WO2010026760A1 - Compositions wherein bioactive components are stably sealed - Google Patents

Compositions wherein bioactive components are stably sealed Download PDF

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Publication number
WO2010026760A1
WO2010026760A1 PCT/JP2009/004354 JP2009004354W WO2010026760A1 WO 2010026760 A1 WO2010026760 A1 WO 2010026760A1 JP 2009004354 W JP2009004354 W JP 2009004354W WO 2010026760 A1 WO2010026760 A1 WO 2010026760A1
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compound
composition according
biopolymer
composition
organic fluorine
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PCT/JP2009/004354
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French (fr)
Japanese (ja)
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大屋章二
中村健太郎
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富士フイルム株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a biopolymer composition in which a compound having low stability is stably encapsulated, and a method for producing the same.
  • oxidizable compounds such as astaxanthin and vitamins are widely used as active ingredients.
  • Each of the above active ingredients has a unique function in the body, and greatly contributes to maintaining the functions of the living body and promoting health.
  • the active ingredient is generally susceptible to oxidation and decomposition under conditions such as light, heat, oxygen, and humidity. Therefore, additives such as various stabilizers and antioxidants are mixed in order to produce the above composition.
  • an antioxidant such as ascorbic acid or citric acid is often used.
  • biodegradable polymers that decompose in the body are used as medical compositions for implantation in the body.
  • biodegradable polymers synthetic polymers typified by polylactic acid and polyglycolic acid, and biopolymers typified by collagen and gelatin are widely used.
  • the latter is generally highly hydrophilic and is often used in a form containing a large amount of moisture. Therefore, it is difficult to stably encapsulate a drug in order to prepare a preparation in which a drug with low stability is encapsulated in these biopolymer compositions. That is, there is a limit to the stable encapsulation of the drug only by adding a normal antioxidant.
  • compositions stabilized vitamin D Patent Document 1
  • a stable vitamin D 3 containing solid pharmaceutical composition comprising a vitamin D 3 and sodium benzoate
  • Patent Document 2 contains a composition obtained by dispersing active vitamin D in a basic polymer, an excipient that is easily soluble in an organic solvent, active vitamin D 2 and a basic substance.
  • a composition obtained by uniformly dispersing a finely powdered active vitamin D in a basic substance and an excipient that is easily soluble in water all of the compositions described in these documents attempt to stabilize vitamin D using components other than vitamin D, which is a physiologically active component.
  • hydrophobic and hydrophilic compounds are hydrophobic, biopolymers are hydrophilic, and it is very difficult to combine base materials having such conflicting properties.
  • a surfactant is used to make the hydrophobic and hydrophilic compounds uniform.
  • surfactants are often toxic per se, and when present in a medical composition for implantation in the body, there is a problem in the toxicity of the preparation.
  • Non-Patent Document 1 discloses a fiber-like material in which a gelatin chain and a poly ( ⁇ -caprolactone: PLCA) chain created by an electrospinning method are entangled. This material is a constituent of the present invention. Unlike the above, the fiber diameter of the nonwoven fabric composition physically solves the problem of flexibility.
  • PLCA poly ( ⁇ -caprolactone: PLCA) chain created by an electrospinning method
  • the present invention has an object to be solved by providing a composition in which a compound that can be easily oxidized is stably encapsulated in a base material without using a conventional antioxidant or excipient.
  • the present inventors have added a hydrophobic biodegradable synthetic polymer used as a medical base material to a biopolymer composition and mixed it uniformly.
  • the inventors have found that a medical composition in which a compound susceptible to oxidation can be stably encapsulated can be produced, and the present invention has been completed.
  • a composition comprising a biopolymer, a biodegradable synthetic polymer and a physiologically active ingredient.
  • the biopolymer is a protein or a polysaccharide.
  • the protein is at least one selected from the group consisting of collagen, gelatin, albumin, casein, fibroin, fibrin, laminin, fibronectin, and vitronectin.
  • the biopolymer is crosslinked by heat, light, or a crosslinking agent.
  • the biodegradable synthetic polymer is a compound, copolymer, or derivative selected from the group consisting of polylactic acid, polyglycolic acid, poly ( ⁇ -caprolactone), trimethylene carbonate, and polyhydroxyl alkanoate.
  • the physiologically active ingredient is a compound having an unsaturated bond not contained in the aromatic ring.
  • the physiologically active ingredient is vitamins, anticancer agents, immunosuppressive agents, anti-inflammatory agents, or antioxidants.
  • the physiologically active ingredient is vitamin D, a vitamin D derivative, or astaxanthin.
  • the composition of the present invention is used as a transdermally absorbable agent, a topical therapeutic agent, an oral therapeutic agent, a cosmetic product, a supplement, or a color material.
  • step (a) a step of preparing a mixture comprising a biopolymer, a biodegradable synthetic polymer, a bioactive component, and an organic fluorine compound; and (b) a mixture obtained in step (a).
  • a method for producing the above-described composition of the present invention which comprises the step of removing the organic fluorine compound from the above.
  • the organic fluorine compound is a compound having 2 to 8 carbon atoms.
  • the organic fluorine compound is a compound having 2 to 3 carbon atoms.
  • the organic fluorine compound is 1,1,1,3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, or hexafluoroacetone.
  • an effective drug can be obtained using a biocompatible biodegradable polymer without adding various additives that affect the physical, chemical, and biological properties of the medical composition. It has become possible to provide a stably encapsulated medical composition. Furthermore, no harmful surfactant is required for the production of the composition of the present invention, and the concern about toxicity to the living body can be greatly reduced.
  • composition of the present invention comprises a biopolymer, a biodegradable synthetic polymer and a bioactive component.
  • the biopolymer used in the present invention may be any of polysaccharides, proteins, and derivatives thereof.
  • the polysaccharide glycosaminoglycan, chitosan, and chitin are preferable.
  • the protein is preferably a protein such as globular or fibrous, preferably collagen, gelatin, albumin, casein, fibroin, fibrin, laminin, fibronectin, or vitronectin, more preferably collagen, gelatin, albumin, casein, fibroin, Laminin. Most preferred are collagen, gelatin, albumin, and casein, and among these, gelatin is most preferred.
  • origin of the protein is not particularly limited, and any of cows, pigs, fish, and gene recombinants can be used.
  • gene recombinant those described in, for example, EP0926543B, WO2004 / 085473, EP1398324A, EP1014176A, US6645712 can be used.
  • the biodegradable synthetic polymer used in the present invention is preferably a compound, copolymer, or derivative selected from the group consisting of polylactic acid, polyglycolic acid, poly ( ⁇ -caprolactone), trimethylene carbonate, and polyhydroxylalkanoate. .
  • the organic fluorine compound used in the present invention is not particularly limited, but must be capable of dissolving or suspending both the biopolymer and the biodegradable synthetic polymer, and is preferably liquid at room temperature. Furthermore, a solvent that can be distilled off when the solution or suspension containing the biopolymer and the biodegradable synthetic polymer is applied is preferable. Of these, non-aromatic organic fluorine compounds having 2 to 8 carbon atoms or aromatic fluorine-containing esters, carboxylic acids and nitriles having 6 to 12 carbon atoms are preferable.
  • non-aromatic organic fluorine compound having 2 to 8 carbon atoms fluorine-containing alcohols, fluorine-containing amides, fluorine-containing esters, fluorine-containing carboxylic acids and fluorine-containing ethers having 2 to 8 carbon atoms are preferable. It may be partially substituted with a halogen atom other than fluorine. Of these, a fluorine-containing alcohol having 2 to 3 carbon atoms is more preferable. Most preferred are 1,1,1-3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, hexafluoroacetone, trifluoroacetic acid, and pentafluoropropionic acid. Further, since the solvent is compatible with various solvents, it may be used as a mixed solvent with a compatible solvent.
  • the composition of the present invention is produced by drying a mixture containing a biopolymer, a biodegradable synthetic polymer, a bioactive component, and an organic fluorine compound.
  • a film can be formed by pouring a mixture containing a biopolymer, a biodegradable synthetic polymer, a physiologically active ingredient, and an organic fluorine compound onto a substrate or a mold and drying.
