WO1998005358A1 - Preparations pour injection a liberation prolongee, contenant du gabexate-mesylate - Google Patents

Preparations pour injection a liberation prolongee, contenant du gabexate-mesylate Download PDF

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Publication number
WO1998005358A1
WO1998005358A1 PCT/JP1997/002636 JP9702636W WO9805358A1 WO 1998005358 A1 WO1998005358 A1 WO 1998005358A1 JP 9702636 W JP9702636 W JP 9702636W WO 9805358 A1 WO9805358 A1 WO 9805358A1
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WO
WIPO (PCT)
Prior art keywords
fibrinogen
thrombin
mesylate
preparation
active ingredient
Prior art date
Application number
PCT/JP1997/002636
Other languages
English (en)
Japanese (ja)
Inventor
Shunji Nagata
Kazuo Takeshima
Horonao Kobayashi
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU37068/97A priority Critical patent/AU3706897A/en
Publication of WO1998005358A1 publication Critical patent/WO1998005358A1/fr

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Classifications

    • 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/363—Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • 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

Definitions

  • the present invention relates to a sustained-release preparation for injection, which is useful for sustaining the efficacy of various pharmaceutically active ingredients. More specifically, the present invention relates to a sustained-release preparation for injection containing a pharmaceutically active ingredient, fibrinogen, blood coagulation factor 13, thrombin and gabexate mesylate, and a kit for preparing the same at the time of use. They are particularly suitable for administering proteinaceous drugs subcutaneously or intramuscularly.
  • fibrin clot As preparations for maintaining the efficacy of pharmaceutically active ingredients, there are already some preparations that utilize the mechanism of fibrin clot formation (hereinafter referred to as fibrin clot or simply clot) by coagulation of fibrinogen. It has been reported.
  • Japanese Patent Application Laid-Open No. Hei 6-333644 discloses a sustained-release pharmaceutical composition containing fibrinogen and fibrin or fibrin.
  • the applied drug is a fat-soluble drug, and an anionic surfactant is essential as an additive.
  • the blending ratio of fibrinogen and thrombin when preparing fibrin is such that thrombin is 30 to 500 units per 80 mg of fibrinogen.
  • Japanese Patent Application Laid-Open No. 7-41432 discloses a sustained-release pharmaceutical composition in which drug-encapsulated ribosomes or lipid microspheres are uniformly dispersed in fiprinogen or fiprin. .
  • the blending ratio of fibrinogen to thrombin in preparing fibrin is such that thrombin is 120 to 2000 units per 8 O mg of fibrinogen.
  • the mixing ratio of thrombin to fibrinogen is relatively high, and typically, for example, 80 mg of fibrinogen is used.
  • thrombin accounts for about 250 units. Therefore, when the two components are mixed, a fibrin clot is formed in a relatively short time and the injection solution solidifies, so that it may be impossible to administer the solution in a solution state. Therefore, when administering as an injection, a mixed solution containing the drug, fibrinogen and thrombin is prepared, and then immediately set in a syringe and administered immediately, or the fibrinogen is used. And the solution containing thrombin had to be injected separately.
  • the present inventors have conducted intensive studies in view of the above problems, and as a result, have found that the control of fibrin clot formation is
  • the present inventors have found that the use of gabexate mesylate as an additive for the drug provides a sustained-release preparation for injection that does not require any special technique at the time of use. That is, the present invention provides a sustained-release preparation for injection, which comprises a pharmaceutically active ingredient, fibrinogen, blood coagulation factor 13, thrombin, and gabexate mesylate (hereinafter referred to as the present preparation). ) Is provided.
  • the preparation of the present invention does not immediately coagulate at room temperature after being prepared as an injection solution, but after in vivo administration, a fibrin clot is rapidly formed before the drug is released, and the drug is placed in the clot. It is an injectable composition that can take up and then slowly release the drug.
  • Preferred forms of the preparation of the present invention include, for example, (1) the mixing ratio of fibrinogen to gabexate mesilate is such that the ratio of gabexate mesylate is 0 to 80 mg of fibrinogen; (2) The mixing ratio of fibrinogen and gabexate mesylate is equivalent to 80 to 30 mg of fibrinogen. 0.5-: The ratio is equivalent to L Omg. (3) Mixing ratio of fibrinogen and thrombin 1--30 thrombin for 8 Omg of fibrinogen. (4) The mixing ratio of fibrinogen to thrombin is 80 mg of fibrinogen and 1 to 30 units of thrombin for 80 mg of fibrinogen.
