
段階５：内部気孔形成誘導物質を除去して多孔性付与
前記段階４で得たＰＬＬＡビードを蒸溜水（Ｄ．Ｗ．）で数回洗浄した後、凍結乾燥器を利用して植物性油を除去して均一な大きさの中空多孔性微小球の多孔性ＰＬＬＡビードを製造した。
Step 5: Removal of internal pore formation inducing substance to provide porosity After the PLLA bead obtained in Step 4 is washed several times with distilled water (DW), vegetable oil is added using a freeze dryer. A hollow PLLA bead having hollow porous microspheres of uniform size was produced by removing.
［実施例３］中空多孔性微小球を含有する注射用組成物の製造
本発明の一実施例として、前記中空多孔性微小球及び多孔性微小球を含む組成物の粘性と安定性を向上するためのヒアルロン酸（ｈｙａｌｕｒｏｎｉｃ ａｃｉｄ）、カルボキシメチルセルロース（ｃａｒｂｏｘｙｍｅｔｈｙｌ ｃｅｌｌｕｌｏｓｅ）等の水溶性高分子を混合して注射用組成物を製造した。
[Example 3] Production of injectable composition containing hollow porous microspheres As an example of the present invention, the viscosity and stability of the hollow porous microspheres and the composition containing the porous microspheres are improved. An injectable composition was prepared by mixing water-soluble polymers such as hyaluronic acid and carboxymethyl cellulose.
このとき、各組成の含有量は下記の表１と表２に表したとおりであり、各組成の含有量による中空多孔性微小球を含有する注射用組成物の注射圧測定結果を共に表した。 At this time, the content of each composition is as shown in Table 1 and Table 2 below, and both the injection pressure measurement results of the injectable composition containing hollow porous microspheres according to the content of each composition are shown. .
［試験例１］皮膚組織細胞の培養
本発明の一実施例に係る中空多孔性微小球の中空形成の有無による細胞移動性及び増殖効能を比べるための実験を下記のように行った。
[Test Example 1] Culture of skin tissue cells An experiment for comparing cell mobility and proliferation efficacy depending on the presence or absence of hollow formation of hollow porous microspheres according to an example of the present invention was performed as follows.
比較例として、中空を含まない多孔性微小球（ｓｍａｌｌ ｐｏｒｅｓ：トリデカン３質量％）及び前記実施例１の中空を含む多孔性微小球（Ｌａｒｇｅ ｐｏｒｅｓ：アルカン類でトリデカンを６質量％含む）をそれぞれ７０％エタノールで滅菌処理した後、ＰＢＳで十分に洗浄し、ＮＩＨ３Ｔ３線維芽細胞を移植して細胞増殖の挙動を観察した。ＮＩＨ３Ｔ３線維芽細胞を１×１０３ｃｅｌｌｓ／ｍＬの濃度で培養培地に分散させスピンナーフラスコ（ｓｐｉｎｎｅｒ ｆｌａｓｋ）を利用して６時間撹拌した後、多孔性粒子を培養容器（ｃｕｌｔｕｒｅ Ｐｌａｔｅ）に移して培養した。細胞培養して１、３、７、１０日目に前記培養した各多孔性微小球粒子をＬＩＶＥ／ＤＥＡＤ染色した後、細胞の付着及び増殖の有無を共焦点顕微鏡とＭＴＴ ａｓｓａｙによって確認した。図２及び図３に示したように、中空を含む中空多孔性微小球（Ｌａｒｇｅ ｐｏｒｅｓ）が、中空を含まず微細気孔のみを含む多孔性微小球（Ｓｍａｌｌ ｐｏｒｅｓ）に比べて、内部気孔へのＮＩＨ３Ｔ３線維芽細胞の浸透及び増殖が１０日目までに順調になされることを確認することができる。これは、多孔性微小球内に含まれた中空が細胞の浸透及び増殖において大きな効果があることを意味する。 As comparative examples, porous microspheres without hollow (small pores: tridecane 3 mass%) and porous microspheres with hollow in Example 1 (large pores: alkanes containing 6 mass% of tridecane), respectively After sterilizing with 70% ethanol, the cells were thoroughly washed with PBS, and NIH3T3 fibroblasts were transplanted to observe the behavior of cell proliferation. NIH3T3 fibroblasts are dispersed in a culture medium at a concentration of 1 × 10 3 cells / mL and stirred for 6 hours using a spinner flask, and then the porous particles are transferred to a culture plate (culture plate) and cultured. did. After culturing the cells, the cultured porous microsphere particles were stained with LIVE / DEAD on the first, third, seventh, and tenth days, and the presence or absence of cell attachment and proliferation was confirmed by a confocal microscope and MTT assay. As shown in FIGS. 2 and 3, the hollow porous microspheres including the hollow are more porous to the internal pores than the small micropores including only the fine pores without including the hollows. It can be confirmed that the penetration and proliferation of NIH3T3 fibroblasts is successful by the 10th day. This means that the hollow contained in the porous microspheres has a great effect on cell penetration and proliferation.
