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WO2003066083A1 - Preparations pour le traitement de fracture osseuse de deperdition osseuse ou d'augmentation la densite osseuse - Google Patents

Preparations pour le traitement de fracture osseuse de deperdition osseuse ou d'augmentation la densite osseuse Download PDF

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Publication number
WO2003066083A1
WO2003066083A1 PCT/JP2003/000966 JP0300966W WO03066083A1 WO 2003066083 A1 WO2003066083 A1 WO 2003066083A1 JP 0300966 W JP0300966 W JP 0300966W WO 03066083 A1 WO03066083 A1 WO 03066083A1
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WO
WIPO (PCT)
Prior art keywords
bmp
preparation
bone
solid preparation
collagen
Prior art date
Application number
PCT/JP2003/000966
Other languages
English (en)
Japanese (ja)
Inventor
Hiroo Maeda
Akihiko Sano
Rebecca H. Li
John M. Wozney
Howard J. Seeherman
Original Assignee
Sumitomo Pharmaceuticals Company, Limited
Wyeth
Koken 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 Sumitomo Pharmaceuticals Company, Limited, Wyeth, Koken Co., Ltd. filed Critical Sumitomo Pharmaceuticals Company, Limited
Priority to AU2003244459A priority Critical patent/AU2003244459A1/en
Publication of WO2003066083A1 publication Critical patent/WO2003066083A1/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
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/102—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to a means for treating or preventing a condition requiring bone repair.
  • the present invention relates to a treatment for fracture, treatment for treating bone loss or increasing bone density, and a method for treating fracture, treating bone loss or increasing bone density by administering the preparation.
  • Osteoporosis is a disease characterized by low bone mass and disruption of the microstructure of bone tissue, and is a disease that leads to progression of bone fragility and an increased risk of fracture.
  • the term “low bone mass” refers to a state where bone mass or bone density is low.
  • a decrease in bone mass or bone density leads to disruption such as fragmentation of the microstructure of bone, resulting in increased bone fragility, that is, mechanical weakening and fracture easily.
  • Patients with osteoporosis include those who are at increased risk of fracture but have not yet developed a fracture, and those who have already developed a fracture.
  • a fracture site frequently occurring clinically includes, for example, a femoral neck, a distal end of a radius, and a proximal end of a humerus.
  • femoral neck fractures are the most common fracture in the elderly, with 250,000 cases occurring annually (Praemer et al. Musculoskeletal Conditions in the United States, American Academy of Orthopaedic Surgeons, Park Ridge, IL (1992)].
  • treating or preventing a fracture in osteoporosis is important in medical treatment, and the development of an effective drug for treating or preventing a fracture in osteoporosis is a very important task.
  • an injectable preparation containing bone morphogenetic protein (BMP) as an active substance and collagen gel as a carrier, that is, collagen gel containing BMP is used as a bone tissue site.
  • BMP bone morphogenetic protein
  • Japanese Patent Publication No. 2 6 4 1 7 5 5 discloses that a very wide range of biologically active proteins and peptides including active ingredients such as inuichi leukin, interferon, colony stimulating factor, etc.
  • BMP is disclosed as an example of such a protein.
  • the release of the active ingredient from the preparation can be controlled by an acidic substance
  • its effectiveness in treating or preventing fracture is unknown.
  • the therapeutic effect of maintaining the active ingredient at a high concentration where necessary for treatment or prevention is a therapeutic effect
  • the formation of ectopic bone is shown by showing an osteogenic response only near the administration site. The effect of being able to reduce it is unknown.
  • the present invention is a.
  • the preparation of the present invention includes: (a) a carrier comprising collagen; (b) BMP; and (c) at least one selected from the group consisting of neutral amino acids, monosaccharides, disaccharides, organic acidic substances, and polysaccharides.
  • a solid preparation containing one compound [hereinafter, the component (c) may be abbreviated as “neutral amino acid or the like” in some cases.
  • Solid preparations having various shapes), and preparations having properties suitable for fracture treatment, bone defect treatment or bone density increase ie, preparations for fracture treatment, bone defect treatment or bone density increase).
  • the preparation of the present invention is a solid in which BMP and collagen are uniformly dispersed, according to the preparation, it is possible to remain at the administration site without flowing from the administration site unlike collagen gel. Become. Therefore, it is possible to suppress the formation of undesirable ectopic bone.
  • BMP and collagen stay together at the administration site or diffuse only in the vicinity of the administration site, so that the BMP concentration can be increased at the targeted administration site. Can be maintained. Because of this, Compared with Gengel, it is possible to maintain the effect of BMP for a long period of time.
  • the preparation of the present invention contains an organic acidic substance or polysaccharide
  • the preparation can control the release of BMP from the preparation, that is, the preparation can regulate the supply of BMP from the preparation to a living body.
  • the preparation also includes a solid preparation that exhibits a good shape by further containing a neutral amino acid, a monosaccharide, a disaccharide, or a borosaccharide.
  • a carrier comprising collagen, (b) BMP, (c) a neutral amino acid, etc., and a basic fibroblast growth factor (a growth factor effective for bone formation).
  • bFGF basic fibroblast growth factor
  • Another embodiment of the present invention is a method for increasing the bone density around the administration site by administering the above-mentioned preparation into or near the bone.
