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WO1995028950A1 - Administration de facteur de croissance derive de plaquettes et de medicaments osteotropes pour l'osteoporose et la regeneration osseuse - Google Patents

Administration de facteur de croissance derive de plaquettes et de medicaments osteotropes pour l'osteoporose et la regeneration osseuse Download PDF

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Publication number
WO1995028950A1
WO1995028950A1 PCT/US1995/005047 US9505047W WO9528950A1 WO 1995028950 A1 WO1995028950 A1 WO 1995028950A1 US 9505047 W US9505047 W US 9505047W WO 9528950 A1 WO9528950 A1 WO 9528950A1
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WO
WIPO (PCT)
Prior art keywords
bone
pdgf
mammal
growth factor
platelet
Prior art date
Application number
PCT/US1995/005047
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English (en)
Inventor
Harry N. Antoniades
Samuel E. Lynch
Richard D. Finkelman
Original Assignee
Institute Of Molecular Biology, 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 Institute Of Molecular Biology, Inc. filed Critical Institute Of Molecular Biology, Inc.
Priority to AU22973/95A priority Critical patent/AU2297395A/en
Publication of WO1995028950A1 publication Critical patent/WO1995028950A1/fr

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Classifications

    • 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
    • A61K38/1858—Platelet-derived growth factor [PDGF]