［試験例２］動物実験による中空多孔性微小球の細胞移動性及び組織再生効能の評価
本発明の一実施例に係る中空多孔性微小球の中空形成の有無による細胞移動性及び組織再生効能を比べるための実験を下記のように行った。
Test Example 2 Evaluation of Cell Mobility and Tissue Regeneration Efficacy of Hollow Porous Microspheres by Animal Experiments Cell mobility and tissue regeneration efficacy depending on presence or absence of hollow formation of hollow porous microspheres according to one embodiment of the present invention. An experiment for comparison was performed as follows.
比較例として、中空を含まない多孔性微小球（ｓｍａｌｌ ｐｏｒｅｓ：トリデカン３質量％）及び前記実施例１の中空を含む多孔性微小球（Ｌａｒｇｅ ｐｏｒｅｓ：アルカン類でトリデカンを６質量％含む）をそれぞれ７０％エタノールで滅菌処理した。これをＰＢＳで十分に洗浄し、ヌードマウスの皮下に２３ゲージ針を利用して多孔性ＰＬＬＡ粒子をＰＢＳ相に分散させて注入し、多孔性微小球内の細胞浸透及び細胞増殖の有無を８週に亘り観察した。多孔性微小球を注入してから２、４、６、８週目にそれぞれヌードマウスの皮膚と皮下粒子の部分まで切開して４％ホルムアルデヒドに３時間固定した後、当該組織を３０％サッカロース（ｓａｃｃｈａｒｏｓｅ）溶液に１２時間浸漬させた。次いで、クライオ・ミクロトーム（ｃｒｙｏ ｍｉｃｒｏｔｏｍｅ）によって２０μm大きさのクライオ切片（ｃｒｙｏ ｓｅｃｔｉｏｎ）を製作した。クライオ切片にした組織をスライドガラスに張って、５０℃の加熱板（ｈｅａｔｉｎｇ ｂｌｏｃｋ）にて３時間乾燥して、スライドガラスに組織がよく張り付くようにした。当該組織切片をＨ＆Ｅ染色をして、多孔性ＰＬＬＡ微小球周辺の組織反応を観察した。 As comparative examples, porous microspheres without hollow (small pores: tridecane 3 mass%) and porous microspheres with hollow in Example 1 (large pores: alkanes containing 6 mass% of tridecane), respectively Sterilized with 70% ethanol. This was thoroughly washed with PBS, and porous PLLA particles were dispersed and injected into the PBS phase using a 23-gauge needle subcutaneously in nude mice, and the presence or absence of cell penetration and cell proliferation in the porous microspheres was confirmed. Observed over a week. At 2, 4, 6, and 8 weeks after the injection of porous microspheres, the skin and subcutaneous particles of nude mice were incised and fixed in 4% formaldehyde for 3 hours, and then the tissue was treated with 30% saccharose ( saccharose) solution for 12 hours. Next, a cryo section having a size of 20 μm was prepared by a cryo microtome. The tissue cut into cryosections was stretched on a slide glass and dried with a heating block at 50 ° C. for 3 hours so that the tissue adhered well to the slide glass. The tissue section was subjected to H & E staining, and the tissue reaction around the porous PLLA microspheres was observed.