  • the gist of the present invention is:
  • BMP bone morphogenetic protein
  • FIG. 1 shows the in vitro release behavior of solid preparation 1, solid preparation 2, solid preparation 3, solid preparation 4, solid preparation 5, solid preparation 6 and solid preparation 7.
  • the vertical axis indicates the cumulative release of BMP as a percentage () with respect to the BMP amount in the solid preparation before the start of the test, and the horizontal axis indicates the test time (days).
  • FIG. 2 shows the in vitro release behavior of Solid Preparation 8, Solid Preparation 9 and Solid Preparation 10 respectively.
  • the vertical and horizontal axes are the same as in FIG.
  • FIG. 3 shows the in vitro release behavior of the solid preparations 12 and 13 respectively.
  • the vertical and horizontal axes are the same as in FIG.
  • Figure 4 shows the time course of the amount of BMP in the solid preparation after subcutaneous administration to each mouse of Solid Preparation 1, Solid Preparation 2, Solid Preparation 3, Solid Preparation 4, Solid Preparation 5, Solid Preparation 6, and Solid Preparation 7. Indicates a change.
  • the vertical axis indicates the amount of BMP remaining in the solid preparation before the start of the test. It is shown as a percentage (%) with respect to the amount of BMP in the solid preparation, and the horizontal axis shows the test time (say).
  • FIG. 5 shows the time course of the amount of BMP in the solid preparation after subcutaneous administration of each of Solid Preparation 8, Solid Preparation 9 and Solid Preparation 10 to mice.
  • the vertical and horizontal axes are the same as in FIG.
  • FIG. 6 shows the change over time in the amount of BMP in the solid preparations after subcutaneous administration of each of Solid Preparations 12 and 13 to mice.
  • the vertical and horizontal axes are the same as in FIG.
  • FIG. 7 shows the time course of the BMP amount in the solid preparation after subcutaneous administration of solid preparation 52, solid preparation 53, and solid preparation 54 to mice.
  • the vertical and horizontal axes are the same as in FIG.
  • FIG. 8 is a diagram showing the ectopic bone formation reaction at the administration site one month after administration of the control preparation 2 and the solid preparation 6 subcutaneously to mice.
  • panel A is a diagram of control formulation 2
  • panel B is a diagram of solid formulation 6
  • each left panel [(a)] is a diagram showing the periphery of the administration site
  • each middle panel [(b )] Shows a soft X-ray image
  • each right panel [(c)] shows a HE-stained image.
  • FIG. 9 is a view showing the ectopic bone formation reaction at the administration site after the subcutaneous administration of each of the solid preparations 14, 15 and 16.
  • the left panel [(a)] is a diagram showing the vicinity of the administration site, and the right panel [(b)] is a diagram showing a soft X-ray image.
  • Figure 10 shows that BMP aqueous solution A (1500 zgZml), BMP aqueous solution B (300 iL g / m1) and BMP aqueous solution C (60 ⁇ g / m1) were administered subcutaneously to mice.
  • FIG. 9 is a diagram showing an ectopic bone formation reaction at a later administration site.
  • Panel A shows the figure for administration of BMP aqueous solution A
  • Panel B shows the figure for administration of BMP aqueous solution B
  • Panel C shows the figure for administration of BMP aqueous solution C.
  • Panel A ⁇ C In each panel, the left panel [(a)] is a diagram showing the vicinity of the administration site, and the right panel [(b)] is a diagram showing a soft X-ray image.
  • Fig. 11 shows the results of ectopic bone formation at the administration site 3 weeks after the subcutaneous administration of solid preparation 1, solid preparation 12, solid preparation 13, solid preparation 13, control preparation 1, and control preparation 3 to mice. It is a figure which shows a reaction.
  • panel A is for solid preparation 1
  • panel B is for solid preparation 12
  • panel C is for solid preparation 13
  • panel D is for control preparation 1
  • panel E is for control preparation 3.
  • the left panel [(a)] is a diagram showing the vicinity of the administration site
  • the right panel ((b)] is a diagram showing a soft X-ray image.
  • Fig. 12 shows solid preparation 9 (panel A), solid preparation 60 (panel B), solid preparation 61 (panel C), solid preparation 63 (panel D), solid preparation 74 (panel E), It is a figure which shows the shape of the solid preparation 75 (panel F), the solid preparation 77 (panel G), the solid preparation 4 (panel H), and the solid preparation 54 (panel I) before cutting.
  • FIG. 13 shows the time course of bone density near each administration site after intraosseous administration of a solid preparation to normal male cynomolgus monkeys according to the contents shown in Table 2.
  • the vertical axis indicates the rate of change (%) of the bone density measured by PQCT relative to the bone density before administration of the solid preparation, and the horizontal axis indicates the test time (months).
  • FIG. 14 shows the histology of solid preparation 11 or control preparation 3 administered to the proximal femur of a cynomolgus monkey (osteoporosis model) 3 years after ovarian removal, and 6 months after administration.
  • FIG. Panel A shows the histology of the control formulation 3 administration
  • Panel B shows the histology of the solid formulation 11 administration.
  • the left panel [(a)] shows trochanteric tissue
  • the middle panel [(b)] shows cervical tissue
  • the right panel [(c)] shows head tissue.
