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WO1993015767A1 - Implant therapeutique servant a la stimulation de la croissance osseuse - Google Patents

Implant therapeutique servant a la stimulation de la croissance osseuse Download PDF

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Publication number
WO1993015767A1
WO1993015767A1 PCT/US1993/000946 US9300946W WO9315767A1 WO 1993015767 A1 WO1993015767 A1 WO 1993015767A1 US 9300946 W US9300946 W US 9300946W WO 9315767 A1 WO9315767 A1 WO 9315767A1
Authority
WO
WIPO (PCT)
Prior art keywords
pge
bone
site
polymer
bone 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.)
Ceased
Application number
PCT/US1993/000946
Other languages
English (en)
Inventor
Leah E. Appel
Gaylen M. Zentner
Gideon A. Rodan
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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 Merck and Co Inc filed Critical Merck and Co Inc
Publication of WO1993015767A1 publication Critical patent/WO1993015767A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • 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
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A61L2300/222—Steroids, e.g. corticosteroids
    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Definitions

  • SUBSTITUTE SHEET The function of this device is dependent upon proper placement in or near the bone in need of therapy.
  • the device is positioned as close as possible to the site of therapy, thereby maximizing target site drug delivery while minimizing the systemic uptake of drug. That is, by placing the device in close proximity to the target treatment area, higher concentration of the released PGE 2 can be utilized in the bone formation process. This allows for delivery of higher therapeutic levels of PGE 2 to the bone and less distribution to other organs and tissue of the body.
  • SUBSTITUTESHEET are involved in resorption. Hayward, M. and Fiedler-Nagy, Ch. , Agents and Actions, 22, 251-254 (1987). PGE 2 has also been implicated in bone loss. See Hayward, M. A. and Caggiano, T. J. , Annual Reports in Medicinal Chemistry, 22, Sect. IV, Chapter 17, 169-178 (1987).
  • U.S. patent 4,621,100 discloses a method for treatment or prevention of non-growth related osteoporosis in an animal, based upon oral administration of PGE 2 and intravenous administration of prostaglandin E, . Bone growth effects were observed after ninety days of oral PGE 2 therapy. These results included an increase in bone turnover, including increased activation, resorption and formation rates. Side effects of oral dosing of GE 2 such as loose stools, diarrhea, vomiting, injected sclerae, and increased serum alkaline phosphatase were observed during the dosing period. Toxicity, due to systemic distribution of
  • PGE 2 has reduced the pharmaceutical utility of this compound. Delivery of PGE 2 in a non-specific manner requires elevated concentrations of the drug and as noted in U.S. patent 4,621,100 results in unwanted side effects.
  • British patent 1,494,463 discloses that therapeutic levels of PGE 2 results in increased blood pressure, stimulated smooth muscle reactions, inhibited gastric secretion, controlled spasm and facilitated breathing in asthmatic conditions, decongested nasal passages, decreased blood platelet adhesion and has affected the reproductive organs of
  • WO-90-15586 teaches a controlled release drug delivery device comprising a bioerodible polymer admixed with gentamicin.
  • the device was implanted in bone that had been inoculated with Staphylococcus aureus to induce osteomyelitis in rats.
  • a polymer composed of poly(propylene fu arate) prepolymer crosslinked with methylmethacrylate was used as a matrix for the implantation and controlled release of the antibiotic.
  • the medicament supplied as a paste composed of the polymer and the antiboitic was able to reduce the degree of infection.
  • the polymer used by this system decomposed to non-toxic residues.
  • WO-90-15586 further teaches the use of this paste for the delivery of Insulin Growth Factor 1, hereinafter IGF, as a means of enhancing bone formation. A twelve week treatment period is recommended.
  • controled release dosage from containing PGERAN By placing the controled release dosage from containing PGERAN at the site where bone growth stimulation is required, side effects normally seen during treatment by traditional routes of administration with this compound were not observed.
  • the stimulation of bone growth is useful in the treatment of bone fractures, osteoporosis, osteopenia or the like.
  • free PGE 2 refers to the PGE 2 which is released from the dosage form and available for therapeutic use.
  • Free PGE 2 is the PGE 2 medicament which is administered to the site where bone growth stimulation is desired, in a controlled release manner.
  • site at which bone growth stimulation is desired is meant, both the area adjacent to a section of bone of group of bones in need of
  • Stimulation at the site where bone growth is desired also may be accomplished by infusing a solution containing PGE 2 into the treatment area.
