NZ243018A - Bone-growth composition including "bone morphogenic proteins" and vitamin d derivatives - Google Patents
Bone-growth composition including "bone morphogenic proteins" and vitamin d derivativesInfo
- Publication number
- NZ243018A NZ243018A NZ243018A NZ24301892A NZ243018A NZ 243018 A NZ243018 A NZ 243018A NZ 243018 A NZ243018 A NZ 243018A NZ 24301892 A NZ24301892 A NZ 24301892A NZ 243018 A NZ243018 A NZ 243018A
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- Prior art keywords
- vitamin
- bmp
- bone
- issued
- composition
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Classifications
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- 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
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- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
New Zealand Paient Spedficaiion for Paient Number £43018
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Priority Dalo(s):
Complete Specification Filed:
Class:
Publication Date:
P.O. Journal Nc:
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No.: Date:
NEW ZEALAND
PATENTS ACT, 1953
COMPLETE SPECIFICATION
THERAPEUTIC COMPOSITIONS FOR OSTEOINDUCTION
We, THE PROCTER & GAMBLE COMPANY, a corporation organized under the laws of the State of Ohio, United States of America, located at One Procter & Gamble Plaza, Cincinnati, Ohio 45202, United States of America hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
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THERAPEUTIC COMPOSITIONS FOR OSTEOINDUCTION
TECHNICAL FIELD
The present invention relates to the field of osteoinduction (bone growth). Specifically, the present invention relates to novel therapeutic formulations comprising the administration of bone morphogenetic proteins and a Vitamin D compound, resulting in synergistic bone growth.
BACKGROUND OF THE INVENTION
In healthy individuals bone growth generally proceeds normally and fractures heal without the need for pharmacologic intervention. Nonetheless, in certain instances bones may be weakened or may fail to heal properly. For example, healing may proceed slowly in the elderly and in patients undergoing treatment with corticosteroids, such as transplant patients and those being treated for chronic lung disease. Another example is osteoporosis. Osteoporosis is an abnormal loss of bony tissue often occurring in post-menopausal woman and elderly men. The disorder increases the risks of small fractures occurring in the bones, particularly the spine. At present, osteoporosis is treated mainly by supplements of calcium, vitamin D, estrogen, or calcitonin, a hormone which controls the body's use of calcium. Unfortunately, these treatments are merely preventative against the further loss of bone. There is a need in the art for treatments that go beyond the prevention of bone loss and promote bone formation and/or reverse bone loss.
(1989) "Bone Morphogenic Proteins and Vitamin D", Nutrition Reviews. Vol. 47, pp. 364-366 concludes that Vitamin D in the diet prevents the loss of the osteoinductive activity of bone matrix.
Turner, R. T., J. Farley, J. J. Vandersteenhoven, S. Epstein, N. H. Bell, and D. J. Baylink, (1988) "Demonstration of Reduced Mitogenic and Osteoinductive Activities in Demineralized Allogeneic Bone Matrix from Vitamin D-deficient Rats", The Journal of Clinical Investigation. Inc.. Vol. 82, pp. 212-217, discloses the
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implantation of demineralized bone matrix from Vitamin D-deficient rats into normal rats. The demineralized bone matrix from Vitamin D-deficient rats did not promote osteoinduction as effectively as demineralized bone matrix from normal rats.
Sampath, T. K., S. Weintraub, and A. H. Reddi, (1984) "Extracellular Matrix Proteins Involved in bone Induction are Vitamin D Dependent", Biochemical and Biophysical Research Communications. Vol. 124, pp. 829-835, discloses a study involving implantation of demineralized bone matrix from normal rats and demineralized bone matrix from rachitic rats wherein the rachitic bone matrix did not induce bone growth while the normal bone matrix did. The study concluded that these results demonstrate that Vitamin D is necessary to produce bone inductive proteins in the bone matrix of a living rat.
U.S. Patent No. 4,761,471, Urist, assigned to the Regents of the University of California, issued August 2, 1988, discloses a bone morphogenetic protein composition comprising BMP factor and BMP associated protein having a molecular weight of 34,000 daltons. Use of such factors and compositions to induce bone formation in mammals is also disclosed.
U.S. Patent No. 4,455,256, Urist, assigned to the Regents of the University of California, issued June 19, 1984, discloses a bone morphogenetic protein having a molecular weight in the range of 1,000 to 100,000 daltons.