  • Figure 15 shows the solid preparation 76, solid preparation 77, solid preparation 78, solid preparation 79, solid preparation 80, solid preparation 81, solid preparation 82, solid preparation 83, control preparation 1 3 weeks after subcutaneous administration of each preparation of control product 3 to the back of mice (BALB / c, male)
  • the amount of calcium formed (mg) is shown (mean value SD).
  • FIG. 16 shows that each of the narrow formulation, solid formulation 84a, solid formulation 84b, solid formulation 85a, solid formulation 85b, solid formulation 86a, and solid formulation 86b was administered to mice (BA LB / c
  • FIG. 4 is a graph showing the amount of calcium generated three weeks after subcutaneous administration to the back of a male (average soil SD).
  • the preparation of the present invention comprises the following components (a :) to (c):
  • a solid preparation for administration especially for injection, and a solid preparation for treating fracture, treating bone defect or increasing bone density.
  • BMP required for fracture treatment, bone defect treatment or bone density increase can be delivered to the target site of fracture treatment, bone defect treatment, or fracture prevention.
  • an excellent effect that the BMP concentration can be maintained at a high concentration is exhibited.
  • the bone morphogenetic protein Cbone morphogene tic protein (BMP) used in the present invention is capable of inducing differentiation of undifferentiated mesenchymal cells into chondrocytes and osteoblasts, or precursor cells of cartilage and osteoblasts (0 ste 0 pr 0 genitor) and has biological activities such as promoting cartilage or bone formation locally in vivo.
  • the amount of BMP in the preparation of the present invention is set together with other substances depending on the bone disease to be treated or prevented. However, from the viewpoint of manufacturing the preparation, the ratio of the weight of BMP to the total weight of the preparation is 80 w, w96 or less, preferably 50 w / w% or less, more preferably 30 wZ w% or less. Good.
  • the BMP may form a complex (or salt) as long as it exhibits the biological activity.
  • the collagen used in the present invention is preferably soluble collagen or solubilized collagen.
  • soluble collagen examples include, for example, collagen which is soluble in acidic or neutral water or water containing salt.
  • isolated collagen includes, for example, an enzyme-solubilized collagen solubilized by an enzyme, an alkaline solubilized collagen solubilized by an alkali, and the like.
  • collagens can pass through a membrane filter having a pore size of 1 micrometer.
  • the collagen used in the present invention is, for example, preferably a trimer or less, more preferably a dimer or less.
  • the molecular weight of collagen is preferably about 300,000 to about 900,000, and more preferably about 300,000 to about 600,000.
  • the collagen may be natural collagen extracted from any animal species, or may be collagen produced by genetic engineering.
  • the collagen is preferably natural collagen extracted from vertebrates or genetically modified recombinant collagen, more preferably natural collagen extracted from mammals, birds and fish. Collagen or genetically engineered recombinant collagen is preferred.
  • the collagen may be of any type, such as natural type IV collagen, genetically engineered recombinant type IV collagen; and the natural or genetically modified type IV collagen. A mixture of at least two collagens is desirable.
  • type I collagen extracted from the dermis of a mammal with acid a mixture of the type I collagen and type II collagen extracted from a dermis of a mammal with acid; Recombinant type I collagen; a mixture of the gene-recombinant type I collagen and genetically engineered recombinant type 111 collagen and the like.
  • type I collagen extracted by acid from calf dermis; genetically engineered recombinant type I collagen and the like can be mentioned.
  • the genetically engineered recombinant type I collagen is preferably derived from calf dermis or human dermis.
  • telocollagen from which telopeptides having high antigenicity have been removed or genetically engineered recombinant mouth collagen is preferable, and preferably 3 tyrosine residues per molecule.
  • the following atelocollagen is desirable.
  • the telopeptide is the major antigenic determinant of collagen.
  • the aforesaid collagen is a substance obtained by removing collagen by treating the collagen with an enzyme (for example, pepsin) or the like, and the antigenicity is almost a problem in terms of safety. It is said that it is not a level.
  • the collagen used in the preparation of the present invention is obtained, for example, by culturing primary cultured cells or cell lines that produce collagen, and separating and purifying the target collagen from the obtained culture (culture supernatant, cultured cells). can get.
  • a nucleic acid encoding collagen is inserted into an appropriate vector by a genetic engineering technique, and the nucleic acid is introduced into an appropriate host for transformation. From the culture supernatant of the transformant, the target recombinant collagen is obtained.
  • the host cell include various host cells conventionally used in genetic engineering techniques. Specifically, for example, Escherichia coli, Bacillus subtilis, yeast, plant cells, or animal cells Can be used.
  • the collagen may form a complex (or salt) as long as the collagen exhibits the biological activity.
  • the preparation of the present invention may have any shape as long as it can be injected. Examples of the form of the preparation include a columnar shape, a needle shape, and a particle shape.
  • the column is preferably a column because a commonly used injection needle can be used.
  • the size of the preparation of the present invention may be, for example, in the case of a columnar preparation as long as it is in an injectable range, and has a diameter of 0.3 mm to 2 mm, preferably 0.5 mm to 1.2 mm. Yes, and the length is desirably 3 mm to 30 mm, preferably 5 mm to 15 mm.
  • the largest part of the particle diameter is preferably 500 m or less, and is suspended in a solvent for injection or an injectable oily solution, and a usual injection needle is used. It is useful to administer
  • the preparation of the present invention can be administered by a known method.
