WO2010026760A1 - Compositions dans lesquelles des composants bioactifs sont operculés de façon stable - Google Patents

Compositions dans lesquelles des composants bioactifs sont operculés de façon stable 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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WIPO (PCT)
Prior art keywords
compound
composition according
biopolymer
composition
organic fluorine
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PCT/JP2009/004354
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English (en)
Japanese (ja)
Inventor
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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Publication of WO2010026760A1 publication Critical patent/WO2010026760A1/fr

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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

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur des compositions dans lesquelles des composés facilement oxydés sont operculés de façon stable dans un matériau de base sans utiliser d'antioxydants ni d'excipients classiques. L'invention porte sur des compositions qui comprennent des biopolymères, des polymères synthétiques biodégradables et des composants bioactifs.
PCT/JP2009/004354 2008-09-03 2009-09-03 Compositions dans lesquelles des composants bioactifs sont operculés de façon stable WO2010026760A1 (fr)

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JP2008225863 2008-09-03
JP2008-225863 2008-09-03

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WO2010026760A1 true WO2010026760A1 (fr) 2010-03-11

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04173746A (ja) * 1990-11-07 1992-06-22 Unitika Ltd 徐放性機能を有する薬剤・ポリマー複合体
WO1996010426A1 (fr) * 1994-09-30 1996-04-11 Yamanouchi Pharmaceutical Co., Ltd. Greffon osteoplastique
JPH08225454A (ja) * 1995-02-23 1996-09-03 Chugai Pharmaceut Co Ltd マイクロスフェア製剤
WO2001017562A1 (fr) * 1999-09-02 2001-03-15 Yamanouchi Pharmaceutical Co., Ltd. Agents promoteurs de l'osteogenese
JP2003533468A (ja) * 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 タンパク質マトリクス物質、製造並びにその製造及び使用
WO2008062840A1 (fr) * 2006-11-21 2008-05-29 Fujifilm Corporation Procédé d'élimination d'un solvant organique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04173746A (ja) * 1990-11-07 1992-06-22 Unitika Ltd 徐放性機能を有する薬剤・ポリマー複合体
WO1996010426A1 (fr) * 1994-09-30 1996-04-11 Yamanouchi Pharmaceutical Co., Ltd. Greffon osteoplastique
JPH08225454A (ja) * 1995-02-23 1996-09-03 Chugai Pharmaceut Co Ltd マイクロスフェア製剤
WO2001017562A1 (fr) * 1999-09-02 2001-03-15 Yamanouchi Pharmaceutical Co., Ltd. Agents promoteurs de l'osteogenese
JP2003533468A (ja) * 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 タンパク質マトリクス物質、製造並びにその製造及び使用
WO2008062840A1 (fr) * 2006-11-21 2008-05-29 Fujifilm Corporation Procédé d'élimination d'un solvant organique

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