WO2009116556A1 - Pharmaceutical composition for injection - Google Patents

Pharmaceutical composition for injection Download PDF

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Publication number
WO2009116556A1
WO2009116556A1 PCT/JP2009/055243 JP2009055243W WO2009116556A1 WO 2009116556 A1 WO2009116556 A1 WO 2009116556A1 JP 2009055243 W JP2009055243 W JP 2009055243W WO 2009116556 A1 WO2009116556 A1 WO 2009116556A1
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Prior art keywords
gelatin
pharmaceutical composition
composition according
anticancer agent
injectable
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PCT/JP2009/055243
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French (fr)
Japanese (ja)
Inventor
健太郎 中村
章二 大屋
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富士フイルム株式会社
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Publication of WO2009116556A1 publication Critical patent/WO2009116556A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an injectable pharmaceutical composition
  • an injectable pharmaceutical composition comprising gelatin particles encapsulating an anticancer component in an injectable base solution.
  • Cancer treatment methods are mainly surgery, radiation therapy, and chemotherapy. In general, surgery is often used. Radiation therapy and chemotherapy are used as inoperable sites and as ancillary procedures. However, the therapeutic effect is greatly increased by performing multidisciplinary treatment combining different treatment methods, and various combinations are being studied.
  • Chemotherapy is mainly performed by intravenously injecting an anticancer drug and delivering it to the cancer site through the bloodstream.
  • anticancer agents are highly toxic and induce severe side effects.
  • a drug delivery system it has been studied to effectively treat a diseased or damaged tissue by combining a base material (matrix) and a drug.
  • anticancer agents are encapsulated in polymer micelles and proteins and nano-dispersed in water, thereby accumulating anticancer agents in cancer tissues and reducing toxicity.
  • Non-Patent Document 1 polyethylene glycol (PEG) and polylactic acid-polyglycolic acid copolymer (PLGA) copolymers have been studied as injectable topical anticancer agents using the solidification of anticancer agents in vivo.
  • PEG polyethylene glycol
  • PLGA polylactic acid-polyglycolic acid copolymer
  • Non-patent Document 2 a dosage form in which an anticancer agent is encapsulated in fibrin or chitosan particles has been studied (Non-patent Document 2).
  • Fibrin is a blood-derived material and has a high risk of infection.
  • chitosan has strong tissue adhesiveness and has a risk of inducing adhesion between organs after surgery in the abdomen. Therefore, the risk is high when applied to the affected area after surgery.
  • an object of the present invention is to provide an injectable anticancer agent-containing composition that does not have a non-degradable portion and has a low infection risk.
  • the inventors of the present invention formed gelatin particles encapsulating an anticancer agent using gelatin as a base material for forming particles containing the anticancer agent. It was found that a pharmaceutical composition for injection that can be injected into a living tissue can be provided by suspending it in a solution. The present invention has been completed based on these findings.
  • an injectable pharmaceutical composition that can be injected into a living tissue, comprising particles having an average particle size of 100 nm to 1 mm made of gelatin and an anticancer agent in an injectable base solution.
  • the anticancer agent is one or a combination of two or more selected from 5-FU (fluorouracil), cisplatin, paclitaxel, docetaxel, nedaplatin, or irinotecan.
  • the anticancer agent is one or a combination of two selected from paclitaxel and 5-FU.
  • the anticancer agent is paclitaxel.
  • the gelatin is genetically modified gelatin.
  • the particle size of the anticancer agent present in the gelatin is 10 nm or more and 600 nm or less.
  • the gelatin is crosslinked during and / or after the formation of gelatin particles.
  • the crosslinking is a chemical crosslinking agent or enzymatic crosslinking.
  • the pharmaceutical composition for injection of the present invention is produced at a temperature lower than the boiling point of the solvent used in the production process.
  • the temperature of the manufacturing process is 0 ° C to 60 ° C.
  • the applicable diseases are head and neck cancer, esophageal cancer, pharyngeal cancer, brain tumor, breast cancer.
  • the injectable pharmaceutical composition of the present invention is a gel or liquid having a viscosity of 1.0 ⁇ 10 ⁇ 4 to 4.5 ⁇ 10 7 P.
  • gelatin as a base material for forming particles containing an anticancer agent, particles made of gelatin and an anticancer agent are formed and suspended in an aqueous solution that is an injection base material. It has become possible to provide an injectable anticancer agent-containing composition that does not have a degradable portion and has a low risk of infection.
  • the origin of the gelatin used in the present invention is not particularly limited, and any of cows, pigs, fish, and genetically modified organisms can be used.
  • the genetically modified gelatin for example, those described in EP0926543B, WO2004-085473, EP1398324A, EP1014176A, US6645712 can be used, but are not limited thereto.
  • the gelatin used in the present invention may be used alone or in combination of two or more.
  • Anticancer agents include, for example, BCG, actinomycin D, asparaginase, acegraton, anastrozole, allopurinol, anthracycline, bicalutamide, antiandrogen, idarubicin, ifosfamide, imatinib, irinotecan, interferon, interferon alfa, interleukin-2, ubenimex, Exemestane, estramustine, estrogen, etoposide, enocitabine, epirubicin, oxaliplatin, octreotide, capecitabine, carbocon, carboplatin, carmofur, cladribine, clarithromycin, krestin, ketoconazole, gefitini
  • 5-FU fluorouracil
  • cisplatin paclitaxel
  • docetaxel docetaxel
  • nedaplatin nedaplatin
  • irinotecan irinotecan
  • Said anticancer agent may be used independently and can also be used in combination of 2 or more types of anticancer agents.
  • the average particle size of the particles of the present invention is 100 nm or more and 1 mm or less, preferably 1 ⁇ m or more and 500 ⁇ m or less, particularly preferably 40 ⁇ m or more and 300 ⁇ m or less. It is possible to remain in the tissue such as subcutaneous and intradermal.
  • the amount of the anticancer agent contained in the particles of the present invention is not particularly limited, but generally 0.1 to 100% by weight of the anticancer agent can be contained relative to the weight of gelatin.
  • the particle size of the anticancer agent present in the gelatin is 1 nm or more and 1 ⁇ m or less, preferably 10 nm or more and 600 nm or less, particularly preferably 50 nm or more and 300 nm or less.
  • All the particles of the present invention can be prepared by a known method. For example, it can be produced according to the method described in JP-A-6-79168 or by C. Coester, Journal Microcapsulation, 2000, Vol. 17, p.187-193.
  • the anticancer agent may be added at the time of particle formation, or may be added after particle formation.
  • HFIP 1,1,1-3,3,3-hexafluoro-2-propanol
  • PCT / JP2007 / 070331 can also be used.
  • the particles of the present invention are preferably cross-linked.
  • a chemical crosslinking agent or an enzyme crosslinking agent can be used.
  • the chemical crosslinking agent for example, glutaraldehyde and carbodiimide can be used.