  • the shape of the composition may be any film, fiber, powder, sponge, non-woven fabric, particulate or the like that can be molded, but according to a preferred embodiment of the present invention, the composition of the present invention
  • the film or medical material obtained as described above is preferably coated on a stent. Since the thickness of the composition provided by the present invention can be arbitrarily changed, it is not particularly limited as long as the effect of the present invention can be achieved, but is generally from 0.1 mm to 1 mm, preferably from 1 mm. 200 ⁇ m.
  • composition in which the physiologically active ingredient prepared by this method is encapsulated in a biopolymer and a biodegradable synthetic polymer may be crosslinked as necessary.
  • degree of crosslinking between the biopolymer and the biodegradable synthetic polymer various properties such as biodegradability, strength, and structure can be created separately.
  • the crosslinking method is not particularly limited. Examples of the crosslinking method include physical crosslinking, chemical crosslinking, thermal crosslinking, photocrosslinking, enzyme crosslinking and the like.
  • chemical crosslinking or enzymatic crosslinking using a crosslinking agent chemical crosslinking agent or enzyme).
  • Commonly widely used chemical crosslinking agents include aldehydes such as glutaraldehyde and formaldehyde, condensing agents such as carbodiimide and cyanamide, and photodimerizable groups such as vinyl sulfones, diepoxides, cinnamyl groups, vinyl groups, and coumarins.
  • aldehydes such as glutaraldehyde and formaldehyde
  • condensing agents such as carbodiimide and cyanamide
  • photodimerizable groups such as vinyl sulfones, diepoxides, cinnamyl groups, vinyl groups, and coumarins.
  • the crosslinking agent containing is mentioned. More preferred are glutaraldehyde and transglutaminase. Most preferred is enzyme crosslinking with glutaraldehyde.
  • a material having desired flexibility can be obtained by changing the concentration and blending ratio of the biopolymer, the biodegradable synthetic polymer and the crosslinking agent.
  • the composition produced by the production method of the present invention may have a “microphase separation structure”.
  • “Microphase separation structure” means a structure in which the arrangement of chemically different components on the nanometer scale is controlled, specifically a hydrophilic region composed of biopolymers and a hydrophobic region composed of biodegradable synthetic polymers Refers to the structure in which is placed.
  • the microphase separation structure can be confirmed with a TEM, a confocal laser scanning microscope, or the like.
  • the domain size is preferably in the range of “1 to 300 nm” as an average diameter, and more preferably in the range of “10 to 100 nm”.
  • the composition prepared by the production method of the present invention can encapsulate physiologically active ingredients such as drugs in a finely dispersed state. If the method of the present invention is used, it is possible to encapsulate particularly poorly water-soluble compounds.
  • the finely dispersed state referred to in the present specification is a state in which a compound having a size that cannot be detected by the stereomicroscope (MZ16A, manufactured by Leica) is uniformly dispersed in the matrix. Or the drug is in a state of molecular dispersion. More specifically, it refers to a state where the particle size of the encapsulated compound is uniformly dispersed at 0.001 ⁇ m to 10 ⁇ m when observed with a scanning microscope (SEM).
  • the particle size of the compound is preferably 0.01 ⁇ m to 2 ⁇ m, and most preferably 0.01 ⁇ m to 0.5 ⁇ m.
  • a compound having low oxidation stability can be used as the physiologically active ingredient used in the present invention.
  • a compound having an unsaturated bond that is not contained in the aromatic ring can be used.
  • a compound containing polyene or enyne as an unsaturated bond not included in the aromatic ring can be used.
  • the physiologically active ingredient may be, for example, a color material, a drug, etc., and the type is not limited.
  • Bioactive compounds may be poorly water-soluble compounds.
  • the logarithm (Log P) of the distribution coefficient of 1-octanol / water (pH 7.4 buffer solution) obtained by the flask-shaking method is widely used as an index of hydrophilic-hydrophobicity of a compound. You may obtain
  • Encapsulation of hydrophilic compounds with negative LogP in a hydrophilic matrix is easy and has already been reported.
  • a poorly water-soluble compound that is, a compound having a Log P of 1 or more in a hydrophilic matrix.
  • its Log P is preferably 1 or more and 20 or less, more preferably 1 or more and 15 or less, particularly preferably 2 or more and 10 or less, Most preferably, it is 3 or more and 5 or less.
  • preferred compounds are those having a solubility in 1,1,1-3,3,3-hexafluoro-2-propanol of 50 mg / ml to 1000 mg / ml, More preferred is a compound of 100 mg / ml to 500 mg / ml. These compounds can maintain the finely dispersed state referred to in the present invention even at a high concentration.
  • solubility with respect to the hexafluoroisopropanol of this invention is measured as follows.
  • Drugs can be used as physiologically active ingredients. Specific examples include transdermal absorption agents, topical therapeutic agents, oral therapeutic agents, cosmetic ingredients, and supplement ingredients. Specific examples of the drug are preferably an immunosuppressant (eg, rapamycin, tacrolimus, cyclosporine), an anticancer agent (eg, paclitaxel, topotecin, taxotere, docetaxel, enocitabine, 17-AAG), an antipyretic analgesic (eg, aspirin, Acetaminophen, sulpyrine), antiepileptic agents (eg phenytoin, acetazolamide, carbamazepine, clonazepam, diazepam, nitrazepam), anti-inflammatory analgesics (eg alclofenac, aluminoprofen, ibuprofen, indomethacin, epirizole, oxaprozin, ketoprofen, dicloflunac
  • composition produced by the method of the present invention is not particularly limited, but is preferably a medical use as described above.
  • a biopolymer having biodegradability can be used for the hydrophilic matrix to be coated, and the bioactive component can be encapsulated in the hydrophilic matrix at a high concentration. It can be expected that the hydrophilic matrix will degrade after release for a period of time.
  • many of these physiologically active ingredients are poorly water-soluble, it is difficult to enclose the physiologically active ingredient in a hydrophilic matrix.
  • an immunosuppressant or an anticancer agent as a physiologically active ingredient can be expected.
  • it can be applied to transdermal absorption agents, topical therapeutic agents, oral therapeutic agents, cosmetics, supplements, color materials, and the like.
  • Additives that can be used in the present invention include humectants (for example, agar, diglycerin, distearyldimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, sodium hyaluronate, hexylene glycol, yoquinin extract, petrolatum.
  • humectants for example, agar, diglycerin, distearyldimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, sodium hyaluronate, hexylene glycol, yoquinin extract, petrolatum.
  • Softeners eg, glycerin, mineral oil
  • emollient ingredients eg, isopropyl isostearate, polyglyceryl isostearate, isotridecyl isononanoate, octyl isononanoate, oleic acid, glyceryl oleate, cocoa butter, cholesterol, mixed fatty acid triglycerides, Dioctyl succinate, sucrose acetate stearate, cyclopentasiloxane, sucrose distearate, octyl palmitate, hydroxy stearate Octylate, aralkyl behenate, sucrose polybehenate, polymethylsilsesquioxane, myristyl alcohol, cetyl myristate, myristyl myristate, hexyl laurate), and transdermal absorption enhancers (eg, ethanol, isopropyl myristate, Citric acid,
  • Example 1 Preparation of vitamin D3-encapsulated gelatin film 1,1,1,3,3,3-hexafluor containing porcine skin acid-treated gelatin (180 mg, PSK gelatin, Nippi) and vitamin D3 (9 mg)
  • Raw 2-propanol (HFIP) solution (0.9 mL) was poured into a silicone mold (3 cm x 3 cm) placed on a polypropylene sheet. The solution was allowed to stand at room temperature for 3 hours and then allowed to stand at ⁇ 80 ° C. for 3 hours. The frozen body was freeze-dried (this is a reference example).
  • an HFIP solution (0.9 mL) containing PSK gelatin and a predetermined synthetic polymer was prepared.
  • Vitamin D3 (9 mg) was added to the solution to obtain an HFIP solution containing PSK gelatin, synthetic polymer and vitamin D3.
  • the vitamin D3-containing mixed solution was poured into a silicone mold on the above-described polypropylene sheet. The solution poured into the mold was allowed to stand at room temperature for 3 hours, and then allowed to stand at ⁇ 80 ° C. for 3 hours. The frozen body was lyophilized.
  • Vitamin D3-encapsulated albumin was obtained by the same experiment using bovine serum albumin as in PSK gelatin.