Various other bone morphogenetic proteins/factors, osteoinductive factors, osteogenic factors and other proteins/factors related to bone growth are disclosed in the following publications: U.S. Patent 4,968,590, Kubersampath and Rueger, issued November 6, 1990; U.S. Patent 4,698,328, Neer, Potts and Slovik, issued October 6, 1987; U.S. Patent 4,877,864, Wang, Wozney and Rosen, issued October 31, 1989; U.S. Patent 4,861,757, Antoniades, Lynch and Williams, issued August 29, 1989; U.S. Patent 4,810,691, Seyedin, Thomas, Bentz, Ellingsworth and Armstrong, issued March 7, 1989; U.S. Patent 4,804,744, Sen, issued February 14, 1989; U.S. Patent 4,795,804, Urist, issued January 3, 1989; U.S. Patent 4,789,663, Wallace, Smestad, McPherson, Piez and Ross, issued December 6, 1988; U.S. Patent 4,789,732, Urist, issued December 6, 1988; U.S. Patent 4,774,322, Seyedin, Thomas, Bentz, Ellingsworth and Armstrong, issued September 27, 1988; U.S. Patent 4,698,328,
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Neer and Slovik, issued October 6, 1987; U.S. ^a£ent 4,627|j£2, Seydin and Thomas, issued December 9, 1986; U.S. P¥t^t'J44|^f989,
Urist, issued October 28, 1986; U.S. Patent 4,596,574, Urist,
issued June 24, 1986; U.S. Patent 4,563,489, Urist, issued January 7, 1986; U.S. Patent 4,563,350, Nathan, Seyedin and Bentz, issued January 7, 1986; U.S. Patent 4,526,909, Urist, issued July 2, 1985; U.S. Patent 4,434,894, Seyedin and Thomas, issued February 23, 1984; U.S. Patent 4,294,753, Urist, issued October 13, 1981; European Patent Application 349 048, Bab, Muhlrad, Gazit and Shteyer, published January 3, 1990; European Patent Application 309 241, Chu, Nathan and Seyedin, published March 29, 1989; European Patent Application 336 760, Bentz, Nathan, Rosen, Dasch and Seyedin, published October 11, 1989; European Patent Application 145 155, Sen, published July 10, 1985; World Patent Application 89/10934, Roos, Burns, Guy and McKnight, published November 16, 1989; World Patent Applications 89/09787 and 89/09788, Oppermann, Kubersampath, Rueger and Ozkaynak, published October 19, 1989; and World Patent Application 88/00205, Wang, Wozney and Rosen, published Janaury 14, 1988.
OBJECTS OF THE PRESENT INVENTION It is an object of the present invention to provide a method for generating new bone growth in a mammal.
It is a further object of the present invention to provide a pharmaceutical composition which can be used to generate new bone growth in a mammal.
SUMMARY OF THE INVENTION The present invention relates to a method of generating new bone growth in mammals comprising administration to a mammal a combination of a safe and effective amount of a Vitamin D compound, and a safe and effective amount of one or more BMPs or osteoinductive extract comprising one or more BMPs.
The present invention further relates to a composition for generating new bone growth in mammals comprising a safe and effective amount of a Vitamin D compound; a safe and effective amount of one or more BMPs or osteoinductive extract comprising one or more BMPs; and a pharmaceutically-acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION The present invention comprises the administration to a mammal of a combination of a safe and effective amount of a
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Vitamin D compound amd a safe and effective amount of one or more BMPs or an osteoinductive extract comprising one or more BMPs. It has been determined -hat treatment with a Vitamin D compound, BMP or osteoinductive extract alone increases bone growth. Surpris-5 ingly, it has been further determined that treatment with a
Vitamin D compound iin combination with osteoinductive extract or in combination with at least one BMP results in a level of new bone growth greater than that achieved through administration of the BMP, osteoinductive extract or Vitamin D compound alone. 10 Subjects in need or such treatment suffer from a variety of ailments which may ne treated via this procedure, including but not limited to, borne fractures (closed and open), non-union fractures, congenita" defects, as an adjunct in plastic surgery, in treating oncological resections, all diseases classified as 15 osteoporosis, rheunmetoid arthritis, osteoarthritis, septic arthritis, rickets, xtrganic incorporation of prosthetic joints and dental implants, per-iodcntal disease and defects, as well as osteopenic and osteomalacic conditions and disease.
As used herein, "safe and effective amount" means an amount 20 of compound or composition sufficient to significantly induce a positive modification! in the condition to be treated, but low enough to avoid serimus side effects (at a reasonable benefit/risk ratio), within the s;cope of sound medical judgment. The safe and effective amount of ~he compound or composition will vary with the 25 particular condition beir-g treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharma-ceutically-acceptabl'i carrier utilized, and like factors within 30 the knowledge and expertise of the attending physician.
As used herein, "fracture reduction" means the restoration of a bone fracture by surgical or manipulative means to its normal anatomical relation.
As used herein, "BMP' means bone morphogenetic protein. 35 As used herein, "q.s.* means quantity sufficient.
As used herein, all percentages are by weight unless otherwise specified.