  • the enzyme crosslinking agent transglutaminase can be used. Transglutaminase may be derived from a mammal or a microorganism, and a genetic recombinant can be used.
  • Activa series manufactured by Ajinomoto Co., Inc. mammal-derived transglutaminase released as a reagent, for example, guinea pig liver-derived trans from Oriental Yeast Co., Ltd., Upstate USA Inc., Biodesign International, etc.
  • Examples include glutaminase, goat-derived transglutaminase, rabbit-derived transglutaminase, and human-derived recombinant transglutaminase.
  • the particles of the present invention are preferably produced at a temperature at which the used drug and gelatin are not easily decomposed, and more preferably produced at a temperature lower than the boiling point of the solvent used.
  • the particles of the present invention are dissolved in an injectable base solution and provided as a gel-form preparation that can be injected into a living tissue.
  • the base solution for injection that can be used in the present invention include physiological saline, purified water for injection, distilled water for injection, PBS solution (phosphate buffered saline), ringle solution, glucose and the like.
  • injectable is meant a composition that can be injected into living tissue by means of a syringe that can generally be used for medical purposes.
  • the viscosity of the injectable pharmaceutical composition of the present invention is preferably a liquid or gel composition of 1.0 ⁇ 10 ⁇ 4 to 4.5 ⁇ 10 7 P. More preferred is a liquid or gel composition having a viscosity of 8.0 ⁇ 10 ⁇ 3 to 10 5 P.
  • Preferable methods for injecting the pharmaceutical composition for injection of the present invention include intradermal injection, subcutaneous injection, intraperitoneal administration, intramuscular injection, and intravenous injection, but intradermal, subcutaneous, intraperitoneal administration, intramuscular. Injection is particularly preferred.
  • the administration site include blood vessels, head, neck, and chest, and preferably esophagus, pharynx, and brain.
  • the pharmaceutical composition for injection can contain an additive.
  • Soothing agents such as benzyl alcohol, procaine hydrochloride, xylocaine hydrochloride, chlorobutanol, benzoic acid, sodium benzoate, paraben, ethyl paraben, methyl paraben, propyl paraben, butyl paraben, sorbine Potassium acid, sodium sorbate, sorbic acid, sodium dehydroacetate, hydrogen peroxide, formic acid, ethyl formate, sodium dichlorite, propionic acid, sodium propionate, calcium propionate, pectin degradation product, polylysine, phenol, isopropylmethyl Preservatives such as phenol, orthophenylphenol, phenoxyethanol, resorcin, thymol, thiram, tea tree oil, vitamin C and its derivatives, vitamin E, kinetin, polypheno , SOD, phytic
  • the dosage of the injectable pharmaceutical composition of the present invention can be appropriately set according to the type and amount of the active ingredient, the weight of the patient, the state of the disease, etc.
  • a weight of particles comprising gelatin and an anticancer agent about 10 ⁇ g to 100 mg / kg can be administered, and preferably about 20 ⁇ g to 50 mg / kg can be administered.
  • Example 1 The following operations were all performed in a sterilized state. Various solutions used were sterilized. To distilled water for injection (17.6 mL) containing 2 g of medical gelatin (Medigelatin HMG-BP manufactured by Nippi), 2.5% glutaraldehyde aqueous solution (2.4 mL) was added and stirred. The mixture was poured into a 5 cm ⁇ 10 cm mold and left at 4 ° C. overnight. The obtained crosslinked gelatin was immersed in a large excess of glycine solution (100 mM) at 37 ° C. for 1 hour, and then immersed in an excessive amount of distilled water for injection for 1 hour.
  • medical gelatin Medigelatin HMG-BP manufactured by Nippi
  • glutaraldehyde aqueous solution 2.4 mL
  • the prepared gelatin cross-linked product was hollowed out with a punch having a diameter of 12 mm and then freeze-dried to prepare a gelatin sponge.
  • the prepared gelatin sponge was immersed in an aqueous solution of 5-FU having a weight concentration of 0.1% and 1% at 37 ° C. for 1 hour and freeze-dried to obtain two types of 5-FU-containing gelatin having different concentrations.
  • the 5-FU-containing gelatin solids were each pulverized for 2 minutes with a pulverizer (Wonder Blender: Osaka Chemical Co., Ltd.) to obtain 5-FU-containing gelatin particles (average particle size: about 100 ⁇ m).
  • 0.1 g of the obtained 5-FU-containing gelatin particles were dissolved in 20 mL of physiological saline to obtain a viscous liquid. (As a result, two types of liquids with different 5-FU concentrations were obtained)
  • Example 2 The following operations were all performed in a sterilized state. Various solutions used were sterilized. Similarly to Example 1, the produced 12 mm diameter gelatin sponge was immersed in an aqueous solution of CDDP (cisplatin) having a weight concentration of 0.1% and 1% at 37 ° C. for 1 hour and freeze-dried. Containing gelatin was obtained. The CDDP-containing gelatin solids were each pulverized for 2 minutes with a pulverizer (Wonder Blender: Osaka Chemical Co., Ltd.) to obtain CDDP-containing gelatin particles (average particle size: about 100 ⁇ m). 0.1 g of the obtained CDDP-containing gelatin particles were dissolved in 20 mL of physiological saline to obtain a viscous liquid. (As a result, two types of liquids with different CDDP concentrations were obtained.)
  • CDDP cisplatin
  • Example 3 The following operations were all performed in a sterilized state. Various solutions used were sterilized.
  • the prepared gelatin sponge was added to an HFIP (1,1,1-3,3,3-hexafluoro-2-propanol) solution containing 0.1% by weight and 1% PTX (paclitaxel). After soaking at 37 ° C. for 1 hour, it was allowed to stand at 50 ° C. (humidity 95%) for 1 day, and then freeze-dried to obtain two types of PTX-containing gelatins having different concentrations.
  • HFIP 1,1,1-3,3,3-hexafluoro-2-propanol
  • the PTX-containing gelatin solids were each pulverized for 2 minutes with a pulverizer (Wonder Blender: Osaka Chemical Co., Ltd.) to obtain PTX-containing gelatin particles having an average particle diameter of about 100 ⁇ m.
  • a pulverizer Wood Blender: Osaka Chemical Co., Ltd.
  • 0.1 g of the obtained PTX-containing gelatin particles were dissolved in 20 mL of physiological saline to obtain a viscous liquid. (As a result, two liquids with different PTX concentrations were obtained)
  • Example 4 The following operations were all performed in a sterilized state. Various solutions used were sterilized. A solution in which all of PTX, CDDP, and 5-FU were dissolved was prepared as a drug mixture solution. Each of PTX, CDDP, and 5-FU was dissolved in HFIP solvent at a weight concentration of 0.1% to prepare a drug mixed solution. Gelatin sponge produced in the same manner as in Example 1 was immersed in the above drug mixture solution at 37 ° C. for 1 hour, allowed to stand at 50 ° C. (humidity 95%) for 1 day, and then freeze-dried to contain mixed drug-containing gelatin. A solid was obtained.