Definitions

  • the invention relates to pharmaceutical formulations useful for treating bone loss.
  • Bone loss in mammals commonly results from a number of conditions including, for example, osteoporosis, traumatic injuries, rheumatoid arthritis, malignancies, and periodontal diseases.
  • Osteoporosis is a disease process in which bone mass is progressively lost in almost all sites in the skeletal system.
  • Post-menopausal osteoporosis (Type I) dramatically increases the rate at which bone mass decreases in women. Prior to menopause, women over the age of 35 lose cortical bone mass at a rate of 0.3 - 0.5% per year.
  • Age-related osteoporosis (Type II) affects almost all aging women, and it can affect men as well.
  • osteoporosis Currently available treatments for osteoporosis, such as estrogen or calcitonin therapy, are of limited efficacy. While these therapies may prevent the loss of bone mass due to Type I osteoporosis, the current treatments fail to reverse the effects of the disease, and they fail to halt Type II osteoporosis. Furthermore, estrogen therapy is not acceptable for women with a history of, or predisposition for, thromboembolic disorders, diabetes, cancer, or liver disorders. Estrogen replacement therapy also is not an acceptable treatment for men with osteoporosis.
  • Growth factors also referred to as tissue growth promoting factors, are polypeptides which interact with specific cell surface receptors in defined target cells, resulting in specific cell effects. Growth factors are often multifunctional, and they may either stimulate or inhibit cell proliferation. They may also affect differentiated cell function. Examples of growth factors include, but are not limited to, platelet-derived growth factors (PDGFs) (R. Ross et al. (1986) Cell 46:155-169), insulin-like growth factors (IGFs) (V.R. Sara and K. Hall (1990) Physiol. Rev. 70:591-614) fibroblast growth factors (FGFs) (D. Gospodarowicz et al. (1987)
  • PDGFs platelet-derived growth factors
  • IGFs insulin-like growth factors
  • FGFs fibroblast growth factors
  • EGFs epidermal growth factors
  • NGFs nerve growth factors
  • TGFs transforming growth factors
  • BMPs bone morphogenetic proteins
  • BMPs which are part of the TGF-,9 superfamily, are characterized by their unique ability to induce osteoblastic differentiation.
  • growth factors such as PDGF, TGF-3, IGF-I, IGF-II, basic (b)-FGF, and bone morphogenetic proteins are cationic at physiological pH.
  • Tissue growth promoting factors have been shown to promote bone formation in vitro and in vivo.
  • the combinations of PDGF and IGF-I, and PDGF and IGF-II promote bone formation or regeneration (See, for example, S. E. Lynch et al. (1991) J. Periodontol . 62:458-467; and U.S. Patents 4,861,757 and 5,019,559).
  • bisphosphonate drugs are known to be direct inhibitors of osteoclastic bone resorption (H. Fleisch (1983) in: Bone and Mineral Research Annual 1:319-357).
  • bisphosphonates include etidronate, clodronate, tiludronate, pamidronate, alendronate, and risedronate.
  • the invention features a method for treating bone loss, which includes systemically administering to a mammal PDGF which is not covalently bonded to any other component of the composition.
  • the composition used in this method also includes an anti-resorptive agent.
  • the invention also features a pharmaceutical formulation for treating bone loss, including PDGF, a bone-targeting anionic compound having at least one negative charge at pH 6.8, and a physiologically acceptable excipient, wherein the PDGF is not covalently bonded to any other compound in the formulation.
  • the association of PDGF with the bone-targeting anionic compound is sufficiently strong that the two components remain associated in vivo for a period of time sufficient for delivery of PDGF to bone by the anionic compound.
  • the fact that PDGF and the anionic compound do not have to be covalently bonded greatly reduces the cost of producing the bone-targeting pharmaceutical formulation, as simply mixing the two components in solution is all that is required.
  • This pharmaceutical formulation may contain in addition another growth-promoting factor, such as IGF-I, IGF-II, TGF-3, aFGF, bFGF, EGF, NGF, or a bone morphogenetic protein.
  • the invention also features a pharmaceutical composition consisting of PDGF and an anti-resorptive agent; this composition may also contain another growth- promoting factor.
  • the non-covalent association of PDGF and the anionic compound involves at least in part an ionic attraction between the negatively charged anionic compound and PDGF, which is positively charged at pH 6.8.
  • the positive charge on PDGF can be increased by addition of one or more cationic groups such as amino groups, or by point mutations which substitute positively charged amino acids such as lysine for neutral or negatively-charged amino acids; these modifications can be carried out by standard techniques.
  • PDGF and the other growth factors useful in the invention may be derived from natural sources, produced by recombinant DNA technology, or chemically synthesized.
  • the growth factor is purified and deemed to be at least 90% pure, by weight, as determined by techniques such as gel electrophoresis and amino acid sequence analysis.
  • PDGF includes all forms of biologically active PDGF including all isoforms, homodimeric and hete ⁇ odimeric forms, and analogs.
  • the bone-targeting anionic compound can serve as the bone-targeting anionic compound, including sulfonates, phosphonates, and dicarboxylates (e.g.. oxalic acids) .
  • the anionic compound has at least 1 negative charge at pH 6.8. More preferably, the anionic compound has at least 2 negative charges at pH 6.8. Still more preferably, the anionic compound is a bisphosphonate of the formula:
  • R x is hydrogen, fluorine, chlorine, hydroxyl, or methyl
  • R 2 is hydrogen, fluorine, chlorine, methyl, S- C 6 H 5 -C1, (CH 2 ) 2 NH 3 , (CH 2 ) 3 NH 3 , (CH 2 ) 2 N(CH 3 )C 5 H U , CH 2 -pyridine, or NHC 7 H 14 .
  • bisphosphonates include, but are not limited to, etidronate, clodronate, tiludronate, pamidronate, alendronate, and risedronate.
  • at least one negative charge of the anionic compound interacts with PDGF, and at least one negative charge interacts with calcium on the bone.
  • the anti-resorptive agent is a phosphonate, and more preferably, it is a bisphosphonate.
  • Methods for preparing anti-resorptives are well-known in the art.
  • the formulation of the invention is administered to a mammal in an amount between about 0.001 and 50 mg/kg of the body weight of the mammal (preferably a human), more preferably in an amount between about 0.01 and 10.0 mg/kg of the body weight of the mammal.
  • PDGF treatment of bone increases bone mineral density compared with saline treatment of bone.
  • Applicants have also found that the combination of PDGF and an anionic compound, such as a bisphosphonate, has a greater effect on both whole skeleton bone mineral density and spinal bone mineral density (than either compound alone does) .
  • the formulations of this invention can be used to treat or prevent osteoporosis in a mammal.
