EP1091730A1 - Utilisation de facteurs de croissance pour la production d'un medicament - Google Patents

Utilisation de facteurs de croissance pour la production d'un medicament

Info

Publication number
EP1091730A1
EP1091730A1 EP99926216A EP99926216A EP1091730A1 EP 1091730 A1 EP1091730 A1 EP 1091730A1 EP 99926216 A EP99926216 A EP 99926216A EP 99926216 A EP99926216 A EP 99926216A EP 1091730 A1 EP1091730 A1 EP 1091730A1
Authority
EP
European Patent Office
Prior art keywords
growth factors
medicament
medicament according
insulin
growth
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99926216A
Other languages
German (de)
English (en)
Inventor
Oscar E. Illi
Clarence Feldmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
White Spot AG
Original Assignee
White Spot AG
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 White Spot AG filed Critical White Spot AG
Publication of EP1091730A1 publication Critical patent/EP1091730A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61L24/106—Fibrin; Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • 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
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to the use of growth factors for the manufacture of a medicament for local use in the treatment of fixed bone fractures according to claim 1.
  • the external fixation of fractures essentially entails the same problems as described above for fixation by means of implants.
  • fixators 3 After initial rigid fixation, dynamization can take place, and a certain preload can be exerted on the fracture area F a . This avoids the bone loss caused by the rigid fixation during fracture healing.
  • the areas F f between the bulwark see screws 31, 32, 33, 34 are practically not affected by the bone degradation owing to the possibility of dynamization and the use of the fixator 3 for a very limited time.
  • This object is achieved by a medicament for local use in the treatment of bone fractures with internal or external fixation of the fracture parts to one another, which has the features of claim 1 and solved a use of growth factors for the manufacture of a medicament for local use in the treatment of fixed fractures.
  • GFs growth factors
  • Soluble low molecular weight proteins such as insulin-like growth factors (IGFs) have long been known for their local effects on the growth of cartilage and bone (Canalis, E. and LG Raisz, Endocr. Rev. 4: 62-77, 1983) known. The same authors demonstrated a positive effect of IGF on bone DNA synthesis in periosteal and non-periosteal bone.
  • IGFs insulin-like growth factors
  • IGF-1 In degenerative joint diseases, local application of IGF-1 to stimulate osteoblast activity and collagen production has been postulated.
  • An advantage of using IGF in wound and fracture treatment is that IGF has no known relationship to oncogenes.
  • IGF-1 also known as Somatomedin C
  • Somatomedin C is a basic polypeptide consisting of 70 amino acids and has a molecular weight of 7649 D.
  • IGF-1 stimulates inter alia the incorporation of proteoglycan into cartilage by chondrocytes (Froger-Graillard et al., Endocrinology 124: 2365-2372, 1989) and also the synthesis of DNA, RNA and proteins.
  • the slightly acidic polypeptide IGF-2 consists like IGF-
  • IGF 2 consists of 67 amino acids. IGFs are primarily dependent on growth hormone (somatotropin; GH). IGF-1 is predominantly active in adults, while IGF-2 is the main growth factor in the fetus.
  • somatotropin somatotropin
  • BMP Bone Morphogenetic Protein
  • hOP-1 human Osteogenetic Protein-1
  • BMP-7 three-dimensional structure of osteogenic protein 1 (OPl; BMP-7), which can induce bone formation in vivo.
  • BMP-4 and BMP-7 are available as recombinant proteins from the BMPs which are members of the TGF beta superfamily.
  • recombinant BMPs appear to be able to induce osteogenesis in vivo only if they are bound to suitable carriers or carriers (E. Tsuruga et al., J. Biochem. 121: 317-324, 1997).
  • suitable carriers or carriers E. Tsuruga et al., J. Biochem. 121: 317-324, 1997.
  • rhBMP-2 recombinant human BMP-2
  • suitable carrier materials to accelerate and ensure the healing of bone defects (20 mm long critical-sized defects in the radius of rabbits was described by Zegzula, HD et al. tested and described in the Journal of Bone ans Joint Surgery, 79-A (12) 1778-1790, 1990.
  • the carrier material cylinders made of porous polylactide are intended to serve as placeholders and scaffolds for the newly formed bone tissue.
  • the collagen claimed in EP-A 0 206 801 has a very good tissue affinity and acts as a carrier material for BMP in the form of ribbons or solid bodies.
  • these collagen preparations have a certain inherent antigenic effect, which is probably attributable to the telopeptides present and which disrupt ectopic bone formation.
  • the increase in bone stability is a dynamic process that is expressed in a sigmoid curve.
  • the osteosynthesis implant or external fixation can usually be removed when the stability of the fracture area has reached a certain threshold.
  • Figure 3 shows the hypothetical course of fracture healing using only an osteosynthesis implant or external fixation.
  • the implant / fixation must be able to take over the full mechanical load at time 0 and can only be removed when the increase in the stability of the healing bone tissue (plus a certain mechanical stability reserve) can bear these loads again.
  • the implant / fixation has to fix the bone fragments in a certain relative position to one another until the bone material newly formed between them can take over this function again, the mechanical loads that act on the broken bone, however, must last from stabilization until the healing bone has regained such a high percentage of its mechanical properties that no additional stabilization is required. This does not mean that the bone has already regained its full mechanical strength when the external stabilization is removed. got to. All methods have in common that the affected area is immobilized for a long time, and next. the already mentioned bone loss the reduced muscle activity leads to muscle loss and a deterioration in mobility. Around to achieve again, time and cost-intensive therapies have to be carried out after removing the external stabilizing agents.
  • the growth factors (GF) that can be used in the present invention come from the group of epidermal growth factors (EGF) or insulin growth factors (IGF) or transforming growth factors beta (TGF-beta) or fibrobalast growth factors (FGF). Suitable combinations of two or more of them can of course also be used. Many of the above growth factors are commercially available as lyophilized powders.
  • the growth factors are in an injectable formulation. This makes it possible to inject the growth factors directly into the fracture area or m its immediate vicinity and m the rigidly fixed areas F on the bone.
  • the growth factors are bound to a suitable biodegradable carrier material or encapsulated in one.
  • the size of the individual carrier material particles or the capsules is dimensioned so that the ability to inject is retained.
  • the particles or capsules loaded with growth factors can in turn be suspended in auxiliary liquids or gels that improve their ability to inject.
  • the growth factors are converted into the following formulations:
  • Encapsulated or embedded in biodegradable polymer material wherein the growth factors can be encapsulated in micro- or nanocapsules, made of a suitable biodegradable material such as polylactide, for example by means of "in water drying" of w / o / w emulsions.
  • Solid microspheres can be made from one GF-polymer-solvent mixture can be produced, for example, by means of “spray drying”.
  • FIG. 3 shows schematically the healing process of a fracture in conventional therapy using only a fixation and using the medicament according to the invention.
  • the solid line shows on the one hand the accelerated temporal course of the new bone formation, respectively the increase in the mechanical strength of the healing bone in the fracture area F a .
  • the slower increase without using growth factors is shown with the dashed line.
  • the fracture must still be provided with a fixation at time 0, which can take over the full mechanical load, but since this only has to be carried for a much shorter period of time, the fixation can be removed much earlier.
  • the substantial reduction ( ⁇ t) in the time that the external or internal stabilizing agents have to be worn also reduces the time in which bone material is broken down in the rigidly fixed areas.
  • the medicament according to the invention was applied only in the fracture area, the quicker healing of the fracture and the earlier removal of the fixation would have been enough in turn, an earlier resumption of the movement of the affected area reduces a very decisive effect on reducing the duration of the illness and also on the time and financial expenditure required for the after-treatment.
  • the growth factors according to the present invention are also injected into the rigidly fixed regions F, F f on the bone, they directly counteract the breakdown of bone material here.
  • the medicine may also be injected retrospectively, even in cases where the implants remain in the patient.