  • the mixed drug-containing gelatin solid was pulverized with a pulverizer (Wonder Blender: Osaka Chemical Co., Ltd.) for 2 minutes to obtain mixed drug-containing gelatin particles (average particle: 100 ⁇ m).
  • a pulverizer Wood Blender: Osaka Chemical Co., Ltd.
  • 0.1 g of the obtained mixed drug-containing gelatin particles were dissolved in 20 mL of physiological saline to obtain a viscous liquid.
  • Example 5 Using Balb / c mice (nude mice) (10-12 weeks old, female, 25-30 g), using Detroit-562 (human hypopharyngeal cancer cells) to produce tumor-bearing mice on the dorsal subcutaneous tissue of mice, The anticancer activity of the anticancer agent-containing gelatin injection composition prepared in Examples 1 to 4 was examined. The method for preparing tumor-bearing mice was based on Int. J. Radiation Oncology Biol. Phys. 40 (1), 177-187, 1998.
  • a Detroit-562 tumor-bearing mouse with a tumor size of 60-100 mm 3 was prepared.
  • the gelatin injection composition containing the anticancer agent prepared in Examples 1 to 4 was injected into each tumor-bearing mouse at 30 ⁇ L at 4 sites, 120 ⁇ L per mouse, into the tumor surrounding area.
  • the tumor size was measured 2 weeks later, as an effect of the anticancer agent-containing gelatin injection composition prepared in Examples 1 to 4, the tumor size was increased in mice injected only with physiological saline as a control (average 270).
  • mice injected with the anti-cancer agent-containing gelatin injection composition tumor growth was significantly suppressed (average 136%).
  • Sections of the PTX-containing gelatin solid prepared in Example 3 were prepared and observed using a scanning electron microscope. PTX particles dispersed in gelatin were observed with a particle size of 197 ⁇ 54 nm.

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Abstract

Disclosed is a composition containing an anti-cancer agent, which has no non-degradable moiety, has a low risk of infection, and can be injected. Specifically disclosed is a pharmaceutical composition for injection, which comprises a base injection solution and particles each comprising gelatin and an anti-cancer agent and having an average particle diameter of 100 nm to 1 mm, and which can be injected into a biological tissue.

Description

注射用医薬組成物Pharmaceutical composition for injection
　本発明は、抗癌成分を内包したゼラチン粒子を注射用基剤液中に含む、注射用医薬組成物に関する。 The present invention relates to an injectable pharmaceutical composition comprising gelatin particles encapsulating an anticancer component in an injectable base solution.
　癌の治療方法は主に、手術、放射線療法、および化学療法である。一般に、手術が多く利用されている。放射線療法や化学療法は手術不可能な部位および手術の補助的手法として利用されている。しかし、異なる治療方法を組み合わせた集学的治療を行うことにより、治療効果が大幅に増加することから、種々の組み合わせが検討されている。 Cancer treatment methods are mainly surgery, radiation therapy, and chemotherapy. In general, surgery is often used. Radiation therapy and chemotherapy are used as inoperable sites and as ancillary procedures. However, the therapeutic effect is greatly increased by performing multidisciplinary treatment combining different treatment methods, and various combinations are being studied.
　化学療法は主に抗癌剤を静脈注射し、血流を通して癌部位へ送達することが行われている。しかしながら、一般に抗癌剤は毒性が強く、ひどい副作用を誘起する。近年、ドラッグデリバリーシステムにおいて、基材（マトリックス）と薬を組み合わせることで、効果的に病気や損傷した組織を治療することが検討されている。例えば、抗癌剤を高分子ミセルやタンパク質に封入し水中でナノ分散させることで、癌組織に抗癌剤を集積させ、毒性を軽減している。 Chemotherapy is mainly performed by intravenously injecting an anticancer drug and delivering it to the cancer site through the bloodstream. However, in general, anticancer agents are highly toxic and induce severe side effects. In recent years, in a drug delivery system, it has been studied to effectively treat a diseased or damaged tissue by combining a base material (matrix) and a drug. For example, anticancer agents are encapsulated in polymer micelles and proteins and nano-dispersed in water, thereby accumulating anticancer agents in cancer tissues and reducing toxicity.
　一方、癌の化学療法として、一部の疾患において抗癌剤の局所投与が検討されている。抗癌剤を含む水溶液を癌組織内部または周辺に注入することで、一定の効果を示す。しかし、抗癌剤単独では組織液等により速やかに患部から除去される。より長期の抗癌剤の留置を達成するため、抗癌剤を生体適合性の高い基材に封入し癌組織周辺に投与することが検討されている。基材として、ポリ乳酸やポリグリコール酸に代表される合成高分子やコラーゲンに代表される生体高分子が利用されている。例えば、抗癌剤を含んだ基材を体内に埋め込むため、スポンジやフィルム形状の組成物を手術により埋め込む手法が行われた。しかし、手術により基材を埋め込むことは、患者のコンプライアンスが非常に悪く、手術を行わない投与方法が求められた。 On the other hand, local administration of anticancer drugs is being studied in some diseases as cancer chemotherapy. A certain effect is shown by injecting an aqueous solution containing an anticancer agent into or around a cancer tissue. However, the anticancer agent alone is quickly removed from the affected area by tissue fluid or the like. In order to achieve indwelling of an anticancer agent for a longer period, it has been studied to encapsulate an anticancer agent in a highly biocompatible substrate and administer it around the cancer tissue. As the base material, synthetic polymers represented by polylactic acid and polyglycolic acid and biopolymers represented by collagen are used. For example, in order to embed a base material containing an anticancer agent in the body, a technique of embedding a sponge or film-shaped composition by surgery has been performed. However, implanting a substrate by surgery has a very poor patient compliance, and an administration method that does not perform surgery has been required.
　近年、ポリエチレングリコール（PEG）とポリ乳酸-ポリグリコール酸共重合体（PLGA）の共重合体が生体内で抗癌剤を封入したまま固化することを利用し、注入可能な局所抗癌剤として検討されている（非特許文献１）。しかし、該手法では、非分解性のPEGが一部含まれており、部分的に体内に長期に存在する可能性がある。また、適用部位が例えば頭部・頭頸部といった部位となった場合、非分解物の存在によるリスクが高まることが懸念される。また、分解性の高分子として、フィブリンやキトサン粒子に抗癌剤を封入した剤型も検討されている（非特許文献２）。フィブリンは血液由来の材料であり、感染症のリスクが高い。また、キトサンは組織接着性が強く、腹部において術後の臓器間の癒着を誘発するリスクがある。従って、術後患部に適用する場合においては、リスクが高い。 In recent years, polyethylene glycol (PEG) and polylactic acid-polyglycolic acid copolymer (PLGA) copolymers have been studied as injectable topical anticancer agents using the solidification of anticancer agents in vivo. (Non-Patent Document 1). However, in this method, a part of non-degradable PEG is included, and there is a possibility that the PEG is partially present in the body for a long time. In addition, when the application site is a site such as the head or head and neck, there is a concern that the risk due to the presence of non-degraded products increases. Further, as a degradable polymer, a dosage form in which an anticancer agent is encapsulated in fibrin or chitosan particles has been studied (Non-patent Document 2). Fibrin is a blood-derived material and has a high risk of infection. In addition, chitosan has strong tissue adhesiveness and has a risk of inducing adhesion between organs after surgery in the abdomen. Therefore, the risk is high when applied to the affected area after surgery.