  • biodegradable synthetic polymers PLA, PLGA, PCL

Abstract

Provided are compositions, wherein compounds that are easily oxidized are stably sealed in a base material without using conventional antioxidants and excipients. Provided are compositions that comprise biopolymers, biodegradable synthetic polymers, and bioactive components.

Description

生理活性成分を安定に封入した組成物Composition in which a physiologically active ingredient is stably encapsulated
　本発明は、安定性の低い化合物を安定に封入した生体高分子組成物、並びにその製造方法に関する。 The present invention relates to a biopolymer composition in which a compound having low stability is stably encapsulated, and a method for producing the same.
　医療用組成物、サプリメント、および化粧品組成物においてアスタキサンチン等やビタミン等の酸化しやすい化合物が有効成分として広く利用されている。上記有効成分はそれぞれ体内において特異な機能を有し、生体の機能維持や健康増進への寄与が甚大である。しかし、該有効成分は一般に光、熱、酸素、多湿等の条件により、酸化や分解を受けやすい。従って、上記組成物を作製するため、各種安定化剤や抗酸化剤等の添加剤が混合されている。該添加剤として、多くはアスコルビン酸やクエン酸等の抗酸化剤が用いられている。 In the medical compositions, supplements, and cosmetic compositions, oxidizable compounds such as astaxanthin and vitamins are widely used as active ingredients. Each of the above active ingredients has a unique function in the body, and greatly contributes to maintaining the functions of the living body and promoting health. However, the active ingredient is generally susceptible to oxidation and decomposition under conditions such as light, heat, oxygen, and humidity. Therefore, additives such as various stabilizers and antioxidants are mixed in order to produce the above composition. As the additive, an antioxidant such as ascorbic acid or citric acid is often used.
　特に、体内へ埋め込み用の医療用組成物として、体内にて分解する生分解性高分子が利用されている。生分解性高分子としては、ポリ乳酸、ポリグリコール酸に代表される合成高分子、コラーゲンやゼラチンに代表される生体高分子が広く利用されている。後者は一般に親水性が高く、水分を多く含んだ形で用いられることが多い。従って、安定性の低い薬剤をこれら生体高分子組成物に封入した製剤を作製するには、薬剤を安定に封入することが困難である。すなわち、通常の抗酸化剤の添加のみでは薬剤の安定な封入には限界がある。 In particular, biodegradable polymers that decompose in the body are used as medical compositions for implantation in the body. As biodegradable polymers, synthetic polymers typified by polylactic acid and polyglycolic acid, and biopolymers typified by collagen and gelatin are widely used. The latter is generally highly hydrophilic and is often used in a form containing a large amount of moisture. Therefore, it is difficult to stably encapsulate a drug in order to prepare a preparation in which a drug with low stability is encapsulated in these biopolymer compositions. That is, there is a limit to the stable encapsulation of the drug only by adding a normal antioxidant.
　例えば、ビタミンＤを安定化した組成物の例としては、特許文献１には、ビタミンＤ3と安息香酸ナトリウムとを含有してなる安定なビタミンＤ3含有固形製剤組成物が記載されている。また、特許文献２には、活性型ビタミンＤ類を塩基性高分子中に分散してなる組成物、有機溶媒に易溶性の賦形剤，活性型ビタミンＤ2類および塩基性物質を含有してなる組成物、あるいは微粉状の活性型ビタミンＤ類を塩基性物質および水に易溶性の賦形剤に均一に分散させてなる組成物が記載されている。しかし、これらの文献に記載の組成物はいずれも、生理活性成分であるビタミンＤ以外の成分を用いてビタミンＤの安定化を図っている。 For example, examples of compositions stabilized vitamin D, Patent Document 1, a stable vitamin D 3 containing solid pharmaceutical composition comprising a vitamin D 3 and sodium benzoate are described. Patent Document 2 contains a composition obtained by dispersing active vitamin D in a basic polymer, an excipient that is easily soluble in an organic solvent, active vitamin D 2 and a basic substance. Or a composition obtained by uniformly dispersing a finely powdered active vitamin D in a basic substance and an excipient that is easily soluble in water. However, all of the compositions described in these documents attempt to stabilize vitamin D using components other than vitamin D, which is a physiologically active component.
　一般に、合成高分子は疎水性であり、生体高分子は親水性であり、これらのように相反する性質を有する基材の複合化は非常に困難である。疎水性と親水性の化合物を均一化するには、界面活性剤を用いる。しかし、界面活性剤はそれ自身毒性を有することが多く、体内埋め込み用の医療用組成物中に存在する場合は、製剤の毒性面で問題である。 Generally, synthetic polymers are hydrophobic, biopolymers are hydrophilic, and it is very difficult to combine base materials having such conflicting properties. A surfactant is used to make the hydrophobic and hydrophilic compounds uniform. However, surfactants are often toxic per se, and when present in a medical composition for implantation in the body, there is a problem in the toxicity of the preparation.
　また、非特許文献１には、エレクトロスピニング法にて作成されたゼラチン鎖とポリ（ε―カプロラクトン：ＰＬＣＡ）鎖を絡みあわせたファイバー状材料が開示されているが、この材料は本発明の構成とは異なり、又、不織布状組成物のファイバー径によって物理的に柔軟性の問題を解決している。 Non-Patent Document 1 discloses a fiber-like material in which a gelatin chain and a poly (ε-caprolactone: PLCA) chain created by an electrospinning method are entangled. This material is a constituent of the present invention. Unlike the above, the fiber diameter of the nonwoven fabric composition physically solves the problem of flexibility.
特開平５－２４６８５５号公報JP-A-5-246855 特開平５－２７９２６０号公報JP-A-5-279260
　本発明は、従来の酸化防止剤や賦形剤を用いることなく、容易に酸化される化合物を基材に安定に封入した組成物を提供することを解決すべき課題とした。 The present invention has an object to be solved by providing a composition in which a compound that can be easily oxidized is stably encapsulated in a base material without using a conventional antioxidant or excipient.
　本発明者らは上記課題を解決するために鋭意検討した結果、医療用の基材として用いられる疎水性の生分解性合成高分子を生体高分子組成物に添加して均一に混合することによって、酸化を受けやすい化合物を安定に封入した医療用組成物の作製できることを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have added a hydrophobic biodegradable synthetic polymer used as a medical base material to a biopolymer composition and mixed it uniformly. The inventors have found that a medical composition in which a compound susceptible to oxidation can be stably encapsulated can be produced, and the present invention has been completed.
　即ち、本発明によれば、生体高分子、生分解性合成高分子及び生理活性成分を含む組成物が提供される。
　好ましくは、生体高分子はタンパク質又は多糖である。
　好ましくは、タンパク質はコラーゲン、ゼラチン、アルブミン、カゼイン、フィブロイン、フィブリン、ラミニン、フィブロネクチン、及びビトロネクチンからなる群より選ばれる少なくとも一種である。
　好ましくは、生体高分子は、熱、光、または架橋剤により架橋されている。 That is, according to the present invention, a composition comprising a biopolymer, a biodegradable synthetic polymer and a physiologically active ingredient is provided.
Preferably, the biopolymer is a protein or a polysaccharide.
Preferably, the protein is at least one selected from the group consisting of collagen, gelatin, albumin, casein, fibroin, fibrin, laminin, fibronectin, and vitronectin.
Preferably, the biopolymer is crosslinked by heat, light, or a crosslinking agent.
　好ましくは、生分解性合成高分子は、ポリ乳酸、ポリグリコール酸、ポリ（ε―カプロラクトン）、トリメチレンカーボネート、及びポリヒドロキシルアルカノエートからなる群から選ばれる化合物、共重合体、あるいは誘導体である。
　好ましくは、生理活性成分は、芳香環に含まれない不飽和結合を有する化合物である。
　好ましくは、生理活性成分は、ビタミン類、抗癌剤、免疫抑制剤、抗炎症剤、又は抗酸化剤である。
　好ましくは、生理活性成分は、ビタミンD、ビタミンD誘導体、またはアスタキサンチンである。
　好ましくは、本発明の組成物は、経皮吸収剤、局所治療剤、経口治療剤、化粧品、サプリメント、又は色素材として使用される。 Preferably, the biodegradable synthetic polymer is a compound, copolymer, or derivative selected from the group consisting of polylactic acid, polyglycolic acid, poly (ε-caprolactone), trimethylene carbonate, and polyhydroxyl alkanoate. .