Abstract

La présente invention concerne un médicament injectable à utiliser localement lors du traitement de fractures osseuses pendant lequel les parties de l'os fracturé sont stabilisées mécaniquement au moyen d'un implant d'ostéosynthèse ou d'un dispositif d'immobilisation extérieure. Ledit médicament contient des facteurs de croissance qui stimulent la régénération du tissu osseux dans la zone de la fracture et sont incorporés à une matière de base biodégradable à partir de laquelle sont formées des microcapsules ou des nanocapsules, ou bien des microsphères ou des nanosphères. L'invention concerne également l'utilisation de facteurs de croissance pour la production d'un tel médicament.
EP99926216A 1998-06-29 1999-06-29 Utilisation de facteurs de croissance pour la production d'un medicament Withdrawn EP1091730A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH137598 1998-06-29
CH137598 1998-06-29
PCT/CH1999/000278 WO2000000180A1 (fr) 1998-06-29 1999-06-29 Utilisation de facteurs de croissance pour la production d'un medicament

Publications (1)

Publication Number Publication Date
EP1091730A1 true EP1091730A1 (fr) 2001-04-18

Family

ID=4208961

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99926216A Withdrawn EP1091730A1 (fr) 1998-06-29 1999-06-29 Utilisation de facteurs de croissance pour la production d'un medicament

Country Status (4)

Country Link
EP (1) EP1091730A1 (fr)
JP (1) JP2002519317A (fr)
AU (1) AU4356299A (fr)
WO (1) WO2000000180A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058426A1 (fr) * 2000-02-09 2001-08-16 White Spot Ag Composition a liberation prolongee contenant un facteur de croissance de type insuline
KR100720052B1 (ko) 2005-10-07 2007-05-18 (주) 차바이오텍 성장인자를 함유한 나노입자가 코팅된 연골 조직 재건 및재생을 위한 마이크로스피어 또는 마이크로비드
US20100221345A1 (en) * 2006-01-18 2010-09-02 National University Corporation Tokyo Medical And Osteogenic biomaterial containing osteogenesis promoting substance and nanogel

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE252894T1 (de) * 1995-01-05 2003-11-15 Univ Michigan Oberflächen-modifizierte nanopartikel und verfahren für ihre herstellung und verwendung
KR100236771B1 (ko) * 1997-04-01 2000-02-01 성재갑 히아루론산을 이용한 약물의 서방성 미세입자 제형
US6214008B1 (en) * 1997-04-16 2001-04-10 White Spot Ag Biodegradable osteosynthesis implant
ATE220564T1 (de) * 1997-08-14 2002-08-15 Sulzer Innotec Ag Zusammensetzung und vorrichtung zur reparatur von knorpelgewebe in vivo bestehend aus nanokapseln mit osteoinduktiven und/oder chondroinduktiven faktoren

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0000180A1 *

Also Published As

Publication number Publication date
JP2002519317A (ja) 2002-07-02
AU4356299A (en) 2000-01-17
WO2000000180A1 (fr) 2000-01-06

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