　本発明は、上記した従来技術の問題点を解消することを解決すべき課題とした。即ち、本発明は、非分解性部分を持たず、かつ感染リスクの低い注入可能な抗癌剤含有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 made it a problem to be solved to solve the above-mentioned problems of the prior art. That is, an object of the present invention is to provide an injectable anticancer agent-containing composition that does not have a non-degradable portion and has a low infection risk.
　本発明者らは上記の課題を解決すべく鋭意研究を行った結果、抗癌剤を含有する粒子を形成するための基材としてゼラチンを用いて、抗癌剤を封入したゼラチン粒子を形成し、これを水溶液に懸濁することによって、生体組織へ注入可能な注射用医薬組成物を提供できることを見出した。本発明はこれらの知見に基づいて完成したものである。 As a result of diligent research to solve the above-mentioned problems, the inventors of the present invention formed gelatin particles encapsulating an anticancer agent using gelatin as a base material for forming particles containing the anticancer agent. It was found that a pharmaceutical composition for injection that can be injected into a living tissue can be provided by suspending it in a solution. The present invention has been completed based on these findings.
　即ち、本発明によれば、ゼラチンと抗癌剤からなる平均粒径100 nm～1mmの粒子を注射用基剤液中に含む、生体組織へ注入可能な注射用医薬組成物が提供される。
　好ましくは、抗癌剤は、5-FU（フルオロウラシル）、シスプラチン、パクリタキセル、ドセタキセル、ネダプラチン、又はイリノテカンから選択される1種又は２種以上の組み合わせである。
　好ましくは、抗癌剤は、パクリタキセル、5-FUから選択される１種又は２種の組み合わせである。
　好ましくは、抗癌剤は、パクリタキセルである。
　好ましくは、ゼラチンは、遺伝子組み換えゼラチンである。
　好ましくは、ゼラチン中に存在する抗癌剤の粒径は、10nm以上600nm以下である。 In other words, according to the present invention, there is provided an injectable pharmaceutical composition that can be injected into a living tissue, comprising particles having an average particle size of 100 nm to 1 mm made of gelatin and an anticancer agent in an injectable base solution.
Preferably, the anticancer agent is one or a combination of two or more selected from 5-FU (fluorouracil), cisplatin, paclitaxel, docetaxel, nedaplatin, or irinotecan.
Preferably, the anticancer agent is one or a combination of two selected from paclitaxel and 5-FU.
Preferably, the anticancer agent is paclitaxel.
Preferably, the gelatin is genetically modified gelatin.
Preferably, the particle size of the anticancer agent present in the gelatin is 10 nm or more and 600 nm or less.
　好ましくは、ゼラチン粒子の形成中および／又は形成後に、該ゼラチンが架橋処理されている。
　好ましくは、架橋は、化学架橋剤又は酵素による架橋である。
　好ましくは、本発明の注射用医薬組成物は、製造工程において、使用溶媒の沸点よりも低い温度下で製造される。
　好ましくは、製造工程の温度は、０℃から６０℃である。
　好ましくは、適用疾患は、頭頸部癌、食道癌、咽頭癌、脳腫瘍、乳癌である。
　好ましくは、本発明の注射用医薬組成物は、粘度が1.0×10-4～4.5×107 Pのゲル状又は液状である。 Preferably, the gelatin is crosslinked during and / or after the formation of gelatin particles.
Preferably, the crosslinking is a chemical crosslinking agent or enzymatic crosslinking.
Preferably, the pharmaceutical composition for injection of the present invention is produced at a temperature lower than the boiling point of the solvent used in the production process.
Preferably, the temperature of the manufacturing process is 0 ° C to 60 ° C.
Preferably, the applicable diseases are head and neck cancer, esophageal cancer, pharyngeal cancer, brain tumor, breast cancer.
Preferably, the injectable pharmaceutical composition of the present invention is a gel or liquid having a viscosity of 1.0 × 10 −4 to 4.5 × 10 7 P.
　本発明によれば、抗癌剤を含有する粒子を形成するための基材としてゼラチンを用いてゼラチンと抗癌剤からなる粒子を形成し、これを注射用基材である水溶液に懸濁させることによって、非分解性部分を持たず、感染リスクの低い注入可能な抗癌剤含有組成物を提供することが可能になった。 According to the present invention, by using gelatin as a base material for forming particles containing an anticancer agent, particles made of gelatin and an anticancer agent are formed and suspended in an aqueous solution that is an injection base material. It has become possible to provide an injectable anticancer agent-containing composition that does not have a degradable portion and has a low risk of infection.
　以下、本発明の実施の形態についてさらに具体的に説明する。
　本発明で用いるゼラチン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。遺伝子組み換えゼラチンとしては、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がこれらに限定されるものではない。本発明に用いられるゼラチンは、単独で使用してもよいし、２種以上を組み合わせて用いることもできる。 Hereinafter, embodiments of the present invention will be described more specifically.
The origin of the gelatin used in the present invention is not particularly limited, and any of cows, pigs, fish, and genetically modified organisms can be used. As the genetically modified gelatin, for example, those described in EP0926543B, WO2004-085473, EP1398324A, EP1014176A, US6645712 can be used, but are not limited thereto. The gelatin used in the present invention may be used alone or in combination of two or more.