Preferably, the physiologically active ingredient is a compound having an unsaturated bond not contained in the aromatic ring.
Preferably, the physiologically active ingredient is vitamins, anticancer agents, immunosuppressive agents, anti-inflammatory agents, or antioxidants.
Preferably, the physiologically active ingredient is vitamin D, a vitamin D derivative, or astaxanthin.
Preferably, the composition of the present invention is used as a transdermally absorbable agent, a topical therapeutic agent, an oral therapeutic agent, a cosmetic product, a supplement, or a color material.
　本発明によればさらに、(a) 生体高分子、生分解性合成高分子、生理活性成分、及び有機フッ素化合物を含む混合物を調製する工程；及び(b) 工程(a)で得られた混合物から有機フッ素化合物を除去する工程を含む、上記した本発明の組成物の製造方法が提供される。
　好ましくは、有機フッ素化合物は、炭素数２から８の化合物である。
　好ましくは、有機フッ素化合物は、炭素数２から３の化合物である。
　好ましくは、有機フッ素化合物は、１，１，１，３，３，３－ヘキサフルオロ－２－プロパノール、２，２，２－トリフルオロエタノール、又はヘキサフルオロアセトンである。 According to the present invention, (a) a step of preparing a mixture comprising a biopolymer, a biodegradable synthetic polymer, a bioactive component, and an organic fluorine compound; and (b) a mixture obtained in step (a). There is provided a method for producing the above-described composition of the present invention, which comprises the step of removing the organic fluorine compound from the above.
Preferably, the organic fluorine compound is a compound having 2 to 8 carbon atoms.
Preferably, the organic fluorine compound is a compound having 2 to 3 carbon atoms.
Preferably, the organic fluorine compound is 1,1,1,3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, or hexafluoroacetone.
　本発明により、医療用組成物の物理的、化学的、および生物学的性質に影響を及ぼす各種添加剤を加えることなく、生体適合性の高い生体内分解性高分子を用いて有効な薬剤を安定に封入した医療用組成物を提供することが可能になった。さらに、本発明の組成物の製造には、有害な界面活性剤は必要ではなく、生体への毒性の懸念を大幅に減少できる。 According to the present invention, an effective drug can be obtained using a biocompatible biodegradable polymer without adding various additives that affect the physical, chemical, and biological properties of the medical composition. It has become possible to provide a stably encapsulated medical composition. Furthermore, no harmful surfactant is required for the production of the composition of the present invention, and the concern about toxicity to the living body can be greatly reduced.
　以下、本発明についてさらに具体的に説明する。
　本発明の組成物は、生体高分子、生分解性合成高分子及び生理活性成分を含むことを特徴とする。 Hereinafter, the present invention will be described more specifically.
The composition of the present invention comprises a biopolymer, a biodegradable synthetic polymer and a bioactive component.
　本発明で用いる生体高分子は、多糖、タンパク質、およびそれらの誘導体のいずれでも構わない。多糖としてはグリコサミノグリカン、キトサン、キチンが好ましい。タンパク質としては、球状、繊維状等のタンパク質が好ましく、好ましくはコラーゲン、ゼラチン、アルブミン、カゼイン、フィブロイン、フィブリン、ラミニン、フィブロネクチン、又はビトロネクチンである、より好ましくはコラーゲン、ゼラチン、アルブミン、カゼイン、フィブロイン、ラミニンである。最も好ましくはコラーゲン、ゼラチン、アルブミン、カゼインであり、このなかでもゼラチンが最も好ましい。また、タンパク質の由来は特に限定するものではなく、牛、豚、魚、および遺伝子組み換え体のいずれも用いることができる。遺伝子組み換え体としては、例えばEP0926543B,WO2004／085473号明細書、EP1398324A、EP1014176A、US6645712に記載のものを用いることができる。 The biopolymer used in the present invention may be any of polysaccharides, proteins, and derivatives thereof. As the polysaccharide, glycosaminoglycan, chitosan, and chitin are preferable. The protein is preferably a protein such as globular or fibrous, preferably collagen, gelatin, albumin, casein, fibroin, fibrin, laminin, fibronectin, or vitronectin, more preferably collagen, gelatin, albumin, casein, fibroin, Laminin. Most preferred are collagen, gelatin, albumin, and casein, and among these, gelatin is most preferred. In addition, the origin of the protein is not particularly limited, and any of cows, pigs, fish, and gene recombinants can be used. As the gene recombinant, those described in, for example, EP0926543B, WO2004 / 085473, EP1398324A, EP1014176A, US6645712 can be used.
　本発明で用いる生分解性合成高分子は、ポリ乳酸、ポリグリコール酸、ポリ（ε―カプロラクトン）、トリメチレンカーボネート、ポリヒドロキシルアルカノエートからなる群から選ばれる化合物、共重合体、あるいは誘導体が好ましい。 The biodegradable synthetic polymer used in the present invention is preferably a compound, copolymer, or derivative selected from the group consisting of polylactic acid, polyglycolic acid, poly (ε-caprolactone), trimethylene carbonate, and polyhydroxylalkanoate. .
　本発明に用いる有機フッ素化合物は特に限定するものではないが、生体高分子と生分解性合成高分子をともに溶解または懸濁できることが必要であり、常温で液体のものが好ましい。さらに、生体高分子と生分解性合成高分子を含む該溶液または懸濁液を、塗布した際に溶媒が留去可能である溶媒が好ましい。このうち、好ましくは炭素数２～８である非芳香族有機フッ素化合物又は炭素数６～１２の芳香族含フッ素エステル類、カルボン酸類、ニトリル類である。炭素数２～８である非芳香族有機フッ素化合物としては、炭素数２～８のフッ素含有アルコール類、フッ素含有アミド類、フッ素含有エステル類、フッ素含有カルボン酸、フッ素含有エーテル類が好ましい。フッ素以外のハロゲン原子で一部が置換されていても構わない。このうちより好ましくは炭素数が２から３であるフッ素含有アルコールである。最も好ましくは1,1,1-3,3,3-ヘキサフルオロ-2-プロパノール、2,2,2-トリフルオロエタノール、ヘキサフルオロアセトン、トリフルオロ酢酸、およびペンタフルオロプロピオン酸である。また、該溶媒は種々の溶媒と相溶性があるため、相溶性のある溶媒との混合溶媒として利用しても構わない。 The organic fluorine compound used in the present invention is not particularly limited, but must be capable of dissolving or suspending both the biopolymer and the biodegradable synthetic polymer, and is preferably liquid at room temperature. Furthermore, a solvent that can be distilled off when the solution or suspension containing the biopolymer and the biodegradable synthetic polymer is applied is preferable. Of these, non-aromatic organic fluorine compounds having 2 to 8 carbon atoms or aromatic fluorine-containing esters, carboxylic acids and nitriles having 6 to 12 carbon atoms are preferable. As the non-aromatic organic fluorine compound having 2 to 8 carbon atoms, fluorine-containing alcohols, fluorine-containing amides, fluorine-containing esters, fluorine-containing carboxylic acids and fluorine-containing ethers having 2 to 8 carbon atoms are preferable. It may be partially substituted with a halogen atom other than fluorine. Of these, a fluorine-containing alcohol having 2 to 3 carbon atoms is more preferable. Most preferred are 1,1,1-3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, hexafluoroacetone, trifluoroacetic acid, and pentafluoropropionic acid. Further, since the solvent is compatible with various solvents, it may be used as a mixed solvent with a compatible solvent.