  • an injection needle for example, an injection needle, a barrel having a nozzle for inserting the injection needle, and a movable head attached to the barrel
  • a solid preparation administration device containing a plunger Japanese Patent Publication No. 5-86262
  • the “near the bone” is preferably a portion within about 5 mm from the bone.
  • intraosseous administration use a hollow needle with an oblique tip and a trocar or stylet.
  • the stylet is inserted into the interior of the needle and partially extends out from the beveled tip of the needle, then the assembly of needle and trocar is pushed through the bone, penetrating the cortex, and the needle And advance the tip of the trocar.
  • the trocar is withdrawn, the open end of the needle is positioned at the intended administration section, and the preparation of the present invention can be administered by inserting and pushing the preparation of the present invention from outside the body of the needle.
  • the preparation of the present invention can be easily administered by using an intraosseous injection needle (Japanese Patent Publication No. 6-6162).
  • Symptoms that can be applied by the preparation of the present invention include bone fractures.
  • Treatable fractures include, for example, fractures associated with osteoporosis, fractures associated with osteomalacia, fractures associated with malignant tumors, and fractures associated with multiple myeloma.
  • Fractures associated with congenital osteogenesis imperfecta, fractures associated with osteocystosis, fractures associated with suppurative osteomyelitis, fractures associated with marble disease, fractures associated with malnutrition, traumatic fractures, fatigue Includes fractures.
  • the fractures that can be treated by the preparation of the present invention include the above-mentioned fractures.
  • the treatment can be effectively performed by administering the preparation of the present invention in the vicinity of or between fracture sites.
  • a fracture associated with any of the above-mentioned diseases that is, a fracture associated with osteoporosis, a fracture associated with osteomalacia, a fracture associated with a malignant tumor, and multiple occurrences Fractures associated with myeloma, congenital bone dysplasia, osteocystosis, suppurative osteomyelitis, fractures associated with marble disease, malnutrition, etc., especially osteoporotic individuals It is useful for preventing fractures in children.
  • Sites to which the formulations of the present invention are administered include the spine, femoral neck, distal radius, and proximal humerus.
  • administration to the femoral neck is an important site to prevent fractures in osteoporotic individuals.
  • prevention of fracture means reducing the severity and / or incidence of fracture.
  • Bone defects include defects associated with tumor resection, traumatic defects, and bone section gaps in bone distraction.
  • One embodiment of the present invention is a solid preparation containing collagen and BMP and an organic acidic substance, which is an injectable solid preparation. It is an augmentation formulation (solid formulation a).
  • the organic acidic substance used in the preparation of the present invention may be a salt thereof.
  • the preparation of the present invention contains an organic acidic substance or a salt thereof, the release of BMP from the preparation can be controlled, that is, the supply of BMP from the preparation to a living body can be regulated. Demonstrates excellent effects.
  • control of the release of BMP in a preparation containing the organic acidic substance or a salt thereof is to control the solubility of BMP and the disintegration of Z or the preparation by adding the organic acidic substance or a salt thereof.
  • the organic acidic substance is an organic compound having a pH of 7 or less when dissolved in water, and a pharmaceutically acceptable compound.
  • a pharmaceutically acceptable compound for example, glutamic acid, asparaginic acid, cuenic acid, tartaric acid, And succinic acids and their salts.
  • the content of the organic acidic substance in the preparation of the present invention can be appropriately set according to the treatment or prevention plan, but is preferably 1 to 30 wZw% of the total preparation weight, more preferably It is desirable to set the content in the range of 1-2 Ow / w%.
  • the organic acidic substance may form a complex (or salt) as long as it exhibits the biological activity.
  • release of BMP means that BMP or a complex of BMP and an additive is eluted and released from a drug product; BMP or BMP is caused by disintegration, diffusion, or dissolution of the drug product itself. Means that the complex of the compound and the additive is released. That is, in the in vitro release test, the term “release of BMP” refers to the dissolution of BMP into the release test solution or the dissolution of the complex of BMP and the additive into the release test solution, and the administration of the preparation to animals. In experiments, it means the supply of BMP from a pharmaceutical to a living body or the supply of a complex of BMP and an additive from a pharmaceutical to a living body.
  • additive refers to a substance that can be added to a drug product and refers to a substance other than BMP and collagen, such as the neutral amino acid.
  • One embodiment of the present invention is a formulation for treating bone fracture, treating bone loss or increasing bone density, which is a solid formulation that contains BMP and polysaccharide in a carrier made of collagen and that can be administered, especially injected. Yes (solid preparation b).
  • the polysaccharide used in the preparation of the present invention may be a salt thereof.
  • the preparation of the present invention contains polysaccharide (or a salt thereof), it can control the release of BMP from the preparation, that is, it can regulate the supply of BMP from the preparation to the living body. Demonstrates excellent effects.
  • the polysaccharide refers to a saccharide produced by dehydration condensation of several or more monosaccharides.
  • Bolisaccharides are classified by various methods, for example, simple polysaccharides, complex polysaccharides, acidic polysaccharides, neutral polysaccharides, and a group of polysaccharides conventionally called mucopolysaccharides.
  • sodium chondroitin sulfate, carboxymethylcellulose, hydroxypropylcellulose and the like are particularly preferable.