　本発明に用いられる抗癌剤の具体例を以下に列挙するが、本発明で用いる抗癌剤の種類は本発明の効果を損なわない限り特には限定されず、下記の化合物に限定されるものではない。抗癌剤としては、例えば、BCG、アクチノマイシンD、アスパラギナーゼ、アセグラトン、アナストロゾール、アロプリノール、アントラサイクリン、ビカルタミド、抗アンドロゲン、イダルビシン、イホスファミド、イマチニブ、イリノテカン、インターフェロン、インターフェロンアルファ、インターロイキン-2、ウベニメクス、エキセメスタン、エストラムスチン、エストロゲン、エトポシド、エノシタビン、エピルビシン、オキサリプラチン、オクトレオチド、カペシタビン、カルボコン、カルボプラチン、カルモフール、クラドリビン、クラリスロマイシン、クレスチン、ケトコナゾール、ゲフィチニブ、ゲムシタビン、ゲムツズマブ、ゴセレリン、シクロホスファミド、シスプラチン、シゾフィラン、シタラビン、シプロヘプタジン、ジノスタチンスチマラマー、セツキシマブ、ソブゾキサン、タモキシフェン、ダウノルビシン、ダカルバジン、ダクチノマイシン、チオテパ、テガフール、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム、デキサメタゾン、トポテカン、トラスツズマブ、トリプトレリン、トレチノイン、トレミフェン、ドキシフルリジン、ドキソルビシン、ドセタキセル、ニムスチン、ネオカルチノスタチン、ネダプラチン、パクリタキセル、ヒドロキシウレア、ヒドロキシカルバミド、ビカルタミド、ビノレルビン、ビンクリスチン、ビンデシン、ビンブラスチン、ピシバニール、ピラルビシン、ファドロゾール、フルオロウラシル、フルタミド、フルダラビン、ブスルファン、ブレオマイシン、プレドニゾン、プロカルバジン、プロゲスチン、ペプロマイシン、ペントスタチン、ポルフィマーナトリウム、マイトマイシン、ミトキサントロン、ミトタン、メスナ、メトトレキサート、メドロキシプロゲステロン、メルカプトプリン、メルファラン、ラニムスチン、リツキシマブ、リュープロライド、レンチナン、ロイコボリン、放射性ヨウ素-131、などを用いることができる。これらのうち好ましくは、5-FU（フルオロウラシル）、シスプラチン、パクリタキセル、ドセタキセル、ネダプラチン、イリノテカンを用いることができる。上記の抗癌剤は単独で用いてもよいし、２種類以上の抗癌剤を組み合わせて使用することもできる。 Specific examples of the anticancer agent used in the present invention are listed below, but the type of the anticancer agent used in the present invention is not particularly limited as long as the effect of the present invention is not impaired, and is not limited to the following compounds. Anticancer agents include, for example, BCG, actinomycin D, asparaginase, acegraton, anastrozole, allopurinol, anthracycline, bicalutamide, antiandrogen, idarubicin, ifosfamide, imatinib, irinotecan, interferon, interferon alfa, interleukin-2, ubenimex, Exemestane, estramustine, estrogen, etoposide, enocitabine, epirubicin, oxaliplatin, octreotide, capecitabine, carbocon, carboplatin, carmofur, cladribine, clarithromycin, krestin, ketoconazole, gefitinib, gemcitabine, gomselumab Cisplatin, schizophyllan, cytarabine, cyproheptadine Dinostatin stimamarer, cetuximab, sobuzoxane, tamoxifen, daunorubicin, dacarbazine, dactinomycin, thiotepa, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, dexamethasone, topotecan, trastuzumab, tryptoleline, tretinodine, tretinodine Doxorubicin, docetaxel, nimustine, neocalcinostatin, nedaplatin, paclitaxel, hydroxyurea, hydroxycarbamide, bicalutamide, vinorelbine, vincristine, vindesine, vinblastine, picibanil, pirarubicin, fadrozole, fluorouracil, flutamide, fludarabine, fludarabine, fludarabine Progestin, pepromycin, pentostatin, porfimer sodium, mitomycin, mitoxantrone, mitotane, mesna, methotrexate, medroxyprogesterone, mercaptopurine, melphalan, ranimustine, rituximab, leuprolide, lentinan, leucovorin, radioactive iodine-131, Etc. can be used. Of these, 5-FU (fluorouracil), cisplatin, paclitaxel, docetaxel, nedaplatin, and irinotecan can be preferably used. Said anticancer agent may be used independently and can also be used in combination of 2 or more types of anticancer agents.
　本発明の粒子の平均粒径は、１００ｎｍ以上１ｍｍ以下であり、好ましくは１μｍ以上５００μｍ以下、特に好ましくは４０μｍ以上３００μｍ以下であり、上記したようなサイズを有することにより、本発明の粒子は、皮下、皮内といった組織中に留まることが可能となる。 The average particle size of the particles of the present invention is 100 nm or more and 1 mm or less, preferably 1 μm or more and 500 μm or less, particularly preferably 40 μm or more and 300 μm or less. It is possible to remain in the tissue such as subcutaneous and intradermal.
　本発明の粒子に含まれる抗癌剤の量は特に限定されないが、一般的には、ゼラチン重量に対して、０.１～１００重量％の抗癌剤を含有させることができる。 The amount of the anticancer agent contained in the particles of the present invention is not particularly limited, but generally 0.1 to 100% by weight of the anticancer agent can be contained relative to the weight of gelatin.
　本発明の粒子において、ゼラチン中に存在する抗癌剤の粒子サイズは1nm以上1μm以下であり、好ましくは、10nm以上600nm以下、特に好ましくは50nm以上300nm以下である。 In the particles of the present invention, the particle size of the anticancer agent present in the gelatin is 1 nm or more and 1 μm or less, preferably 10 nm or more and 600 nm or less, particularly preferably 50 nm or more and 300 nm or less.
　本発明の粒子は全て公知の方法によって作成することが可能である。たとえば特開平６－７９１６８号公報、又はC.Coester著、ジャーナル・ミクロカプスレーション、２０００年、１７巻、p.１８７－１９３に記載の方法に準じて作製することができる。抗癌剤は粒子形成時に添加してもよいし、粒子作成後に添加してもよい。なお、抗癌剤が難溶性の場合は、PCT/JP2007/070331に記載のHFIP（1,1,1-3,3,3-ヘキサフルオロ-2-プロパノール）を用いることもできる。 All the particles of the present invention can be prepared by a known method. For example, it can be produced according to the method described in JP-A-6-79168 or by C. Coester, Journal Microcapsulation, 2000, Vol. 17, p.187-193. The anticancer agent may be added at the time of particle formation, or may be added after particle formation. When the anticancer agent is sparingly soluble, HFIP (1,1,1-3,3,3-hexafluoro-2-propanol) described in PCT / JP2007 / 070331 can also be used.
　本発明の粒子は、架橋されていることが好ましい。架橋剤としては、化学架橋剤、酵素架橋剤を用いることが出来る。化学架橋剤としては、例えばグルタルアルデヒド、カルボジイミドを用いることができる。酵素架橋剤としては、トランスグルタミナーゼを用いることができる。トランスグルタミナーゼは、哺乳類由来のものであっても、微生物由来のものであってもよく、遺伝子組み換え体を用いることができる。具体的には、味の素（株）製アクティバシリーズ、試薬として発売されている哺乳類由来のトランスグルタミナーゼ、例えば、オリエンタル酵母工業（株）製、Upstate USA Inc.製、Biodesign International製などのモルモット肝臓由来トランスグルタミナーゼ、ヤギ由来トランスグルタミナーゼ、ウサギ由来トランスグルタミナーゼ、ヒト由来リコンビナントトランスグルタミナーゼなどが挙げられる。 The particles of the present invention are preferably cross-linked. As the crosslinking agent, a chemical crosslinking agent or an enzyme crosslinking agent can be used. As the chemical crosslinking agent, for example, glutaraldehyde and carbodiimide can be used. As the enzyme crosslinking agent, transglutaminase can be used. Transglutaminase may be derived from a mammal or a microorganism, and a genetic recombinant can be used. Specifically, Activa series manufactured by Ajinomoto Co., Inc., mammal-derived transglutaminase released as a reagent, for example, guinea pig liver-derived trans from Oriental Yeast Co., Ltd., Upstate USA Inc., Biodesign International, etc. Examples include glutaminase, goat-derived transglutaminase, rabbit-derived transglutaminase, and human-derived recombinant transglutaminase.