  • the mixing ratio of each additive is 80 mg of fibrinogen,
  • the ratio of gabexate is 0.05 to 30 mg, preferably 0.5 to 10 mg, and thrombin is 1 to 300 units, preferably 1 to 30 units.
  • the preparation of the present invention further contains calcium ion or a calcium salt>
  • the preparation of the present invention further contains hyaluronic acid,
  • the pharmaceutically active ingredient is a proteinaceous drug
  • the pharmaceutically active ingredient is inulin-leukin-12 or interferon-7 ";
  • the preparation of the present invention is an aqueous solution; and (11) the preparation of the present invention is a lyophilized preparation. Cases are shown.
  • the present invention provides a method for preparing the above-mentioned preparation of the present invention, which comprises a pharmaceutically active ingredient, fibrinogen, blood coagulation factor 13, trombin, and gabexyl sylate.
  • a kit (hereinafter, referred to as a kit of the present invention) is provided.
  • kits of the present invention include, for example, (1) when fibrinogen and thrombin are housed in separate containers, (2) the following containers: (A) fibrinogen and A container containing blood coagulation factor 13 and (B) a container containing thrombin (provided that the pharmaceutically active ingredient and gabexate mesylate are contained in either container, respectively) (3) When the pharmaceutically active ingredient is contained in the container (A) and the gabexate mesylate is contained in the container (B), (4) When at least one of the components is contained as a freeze-dried product, 5> Examples further include the case of further containing a calcium salt, etc.
  • the present invention will be described in more detail.
  • Pharmaceutical active ingredients applicable to the present invention are desired to have prolonged drug efficacy, and are administered subcutaneously or intramuscularly by injection, and locally or locally in the vicinity thereof or migrate to the blood and systemically.
  • drugs that can act are applicable. Specifically, calcitonin, elcitonin, bone morphogenetic factor (BMP), parathyroid hormone, etc.
  • TPO thrombopoietin
  • Epithelial cell growth factor EGF
  • FGF fibroblast growth factor
  • I insulin-like growth factor
  • PDGF platelet-derived growth factor
  • SCF blood stem cell growth factor
  • HGF hepatocyte growth factor
  • Transformi Gastrointestinal hormones such as gastrin, glucagon, secretin, bombesin, motilin, cholecystokinin, etc .
  • cancer-related substances such as methionase and neocarzinostatin; and insulin and other substances.
  • Cetrorelix as a derivative of its derivative, Eris mouth boetin (EPO), human growth hormone, antisense drugs, vaccines, immunosuppressants, and pituitary gonadotropin-releasing hormone (LHRH) ) And the like.
  • EPO Eris mouth boetin
  • human growth hormone a derivative of its derivative
  • antisense drugs a derivative of human growth hormone
  • antisense drugs a derivative of its derivative
  • vaccines e.g., immunosuppressants
  • LHRH pituitary gonadotropin-releasing hormone
  • LHRH pituitary gonadotropin-releasing hormone
  • protein drugs such as interleukin and interferon.
  • the amount of the pharmaceutically active ingredient may be appropriately set in consideration of the type, target disease, patient condition, number of administrations, and the like.
  • the activated thrombin acts on fibrinogen to form a fibrin monomer. Then, a fibrin polymer is formed. The agent is cross-linked by a factor, and finally a fibrin clot is formed in a form incorporating a part or all of the pharmaceutically active ingredient. Thereafter, sustained release of the drug from the clot achieves sustained efficacy.
  • Gabexate mesylate prevents the formation and coagulation of fibrin clot between the time when the preparation of the present invention is prepared as an aqueous solution and the time when the preparation is administered in vivo.
  • the amount added depends on the type of the contained pharmaceutically active ingredient, the intended degree of sustained release, the amount of thrombin, and the like, and is generally difficult to define. However, in the preparation of the present invention, fibrino is usually used.
  • Gabexate mesylate is used in an amount of about 0.05 to 30 mg, preferably about 0.5 to 10 mg, more preferably about 1 to 10 mg, and particularly about 1 to 5 mg per 80 mg of a gene.
  • the preferred amount of gabexate mesylate is specified in relation to the amount of thrombin, for example, about 0.1 to 3 mg for 3 units of thrombin and about 2 to 8 mg for 30 units of thrombin It is.
  • the mixing ratio of thrompine to fibrinogen may be appropriately set according to the type of the contained pharmaceutically active ingredient, the intended degree of sustained release, the amount of gabexate mesylate, and the like.