その結果、図４に示したように、中空を含まず微細気孔のみを含む多孔性微小球（Ｓｍａｌｌ ｐｏｒｅｓ）は８週目まで細胞の大半が外部に存在していたのに対し、中空を含む中空多孔性微小球（Ｌａｒｇｅ ｐｏｒｅｓ）は細胞が粒子内部まで浸透して新規組織生成を誘導する様相を示した。また、８週後でも粒子が完全に分解していないことから、多孔性微小球の生体内での長期保持可能性を確認することができた。 As a result, as shown in FIG. 4, the porous microspheres (Small pores) containing only the fine pores without containing the hollows contained the hollows whereas the majority of the cells were present outside until the eighth week. Hollow porous microspheres showed the appearance that cells penetrated into the inside of the particles and induced new tissue formation. Moreover, since the particles were not completely decomposed even after 8 weeks, it was possible to confirm the long-term retention possibility of the porous microspheres in the living body.
［試験例３］中空多孔性微小球を含む組成物の注射性能の測定
前記表１と表２で製造した組成物の注射注入の可能有無を測定するための性能試験を実施した。引張力測定機を圧縮強度測定モード（ｍｏｄｅ）に設定し、注射性能を測定した。各中空多孔性微小球を含む組成物を内容物として入れた注射器のキャップ（ｃａｐ）を外し、２３Ｇの規格を有する注射針を取り付けた後、注射器を引張力測定機の測定板に対して注射針が下方に向くように垂直に固定した。引張力測定機を稼動して、１ｍｍ／ｓｅｃの速度で注射器に取り付けられたプランジャ（ｐｌｕｎｇｅｒ）を押しながら、注射器内の内容物が完全に無くなるまでの圧縮にかかる力を測定した。
[Test Example 3] Measurement of injection performance of a composition containing hollow porous microspheres A performance test for measuring the possibility of injection injection of the compositions prepared in Tables 1 and 2 was conducted. The tensile force measuring machine was set to the compression strength measurement mode (mode), and the injection performance was measured. After removing the cap of the syringe containing the composition containing each hollow porous microsphere as a content and attaching the injection needle having the standard of 23G, the syringe is injected into the measuring plate of the tensile force measuring machine. The needle was fixed vertically so that it pointed downward. The tensile force measuring machine was operated, and the force applied to the compression until the contents in the syringe were completely lost was measured while pushing the plunger attached to the syringe at a speed of 1 mm / sec.
その結果を前記表１と２に表した。表１と２から分かるように、中空多孔性微小球をそれぞれ２％ヒアルロン酸、２％カルボキシメチルセルロースに分散させて注射性能を測定した場合、比較製造例１及び２のように組成物内への微小球の含有量が５０質量％を超えた場合、注入が不可能であった。 The results are shown in Tables 1 and 2 above. As can be seen from Tables 1 and 2, when the hollow porous microspheres were dispersed in 2% hyaluronic acid and 2% carboxymethyl cellulose, respectively, and the injection performance was measured, as in Comparative Production Examples 1 and 2, When the content of microspheres exceeded 50% by mass, injection was impossible.
［試験例４］中空多孔性微小球を含む組成物の注射注入前後の形状の比較
本発明の実施例に係る中空多孔性微小球を含む組成物の注射注入後の形状の変化の有無を確認するために、前記表１の製造例６に対し注射性能の試験前と後の試料を収集し、中空多孔性微小球の形状の変化をレーザ顕微鏡（３Ｄ ｍｅａｓｕｒｉｎｇ ｌａｓｅｒ ｍｉｃｒｏｓｃｏｐｅ、オリンパス）によって観察した。その結果を図５に示した。図５から分かるように、製造例６の場合、高い注射圧にも拘わらず、注射前と比べて多孔性微小球の形状をよく保持していることを確認した。
[Test Example 4] Comparison of shape before and after injection injection of a composition containing hollow porous microspheres Confirmation of presence or absence of change in shape after injection injection of a composition containing hollow porous microspheres according to an example of the present invention In order to do this, samples before and after the injection performance test were collected for Production Example 6 in Table 1 above, and the change in the shape of the hollow porous microspheres was observed with a laser microscope (3D measuring laser microscope, Olympus). The results are shown in FIG. As can be seen from FIG. 5, in the case of Production Example 6, it was confirmed that the shape of the porous microspheres was well maintained compared with that before the injection, despite the high injection pressure.