  • PBS phosphate buffered saline
  • DXA dual energy X-ray absorptio etry
  • PDGF can be produced by standard recombinant DNA techniques and purified by conventional chromatography. These techniques are well known to those skilled in the art. 0.285 ml of 2 M Tris-hydrochloride and 3.41 ml of PBS (20 mM phosphate, 150 mM NaCl, pH 7.1) were added to 36.3 ml of 50 mM sodium acetate buffer (pH 5.00) containing PDGF (11.03 mg/ml) to yield a 40 ml solution with a final pH of 7.1. From this solution, six 6-ml portions for subsequent administration were prepared and stored at -20°C.
  • Alendronate (0.015 g) was dissolved in 10 ml of water containing 10 ⁇ l of 10 M sodium hydroxide. To this solution was added 30 ml of PBS (20 mM phosphate, 150 mM NaCl, pH 7.1), yielding a final solution with a pH of 7.1. From this solution, six 6-ml portions for subsequent administration were prepared and stored at - 20°C.
  • Alendronate (0.015 g) was added to 36.3 ml of 50 mM sodium acetate buffer (pH 5.00) containing PDGF (11.03 mg/ml) along with 0.10 ml PBS (20 mM phosphate, 150 mM NaCl, pH 7.1) and 0.20 ml of 10 M NaOH.
  • PBS 20 mM phosphate, 150 mM NaCl, pH 7.1
  • 0.275 ml of 2 M Tris-hydrochloride 0.275 ml of 2 M Tris-hydrochloride and 0.002 ml glacial acetic acid to yield a 40 ml solution with a final pH of 7.04. From this solution, six 6-ml portions for subsequent administration were prepared and stored at -20°C.
  • Alendronate (0.015 g) was added to 3.63 ml of 50 mM sodium acetate buffer (pH 5.00) containing PDGF (11.03 mg/ml) along with 0.10 ml PBS (20 mM phosphate, 150 mM NaCl, pH 7.1) and 0.020 ml of 10 M NaOH. To this solution was added 26.25 ml of PBS (20 mM phosphate, 150 mM NaCl, pH 7.1) to yield a 40 ml solution with a final pH of 7.12. From this solution, six 6-ml portions for subsequent administration were prepared and stored at - 20°C.
  • Ovariectomized rats were injected 3 times per week. Bone mineral was measured by DXA scanning at baseline before treatment and then at 2.5 weeks after the start of treatment. a Different from PBS, p ⁇ 0.05; b different from PBS, p ⁇ 0.001; different from PDGF, p ⁇ 0.001; d different from alendronate, p ⁇ 0.01; e different from PDGF, p ⁇ 0.01. The numbers in parentheses are the number of observations.
  • Bone mineral density in the group treated with the complex of alendronate and low dose PDGF was increased over baseline 25.0% more than the corresponding change from baseline in alendronate-treated animals.
  • Bone mineral density in the group treated with the complex of alendronate and high dose PDGF was increased over baseline 300.0% more than the corresponding change from baseline in PBS-treated animals.
  • Bone mineral density in the group treated with the complex of alendronate and high dose PDGF was increased over baseline 100.0% more than the corresponding change from baseline in PDGF-treated animals.
  • Bone mineral density in the group treated with the complex of alendronate and high dose PDGF was increased over baseline 50.0% more than the corresponding change from baseline in alendronate-treated animals.
  • results presented above indicate that the addition of PDGF to alendronate increased bone density (hence bone formation activity) in long bones as well.
  • results presented above also provide evidence for the dose-dependence of the effect of the PDGF added to alendronate. Stimulation of spinal bone growth by the combination of PDGF plus alendronate
  • Ovariectomized rats were injected 3 times per week. Bone mineral was measured by DXA scanning at baseline before treatment and then at 2.5 weeks after the start of treatment.
  • a Different from PBS p ⁇ 0.05; b different from PBS, p ⁇ 0.001; c different from alendronate, p ⁇ 0.001; d different from PDGF, p ⁇ 0.01; e different from alendronate, p ⁇ 0.05; f different from alendronate plus low dose PDGF, p ⁇ 0.05.
  • the numbers in parentheses are the number of observations.
  • Applicants have found that 2.5 weeks of treatment with either PDGF or the combination of PDGF and alendronate increased spinal bone mineral density compared with PBS-treated animals. Mineral density in PDGF-treated animals, alendronate-treated animals, alendronate plus low-dose PDGF-treated animals, and alendronate plus high-dose PDGF-treated animals was significantly increased over baseline compared with the corresponding change from baseline in PBS-treated control animals. Applicants have also found that treatment with the complex of PDGF and alendronate increased spinal bone mineral density compared with animals treated with alendronate or PDGF alone. Mineral density in low-dose PDGF plus alendronate-treated animals was increased over baseline 100.0% more than the corresponding change from baseline in alendronate-treated animals.
  • compositions of the invention may be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; for oral administration, particularly in the form of tablets or capsules; intranasally; topically; or transdermally.
  • compositions of this invention may also be formulated for implants.
  • the compositions of this invention may be supplied as at least two components, such that the components are either mixed before use or used sequentially, but close enough in time to be therapeutically effective.
  • a composition of the invention may be conveniently administered in unit dosage form, and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences ((1980) Mack Pub. Co., Easton, PA).
  • Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphtalenes, and the like.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphtalenes, and the like.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxethylene- polyoxypropylene copolymers may be useful excipients to control the release of a compound of the invention.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes
  • Formulations for inhalation administration may contain excipients, for example, lactose.
  • Inhalation formulas may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or they may be oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Compositions for parenteral administration may also include glycocholate for buccal administration, or citric acid for vaginal administration.
  • compositions described herein in a physiologically acceptable mixture will vary depending on a number of factors, including the dosage of the compound to be administered, the chemical characteristics of the compositions employed, and the route of administration.
  • the compositions of this invention may be provided in an aqueous physiological buffer solution containing about 0.1 to 10% w/v for parenteral administration. Typical dose ranges are from about 0.001 g PDGF/kg to about 50 g PDGF/kg of body weight per day, given in 1-4 divided doses.
  • the preferred dosage of drug to be administered is likely to depend on such variables as the type and extent of bone loss, the overall health status of the particular patient, the relative biological efficacy of the composition selected, the formulation of the excipients, and its route of administration. Other embodiments are within the following claims. What is claimed is:

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Abstract

Compositions pharmaceutiques utiles pour traiter la perte osseuse, qui peuvent consister en un simple mélange de facteur de croissance dérivé de plaquettes (PDGF) et de composé anionique à ciblage osseux d'au moins un charge négative à un pH de 6,8. La présente invention concerne également une composition contenant PDGF et un agent anti-résorption. Les compositions susmentionnées peuvent également contenir un second facteur de croissance tel que les facteurs de croissance proches de l'insuline I et II (IGF-I et IGF-II), le facteur de croissance des nerfs (NGF), le facteur de croissance de transformation (TGF), le facteur de croissance épidermique (EGF) et le facteur de croissance de base des fibroblastes (bFGF) ou une protéine morphogénétique osseuse. La présente invention concerne en outre des procédés de traitement des os d'un mammifère consistant à administrer de manière systémique PDGF ou les compositions pharmaceutiques susmentionnées en quantité suffisante pour améliorer la formation osseuse ou pour régénérer ou préserver les os.
PCT/US1995/005047 1994-04-20 1995-04-18 Administration de facteur de croissance derive de plaquettes et de medicaments osteotropes pour l'osteoporose et la regeneration osseuse WO1995028950A1 (fr)

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AU22973/95A AU2297395A (en) 1994-04-20 1995-04-18 Administration of platelet-derived growth factor and bone seeking drugs for osteoporosis and bone regeneration

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US23011494A 1994-04-20 1994-04-20
US08/230,114 1994-04-20

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071148A3 (fr) * 1999-05-26 2001-09-27 Brigham & Womens Hospital Utilisations therapeutiques d'agents modulant l'activite de l'actine alpha de muscle lisse
WO2001032197A3 (fr) * 1999-11-02 2002-03-07 Lilly Co Eli Methodes d'utilisation de lp8, une proteine liee au pdgf, afin de traiter les troubles musculosquelettiques
US6710025B1 (en) 1999-05-26 2004-03-23 The Brigham And Women's Hospital, Inc. Treatment of damaged tissue using agents that modulate the activity of alpha-smooth muscle actin
US7473678B2 (en) 2004-10-14 2009-01-06 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods of use thereof
US8257737B2 (en) * 2001-08-09 2012-09-04 Giuseppe Intini Tissue implants and methods for making and using same
US8399409B2 (en) 2006-11-03 2013-03-19 Biomimetic Therapeutics Inc. Compositions and methods for arthrodetic procedures
WO2014087037A1 (fr) * 2012-12-03 2014-06-12 Servicio Andaluz De Salud Utilisation du facteur de croissance dérivé de plaquettes ou d'un agoniste sélectif du récepteur at2 pour le traitement des calcifications vasculaires
US8870954B2 (en) 2008-09-09 2014-10-28 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries
US9161967B2 (en) 2006-06-30 2015-10-20 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
US9642891B2 (en) 2006-06-30 2017-05-09 Biomimetic Therapeutics, Llc Compositions and methods for treating rotator cuff injuries
US10071182B2 (en) 2014-10-14 2018-09-11 Samuel E. Lynch Methods for treating wounds
US10258566B2 (en) 2004-10-14 2019-04-16 Biomimetic Therapeutics, Llc Compositions and methods for treating bone
US11235030B2 (en) 2010-02-22 2022-02-01 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendinopathies

Citations (3)

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US4861757A (en) * 1986-11-14 1989-08-29 Institute Of Molecular Biology Wound healing and bone regeneration using PDGF and IGF-I
US5118667A (en) * 1991-05-03 1992-06-02 Celtrix Pharmaceuticals, Inc. Bone growth factors and inhibitors of bone resorption for promoting bone formation
US5158934A (en) * 1989-09-01 1992-10-27 Genentech, Inc. Method of inducing bone growth using TGF-β

Patent Citations (3)

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US4861757A (en) * 1986-11-14 1989-08-29 Institute Of Molecular Biology Wound healing and bone regeneration using PDGF and IGF-I
US5158934A (en) * 1989-09-01 1992-10-27 Genentech, Inc. Method of inducing bone growth using TGF-β
US5118667A (en) * 1991-05-03 1992-06-02 Celtrix Pharmaceuticals, Inc. Bone growth factors and inhibitors of bone resorption for promoting bone formation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF PERIODONTOLOGY, Volume 62, Number 11, issued November 1991, S.E. LYNCH et al., "Effects of the Platelet-Derived Growth Factor/Insulin-Like Growth Factor-I Combination on Bone Regeneration Around Titanium Dental Implants. Results of a Pilot Study in Beagle Dogs", pages 710-716. *
JOURNAL OF PERIODONTOLOGY, Volume 62, Number 7, issued July 1991, S.E. LYNCH et al., "The Effects of Short-Term Application of a Combination of Platelet-Derived and Insullin Like Growth Factors on Periodontal Wound Healing", pages 458-467. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6710025B1 (en) 1999-05-26 2004-03-23 The Brigham And Women's Hospital, Inc. Treatment of damaged tissue using agents that modulate the activity of alpha-smooth muscle actin
WO2000071148A3 (fr) * 1999-05-26 2001-09-27 Brigham & Womens Hospital Utilisations therapeutiques d'agents modulant l'activite de l'actine alpha de muscle lisse
WO2001032197A3 (fr) * 1999-11-02 2002-03-07 Lilly Co Eli Methodes d'utilisation de lp8, une proteine liee au pdgf, afin de traiter les troubles musculosquelettiques
US8257737B2 (en) * 2001-08-09 2012-09-04 Giuseppe Intini Tissue implants and methods for making and using same
US9545377B2 (en) 2004-10-14 2017-01-17 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US10258566B2 (en) 2004-10-14 2019-04-16 Biomimetic Therapeutics, Llc Compositions and methods for treating bone
US11571497B2 (en) 2004-10-14 2023-02-07 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US11364325B2 (en) 2004-10-14 2022-06-21 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US11318230B2 (en) 2004-10-14 2022-05-03 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
AU2005295919B2 (en) * 2004-10-14 2009-03-26 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods of use thereof
US7473678B2 (en) 2004-10-14 2009-01-06 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods of use thereof
US9161967B2 (en) 2006-06-30 2015-10-20 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
US9642891B2 (en) 2006-06-30 2017-05-09 Biomimetic Therapeutics, Llc Compositions and methods for treating rotator cuff injuries
US10456450B2 (en) 2006-06-30 2019-10-29 Biomimetic Therapeutics, Llc Compositions and methods for treating rotator cuff injuries
US11058801B2 (en) 2006-06-30 2021-07-13 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
US8399409B2 (en) 2006-11-03 2013-03-19 Biomimetic Therapeutics Inc. Compositions and methods for arthrodetic procedures
US11135341B2 (en) 2008-09-09 2021-10-05 Biomimetic Therapeutics, Llc Platelet-derived growth factor composition and methods for the treatment of tendon and ligament injuries
US8870954B2 (en) 2008-09-09 2014-10-28 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries
US11235030B2 (en) 2010-02-22 2022-02-01 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendinopathies
WO2014087037A1 (fr) * 2012-12-03 2014-06-12 Servicio Andaluz De Salud Utilisation du facteur de croissance dérivé de plaquettes ou d'un agoniste sélectif du récepteur at2 pour le traitement des calcifications vasculaires
US10071182B2 (en) 2014-10-14 2018-09-11 Samuel E. Lynch Methods for treating wounds

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