  • thrombin is used in an amount of about 1 to 300 units, preferably about 1 to 30 units, more preferably about 1 to 10 units, for example, 3 units per 80 mg of fibrinogen. If the amount of thrombin is too large, the effectiveness of gabexart mesylate may be reduced, and it may be impossible to control the clot formation of the injection solution before administration. On the other hand, if the amount of thrombin is too small, the clot formation after in vivo administration may be delayed, and sufficient sustained release may not be achieved.
  • the mixing ratio of blood coagulation factor 13 is about 0.05 to 100 units, preferably about 0.1 to 80 units, more preferably about 0.1 to 80 units per 80 mg of fibrinogen. Approximately 0.25 to 60 units. It is considered that there is no particular problem with a large amount of the blood coagulation factor 13 if the amount is too small, the fibrin clot becomes too soft and adversely affects the sustained release of the drug.
  • the preparation of the present invention may optionally contain calcium ions.
  • the presence of calcium ions is essential. If not, a fibrin clot can be formed.
  • the mixing ratio of calcium ions is usually about 5 to 200 mm 01, preferably about 10 to 10 mm for 8 O mg of fibrinogen. 0 01111 0 1, more preferably a ratio corresponding to about 30 to 70 mmo 1.
  • the calcium ion can be formulated as a pharmaceutically acceptable calcium salt such as calcium chloride.
  • the preparation of the present invention may further optionally contain additives such as a preparation stabilizer, a pH regulator, an isotonic agent, a preservative and the like.
  • a preparation stabilizer include human serum albumin, aprotinin, L-ascorbic acid, sodium pyrosulfite, ⁇ -tocopherol and the like.
  • the pii regulator include hydrochloric acid, citrate, acetate, phosphate, and various amino acid salts.
  • the tonicity agent include salt, glucose, mannitol and the like.
  • the preservative include benzyl alcohol, benzoic acid or its esters, and benzalkonium chloride.
  • the preparation of the present invention may contain, in addition to gabexate mesylate, a regulator for sustained release of the drug.
  • a regulator for sustained release of the drug for example, guanidine benzoic acid derivatives (eg, camostat, mesylate, mesylate) Similar to gabexate mesylate, substances that inhibit thrombin enzyme activity, hyaluronic acid, phospholipids, etc. Examples thereof include fine particles (microspheres) of a citric acid / glycolic acid polymer.
  • the type and amount of the above-mentioned additives may be appropriately set in consideration of the purpose of addition, the type of the pharmaceutically active ingredient, the amount thereof, the type of other additives used together, and the like.
  • the preparation of the present invention may be in any form, such as a powder mixture, an aqueous solution having a viscosity such that it can be injected, or a lyophilized product, as long as it contains the above-mentioned components and optional additives.
  • the kit of the present invention described below may be preferably used.
  • the kit of the present invention is for preparing the above preparation of the present invention at the time of use, and comprises a pharmaceutically active ingredient, fibrinogen, blood coagulation 13. It is characterized by containing factor, thrombin and gabexate mesylate.
  • the kit of the present invention contains the same amount of each of the components that can be contained in the preparation of the present invention as in the case of the preparation of the present invention.
  • at least fibrinogen and thrombin are stored in separate containers, for example, in terms of ease of handling when the kit of the present invention is manufactured as a freeze-dried product. Is preferred.
  • the kit of the present invention comprises the following containers: (A) a container containing fibrinogen and blood coagulation factor 13, and (B) a container containing thrombin.
  • the pharmaceutically active ingredient and gabexate mesylate may be contained in any of the containers A and B, respectively. More preferably, the pharmaceutically active ingredient is contained in the container of A and gabexate mesylate.
  • the kit of the present invention preferably contains at least one of the components as a freeze-dried product.
  • the kit of the present invention may further contain a calcium salt.
  • the kit may be present in a container different from the container containing the above-described clot-forming components such as A and B, for example, as an aqueous solution of calcium chloride.
  • the method for preparing the preparation of the present invention using the kit of the present invention is exemplified below.
  • a lyophilized product containing a pharmaceutically active ingredient, fibrinogen and blood coagulation factor 13 (A), and a lyophilized product containing thrombin and gabexate mesylate (B) are produced. After dissolving each in purified water for injection with or without calcium chloride, mix both solutions. The mixing may be performed inside or outside the syringe. (Preparation method 2)