  • the formulation itself often disintegrates after administration to a living body, and the rate and extent of such disintegration contribute to the release of BMP from the formulation.
  • the release of BMP from a preparation containing BMP and collagen, which is administered, particularly in a form having an injectable form, containing borosaccharide or a salt thereof is controlled.
  • it has an excellent effect that it can improve the shape of the preparation.
  • the organic acidic substance and the polysaccharide may be used in combination.
  • the borosaccharide may form a complex (or salt) as long as it controls the release of BMP from the preparation and improves the form of the preparation.
  • a carrier comprising collagen contains BMP and at least one compound J selected from the group consisting of a neutral amino acid, a monosaccharide, a disaccharide and a sugar alcohol, and It is an injectable solid preparation for treating fractures, treating bone defects or increasing bone density (solid preparation c).
  • the at least one compound selected from the group consisting of amino acids, monosaccharides, disaccharides and sugar alcohols may be a salt thereof.
  • the preparation of the present invention comprises a neutral amino acid, a monosaccharide
  • ⁇ at least one compound J selected from the group consisting of neutral amino acids, monosaccharides, disaccharides, and sugar alcohols is further added.
  • a favorable shape j means a shape suitable for administration, particularly for injection.
  • neutral amino acids examples include alanine, glycine, nolin, leucine, isocyanate, fenylalanine, serine, threonine, cystine, cystine, asparagine, glutamine, methionine, tyrosine, tributofan, and proline.
  • the neutral amino acid may form a complex (or salt) as long as it exerts the moldability of the preparation.
  • Examples of the monosaccharides include glucose and fructose.
  • Examples of the disaccharides include sucrose, lactose, and maltose.
  • Examples of the sugar alcohol include xylitol, sorbitol, and mannitol. .
  • the monosaccharide, disaccharide and sugar alcohol may form a complex (or salt) as long as they exhibit the moldability of the preparation.
  • the above-mentioned preparation that is, a solid preparation which contains bone morphogenetic protein (BMP) and an organic acidic substance in a carrier made of collagen and is administered and is particularly injectable, for treating fracture, treating bone defect or increasing bone density
  • the preparation (solid preparation a) contains at least one compound selected from the group consisting of neutral amino acids, monosaccharides, disaccharides and sugar alcohols By including the compound, an excellent effect that the shape of the preparation can be improved is exhibited.
  • a preparation (solid preparation d) further containing at least one compound selected from the group consisting of neutral amino acids, monosaccharides, disaccharides and sugar alcohols in the solid preparation a is also included in the scope of the present invention.
  • a compound selected from the above-mentioned neutral amino acids, monosaccharides, disaccharides, sugar alcohols and the like is contained in the preparation, particularly a solid preparation containing BMP, collagen and an organic acidic substance (solid preparation a). It is possible to control the release of BMP from the preparation, and to provide a preparation having good shape.
  • a columnar preparation containing 20 wZw of glutamate hydrochloride, 5 w / w% of BMP and collagen is used.
  • a preparation having a good shape can be obtained.
  • a preparation having a better shape can be obtained.
  • the present invention includes not only a method for controlling the release rate of BMP, but also a method for improving the shape of the preparation.
  • the preparation of the present invention is administered to a bone disease site to be treated, that is, to a fracture site, a bone defect site or its vicinity, or to a site at a high risk of fracture in osteoporosis or the like.
  • Intraosseous administration makes it possible to treat fractures, treat bone defects or increase bone density, ie, prevent fractures.
  • b FGF basic fibroblast growth factor
  • BMP basic fibroblast growth factor
  • the dose and frequency of administration of the preparation of the present invention vary depending on, for example, the control disease, symptoms, age and body weight, but usually, BMP per preparation is, for example, 0, l to 100 mg.
  • BMP per preparation is, for example, 0, l to 100 mg.
  • BMP per preparation is, for example, 0, l to 100 mg.
  • bFGF is contained, for example, 0.1 to 20 mg can be contained.
  • One or more (for example, 2 to 4) such preparations can be administered to an adult per day.
  • the form of the preparation of the present invention may have a single structure or a multiple structure.
  • the single structure is a structure of a drug product composed of a single layer in which each component is uniformly dispersed in a preparation
  • the multiple structure is a molded product composed of two or more matrices.
  • the matrix refers to a system in which one or more of BMP, additives and the like are uniformly dispersed in collagen, but also includes a system consisting of only collagen. Therefore, a multi-layered drug product is a drug product composed of multiple matrices.
  • a matrix composed of collagen containing an organic acidic substance in the inner layer is used as a component, and the outer layer is formed in the outer layer.
  • the composition of the inner layer and the component of the outer layer may be reversed, and a triple-layered preparation having a layer made of only the third collagen on the outside of the double structure is also given as an example.
  • the production method of the preparation of the present invention is not limited.For example, in the case of a columnar preparation containing BMP, collagen, and an additive such as an organic acidic substance or polysaccharide, for example, the following production process :
  • step 2 a step of drying the mixed solution obtained in the above step 1 by a method such as freeze drying or spray drying,
  • the preparation of the present invention can be obtained by the step of cutting the dried molded product obtained in the above step ⁇ ⁇ into an appropriate length.
  • the above-mentioned production method can be appropriately selected flexibly.
  • the additive may be added to a mixed solution containing collagen and BMP as a powder without using an aqueous solution.