本発明は、一実施例として次の実施形態を提供することができる。 The present invention can provide the following embodiment as an example.
第１実施形態は、中央に形成された空洞；及び前記空洞を取り囲む、微細気孔を含む隔壁を含む中空多孔性微小球を含む、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 A first embodiment provides a composition for injecting skin tissue or increasing volume of skin tissue, comprising a hollow formed in the center; and hollow porous microspheres including a partition wall containing micropores surrounding the cavity. can do.
第２実施形態は、第１実施形態において、前記中空多孔性微小球の空洞の平均径は５〜１５０μｍである、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 The second embodiment can provide the composition for skin tissue regeneration or skin tissue volume-enhancing injection in the first embodiment, wherein the hollow porous microsphere has an average diameter of 5 to 150 μm. .
第３実施形態は、第１実施形態及び第２実施形態のいずれか一つ以上において、前記中空多孔性微小球の平均径は５０〜２００μｍである、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 In the third embodiment, in any one or more of the first embodiment and the second embodiment, the hollow porous microsphere has an average diameter of 50 to 200 μm, or skin tissue regeneration or skin tissue volume enhancement injection. A composition can be provided.
第４実施形態は、第１実施形態〜第３実施形態のいずれか一つ以上において、前記中空多孔性微小球の空洞の体積は、前記中空多孔性微小球の全体積に対し２０〜８０体積％である、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 According to a fourth embodiment, in any one or more of the first to third embodiments, the volume of the hollow porous microsphere is 20 to 80 volume with respect to the total volume of the hollow porous microsphere. %, A composition for injecting skin tissue or increasing volume of skin tissue can be provided.
第５実施形態は、第１実施形態〜第４実施形態のいずれか一つ以上において、前記中空多孔性微小球の微細気孔の平均径は５〜５０μｍである、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 In the fifth embodiment, in any one or more of the first embodiment to the fourth embodiment, the average diameter of the fine pores of the hollow porous microsphere is 5 to 50 μm. Volume enhanced injectable compositions can be provided.
第６実施形態は、第１実施形態〜第５実施形態のいずれか一つ以上において、前記中空多孔性微小球の孔隙率は平均２０〜８０％である、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 The sixth embodiment is the regeneration of skin tissue or the volume of skin tissue according to any one or more of the first to fifth embodiments, wherein the porosity of the hollow porous microspheres is 20 to 80% on average. An enhanced injectable composition can be provided.
第７実施形態は、第１実施形態〜第６実施形態のいずれか一つ以上において、前記中空多孔性微小球は疎水性の生分解性高分子を含む、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 A seventh embodiment is the regeneration of skin tissue or the volume of skin tissue according to any one or more of the first to sixth embodiments, wherein the hollow porous microspheres contain a hydrophobic biodegradable polymer. An enhanced injectable composition can be provided.