　ゼラチンは、６０℃以上では加水分解が起こりやすく、安定性が減少する。本発明の粒子は、作製工程において、使用薬剤及びゼラチンの分解が生じにくい温度で作製することが好ましく、更には使用溶媒の沸点よりも低い温度で作製することが好ましい。好ましくは、温度０℃から６０℃で作製することが望ましく、より好ましくは、温度３７℃から５５℃で作製された組成物である。 Gelatin is easily hydrolyzed at 60 ° C. or higher and its stability is reduced. In the production process, the particles of the present invention are preferably produced at a temperature at which the used drug and gelatin are not easily decomposed, and more preferably produced at a temperature lower than the boiling point of the solvent used. Preferably, it is desirable to prepare at a temperature of 0 ° C. to 60 ° C., more preferably a composition prepared at a temperature of 37 ° C. to 55 ° C.
　本発明の粒子は、注射用基剤液中に溶解され、生体組織へ注入可能なゲル状の製剤として提供される。本発明で用いることができる注射用基剤液としては、生理食塩水、注射用精製水、注射用蒸留水、ＰＢＳ溶液（リン酸緩衝生理食塩水）、リングル液、ブドウ糖等を挙げることができる。注入可能とは、一般に医療用に使用され得る注射器によって、生体組織へ注入出来る組成物であることを意味している。本発明の注射用医薬組成物の粘度は、好ましくは1.0×10-4～4.5×107 Pの液状あるいはゲル状の組成物である。より好ましくは、粘度が8.0×10-3～105 Pである液状あるいはゲル状の組成物である。 The particles of the present invention are dissolved in an injectable base solution and provided as a gel-form preparation that can be injected into a living tissue. Examples of the base solution for injection that can be used in the present invention include physiological saline, purified water for injection, distilled water for injection, PBS solution (phosphate buffered saline), ringle solution, glucose and the like. . By injectable is meant a composition that can be injected into living tissue by means of a syringe that can generally be used for medical purposes. The viscosity of the injectable pharmaceutical composition of the present invention is preferably a liquid or gel composition of 1.0 × 10 −4 to 4.5 × 10 7 P. More preferred is a liquid or gel composition having a viscosity of 8.0 × 10 −3 to 10 5 P.
　本発明の注射用医薬組成物の注射方法として好ましいものは、皮内注射、皮下注射、腹腔内投与、筋肉内注射、静脈内注射が挙げられるが、皮内、皮下、腹腔内投与、筋肉内注射が特に好ましい。投与部位としては、血管・頭部・頸部・胸部が挙げられるが、好ましくは食道・咽頭・脳が挙げられる。 Preferable methods for injecting the pharmaceutical composition for injection of the present invention include intradermal injection, subcutaneous injection, intraperitoneal administration, intramuscular injection, and intravenous injection, but intradermal, subcutaneous, intraperitoneal administration, intramuscular. Injection is particularly preferred. Examples of the administration site include blood vessels, head, neck, and chest, and preferably esophagus, pharynx, and brain.
　本発明においては、注射用医薬組成物には添加物を含むことができる。添加物としては特に限定することはないが、ベンジルアルコール、塩酸プロカイン、塩酸キシロカイン、 クロロブタノールなどの無痛化剤、安息香酸、安息香酸ナトリウム、パラベン、エチルパラベン、メチルパラベン、プロピルパラベン、ブチルパラベン、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、過酸化水素、ギ酸、ギ酸エチル、ジ亜塩素酸ナトリウム、プロピオン酸、プロピオン酸ナトリウム、プロピオン酸カルシウム、ペクチン分解物、ポリリジン、フェノール、イソプロピルメチルフェノール、オルトフェニルフェノール、フェノキシエタノール、レゾルシン、チモール、チラム、ティートリー油などの防腐剤、ビタミンＣおよびその誘導体、ビタミンＥ、カイネチン、ポリフェノール、ＳＯＤ、フィチン酸、ＢＨＴ、ＢＨＡ、没食子酸プロピル、フラーレン、クエン酸などの酸化防止剤、又は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、コハク酸などのpH調整剤などが挙げられる。又、ゼラチンと異なる他の生分解性ポリマーを添加剤として使用出来る。 In the present invention, the pharmaceutical composition for injection can contain an additive. Although it does not specifically limit as an additive, Soothing agents such as benzyl alcohol, procaine hydrochloride, xylocaine hydrochloride, chlorobutanol, benzoic acid, sodium benzoate, paraben, ethyl paraben, methyl paraben, propyl paraben, butyl paraben, sorbine Potassium acid, sodium sorbate, sorbic acid, sodium dehydroacetate, hydrogen peroxide, formic acid, ethyl formate, sodium dichlorite, propionic acid, sodium propionate, calcium propionate, pectin degradation product, polylysine, phenol, isopropylmethyl Preservatives such as phenol, orthophenylphenol, phenoxyethanol, resorcin, thymol, thiram, tea tree oil, vitamin C and its derivatives, vitamin E, kinetin, polypheno , SOD, phytic acid, BHT, BHA, propyl gallate, fullerene, citric acid and other antioxidants, or pH adjusters such as sodium citrate, sodium acetate, sodium hydroxide, potassium hydroxide, phosphoric acid, succinic acid Etc. Also, other biodegradable polymers different from gelatin can be used as additives.
　本発明の注射用医薬組成物の投与量は、活性成分の種類及び使用量、患者の体重、疾患の状態などに応じて適宜設定することができるが、一般的には、１回の投与につき、ゼラチンと抗癌剤からなる粒子の重量として、１０μｇ～１００ｍｇ／ｋｇ程度を投与することができ、好ましくは、２０μｇ～５０ｍｇ／ｋｇ程度を投与することができる。 The dosage of the injectable pharmaceutical composition of the present invention can be appropriately set according to the type and amount of the active ingredient, the weight of the patient, the state of the disease, etc. As a weight of particles comprising gelatin and an anticancer agent, about 10 μg to 100 mg / kg can be administered, and preferably about 20 μg to 50 mg / kg can be administered.
　以下の実施例により本発明を更に具体的に説明するが、本発明の範囲はこれらの実施例に限定されるものではない。 The present invention will be described more specifically with reference to the following examples, but the scope of the present invention is not limited to these examples.