  • the powder may be added and kneaded as it is.
  • the particulate preparation can be produced, for example, by pulverizing the above-mentioned cylindrical preparation.
  • the particulate preparation is obtained by crushing the dried product obtained in step (2) in the above-described example of the method for producing a columnar preparation, or drying the kneaded mixture obtained in step (3) as it is. It can be manufactured by grinding. Further, by sieving the obtained particulate preparation, the size of the particles can be controlled within a certain range.
  • a preparation having a multiple structure is also produced according to the above-described method for producing a columnar preparation.
  • a homogeneous kneaded mixture containing the components constituting each layer is prepared in the same manner as in the case of the columnar preparation described above, and the mixture corresponding to each layer is extruded using multiple nozzles. It can be manufactured by molding and drying.
  • the preparation having a double structure has very excellent characteristics in the production process and in the controlled release.
  • a matrix containing BMP and a matrix containing bFGF are separately prepared, and in a step of extrusion molding, each of the above components is prepared. It is advantageous to extrude into a double structure.
  • the matrix containing bFGF is treated, for example, at a temperature of 15 ° C. or less, preferably 10 ° C. or less, and the collagen used is pH 4 to pH 7, preferably pH 5 to pH 6. Is desirable.
  • bFGF causes mesenchymal cells to proliferate
  • BMP causes the proliferated mesenchymal cells to differentiate into osteoblasts
  • bFGF is contained in the outer layer of the double structure and BMP is contained in the inner layer
  • the release of bFGF and BMP is controlled by adjusting the disintegration and dispersibility between the inner layer and the outer layer. Control is also possible in the present invention.
  • a method for treating fracture, treating bone loss or increasing bone density in osteoporosis or the like can be provided. Specifically, for individuals in need of treatment or prevention,
  • Solid preparation a Injectable solid preparation containing BMP and an organic acidic substance in a collagen carrier, a preparation for treating fracture, treating bone defect or increasing bone density (solid preparation a),
  • Solid preparation b Injectable solid preparation that contains BMP and borosaccharide in a carrier made of collagen and is used for treatment of fracture, treatment of bone defect or increase of bone density (solid preparation b),
  • Collagen carrier containing BMP and a compound selected from the group consisting of neutral amino acids, monosaccharides and disaccharides '' Preparations for treatment or bone density increase (solid preparation c),
  • Fracture which is a solid preparation that contains BMP, an organic acidic substance, and a compound j selected from the group consisting of neutral amino acids, monosaccharides and disaccharides in a carrier made of collagen and is injectable.
  • Treatment, treatment for bone defect or bone density increase (solid preparation d), and 5) The method according to any one of 1) to 4) above, further comprising basic fibroblast growth factor (bFGF) and being an injectable solid preparation, for treating fracture, treating bone defect, or increasing bone density.
  • bFGF basic fibroblast growth factor
  • Example 1 (BMP 5w formulation)
  • Example 4 (BMP 5w / w3 ⁇ 4, Ala 5w / w3 ⁇ 4 formulation)
  • Example 5 (BMP 5w / w3 ⁇ 4, Ala 10w / w3 ⁇ 4 formulation)
  • Example 6 (BMP 5w / w3 ⁇ 4, Ala 20w / w3 ⁇ 4 formulation)
  • Example 8 (BMP 5w. Cunic acid 10w / w% formulation)
  • Example 9 (BMP 5w / w3 ⁇ 4, CS 20w / w% formulation)
  • Example 10 [BMP 5w / 3 ⁇ 4, CS 20w (formulation): small diameter]
  • Example 1 (BMP 20w / 3 ⁇ 4 formulation)
  • Example 1 (BMP 5w, Glu 20w, Ala 20w formulation)
  • Example 14 (BMP 5w / w3 ⁇ 4, Ala 20w / w3 ⁇ 4 formulation)
  • 1.88 w / w% aqueous atelocollagen solution 2 1.O g was mixed with 32 ml of water and 20.0 ml of 5 mg / m 1 L aqueous solution of alanine. Then, 1.75 ml of a 2.86 mg / ml BMP aqueous solution was added to the obtained mixture, and the mixture was stirred uniformly. The obtained mixture was freeze-dried, and the obtained product was swelled by adding water, and kneaded to obtain a gel-like mixed solution. This mixed solution was filled in a syringe and extruded from a nozzle (inner diameter: 6 mm).
  • Example 16 (BMP 0.2w / w3 ⁇ 4, Ala 20w / w3 ⁇ 4 formulation)
  • HPCD Hydroxypropyl cyclote 'xytrin
  • CMC Carpho' xymethylcellulose
  • HPC Hydroxypropylcellulose
  • HPCD Hydroxif 'mouth vircyclo ⁇ xytrin
  • CMC Carpho' xymethylcellulose
  • HPC Human 'mouth xyft. Mouth pill cellulose (*): added as powder during kneading
  • HPCD Hydroxif 'mouth vircyclo II' xytrin
  • CMC Carboxymethylcellulose
  • HPC Hydroxypropylcellulose (*): Added as a powder during kneading
  • Example 78 (BMP 0.5w / w formula) To 25.3 g of a 1.9 Tw / w% aqueous atelocollagen solution, 34 ml of water and 0.453 ml of 5.52 mg / ml BMP aqueous solution were added, and the mixture was stirred uniformly. The obtained mixture was freeze-dried, and the obtained product was swelled by adding water, and kneaded to obtain a gel-like mixed solution. This mixed solution was filled in a syringe and extruded from a nozzle (inner diameter: 6 mm).