第８実施形態は、第７実施形態において、前記疎水性の生分解性高分子は、ポリ乳酸（Ｐｏｌｙ−Ｌ−Ｌａｃｔｉｃ Ａｃｉｄ、ＰＬＬＡ）、ポリグリコール酸（ｐｏｌｙｇｌｙｃｏｌｉｃ ａｃｉｄ、ＰＧＡ）、ポリ乳酸−グリコール酸共重合体（ｐｏｌｙ（ｌａｃｔｉｃ−ｃｏ−ｇｌｙｃｏｌｉｃ ａｃｉｄ）、ＰＬＧＡ）、ポリ−ε−（カプロラクトン）（Ｐｏｌｙｃａｐｒｏｌａｃｔｏｎｅ、ＰＣＬ）、ポリ無水物（ｐｏｌｙａｎｈｙｄｒｉｄｅｓ）、ポリオルトエステル（ｐｏｌｙｏｒｔｈｏｅｓｔｅｒ）、ポリビニルアルコール（ｐｏｌｙｖｉｎｉｙａｌｃｏｈｏｌ）、ポリエチレングリコール（ｐｏｌｙｅｔｈｙｌｅｎｅｇｌｙｃｏｌ）、ポリウレタン（ｐｏｌｙｕｒｅｔｈａｎｅ）、ポリアクリル酸（ｐｏｌｙａｃｒｙｌｉｃ ａｃｉｄ）、ポリ−Ｎ−イソプロピルアクリルアミド（Ｐｏｌｙ−Ｎ−ｉｓｏｐｒｏｐｙｌ ａｃｒｙｌａｍｉｄｅ）、ポリ（エチレンオキサイド）−ポリ（プロピレンオキサイド）−ポリ（エチレンオキサイド）共重合体（ｐｏｌｙ ｅｔｈｙｌｅｎｅ ｏｘｉｄｅ）−ｐｏｌｙ ｐｒｏｐｙｌｅｎｅ ｏｘｉｄｅ−ｐｏｌｙ ｅｔｈyｌｅｎｅ ｏｘｉｄｅ ｃｏｐｏｌｙｍｅｒ）、これらの共重合体及びこれらの混合物からなる群より選択された一つ以上である、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 An eighth embodiment is the seventh embodiment, wherein the hydrophobic biodegradable polymer is polylactic acid (Poly-L-Lactic Acid, PLLA), polyglycolic acid (PGA), polylactic acid-glycol. Acid copolymer (poly (lactide-co-glycolic acid), PLGA), poly-ε- (caprolactone) (Polycaprolactone, PCL), polyanhydrides, polyorthoester, polycohol polyhydrin , Polyethylene glycol (polyethyleneglycol), polyurethane (polyurethane), polyacrylic acid (polyacrylic) acid), poly-N-isopropylacrylamide, poly (ethylene oxide) -poly (propylene oxide) -poly (ethylene oxide) -polypropylene oxide-polyethylene-polyethylene-polyethylene-polyethylene-polyethylene oxide-polyethylene oxide-polyethylene oxide-polyethylene oxide-polyethylene oxide-polyethylene oxide-polyethylene oxide-polyethylene oxide-polyethylene oxide a composition for injecting skin tissue or increasing volume of the skin tissue, which is one or more selected from the group consisting of oxide copolymers), copolymers thereof, and mixtures thereof.
第９実施形態は、第１実施形態〜第８実施形態のいずれか一つ以上において、前記中空多孔性微小球の空洞及び微細気孔形成誘導物質は、疎水性の生分解性高分子と相溶性がなく、且つ密度が水よりも低い疎水性流体である、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 The ninth embodiment is any one or more of the first to eighth embodiments, wherein the hollow porous microsphere cavities and the micropore formation inducer are compatible with a hydrophobic biodegradable polymer. It is possible to provide a composition for injecting skin tissue or increasing volume of skin tissue, which is a hydrophobic fluid having a lower density than water.
第１０実施形態は、第９実施形態において、前記空洞及び微細気孔形成誘導物質は、アルカン（ａｌｋａｎｅ）類、植物性油及びこれらの混合物からなる群より選択された一つ以上である、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 The tenth embodiment is the skin tissue according to the ninth embodiment, wherein the cavity and the micropore formation inducer are one or more selected from the group consisting of alkanes, vegetable oils, and mixtures thereof. A composition for injecting regenerated or volume-enhanced skin tissue can be provided.
第１１実施形態は、第１０実施形態において、前記アルカン類は、オクタン（Ｏｃｔａｎｅ）、ウンデカン（Ｕｎｄｅｃａｎｅ）、トリデカン（Ｔｒｉｄｅｃａｎｅ）、ペンタデカン（Ｐｅｎｔａｄｅｃａｎｅ）及びこれらの混合物からなる群より選択された一つ以上であり、前記植物性油は、大豆油、とうもろこし油、綿実油、オリーブ油、ブドウ種子油、クルミ油、ゴマ油、エゴマ油及びこれらの混合物からなる群より選択された一つ以上である、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 In an eleventh embodiment, in the tenth embodiment, the alkane is one or more selected from the group consisting of octane, undecane, tridecane, pentadecane, and a mixture thereof. The vegetable oil is one or more selected from the group consisting of soybean oil, corn oil, cottonseed oil, olive oil, grape seed oil, walnut oil, sesame oil, sesame oil and mixtures thereof, A composition for injecting regenerative or skin tissue volume can be provided.