  • a freeze-dried product (A) containing a pharmaceutically active ingredient, fibrinogen, blood coagulation factor 13 and gabexate mesylate, and a freeze-dried product (B) containing thrombin are produced. Dissolve each in water for injection with or without calcium chloride and mix both solutions. The mixing may be performed inside or outside the syringe.
  • Freeze-drying is not particularly limited as long as it does not adversely affect the quality of the ingredients, and well-known freeze-drying methods can be applied.
  • an ordinary syringe or a kit-type syringe described in, for example, WO94 / 122,27, WO95 / 179916, etc. may be used. It is possible.
  • Example 1 Amount of Thrombin and Gabexate Mesilate and Time of Clot Formation
  • the preparation of the present invention containing fibrinogen, blood coagulation factor 13, thrombin, calcium ions and gabexate mesylate Then, the formation time of cutout was measured when the amount of added thrombin or gabexate mesylate was changed.
  • Table 1 shows the results. (table 1 )
  • fluorescently labeled dextran having a molecular weight of about 10,000 is encapsulated in the clot formed by the preparation of the present invention, and the effect of thrombin or gabexate on the release of FITC-DEX is reduced. The influence of the bird was investigated.
  • the release of FITC-DEX can be controlled by adjusting the amount of thrombin and gabexate mesylate. The lower the amount of thrombin or the more gabexate mesylate, the greater the amount of FITC-DEX. The release amount tended to increase.
  • Fibrinogen 24 mg, blood coagulation factor 13 18 units, thrombin 0.9 units and rIL-2 are included in 10500 ⁇ RU, and two kinds of books with adjusted amounts of calcium chloride and gadoxide mesylate are adjusted.
  • Inventive formulations (Types I and II) were prepared.
  • the kit of the present invention including rlL-2 composed of the following combinations is prepared.
  • A Lyophilized vial containing 80 mg of fibrinogen, 60 units of blood coagulation factor 13 and 19 mg of human serum albumin, and about 10,000 to 360,000 JRU of rlL-2.
  • B Lyophilized vial containing 3 units of thrombin and 2 mg of gabexyl mesylate.
  • the kit of the present invention including IFN-r composed of the following combinations is created.
  • 80 mg of fibrinogen, 60 units of blood coagulation factor 13 and 19 mg of human serum albumin, rIL-2 about 10,000 to 360,000 JRU, and 3 units of thrombin Prepare a freeze-dried product containing 0.2 mg of dexamethasyl acid and gadoxate mesylate, and dissolve it in 2 ml of water for injection.
  • the formulation of the present invention does not immediately coagulate at room temperature even when prepared into an aqueous solution, but after injection administration, it rapidly becomes a gel or solid state in the body to form a fibrin clot. Drugs contained in the fibrin clot are gradually released in the body as the clot decomposes. Slow release can reduce frequent dosing and can also maintain a constant drug concentration in the tissue. That is, the use of the preparation of the present invention facilitates the injection administration itself, and can be expected to enhance the pharmacological effect of the drug. In addition, reduction of side effects can be expected by suppressing the rapid increase in tissue concentration. Further, by using the kit of the present invention, the preparation of the present invention can be easily prepared at the time of use.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
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  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Emergency Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention, qui porte sur des préparations pour injection à libération prolongée, se caractérisant par le fait qu'elles contiennent des ingrédients médicalement actifs, en l'occurrence du fibrinogène, le facteur 13 de coagulation sanguine, de la thrombine ainsi que du gabexate-mésylate, a également trait à des nécessaires servant à élaborer ces préparations au moment de les utiliser. Lorsqu'elles se présentent sous forme de solutions aqueuses, ces préparations ne se coagulent pas immédiatement à la température ambiante; par contre, une fois injectées, elles se transforment en gel ou se solidifient rapidement in vivo et forment des caillots fibrineux. Il s'ensuit alors une libération prolongée des médicaments qu'elles renferment. Ces préparations qui constituent des agents de formation de caillots fibrineux sont aisément injectables sans qu'il soit nécessaire de recourir à des techniques spécifiques.
PCT/JP1997/002636 1996-08-02 1997-07-30 Preparations pour injection a liberation prolongee, contenant du gabexate-mesylate WO1998005358A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37068/97A AU3706897A (en) 1996-08-02 1997-07-30 Sustained release preparations for injection containing gabexate mesylate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP20457796 1996-08-02
JP8/204577 1996-08-02