  • Example 80 (BMP 20w / w%. Glu 20w / w3 ⁇ 4. Ala 20w / w% formulation)
  • Example 82 (BMP 0.5w, Glu 20w / w3 ⁇ 4, Ala 20w / w3 ⁇ 4 formulation)
  • atelocollagen aqueous solution 15.2 g, 5 mgZm L —2 Oml of aqueous solution of glutamate hydrochloride and 20 ml of 5 mg / m1 L-alanine aqueous solution were added and mixed. Then, 5 ml of water and 0.045 ml of 5.52 mg / 1 BMP aqueous solution were added to the obtained mixture, and the mixture was stirred uniformly. The obtained mixture was freeze-dried, and the obtained product was swelled by adding water, and kneaded to obtain a gel-like mixed solution.
  • Example 85 (BMP 5, Glu 10w. Ala 20w / w formula: small diameter, extra fine diameter)
  • Each of the solid preparation 1, the solid preparation 2, the solid preparation 3, the solid preparation 4, the solid preparation 5, the solid preparation 6, and the solid preparation 7 contained 5 wZw% of polyethylene glycol (molecular weight: 400) as a release test solution. It was added to 1 ml of 3M phosphate buffer (pH 6.3) and left at 37'C. On the 1st, 4th, and 7th day after the start of the test, replace the entire amount of the release test solution, and measure the BMP amount in the release test solution by high performance liquid chromatography. The in vitro release profile of each formulation was determined. Fig. 1 shows the results.
  • the solid preparation 8, the solid preparation 9, and the solid preparation 10 were made up to 1 ml of 0.3M phosphate buffer (pH 6.3) containing 5 w / w% of polyethylene glycol (molecular weight 400), which is a release test solution. Put, 37. It was left at C. On the 1st, 4th and 7th days after the start of the test, the whole amount of the release test solution was replaced, and the in vitro release profile of each preparation was determined by measuring the BMP amount in the release test solution by high performance liquid chromatography.
  • Figure 2 shows the results. The measurement of BMP in the case of Solid Preparation 9 and Solid Preparation 10 was performed after treating the release test solution with chondroitinase.
  • Each of the solid preparations 12 and 13 was placed in 1 ml of 0.3 M phosphate buffer (pH 6.3) containing 5 w / w% of polyethylene glycol (molecular weight: about 400), which is a release test solution, and It was left at ° C. On the 1st, 4th and 7th days after the start of the test, the whole amount of the release test solution was replaced, and the in vitro release profile of each drug product was determined by measuring the amount of BMP in the release test solution by high performance liquid chromatography. Figure 3 shows the results.
  • solid preparation 1, solid preparation 2, solid preparation 3, solid preparation 4, solid preparation 5, solid preparation 6, and solid preparation 7 was administered subcutaneously to the back of mice (BALBZc, male), one per mouse. After dissolving each of the preparations collected 3 days and 7 days after administration, the amount of BMP in the lysate was measured by high-performance liquid chromatography. Changes were examined and in vivo release profiles determined. The results are shown in FIG.
  • a solid preparation containing BMP and collagen can release BMP from the preparation over a long period of time in an evaluation test in an animal body, that is, supply BMP to a living body for a long period of time. It was shown that c
  • Test Example 5 Time course of BMP content in drug product after subcutaneous administration to mice
  • Each of solid preparation 8, solid preparation 9, and solid preparation 10 was administered subcutaneously to the back of mice (BALBZc, male), one per mouse, and the respective preparations collected 3 and 7 days after administration were dissolved Thereafter, the amount of BMP in the lysate was measured by high performance liquid chromatography to determine the change over time in the amount of BMP in the formulation after subcutaneous administration of each formulation to mice, and the in vivo release profile was determined.
  • the measurement of BMP in the lysate was performed after treating the lysate with chondroitinase. The results are shown in FIG.
  • BMP is released from the preparation at various release rates by using a solid preparation containing an organic acidic substance or bolisaccharide, BMP, and collagen. At different speeds It was shown that it can be supplied to living organisms.
  • Test Example 6 Time course of BMP content in the preparation after subcutaneous administration of mice
  • solid preparation 15 25 g / ellet / head
  • solid preparation 16 6.5 ⁇ g / pe 11 et / head
  • BMP aqueous solution A (1500 // g / m1)
  • BMP aqueous solution B 300 zg / ml
  • BMP aqueous solution C 60 zg / m1
  • BMP aqueous solution B 30 g / head
  • BMP aqueous solution C 6 zg / head
  • Solid preparation 9 Solid preparation 60, Solid preparation 61, Solid preparation 63, Solid preparation 74, Solid preparation 75, Solid preparation 77, Solid preparation 4, Solid preparation 4 9 Comparison of shape of each preparation before cutting Was performed. The results are shown in FIG.
  • Test Example 1 Intraosseous administration to normal monkeys
  • Solid male, solid 2, solid 3 and control 1 were administered intraosseously to normal male cynomolgus monkeys using a K-wire and an 18-gauge needle.