  • a controlled release dosage from, designed for controlled delivery of PGE 2 can be implanted at the desired location of, either adjacent to the site or within the bone.
  • the present method is particularly versatile and can be applied to the stimulation of bone growth at the site of a broken bone or a region of bone affected by osteoporosis or osteopenia or the like.
  • the novel method of treatment of this invention is not meant to be limited to these bone conditions, since those skilled in the art would recognize other bone conditions in need of this therapy.
  • broken bone is meant all types of broken bones i.e. green stick fracture, compound fracture, lateral fracture, pathologic fractures resulting from invasive tumors, compression fractures, fractures that require surgical procedures for realignment of bones, etc.
  • osteoporosis in meant a reduction in bone matter associated with an increased risk of bone fracture. This term includes what is sometimes called osteopenia.
  • SUBSTITUTE SHEET Stimulation of bone growth requires the daily delivery of about 0.01 ⁇ g to about 100 ⁇ g of 0GE 2 to the site at which bone growth stimulation is desired.
  • about 0.01 ⁇ g to about 100 ⁇ g of PGE 2 is meant that during the course of any 24 hour period, the procedure requires delivery of an amount of PGE 2 that is within this range and that deviations at either extreme of the range of up to 507_ can be tolerated once the treatment regiment is established.
  • This procedure provides for delivery of PGE , in an uninterrupted manner, for from about 1 to about 28 days.
  • uninterrupted manner is meant, that the device will deliver PGE 2 to the area in need of therapy, for a sustained period of time, at an average daily dose level of PGE 2 of about 0.01 ⁇ g/day to about lOO ⁇ g/day.
  • the actual level of PGE 2 delivered is dependent upon the therapeutic level required for the specific treatment regimen.
  • release of PGE 2 may not occur immediately upon the initiation of treatment. However, within twelve to thirty six hours, delivery of PGE 2 to the area in need of therapy will commence.
  • One embodiment of the novel device of this invention comprises a biodegradable dosage form consisting essentially of a bioerodible polymer and PGE 2 .
  • the dosage form is designed to release free PGE 2 to the area in need of therapy at a desired rate.
  • the novel device of this invention is designed for easy implantation either adjacent to the bone or within the bone in need of therapy.
  • SUBSTITUTE SHEET The procedure involves the surgical implantation of a controlled release dosage form which dispenses PGE 2 at the site of bone fracture. As bioerosion of the polymer occurs, PGE 2 is released directly ot the site where new bone growth is required.
  • surgical implantation is meant utilizing aseptic technique; cutting open the skin, muscle or other tissue to expose the bone in the area where stimulation of bone growth is required; placing the dosage form either into the boen or adjacent to the bone, that is, as close to the bone as possible; and then closing the disturbed tissue, muscle and skin using standard medical techniques.
  • Techniques such as arthroscopy, and any other invasive methods which would allow the placement of the dosage form within or near a bone in need of growth stimulation therapy would also be included within this definition.
  • bioerosion or “bioerodible” or “erosion” or “erodes” is meant the process, including hydrolysis, dissolution, abrasion, and corrosion, by which the dosage form is reduced in size due to the chemical or physical action of the aqueous fluids, bone and tissue present in the area of surgical implantation.
  • bioerodible polymer useful in the novel device of this invention are those that completely degrade to compounds which are water soluble and are easily excreted from the body of a subject in need of treatment, in such a manner that no decomposition residue remains at the implant area following release of all of the PGE 2 .
  • subject is meant humans, other mammals, amphibians and any other animal which is partially composed of bone.
  • the novel device includes sufficient PGE 2 to release O.Ol ⁇ g/day to 100 ⁇ g/day to PGE 2 over a period of time required for ininterrupted therapy.
  • the bioerodible polymer is a poly(ortho ester) such as or a polyacetal such as ....
  • SUBSTITUTE SHEET A further procedure involves mixing the PGE 2 with the monomers prior to the polymerization step. During the polymerization step the mixture is stirred so that the PGE 2 is homogeneously mixed with the forming polymer.
  • the final dosage forms can be prepared by compressing the dried mixture of polymer and PGE 2 into the desired form. Other techniques, known to those skilled in the art can also be utilized.
  • the polymer must reproducibly bioerode, in the environment of use, and result in products that are cleared from tissue surrounding the site of bone fracture and ultimately excreted from the body.
  • the release of PGE 2 from a polymer matrix is dependent on the erosion rate of the polymer with which it is admixed. Therefore, the polymer/PGE 2 formulation must result in a dosage form that erodes, in the environment of use, at a predictable rate, resulting in the complete release of PGE 2 to the site of bone therapy. Side reactions that would retard release of PGE 2 are avoided by proper choice of a polymer.