第１２実施形態は、第１実施形態〜第１１実施形態のいずれか一つ以上において、前記組成物は、アルギン酸（ａｌｇｉｎｉｃ ａｃｉｄ）、ヒアルロン酸（ｈｙａｌｕｒｏｎｉｃ ａｃｉｄ）、カルボキシメチルセルロース（ｃａｒｂｏｘｙｍｅｔｈｙｌ ｃｅｌｌｕｌｏｓｅ）、デキストラン（ｄｅｘｔｒａｎ）、コラーゲン（ｃｏｌｌａｇｅｎ）、ゼラチン（ｇｅｌａｔｉｎ）及びエラスチン（ｅｌａｓｔｉｎ）からなる群より選択される一種以上の水溶性高分子をさらに含む、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 In a twelfth embodiment according to any one or more of the first to eleventh embodiments, the composition comprises alginic acid, hyaluronic acid, carboxymethyl cellulose, dextran ( a composition for injection of skin tissue regeneration or skin tissue volume further comprising at least one water-soluble polymer selected from the group consisting of dextran, collagen, gelatin and elastin. Can be provided.
第１３実施形態は、第１実施形態〜第１２実施形態のいずれか一つ以上において、前記組成物は、前記中空多孔性微小球を組成物の総質量に対し１〜５０質量％で含む、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 In any one or more of the first to twelfth embodiments, the thirteenth embodiment includes the hollow porous microspheres in an amount of 1 to 50% by mass with respect to the total mass of the composition. A composition for injection of skin tissue regeneration or skin tissue volume enhancement can be provided.
第１４実施形態は、第１実施形態〜第１３実施形態のいずれか一つ以上において、前記皮膚組織の再生又は皮膚組織のボリューム増進は、生体内皮膚組織細胞が前記微細気孔を通じて前記中空多孔性微小球内に移動し、中央の空洞で前記移動した皮膚組織細胞が増殖して皮膚組織を再生させ又はボリュームを増進させることである、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 In a fourteenth embodiment, in any one or more of the first to thirteenth embodiments, the regeneration of the skin tissue or the volume increase of the skin tissue is performed by the skin tissue cells in vivo through the fine pores. A composition for injection of skin tissue regeneration or skin tissue volume increase, wherein the moved skin tissue cells grow in a microsphere and the migrated skin tissue cells proliferate to regenerate skin tissue or increase volume. Can be provided.
第１５実施形態は、第１実施形態〜第１４実施形態のいずれか一つ以上において、前記組成物は、皮膚シワ又は皮膚陥没部位の改善フィラー用である、皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物を提供することができる。 The fifteenth embodiment is the regeneration of skin tissue or the volume of skin tissue, in any one or more of the first to fourteenth embodiments, wherein the composition is for a filler for improving skin wrinkles or skin depressions. An enhanced injectable composition can be provided.
前記実施形態は本発明の説明のために開示されたものであり、前記説明は本発明の範囲を制限するものではない。したがって、当該技術分野の通常の技術者であれば本発明の意味及び範囲を逸脱することなく、種々の修正、変形、及び代替が可能である。 The embodiments have been disclosed for the purpose of explaining the present invention, and the above description does not limit the scope of the present invention. Accordingly, various modifications, variations, and alternatives can be made by those skilled in the art without departing from the meaning and scope of the present invention.
Claims (8)
前記空洞の平均径は６０〜１５０μｍであり、
前記微細気孔の平均径は５〜５０μｍであり、
前記中空多孔性微小球は疎水性の生分解性高分子を含む、
皮膚組織の再生又は皮膚組織のボリューム増進注射用組成物。 A hollow porous microsphere including a cavity formed in the center; and a partition wall including fine pores surrounding the cavity;
The average diameter of the cavity is 60 to 150 μm,
The average diameter of the fine pores is 5 to 50 μm,
The hollow porous microsphere comprises a hydrophobic biodegradable polymer,
A composition for injection of skin tissue regeneration or skin tissue volume enhancement.
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