　本発明により提供される組成物の製造方法について説明する。本発明の組成物は、生体高分子と生分解性合成高分子と生理活性成分と有機フッ素化合物を含む混合物を乾燥することによって製造する。例えば、生体高分子と生分解性合成高分子と生理活性成分と有機フッ素化合物を含む混合物を基板上又は型に流し込み、乾燥することによってフィルムを形成することができる。組成物の形状はフィルム状、ファイバー状、粉体、スポンジ状、不織布状、粒子状等成型可能なものであれば何でも構わないが、本発明の好ましい態様によれば、本発明の組成物は、上記のようにして得られるフィルム或いは医療材料上、好ましくはステント上にコーティングされた形態のものである。本発明により提供される組成物の厚さは、任意に変えられるため、本発明の効果が達成できる限りは特に限定されないが、一般的には0.1 μmから1 mmであり、好ましくは1 μmから200μmである。 The method for producing the composition provided by the present invention will be described. The composition of the present invention is produced by drying a mixture containing a biopolymer, a biodegradable synthetic polymer, a bioactive component, and an organic fluorine compound. For example, a film can be formed by pouring a mixture containing a biopolymer, a biodegradable synthetic polymer, a physiologically active ingredient, and an organic fluorine compound onto a substrate or a mold and drying. The shape of the composition may be any film, fiber, powder, sponge, non-woven fabric, particulate or the like that can be molded, but according to a preferred embodiment of the present invention, the composition of the present invention The film or medical material obtained as described above is preferably coated on a stent. Since the thickness of the composition provided by the present invention can be arbitrarily changed, it is not particularly limited as long as the effect of the present invention can be achieved, but is generally from 0.1 mm to 1 mm, preferably from 1 mm. 200 μm.
　該手法により作成した生理活性成分を生体高分子及び生分解性合成高分子に封入した組成物は、必要に応じて架橋を行っても良い。生体高分子及び生分解性合成高分子の架橋度を制御することで、生体内分解性、強度、構造等の各種性質を作り分けることが可能となる。架橋方法は特に限定することはない。架橋方法としては例えば物理架橋、化学架橋、熱架橋、光架橋、酵素架橋等が挙げられる。好ましくは、架橋剤（化学架橋剤又は酵素）を用いる、化学架橋または酵素架橋である。化学架橋剤としては一般的に広く利用されているグルタルアルデヒドやホルムアルデヒド等のアルデヒド類、カルボジイミド、シアナミド等の縮合剤類、ビニルスルホン類、ジエポキシド、シンナミル基、ビニル基、クマリン等の光二量化性基を含む架橋剤が挙げられる。より好ましくはグルタルアルデヒド、トランスグルタミナーゼである。最も好ましくはグルタルアルデヒドによる酵素架橋である。 The composition in which the physiologically active ingredient prepared by this method is encapsulated in a biopolymer and a biodegradable synthetic polymer may be crosslinked as necessary. By controlling the degree of crosslinking between the biopolymer and the biodegradable synthetic polymer, various properties such as biodegradability, strength, and structure can be created separately. The crosslinking method is not particularly limited. Examples of the crosslinking method include physical crosslinking, chemical crosslinking, thermal crosslinking, photocrosslinking, enzyme crosslinking and the like. Preferably, chemical crosslinking or enzymatic crosslinking using a crosslinking agent (chemical crosslinking agent or enzyme). Commonly widely used chemical crosslinking agents include aldehydes such as glutaraldehyde and formaldehyde, condensing agents such as carbodiimide and cyanamide, and photodimerizable groups such as vinyl sulfones, diepoxides, cinnamyl groups, vinyl groups, and coumarins. The crosslinking agent containing is mentioned. More preferred are glutaraldehyde and transglutaminase. Most preferred is enzyme crosslinking with glutaraldehyde.
　本発明の製造方法においては、生体高分子と生分解性合成高分子及び架橋剤の濃度、配合比を変化させることによって、所望の柔軟性を有する材料を得ることができる。 In the production method of the present invention, a material having desired flexibility can be obtained by changing the concentration and blending ratio of the biopolymer, the biodegradable synthetic polymer and the crosslinking agent.
　本発明の製造方法で製造された組成物は、「ミクロ相分離構造」を持つものでもよい。「ミクロ相分離構造」とは、ナノメートルスケールで化学的に異なる成分の配置を制御された構造、具体的には生体高分子からなる親水性領域と生分解性合成高分子からなる疎水性領域が配置される構造を指す。ミクロ相分離構造はＴＥＭ、共焦点レーザー走査型顕微鏡等により確認することができる。本発明においてはドメインの大きさが、直径の平均値で「１～３００ｎｍ」の範囲にあることが好ましく、さらに「１０～１００ｎｍ」の範囲にあることが好ましい。 The composition produced by the production method of the present invention may have a “microphase separation structure”. “Microphase separation structure” means a structure in which the arrangement of chemically different components on the nanometer scale is controlled, specifically a hydrophilic region composed of biopolymers and a hydrophobic region composed of biodegradable synthetic polymers Refers to the structure in which is placed. The microphase separation structure can be confirmed with a TEM, a confocal laser scanning microscope, or the like. In the present invention, the domain size is preferably in the range of “1 to 300 nm” as an average diameter, and more preferably in the range of “10 to 100 nm”.
　本発明の製造方法で作成された組成物は、薬剤等の生理活性成分を微分散状態で封入することができる。本発明の手法を用いれば、特に難水溶性化合物を封入することが可能である。本明細書で言う微分散状態とは、封入されている難水溶性薬剤が、実体顕微鏡（ライカ社製、MZ16A）にて検出不能であるサイズの化合物がマトリックス中に均一に分散している状態か、薬剤が分子分散している状態をさす。更に詳細には、走査型顕微鏡（SEM）で観察した場合に、封入されている化合物の粒径が0.001μｍ～10μｍで均一に分散している状態を言う。化合物の粒径として好ましくは0.01μｍ～2μｍ、最も好ましくは0.01μｍ～0.5μｍである。 The composition prepared by the production method of the present invention can encapsulate physiologically active ingredients such as drugs in a finely dispersed state. If the method of the present invention is used, it is possible to encapsulate particularly poorly water-soluble compounds. The finely dispersed state referred to in the present specification is a state in which a compound having a size that cannot be detected by the stereomicroscope (MZ16A, manufactured by Leica) is uniformly dispersed in the matrix. Or the drug is in a state of molecular dispersion. More specifically, it refers to a state where the particle size of the encapsulated compound is uniformly dispersed at 0.001 μm to 10 μm when observed with a scanning microscope (SEM). The particle size of the compound is preferably 0.01 μm to 2 μm, and most preferably 0.01 μm to 0.5 μm.
　本発明で用いる生理活性成分としては、特に、酸化安定性の低い化合物を用いることができる。酸化安定性の低い化合物としては、芳香環に含まれない不飽和結合を持つ化合物を用いることができる。例えば、芳香環に含まれない不飽和結合としてポリエン又はエンインを含む化合物を用いることができる。 As the physiologically active ingredient used in the present invention, a compound having low oxidation stability can be used. As the compound having low oxidation stability, a compound having an unsaturated bond that is not contained in the aromatic ring can be used. For example, a compound containing polyene or enyne as an unsaturated bond not included in the aromatic ring can be used.
　生理活性成分は、例えば、色素材、薬剤等でもよく、その種類は限定されない。生理活性成は、難水溶性化合物でもよい。一般に化合物の親水－疎水性の指標として、フラスコシェイキング法により得られる１－オクタノール/水（ｐＨ7.4緩衝溶液）の分配係数の対数（Log P）が広く用いられているが、実測する代わりに計算により求めても良い。（本明細書におけるLogPは、Daylight Chemical Information Systems社のシステム：PCModelsに組み込まれたHansch-Leoのフラグメント法CLOGPプログラムを使用して計算している。） The physiologically active ingredient may be, for example, a color material, a drug, etc., and the type is not limited. Bioactive compounds may be poorly water-soluble compounds. In general, the logarithm (Log P) of the distribution coefficient of 1-octanol / water (pH 7.4 buffer solution) obtained by the flask-shaking method is widely used as an index of hydrophilic-hydrophobicity of a compound. You may obtain | require by calculation. (LogP in this specification is calculated using the Hansch-Leo fragment method CLOGP program embedded in the system: PCModels of Daylight Chemical Information Systems)
　LogPが負である親水性化合物の親水性マトリックスへの封入は容易で、既に報告されている。しかし、難水溶性化合物、すなわちLog P が 1以上の化合物の親水性マトリックスへの均一な封入は困難であることが知られていた。本発明で封入する生理活性成分が難水溶性化合物である場合、そのLog Pは好ましくは１以上２０以下であり、さらに好ましくは１以上１５以下であり、特に好ましくは２以上１０以下であり、最も好ましくは３以上５以下である。 Encapsulation of hydrophilic compounds with negative LogP in a hydrophilic matrix is easy and has already been reported. However, it has been known that it is difficult to uniformly encapsulate a poorly water-soluble compound, that is, a compound having a Log P of 1 or more in a hydrophilic matrix. When the physiologically active ingredient encapsulated in the present invention is a poorly water-soluble compound, its Log P is preferably 1 or more and 20 or less, more preferably 1 or more and 15 or less, particularly preferably 2 or more and 10 or less, Most preferably, it is 3 or more and 5 or less.