  • SUBSTITUTESHEET Poly(ortho esters) have been utilized in pharmaceutically acceptable controlled release devices in the past mainly becuase they erode in a controlled manner via hydrolysis.
  • One example of a polymer that meets the criteria of this novel procedure has the formula.
  • the synthesis of this polymer is described in U.S. patent 4,304,767.
  • the polymerization proceeds through a condensation reaction between a ketene acetal and an alcohol. There are no reaction by-products that need to be removed in order to achieve a high molecular weight polymer.
  • the polymer utilized in one embodiment and in example 2 has a molecular weight of about 84,000. That is the molecular weight range, determined by gel permeation chromatography was 84,000 +/- 1000 8/mole.
  • One embodiment of the method utilizes the polyacetal previously described and enough PGE 2 to sssure delivery at a rate of about 1 ug/day over the course of 28 days.
  • the actual concentration of PGE 2 in the dosage form can range from about 0.01% to about 27- by weight.
  • about 0.01% to about 2% is meant that deviations at either extreme of the range of up to 507o can be tolerated in the dosage form prior to implantation.
  • the amount of bioerodable polymer in the dosage form can range from about 99.99% to about 987, by weight of the components. By “about 99.99% to about 98%” is meant that minor deviations in the percentage of bioerodable polymer at either extreme of the range can be tolerated in the dosage form prior to implantation.
  • the desired delivery rate can be assured by first determining the jji vitro dissolution rate of the polymer in 0.15M phosphate buffered saline, pH 7.4 and adjusting the concentration of PGE 2 in the final product so that as the polymer bioerodes, the proper amount of PGE 2 is released.
  • the volume of phosphate buffered saline utilized is based upon the total PGE 2 content of the dosage form.
  • the high dose [what was amount per dosage form for high dose] utilized 75 ml of buffer. Samples were collected daily and the dissolved PGE 2 was quantified using routine analytical procedures.
  • dosage form used in this novel method was prepared using the procedure described in example 2. This dosage form released approximately 807. of the PGE 2 within 10 days in an in vitro dissolution study.
  • SUBSTITUTE SHEET Devices were fabricated in two steps. First, a disk of PGE 2 / polymer material, weighing approximately 35 mg, was made using 1/4" flat punches in a Carver press at 500 psi. The disk was then positioned in the center of a die containing six cylindrical cut-outs. The die and pellet were sandwiched between two KAPTON sheets. This was placed between two heated plates (90°C) for 10 seconds before compression at 1 ton for 10-15 seconds. The die was immediately removed from the plates and placed on a cold steel plate. The devices were punched out of the die and stored at -80°C. Each device was a transparent disk with a diameter of 2 mm and a thickness of 1 mm and weighed about 4 mg.
  • Placebo devices that is those which contain only the polymer, were made by the same method except no E 2 was added.
  • Table 1 shows the PGE 2 nominal content of each group of devices. Devices from groups A, B and C were tested for jji vitro dissolution properties. Five dosage forms from each group were placed in a bottle containing 0.15M phosphate buffered saline at pH 7.4. The lowest two dosages were tested using 75 ml of buffer. The bottles were capped and then rotated constantly for up to 14 days. A sample was removed each day and the PGE 2 released into the buffer was quantified using standard analytical procedures. The results of thes studies are shown in Table II.
  • H ET were in each of the four treatment groups .
  • the animals were anesthetized intraperitoneally using ketamine hydrochloride (KETASET, Aveco, 80 mg/kg).
  • KETASET ketamine hydrochloride
  • a longitudinal incision was made along the medial aspect of the proximal tibia down to the periosteum.
  • Under saline irrigation of 2 mm hole was drilled through the cortex approximately 2 mm inferior to the epiphyseal growth plate using a #8 carbide plain round excavating bur with a high speed dental drill.
  • the devices were placed within the marrow cavity and the incisins closed. The animals recovered without incident and within 24 hours following surgery demonstrated normal locomotion and grooming behavior.
  • Table III lists the cortical bone thickness and percent cancellous bone found for the difference groups in this trial. This histomorphometic data provides evidence for a dose-related increase in metaphyseal bone formed as a result of prostaglandin treatment. Bond volume was 8.66% for the placebo treated group and was significantly increased (p,0.05) threefold with the group A devices. Also, the rate treated with group A devices showed a significant increase in cortical bone thickness.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Neurosurgery (AREA)
  • Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