実施例１：
　以下の作業は全て滅菌状態にて行った。尚、各種溶液は滅菌した物を使用した。
　2ｇの医療用ゼラチン（ニッピ社製メディゼラチンHMG-BP）を含む注射用蒸留水（17.6mL）に、2.5%グルタルアルデヒド水溶液（2.4mL）を添加し、撹拌した。該混合液を5cm×10cmの型枠へ流し込み、4℃で一晩静置した。得られた架橋ゼラチンを大過剰のグリシン溶液（100mM）に37℃で1時間浸漬させ、続いて過剰量の注射用蒸留水に1時間浸漬させた。作製したゼラチン架橋物を直径12mmのパンチでくりぬいた後、凍結乾燥し、ゼラチンスポンジを作製した。作製したゼラチンスポンジを重量濃度0.1%, 1%の5-FU水溶液に37℃で1時間浸漬後、凍結乾燥することで、濃度の異なる2種類の5-FU含有ゼラチンを得た。該5-FU含有ゼラチン固形物を、それぞれ粉砕機（ワンダーブレンダー：大阪ケミカル株式会社）にて2分間粉砕し、5-FU含有ゼラチン粒子（平均粒径：約100μm）を得た。得られた5-FU含有ゼラチン粒子0.1gを20mLの生理食塩水に溶解し、粘度のある液体を得た。（結果、5-FU濃度の異なる2種類の液体を得た） Example 1:
The following operations were all performed in a sterilized state. Various solutions used were sterilized.
To distilled water for injection (17.6 mL) containing 2 g of medical gelatin (Medigelatin HMG-BP manufactured by Nippi), 2.5% glutaraldehyde aqueous solution (2.4 mL) was added and stirred. The mixture was poured into a 5 cm × 10 cm mold and left at 4 ° C. overnight. The obtained crosslinked gelatin was immersed in a large excess of glycine solution (100 mM) at 37 ° C. for 1 hour, and then immersed in an excessive amount of distilled water for injection for 1 hour. The prepared gelatin cross-linked product was hollowed out with a punch having a diameter of 12 mm and then freeze-dried to prepare a gelatin sponge. The prepared gelatin sponge was immersed in an aqueous solution of 5-FU having a weight concentration of 0.1% and 1% at 37 ° C. for 1 hour and freeze-dried to obtain two types of 5-FU-containing gelatin having different concentrations. The 5-FU-containing gelatin solids were each pulverized for 2 minutes with a pulverizer (Wonder Blender: Osaka Chemical Co., Ltd.) to obtain 5-FU-containing gelatin particles (average particle size: about 100 μm). 0.1 g of the obtained 5-FU-containing gelatin particles were dissolved in 20 mL of physiological saline to obtain a viscous liquid. (As a result, two types of liquids with different 5-FU concentrations were obtained)
実施例２：
　以下の作業は全て滅菌状態にて行った。尚、各種溶液は滅菌した物を使用した。
　実施例１と同様に、作製した直径12mmのゼラチンスポンジを重量濃度0.1%, 1%のCDDP（シスプラチン）水溶液に37℃で1時間浸漬し、凍結乾燥させることで、濃度の異なる2種類のCDDP含有ゼラチンを得た。該CDDP含有ゼラチン固形物を、それぞれ粉砕機（ワンダーブレンダー：大阪ケミカル株式会社）にて2分間粉砕し、CDDP含有ゼラチン粒子（平均粒径：約100μm）を得た。得られたCDDP含有ゼラチン粒子0.1gを20mLの生理食塩水に溶解し、粘度のある液体を得た。（結果、CDDP濃度の違う液体を2種類得た） Example 2:
The following operations were all performed in a sterilized state. Various solutions used were sterilized.
Similarly to Example 1, the produced 12 mm diameter gelatin sponge was immersed in an aqueous solution of CDDP (cisplatin) having a weight concentration of 0.1% and 1% at 37 ° C. for 1 hour and freeze-dried. Containing gelatin was obtained. The CDDP-containing gelatin solids were each pulverized for 2 minutes with a pulverizer (Wonder Blender: Osaka Chemical Co., Ltd.) to obtain CDDP-containing gelatin particles (average particle size: about 100 μm). 0.1 g of the obtained CDDP-containing gelatin particles were dissolved in 20 mL of physiological saline to obtain a viscous liquid. (As a result, two types of liquids with different CDDP concentrations were obtained.)
実施例３：
　以下の作業は全て滅菌状態にて行った。尚、各種溶液は滅菌した物を使用した。
　実施例１と同様にして、作製したゼラチンスポンジを重量濃度0.1%, 1%のPTX（パクリタキセル）を含むHFIP（1,1,1-3,3,3-ヘキサフルオロ-2-プロパノール）溶液に37℃で1時間浸漬した後、50℃（湿度95%）で1日間静置した後、凍結乾燥することで濃度の異なる2種類のPTX含有ゼラチンを得た。該PTX含有ゼラチン固形物を、それぞれ粉砕機（ワンダーブレンダー：大阪ケミカル株式会社）にて2分間粉砕し、平均粒径で約100μmのPTX含有ゼラチン粒子を得た。得られたPTX含有ゼラチン粒子0.1gを20mLの生理食塩水に溶解し、粘度のある液体を得た。（結果、PTX濃度の違う液体を2種類得た） Example 3:
The following operations were all performed in a sterilized state. Various solutions used were sterilized.
In the same manner as in Example 1, the prepared gelatin sponge was added to an HFIP (1,1,1-3,3,3-hexafluoro-2-propanol) solution containing 0.1% by weight and 1% PTX (paclitaxel). After soaking at 37 ° C. for 1 hour, it was allowed to stand at 50 ° C. (humidity 95%) for 1 day, and then freeze-dried to obtain two types of PTX-containing gelatins having different concentrations. The PTX-containing gelatin solids were each pulverized for 2 minutes with a pulverizer (Wonder Blender: Osaka Chemical Co., Ltd.) to obtain PTX-containing gelatin particles having an average particle diameter of about 100 μm. 0.1 g of the obtained PTX-containing gelatin particles were dissolved in 20 mL of physiological saline to obtain a viscous liquid. (As a result, two liquids with different PTX concentrations were obtained)
実施例４：
　以下の作業は全て滅菌状態にて行った。尚、各種溶液は滅菌した物を使用した。
　薬剤混合溶液として、PTX, CDDP, 5-FU全てが溶解した溶液を用意した。PTX, CDDP, 5-FUそれぞれを重量濃度0.1%ずつHFIP溶媒に溶解することで、薬剤混合溶液とした。実施例１と同様にして作製したゼラチンスポンジを上記薬剤混合溶液に37℃で1時間浸漬した後、50℃（湿度95%）で1日間静置した後、凍結乾燥することで混合薬剤含有ゼラチン固形物を得た。該混合薬剤含有ゼラチン固形物を粉砕機（ワンダーブレンダー：大阪ケミカル株式会社）にて2分間粉砕し、混合薬剤含有ゼラチン粒子（平均粒子：100μm）を得た。得られた混合薬剤含有ゼラチン粒子0.1gを20mLの生理食塩水に溶解し、粘度のある液体を得た。 Example 4:
The following operations were all performed in a sterilized state. Various solutions used were sterilized.