　本発明で封入される難水溶性化合物のうち、好ましい化合物は、1,1,1-3,3,3-ヘキサフルオロ-2-プロパノールに対する溶解度が50mg/ml～1000mg/mlの化合物であり、更に好ましくは100mg/ml～500mg/mlの化合物である。これらの化合物は高濃度でも本発明でいう微分散状態を保持できる。なお、本発明のヘキサフルオロイソプロパノールに対する溶解度は以下のように測定する。1,1,1-3,3,3-ヘキサフルオロ-2-プロパノールへ、化合物の濃度を段階的に変化させて添加した物を作成し、どの濃度で析出が起きているかを確認することで、その化合物の1,1,1-3,3,3-ヘキサフルオロ-2-プロパノールへの溶解度とした。尚、溶解・不溶解の判断は、上記混合液を超小型遠心機（チビタンII XX42CF00T；テックジャム株式会社製）にて20秒間遠心し、沈殿が生じているかを確認することで行った。 Of the poorly water-soluble compounds encapsulated in the present invention, preferred compounds are those having a solubility in 1,1,1-3,3,3-hexafluoro-2-propanol of 50 mg / ml to 1000 mg / ml, More preferred is a compound of 100 mg / ml to 500 mg / ml. These compounds can maintain the finely dispersed state referred to in the present invention even at a high concentration. In addition, the solubility with respect to the hexafluoroisopropanol of this invention is measured as follows. By creating a compound that was added to 1,1,1-3,3,3-hexafluoro-2-propanol with the concentration of the compound changed stepwise, and confirming at which concentration precipitation occurred The solubility of the compound in 1,1,1-3,3,3-hexafluoro-2-propanol was defined as the solubility. The determination of dissolution / insolubility was performed by centrifuging the above mixed solution for 20 seconds in a micro centrifuge (Chibitan II XX42CF00T; manufactured by Tech Jam Co., Ltd.) and confirming whether precipitation occurred.
　生理活性成分としては薬剤を用いることができる。具体的には経皮吸収剤、局所治療剤、経口治療剤、化粧品成分、サプリメント成分が挙げられる。薬剤の具体例としては、好ましくは、免疫抑制剤（例えば、ラパマイシン、タクロリムス、シクロスポリン）、抗癌剤（例えば、パクリタキセル、トポテシン、タキソテール、ドセタキセル、エノシタビン、17-AAG）、解熱性鎮痛剤（例えばアスピリン、アセトアミノフェン、スルピリン）、抗てんかん剤（例えばフェニトイン、アセタゾラミド、カルバマゼピン、クロナゼパム、ジアゼパム、ニトラゼパム）、消炎鎮痛剤（例えばアルクロフェナク、アルミノプロフェン、イブプロフェン、インドメタシン、エピリゾール、オキサプロジン、ケトプロフェン、ジクロフェナクナトリウム、ジフルニサル、ナプロキセン、ピロキシカム、フェンブフェン、フルフェナム酸、フルルビプロフェン、フロクタフェニン、ペンタゾシン、メチアジン酸、メフェナム酸、モフェゾラク）、脂溶性ビタミン（例えばビタミンA、ビタミンD2、ビタミンD3、1,25-OHビタミンＤ３、25ＯＨビタミンＤ３、ビタミンE、ビタミンK2）、合成抗菌剤（エノキシン、オフロキサシン、シノキサシン、スパルフロキサシン、チアンフェニコール、ナリジクス酸、トシル酸トスフロキサシン、ノルフロキサシン、ピペミド酸三水和物、ピロミド酸、フレロキサシン、レボフロキサシン）、抗真菌剤（例えばイトラコナゾール、ケトコナゾール、フルコナゾール、フルシトシン、ミコナゾール、ピマリシン）、抗生剤（例えばロキシスロマイシン、セフジトレンピボキシル、セフテラムピボキシル、エリスロマイシン、クラリスロマイシン、テリスロマイシン、アジスロマイシン）、抗ウイルス剤（アシクロビル、ガンシクロビル、ジダノシン、ジドブジン、ビタラビン）、ホルモン剤（例えばインスリン亜鉛、プロピオン酸テストステロン、安息香酸エストラジオール）、循環器官用薬（例えばアルプロスタジル）、抗血栓剤、消化器管用薬（オメプラゾール、ランソプラゾール、テプレノン、メトクロプラミド、ソファルコン）、糖尿病用剤（例えば塩酸ピオグリタゾン）、抗酸化剤、抗アレルギー剤（フマル酸クレマスチン、ロラタジン、メキタジン、ザフィルルカスト、プランルカスト、エバスチン、タザノラスト、トラニラスト、ラマトロバン、オキサトミド）、ステロイド抗炎症剤（例えば酢酸コルチゾン、ベタメタゾン、プレドニゾロン、プロピオン酸フルチカゾン、デキサメタゾン、ブデソニド、プロピオン酸ベクロメタゾン、トリアムシノロン、ロトプレドノール、フルオロメトロン、ジフルプレドナード、フランカルボン酸モメタゾン、プロピオン酸クロベタゾール、酢酸ジフロラゾン、吉草酸ジフルコルトロン、フルオシノニド、アムシノニド、ハルシノニド、フルオシノロンアセトニド、トリアムシノロンアセトニド、ピバル酸フルメタゾン、酪酸クロベタゾン）、化粧品成分、サルファ剤（例えばサラゾスルファピリジン、スルファジメトキシン、スルファメチゾール、スルファメトキサゾール、スルファメトピラジン、スルファモノメトキシン）、麻酔薬（例えばフェンタニル）、潰瘍性大腸炎治療剤（例えばメサラジン）またはサプリメント成分を用いることができる。 Drugs can be used as physiologically active ingredients. Specific examples include transdermal absorption agents, topical therapeutic agents, oral therapeutic agents, cosmetic ingredients, and supplement ingredients. Specific examples of the drug are preferably an immunosuppressant (eg, rapamycin, tacrolimus, cyclosporine), an anticancer agent (eg, paclitaxel, topotecin, taxotere, docetaxel, enocitabine, 17-AAG), an antipyretic analgesic (eg, aspirin, Acetaminophen, sulpyrine), antiepileptic agents (eg phenytoin, acetazolamide, carbamazepine, clonazepam, diazepam, nitrazepam), anti-inflammatory analgesics (eg alclofenac, aluminoprofen, ibuprofen, indomethacin, epirizole, oxaprozin, ketoprofen, dicloflunac , Naproxen, piroxicam, fenbufen, flufenamic acid, flurbiprofen, fructophenine, pentazocine, methazidic acid Mefenamic acid, mofezolac), fat-soluble vitamins (eg vitamin A, vitamin D2, vitamin D3, 1,25-OH vitamin D3, 25OH vitamin D3, vitamin E, vitamin K2), synthetic antibacterial agents (enoxin, ofloxacin, synoxacin, spall) Floxacin, thiamphenicol, nalidixic acid, tosufloxacin tosylate, norfloxacin, pipemidic acid trihydrate, pyromidic acid, fleroxacin, levofloxacin), antifungal agents (eg itraconazole, ketoconazole, fluconazole, flucytosine, miconazole, pimaricin), Antibiotics (eg, roxithromycin, cefditoren pivoxil, cefteram pivoxil, erythromycin, clarithromycin, terithromycin, azithromycin), antiviral agents (acyclovir, ganci Clovir, didanosine, zidovudine, vitarabine), hormonal drugs (eg insulin zinc, testosterone propionate, estradiol benzoate), cardiovascular drugs (eg alprostadil), antithrombotic drugs, gastrointestinal drugs (omeprazole, lansoprazole, teprenone) , Metoclopramide, sofalcone), antidiabetic agents (eg pioglitazone hydrochloride), antioxidants, antiallergic agents (clemastine fumarate, loratadine, mequitazine, zafirlukast, pranlukast, ebastine, tazanolast, tranilast, ramatroban, oxatomide), steroids Anti-inflammatory agents (eg cortisone acetate, betamethasone, prednisolone, fluticasone propionate, dexamethasone, budesonide, beclomethasone propionate, triamcinolol , Rotoprednol, fluorometholone, diflupredado, mometasone furan carboxylate, clobetasol propionate, diflurozone acetate, diflucortron valerate, fluocinonide, amsinonide, harcinonide, fluocinolone acetonide, triamcinolone acetonide, flubetasone pivalate, clobetasone pivalate ), Cosmetic ingredients, sulfa drugs (eg salazosulfapyridine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfamethopyrazine, sulfamonomethoxine), anesthetics (eg fentanyl), ulcerative colitis treatment An agent (eg, mesalazine) or a supplement component can be used.