On procède à la stimulation thérapeutique d'une formation osseuse par libération régulée des prostaglandines E1, E2 ou F2α, ou du stéroïde β-estradiol sur le site où on désire obtenir une stimulation de croissance osseuse. On implante sur ledit site une forme galénique de libération régulée solide, rigide et constituée par un polymère bioérodable, ne produisant pas de résidus, et sélectionné entre un poly(ortho ester) ou un polyacétal et une prostaglandine, ou un β-estradiol. La figure 1 illustre la libération de E2 à 0,81 % en poids (groupe A), 0,035 % en poids (groupe B) et 0,003 % en poids (groupe C).
PCT/US1993/000946 1992-02-05 1993-02-04 Implant therapeutique servant a la stimulation de la croissance osseuse Ceased WO1993015767A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US83216792A 1992-02-05 1992-02-05
US832,167 1992-02-05

Publications (1)

Publication Number Publication Date
WO1993015767A1 true WO1993015767A1 (fr) 1993-08-19

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PCT/US1993/000946 Ceased WO1993015767A1 (fr) 1992-02-05 1993-02-04 Implant therapeutique servant a la stimulation de la croissance osseuse

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AU (1) AU3607293A (fr)
WO (1) WO1993015767A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5876452A (en) * 1992-02-14 1999-03-02 Board Of Regents, University Of Texas System Biodegradable implant
WO1999012550A1 (fr) * 1997-09-09 1999-03-18 The Procter & Gamble Company Procede d'augmentation du volume osseux
WO1999012551A1 (fr) * 1997-09-09 1999-03-18 The Procter & Gamble Company Procede d'augmentation du volume osseux a l'aide d'agonistes fp selectifs d'origine non naturelle
US6013853A (en) * 1992-02-14 2000-01-11 The University Of Texas System Continuous release polymeric implant carrier
EP1335686A4 (fr) * 2000-10-24 2005-06-01 Sdgi Holdings Inc Procedes et dispositifs de fusion de vertebres
WO2007083643A1 (fr) * 2006-01-18 2007-07-26 National University Corporation Tokyo Medical And Dental University Biomateriau pour osteogenese contenant un promoteur de l'osteogenese et un nanogel

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4093709A (en) * 1975-01-28 1978-06-06 Alza Corporation Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates)

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4093709A (en) * 1975-01-28 1978-06-06 Alza Corporation Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5876452A (en) * 1992-02-14 1999-03-02 Board Of Regents, University Of Texas System Biodegradable implant
US6013853A (en) * 1992-02-14 2000-01-11 The University Of Texas System Continuous release polymeric implant carrier
WO1999012550A1 (fr) * 1997-09-09 1999-03-18 The Procter & Gamble Company Procede d'augmentation du volume osseux
WO1999012551A1 (fr) * 1997-09-09 1999-03-18 The Procter & Gamble Company Procede d'augmentation du volume osseux a l'aide d'agonistes fp selectifs d'origine non naturelle
US6156799A (en) * 1997-09-09 2000-12-05 The Procter & Gamble Company Method of increasing bone volume using non-naturally-occurring FP selective agonists
AU739275B2 (en) * 1997-09-09 2001-10-11 Procter & Gamble Company, The Method of increasing bone volume using non-naturally-occurring FP selective agonists
EP1335686A4 (fr) * 2000-10-24 2005-06-01 Sdgi Holdings Inc Procedes et dispositifs de fusion de vertebres
EP2085055A1 (fr) * 2000-10-24 2009-08-05 Warsaw Orthopedic, Inc. Dispositif de fusion intervertebrale
US8226729B2 (en) 2000-10-24 2012-07-24 Warsaw Orthopedic, Inc. Spinal fusion methods and devices
US8617252B2 (en) 2000-10-24 2013-12-31 Warsaw Orthopedic, Inc. Spinal fusion methods and devices
WO2007083643A1 (fr) * 2006-01-18 2007-07-26 National University Corporation Tokyo Medical And Dental University Biomateriau pour osteogenese contenant un promoteur de l'osteogenese et un nanogel
JP4843797B2 (ja) * 2006-01-18 2011-12-21 国立大学法人 東京医科歯科大学 骨形成促進物質とナノゲルを含有する骨形成用生体材料

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Publication number Publication date
AU3607293A (en) 1993-09-03

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