  • FIG. 13 shows the results of the time course of the bone density near the site shown in Table 2. As shown in FIG. 13, when the solid preparation containing BMP and collagen was intraosseously administered to normal sal, an increase in bone density was confirmed.
  • Test Example 1 3 Evaluation in Ovariectomized Monkeys Solid preparation 11 or control preparation 3 was intraosseously administered to the proximal femur of a cynomolgus monkey (osteoporosis model) 3 years after ovaries were removed. Six months after administration, the quiz was sacrificed and histological evaluation around the administration site was performed. The results are shown in Figure 14
  • Solid formulation with a small formulation diameter i.e., solid formulation 84a, solid formulation 84b, solid
  • BMP required for fracture treatment, bone defect treatment or bone density increase can be delivered to the target site of fracture treatment, bone defect treatment, or fracture prevention.
  • the BMP concentration can be maintained at a high concentration.

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Abstract

L'invention concerne des préparations destinées au traitement de fracture osseuse, de déperdition osseuse ou de prévention de fracture osseuse, que l'on peut facilement utiliser pour obtenir un effet thérapeutique élevé. Ces préparations, sous la forme de préparations solides, qui permettent de traiter des fractures osseuses, des déperditions osseuses ou d'augmenter la densité osseuse, contiennent (a) un vecteur à base de collagène, (b) une protéine osseuse morphogénétique (BMP) et (c) au moins un composé choisi dans le groupe formé d'acides aminés neutres, de monosaccharides, de disaccharides, de substances acides organiques et de polysaccharides, et peuvent être administrées par injection. L'invention concerne également un procédé de traitement de fracture osseuse, de déperdition osseuse ou d'augmentation de la densité osseuse, qui consiste à administrer une telle préparation en dose efficace à un patient nécessitant un traitement de fracture de l'os, de déperdition osseuse ou d'augmentation de la densité osseuse.
PCT/JP2003/000966 2002-02-04 2003-01-31 Preparations pour le traitement de fracture osseuse de deperdition osseuse ou d'augmentation la densite osseuse WO2003066083A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021795A3 (fr) * 2006-08-14 2008-05-08 Warsaw Orthopedic Inc Matrice de support fluide
US9616153B2 (en) 2008-04-17 2017-04-11 Warsaw Orthopedic, Inc. Rigid bone graft substitute

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62135431A (ja) * 1985-12-07 1987-06-18 Katsuyuki Fujii 液状骨形成剤からなる注射液
EP0326151A2 (fr) * 1988-01-29 1989-08-02 Sumitomo Pharmaceuticals Company, Limited Formulations perfectionnées à libération contrôlée
EP0493737A1 (fr) * 1990-12-19 1992-07-08 Kaken Pharma Co Ltd Agent pour le traitement des maladies osseuses contenant du facteur basique de croissance des fibroblastes.
EP0838219A1 (fr) * 1996-10-09 1998-04-29 Sumitomo Pharmaceuticals Company, Limited Formulation à libération retardée à base de collagène et de glycosaminoglycan
WO2000044401A1 (fr) * 1999-01-28 2000-08-03 Hoffmann La Roche Utilisation d'un facteur d'activite inhibitrice de melanome (mia) pour la reparation de cartilages et d'os

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62135431A (ja) * 1985-12-07 1987-06-18 Katsuyuki Fujii 液状骨形成剤からなる注射液
EP0326151A2 (fr) * 1988-01-29 1989-08-02 Sumitomo Pharmaceuticals Company, Limited Formulations perfectionnées à libération contrôlée
EP0493737A1 (fr) * 1990-12-19 1992-07-08 Kaken Pharma Co Ltd Agent pour le traitement des maladies osseuses contenant du facteur basique de croissance des fibroblastes.
EP0838219A1 (fr) * 1996-10-09 1998-04-29 Sumitomo Pharmaceuticals Company, Limited Formulation à libération retardée à base de collagène et de glycosaminoglycan
WO2000044401A1 (fr) * 1999-01-28 2000-08-03 Hoffmann La Roche Utilisation d'un facteur d'activite inhibitrice de melanome (mia) pour la reparation de cartilages et d'os

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021795A3 (fr) * 2006-08-14 2008-05-08 Warsaw Orthopedic Inc Matrice de support fluide
US7671014B2 (en) 2006-08-14 2010-03-02 Warsaw Orthopedic, Inc. Flowable carrier matrix and methods for delivering to a patient
US7897564B2 (en) 2006-08-14 2011-03-01 Warsaw Orthopedic, Inc Flowable carrier matrix and methods for delivering to a patient
US8080521B2 (en) 2006-08-14 2011-12-20 Warsaw Othopedic, Inc. Flowable carrier matrix and methods for delivering to a patient
US8148326B2 (en) 2006-08-14 2012-04-03 Warsaw Orthopedic, Inc. Flowable carrier matrix and methods for delivering to a patient
US8198238B2 (en) 2006-08-14 2012-06-12 Warsaw Orthopedic, Inc. Flowable carrier matrix and methods for delivering to a patient
US8293232B2 (en) 2006-08-14 2012-10-23 Warsaw Orthopedic, Inc. Flowable carrier matrix and methods for delivering to a patient
US9616153B2 (en) 2008-04-17 2017-04-11 Warsaw Orthopedic, Inc. Rigid bone graft substitute

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