　本発明の方法で製造される組成物の用途は特に限定することはないが、上述したように好ましくは医療用途である。本発明で開発した手法では、コーティングする親水性マトリックスに生体内分解性を有する生体高分子を使用可能であり、かつ生理活性成分を高濃度に該親水性マトリックスに封入できることから、生理活性成分を一定期間放出した後、該親水性マトリックスが分解することが期待できる。また、これらの生理活性成分が難水溶性であるものが多いことから、生理活性成分の親水性マトリックスへの封入が困難である。該手法により、生理活性成分に免疫抑制剤や抗癌剤等を利用している薬剤放出型ステントへの応用の可能性が期待できる。その他、経皮吸収剤、局所治療剤、経口治療剤、化粧品、サプリメント、色素材等に応用が可能である。 The use of the composition produced by the method of the present invention is not particularly limited, but is preferably a medical use as described above. In the method developed in the present invention, a biopolymer having biodegradability can be used for the hydrophilic matrix to be coated, and the bioactive component can be encapsulated in the hydrophilic matrix at a high concentration. It can be expected that the hydrophilic matrix will degrade after release for a period of time. In addition, since many of these physiologically active ingredients are poorly water-soluble, it is difficult to enclose the physiologically active ingredient in a hydrophilic matrix. By this technique, the possibility of application to a drug-releasing stent using an immunosuppressant or an anticancer agent as a physiologically active ingredient can be expected. In addition, it can be applied to transdermal absorption agents, topical therapeutic agents, oral therapeutic agents, cosmetics, supplements, color materials, and the like.
　また、生理活性成分には、各種添加物を加えてもよい。本発明で用いることができる添加物としては、保湿剤（例えば、カンテン、ジグリセリン、ジステアリルジモニウムヘクトライト、ブチレングリコール、ポリエチレングリコール、プロピレングリコール、ヒアルロン酸ナトリウム、へキシレングリコール、ヨクイニンエキス、ワセリン）、柔軟剤（例えば、グリセリン、ミネラルオイル）、エモリエント成分（例えば、イソステアリン酸イソプロピル、イソステアリン酸ポリグリセリル、イソノナン酸イソトリデシル、イソノナン酸オクチル、オレイン酸、オレイン酸グリセリル、カカオ脂、コレステロール、混合脂肪酸トリグリセリド、コハク酸ジオクチル、酢酸ステアリン酸スクロース、シクロペンタシロキサン、ジステアリン酸スクロース、パルミチン酸オクチル、ヒドロキシステアリン酸オクチル、ベヘン酸アラキル、ポリベヘン酸スクロース、ポリメチルシルセスキオキサン、ミリスチルアルコール、ミリスチン酸セチル、ミリスチン酸ミリスチル、ラウリン酸ヘキシル）、及び経皮吸収促進剤（例えば、エタノール、ミリスチン酸イソプロピル、クエン酸、スクワラン、オレイン酸、メントール、N-メチル-2-ピロリドン、アジピン酸ジエチル、アジピン酸ジイソプロピル、セバシン酸ジエチル、セバシン酸ジイソプロピル、パルミチン酸イソプロピル、オレイン酸イソプロピル、オレイン酸オクチルドデシル、イソステアリルアルコール、2-オクチルドデカノール、尿素、植物油、動物油）、防腐剤（例えば、安息香酸、安息香酸ナトリウム、エチルパラベン、ソルビン酸カリウム、ソルビン酸ナトリウム、ソルビン酸、デヒドロ酢酸ナトリウム、メチルパラベン）、色素剤（例えば、カオリン、カルミン、グンジョウ、酸化クロム、酸化鉄）、香料、pH調整剤（例えば、クエン酸ナトリウム、酢酸ナトリウム、水酸化ナトリウム、水酸化カリウム、リン酸）を挙げることができる。また本発明の好ましい態様によれば、本発明の組成物は、添加物として界面活性剤を含まないものである。 In addition, various additives may be added to the physiologically active ingredient. Additives that can be used in the present invention include humectants (for example, agar, diglycerin, distearyldimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, sodium hyaluronate, hexylene glycol, yoquinin extract, petrolatum. ), Softeners (eg, glycerin, mineral oil), emollient ingredients (eg, isopropyl isostearate, polyglyceryl isostearate, isotridecyl isononanoate, octyl isononanoate, oleic acid, glyceryl oleate, cocoa butter, cholesterol, mixed fatty acid triglycerides, Dioctyl succinate, sucrose acetate stearate, cyclopentasiloxane, sucrose distearate, octyl palmitate, hydroxy stearate Octylate, aralkyl behenate, sucrose polybehenate, polymethylsilsesquioxane, myristyl alcohol, cetyl myristate, myristyl myristate, hexyl laurate), and transdermal absorption enhancers (eg, ethanol, isopropyl myristate, Citric acid, squalane, oleic acid, menthol, N-methyl-2-pyrrolidone, diethyl adipate, diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, isopropyl palmitate, isopropyl oleate, octyldodecyl oleate, isostearyl alcohol , 2-octyldodecanol, urea, vegetable oil, animal oil), preservatives (eg, benzoic acid, sodium benzoate, ethyl paraben, potassium sorbate, sodium sorbate, sorbic acid Sodium dehydroacetate, methylparaben), coloring agent (eg, kaolin, carmine, gunjo, chromium oxide, iron oxide), fragrance, pH adjuster (eg, sodium citrate, sodium acetate, sodium hydroxide, potassium hydroxide, phosphoric acid) ). Moreover, according to the preferable aspect of this invention, the composition of this invention does not contain surfactant as an additive.
　以下の実施例により本発明をさらに具体的に説明するが、本発明は実施例によって限定されるものではない。 The following examples further illustrate the present invention, but the present invention is not limited to the examples.
実施例１：ビタミンD3封入ゼラチンフィルムの作製
　ブタ皮膚酸処理ゼラチン（180  mg、PSKゼラチン、ニッピ社製）およびビタミンD3（9  mg）を含む１，１，１，３，３，３－ヘキサフルオロー２－プロパノール（HFIP）溶液（0.9 mL）をポリプロピレンシート上に設置したシリコーンの型（3 cm x 3 cm）に流し込んだ。該溶液を室温にて3時間静置した後、-80℃で3時間静置した。該凍結体を凍結乾燥した（これは参考例である）。 Example 1: Preparation of vitamin D3-encapsulated gelatin film 1,1,1,3,3,3-hexafluor containing porcine skin acid-treated gelatin (180 mg, PSK gelatin, Nippi) and vitamin D3 (9 mg) Raw 2-propanol (HFIP) solution (0.9 mL) was poured into a silicone mold (3 cm x 3 cm) placed on a polypropylene sheet. The solution was allowed to stand at room temperature for 3 hours and then allowed to stand at −80 ° C. for 3 hours. The frozen body was freeze-dried (this is a reference example).