A solution in which all of PTX, CDDP, and 5-FU were dissolved was prepared as a drug mixture solution. Each of PTX, CDDP, and 5-FU was dissolved in HFIP solvent at a weight concentration of 0.1% to prepare a drug mixed solution. Gelatin sponge produced in the same manner as in Example 1 was immersed in the above drug mixture solution at 37 ° C. for 1 hour, allowed to stand at 50 ° C. (humidity 95%) for 1 day, and then freeze-dried to contain mixed drug-containing gelatin. A solid was obtained. The mixed drug-containing gelatin solid was pulverized with a pulverizer (Wonder Blender: Osaka Chemical Co., Ltd.) for 2 minutes to obtain mixed drug-containing gelatin particles (average particle: 100 μm). 0.1 g of the obtained mixed drug-containing gelatin particles were dissolved in 20 mL of physiological saline to obtain a viscous liquid.
実施例５：
　Balb/cマウス（ヌードマウス）（10～12週令、メス、25-30ｇ）を使用し、Detroit-562（ヒト下咽頭癌細胞）を用いてマウス背部皮下組織に担癌マウスを作製し、実施例１～４で作製した抗癌剤含有ゼラチン注入組成物の抗癌作用を調べた。担癌マウスの作成方法はInt. J. Radiation Oncology Biol. Phys. 40(1), 177-187, 1998.に準拠した。 Example 5:
Using Balb / c mice (nude mice) (10-12 weeks old, female, 25-30 g), using Detroit-562 (human hypopharyngeal cancer cells) to produce tumor-bearing mice on the dorsal subcutaneous tissue of mice, The anticancer activity of the anticancer agent-containing gelatin injection composition prepared in Examples 1 to 4 was examined. The method for preparing tumor-bearing mice was based on Int. J. Radiation Oncology Biol. Phys. 40 (1), 177-187, 1998.
　腫瘍サイズが60～100 mm3となったDetroit-562担癌マウスを用意しておいた。実施例１～４で作製した抗癌剤含有ゼラチン注入組成物を、注射器を用い、それぞれ別の担癌マウスへ4箇所に30μLずつ、計一匹当たり120μLを腫瘍周辺部分に注入した。
　2週間後に腫瘍サイズを計測したところ、実施例１～４で作製した抗癌剤含有ゼラチン注入組成物の効果として、コントロールである生理食塩水のみを注入したマウスでは腫瘍サイズが増大している（平均270%）に対して、抗癌剤含有ゼラチン注入組成物を注入したマウスでは、腫瘍の増大を大幅に抑制した（平均136%）。 A Detroit-562 tumor-bearing mouse with a tumor size of 60-100 mm 3 was prepared. Using the syringe, the gelatin injection composition containing the anticancer agent prepared in Examples 1 to 4 was injected into each tumor-bearing mouse at 30 μL at 4 sites, 120 μL per mouse, into the tumor surrounding area.
When the tumor size was measured 2 weeks later, as an effect of the anticancer agent-containing gelatin injection composition prepared in Examples 1 to 4, the tumor size was increased in mice injected only with physiological saline as a control (average 270). On the other hand, in the mice injected with the anti-cancer agent-containing gelatin injection composition, tumor growth was significantly suppressed (average 136%).
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　実施例３にて作製したPTX含有ゼラチン固形物について、切片を作製し、走査型電子顕微鏡を用いて観察を行った。ゼラチン中に分散したPTX粒子は、197±54nmの粒径で観察された。 Sections of the PTX-containing gelatin solid prepared in Example 3 were prepared and observed using a scanning electron microscope. PTX particles dispersed in gelatin were observed with a particle size of 197 ± 54 nm.

Claims (11)

  1. ゼラチンと抗癌剤からなる平均粒径100 nm～1mmの粒子を注射用基剤液中に含む、生体組織へ注入可能な注射用医薬組成物。 An injectable pharmaceutical composition that can be injected into a living tissue, comprising particles having an average particle size of 100 nm to 1 mm made of gelatin and an anticancer agent in an injectable base solution.
  2. 抗癌剤が、5-FU（フルオロウラシル）、シスプラチン、パクリタキセル、ドセタキセル、ネダプラチン、又はイリノテカンから選択される1種又は２種以上の組み合わせである、請求項１記載の注射用医薬組成物。 The pharmaceutical composition for injection according to claim 1, wherein the anticancer agent is one or a combination of two or more selected from 5-FU (fluorouracil), cisplatin, paclitaxel, docetaxel, nedaplatin, or irinotecan.
  3. 抗癌剤が、パクリタキセル、5-FUから選択される１種又は２種の組み合わせである、請求項１に記載の注射用医薬組成物。 The injectable pharmaceutical composition according to claim 1, wherein the anticancer agent is one or a combination of two selected from paclitaxel and 5-FU.
  4. 抗癌剤が、パクリタキセルである、請求項１に記載の注射用組成物。 The injectable composition according to claim 1, wherein the anticancer agent is paclitaxel.
  5. ゼラチンが、遺伝子組み換えゼラチンである、請求項１から４の何れかに記載の注射用医薬組成物。 The injectable pharmaceutical composition according to any one of claims 1 to 4, wherein the gelatin is a genetically modified gelatin.
  6. ゼラチン中に存在する抗癌剤の粒径が、10nm以上600nm以下である、請求項１から５何れかに記載の注射用医薬組成物。 The injectable pharmaceutical composition according to any one of claims 1 to 5, wherein the particle size of the anticancer agent present in the gelatin is 10 nm or more and 600 nm or less.
  7. ゼラチン粒子の形成中および／又は形成後に、該ゼラチンが架橋処理されている、請求項１から６の何れかに記載の注射用医薬組成物。 The injectable pharmaceutical composition according to any one of claims 1 to 6, wherein the gelatin is crosslinked during and / or after the formation of gelatin particles.
  8. 該架橋が、化学架橋剤又は酵素による架橋である、請求項７に記載の注射用医薬組成物。 The injectable pharmaceutical composition according to claim 7, wherein the cross-linking is a cross-linking with a chemical cross-linking agent or an enzyme.
  9. 製造工程において、使用溶媒の沸点よりも低い温度下で製造された、請求項１から８の何れかに記載の注射用医薬組成物。 The injectable pharmaceutical composition according to any one of claims 1 to 8, which is produced at a temperature lower than the boiling point of the solvent used in the production process.
  10. 製造工程の温度が、０℃から６０℃である、請求項９に記載の注射用組成物。 The injectable composition according to claim 9, wherein the temperature of the production process is 0 ° C. to 60 ° C.
  11. 適用疾患が、頭頸部癌、食道癌、咽頭癌、脳腫瘍、乳癌である請求項１から１０の何れかに記載の注射用医薬組成物。 The injectable pharmaceutical composition according to any one of claims 1 to 10, wherein the applicable disease is head and neck cancer, esophageal cancer, pharyngeal cancer, brain tumor, or breast cancer.
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