Publications (1)

Publication Number Publication Date
WO1998005358A1 true WO1998005358A1 (fr) 1998-02-12

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WO (1) WO1998005358A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62174031A (ja) * 1985-10-11 1987-07-30 Sumitomo Pharmaceut Co Ltd 高分子量薬物含有徐放性製剤
JPH0199565A (ja) * 1987-10-12 1989-04-18 Green Cross Corp:The フィブリン糊調製用キット
JPH05970A (ja) * 1991-06-25 1993-01-08 Sumitomo Cement Co Ltd 骨ずい炎治療剤
JPH0940579A (ja) * 1995-07-28 1997-02-10 Chemo Sero Therapeut Res Inst 炎症性腸疾患の術後吻合部再発およびケロイド形成抑制剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62174031A (ja) * 1985-10-11 1987-07-30 Sumitomo Pharmaceut Co Ltd 高分子量薬物含有徐放性製剤
JPH0199565A (ja) * 1987-10-12 1989-04-18 Green Cross Corp:The フィブリン糊調製用キット
JPH05970A (ja) * 1991-06-25 1993-01-08 Sumitomo Cement Co Ltd 骨ずい炎治療剤
JPH0940579A (ja) * 1995-07-28 1997-02-10 Chemo Sero Therapeut Res Inst 炎症性腸疾患の術後吻合部再発およびケロイド形成抑制剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HANDBOOK OF DRUGS, 5th Ed., with Supplement (in Japanese), Edited by OSAKA HOSPITAL PHARMACISTS ASSOCIATION, issued by K.K. YAKUGYO JIHOSHA, (1995), p. 1644-1645. *

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