　一方、PSKゼラチンおよび所定の合成高分子を含むHFIP溶液（0.9 mL）を調製した。該溶液にビタミンD3（9 mg）を加え、PSKゼラチン、合成高分子およびビタミンD3を含むHFIP溶液を得た。該ビタミンD3含有混合溶液を上述のポリプロピレンシート上のシリコーンの型に流し込んだ。該型に流し込んだ溶液を室温にて3時間静置した後、-80℃で3時間静置した。該凍結体を凍結乾燥した。 Meanwhile, an HFIP solution (0.9 mL) containing PSK gelatin and a predetermined synthetic polymer was prepared. Vitamin D3 (9 mg) was added to the solution to obtain an HFIP solution containing PSK gelatin, synthetic polymer and vitamin D3. The vitamin D3-containing mixed solution was poured into a silicone mold on the above-described polypropylene sheet. The solution poured into the mold was allowed to stand at room temperature for 3 hours, and then allowed to stand at −80 ° C. for 3 hours. The frozen body was lyophilized.
　PSKゼラチンと同様にウシ血清アルブミンを用いた同様の実験により、ビタミンD3封入アルブミンを得た。 Vitamin D3-encapsulated albumin was obtained by the same experiment using bovine serum albumin as in PSK gelatin.
実施例２：ビタミンD3の残存率測定
　実施例１にて作製したビタミンD3封入タンパク質をアクチナーゼ処理した後、水―クロロホルムにて抽出した。クロロホルム層を濃縮した後、HPLC（カラム：東ソーTSgel-100V、溶離液：THF/水＝9/1、検出波長：280 nm）にてビタミンD3量を定量した。結果を以下の表１に示す。表１の結果から分かるように、生分解性の合成高分子（ＰＬＡ，ＰＬＧＡ，ＰＣＬ）を添加することで、グリセロールやステアリルアルコールの添加、またはコントロールである無添加物に比べてビタミンD3の残存率の有意な増加を認めた。 Example 2: Measurement of residual ratio of vitamin D3 Vitamin D3 encapsulated protein prepared in Example 1 was treated with actinase and extracted with water-chloroform. After the chloroform layer was concentrated, the amount of vitamin D3 was quantified by HPLC (column: Tosoh TSgel-100V, eluent: THF / water = 9/1, detection wavelength: 280 nm). The results are shown in Table 1 below. As can be seen from the results in Table 1, by adding biodegradable synthetic polymers (PLA, PLGA, PCL), vitamin D3 remains compared to the addition of glycerol or stearyl alcohol, or the additive without control. A significant increase in rate was observed.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001

Claims (13)

  1. 生体高分子、生分解性合成高分子及び生理活性成分を含む組成物。 A composition comprising a biopolymer, a biodegradable synthetic polymer and a bioactive component.
  2. 該生体高分子がタンパク質又は多糖である、請求項１に記載の組成物。 The composition according to claim 1, wherein the biopolymer is a protein or a polysaccharide.
  3. 該タンパク質がコラーゲン、ゼラチン、アルブミン、カゼイン、フィブロイン、フィブリン、ラミニン、フィブロネクチン、及びビトロネクチンからなる群より選ばれる少なくとも一種である、請求項２に記載の組成物。 The composition according to claim 2, wherein the protein is at least one selected from the group consisting of collagen, gelatin, albumin, casein, fibroin, fibrin, laminin, fibronectin, and vitronectin.
  4. 該生体高分子が、熱、光、または架橋剤により架橋されている、請求項１から３の何れかに記載の組成物。 The composition according to any one of claims 1 to 3, wherein the biopolymer is crosslinked by heat, light, or a crosslinking agent.
  5. 該生分解性合成高分子が、ポリ乳酸、ポリグリコール酸、ポリ（ε―カプロラクトン）、トリメチレンカーボネート、及びポリヒドロキシルアルカノエートからなる群から選ばれる化合物、共重合体、あるいは誘導体である、請求項１から４の何れかに記載の組成物。 The biodegradable synthetic polymer is a compound, copolymer, or derivative selected from the group consisting of polylactic acid, polyglycolic acid, poly (ε-caprolactone), trimethylene carbonate, and polyhydroxyl alkanoate. Item 5. The composition according to any one of Items 1 to 4.
  6. 生理活性成分が、芳香環に含まれない不飽和結合を有する化合物である、請求項１から５の何れかに記載の組成物。 The composition according to any one of claims 1 to 5, wherein the physiologically active ingredient is a compound having an unsaturated bond not contained in the aromatic ring.
  7. 生理活性成分が、ビタミン類、抗癌剤、免疫抑制剤、抗炎症剤、又は抗酸化剤である、請求項１から６の何れかに記載の組成物。 The composition according to any one of claims 1 to 6, wherein the physiologically active ingredient is vitamins, anticancer agents, immunosuppressive agents, anti-inflammatory agents, or antioxidants.
  8. 生理活性成分が、ビタミンD、ビタミンD誘導体、またはアスタキサンチンである、請求項１から７の何れかに記載の組成物。 The composition according to any one of claims 1 to 7, wherein the physiologically active ingredient is vitamin D, a vitamin D derivative, or astaxanthin.
  9. 経皮吸収剤、局所治療剤、経口治療剤、化粧品、サプリメント、又は色素材として使用される、請求項１から８の何れかに記載の組成物。 The composition according to any one of claims 1 to 8, which is used as a transdermal absorption agent, a topical therapeutic agent, an oral therapeutic agent, a cosmetic, a supplement, or a color material.
  10. (a) 生体高分子、生分解性合成高分子、生理活性成分、及び有機フッ素化合物を含む混合物を調製する工程；及び(b) 工程(a)で得られた混合物から有機フッ素化合物を除去する工程を含む、請求項１から９の何れかに記載の組成物の製造方法。 (a) a step of preparing a mixture containing a biopolymer, a biodegradable synthetic polymer, a physiologically active ingredient, and an organic fluorine compound; and (b) removing the organic fluorine compound from the mixture obtained in step (a). The manufacturing method of the composition in any one of Claim 1 to 9 including a process.
  11. 該有機フッ素化合物が、炭素数２から８の化合物である、請求項１０に記載の方法。 The method according to claim 10, wherein the organic fluorine compound is a compound having 2 to 8 carbon atoms.
  12. 該有機フッ素化合物が、炭素数２から３の化合物である、請求項１１に記載の方法。 The method according to claim 11, wherein the organic fluorine compound is a compound having 2 to 3 carbon atoms.
  13. 該有機フッ素化合物が、１，１，１，３，３，３－ヘキサフルオロ－２－プロパノール、２，２，２－トリフルオロエタノール、又はヘキサフルオロアセトンである、請求項１０から１２の何れかに記載の方法。 The organic fluorine compound according to any one of claims 10 to 12, wherein the organic fluorine compound is 1,1,1,3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, or hexafluoroacetone. The method described in 1.
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Citations (6)

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JPH04173746A (en) * 1990-11-07 1992-06-22 Unitika Ltd Medicine-polymer complex having sustained release function
WO1996010426A1 (en) * 1994-09-30 1996-04-11 Yamanouchi Pharmaceutical Co., Ltd. Osteoplastic graft
JPH08225454A (en) * 1995-02-23 1996-09-03 Chugai Pharmaceut Co Ltd Microsphere preparation
WO2001017562A1 (en) * 1999-09-02 2001-03-15 Yamanouchi Pharmaceutical Co., Ltd. Osteogenesis promoting agents
JP2003533468A (en) * 2000-02-28 2003-11-11 ゲル−デル テクノロジーズ，インコーポレイティド Protein matrix materials, production and their production and use
WO2008062840A1 (en) * 2006-11-21 2008-05-29 Fujifilm Corporation Method for removing organic solvent

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04173746A (en) * 1990-11-07 1992-06-22 Unitika Ltd Medicine-polymer complex having sustained release function
WO1996010426A1 (en) * 1994-09-30 1996-04-11 Yamanouchi Pharmaceutical Co., Ltd. Osteoplastic graft
JPH08225454A (en) * 1995-02-23 1996-09-03 Chugai Pharmaceut Co Ltd Microsphere preparation
WO2001017562A1 (en) * 1999-09-02 2001-03-15 Yamanouchi Pharmaceutical Co., Ltd. Osteogenesis promoting agents
JP2003533468A (en) * 2000-02-28 2003-11-11 ゲル−デル テクノロジーズ，インコーポレイティド Protein matrix materials, production and their production and use
WO2008062840A1 (en) * 2006-11-21 2008-05-29 Fujifilm Corporation Method for removing organic solvent

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