As used herein "regional treatment" includes treating bone fractures (closed and open), treating non-union fractures,
243018
treating congenital defects, as an adjunct treatment to plastic surgery, treating oncological resections, organic incorporation of prosthetic joints, organic incorporation of dental implants, and treatment of periodontal disease and defects.
As used herein "systemic treatment" includes treating diseases classified as osteoporosis, rheumatoid arthritis, osteoarthritis, septic arthritis, rickets, and osteopenic conditions and diseases.
As used herein, all dose ranges for systemic treatment are recited as the dry weight of the actives per kg body weight of the mammal.
As used herein, all dose ranges for regional treatment are recited as the dry weight of the actives per cm2 surface area of mineralized tissue to be treated.
As used herein, "mineralized tissue" means bone and teeth.
Vitamin D Compounds
One component involved in the method of the invention is a Vitamin D compound. As used herein, "Vitamin D compound" includes Vitamin D, ergocalciferol (Vitamin D2), cholecalciferol (Vitamin 03) and their biologically active metabolites and precursors. Preferred Vitamin D compounds include, but are not limited to, Vitamin D2 (Sigma, St. Louis, MO), Vitamin D3 (Sigma, St. Louis, MO), 1-a-hydroxy Vitamin D3, 1-o-fluoro Vitamin D3, 3-deoxy-l,25-dihydroxy Vitamin 03, 25-hydroxy-5,6-trans Vitamin D3, 25-hydroxy Vitamin D2, 25-hydroxy Vitamin 03 (Hoffman, LaRoche), 1,25-dihydroxy Vitamin D2, 24,25-dihydroxy Vitamin D2, 24,25-dihydroxy Vitamin D3 (Hoffman LaRoche), and 1,25-dihydroxy Vitamin D3 (Duphar, Veenendaal, Holland). Preferably, the Vitamin D compound is selected from 25-hydroxy Vitamin D2, 25-hydroxy Vitamin D3, 1,25-dihydroxy Vitamin D2, 24,25-dihydroxy Vitamin D2, 24,25-dihydroxy Vitamin D3, and 1,25-dihydroxy Vitamin D3, more preferably 1,25-dihydroxy Vitamin D3. Additional Vitamin D compounds useful in the present invention are well known to those skilled in the art and include, but are not limited to, those disclosed by the following U.S. Patents, each of which is incorporated herein by reference: U.S. Patent 4,970,203, DeLuca and Kwiecinski, issued November 13, 1990; U.S. Patent 4,927,815, DeLuca, Kutner, Perlman and Schnoes, issued May 22, 1990; U.S. Patent 4,857,518, DeLuca,
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Ikekawa and Tanaka, issued August 15, 1989; U.S. Patent 4,851,401, DeLuca, Kutner, Perlman and Schnoes, issued July 25, 1989; U.S. Patent 4,851,400, DeLuca, Ikekawa and Tanaka, issued July 25, 1989; U.S. Patent 4,847,012, DeLuca, Kutner, Perlman, Phelps, Schnoes and Sicinski, issued July 11, 1989; U.S. Patent 4,816,417, Dame, DeLuca and Pierce, issued March 28, 1989; U.S. Patent 4,769,181, DeLuca, Schnoes, Sicinski and Tanaka, issued September 6, 1988; U.S. Patent 4,755,329, DeLuca, Lee and Schnoes, issued July 5, 1988; U.S. Patent 4,719,205, DeLuca, Schnoes, Sicinski and Tanaka, issued January 12, 1988; U.S. Patent 4,719,204, DeLuca, Schnoes, Sicinski and Tanaka, issued January 12, 1988; U.S. Patent 4,717,721, DeLuca, Ikekawa, Ostrem and Schnoes, issued January 5, 1988; U.S. Patent 4,689,180, DeLuca, Schnoes, Sicinski and Tanaka, issued August 25, 1987; U.S. Patent 4,619,920, DeLuca, Ikekawa, Kobayashi and Tanaka, issued October 28, 1986; U.S. Patent 4,594,192, DeLuca, Ikekawa, Kobayashi and Tanaka, issued June 10, 1986; U.S. Patent 4,588,716, DeLuca and Schnoes, issued May 13, 1986; U.S. Patent 4,588,528, DeLuca, Ikekawa and Tanaka, issued May 13, 1986; U.S. Patent 4,564,474, DeLuca, Ikekawa, Kobayashi and Tanaka, issued January 14, 1986; U.S. Patent 4,555,364, DeLuca, Lee, Phelps and Schnoes, issued November 26, 1985; U.S. Patent 4,554,106, DeLuca, Lee, Phelps and Schnoes, issued November 19, 1985; U.S. Patent 4,552,698, DeLuca, Ikekawa, Kobayashi and Tanaka, issued November 11, 1985; U.S. Patent 4,512,925, DeLuca, Lee and Schnoes, issued April 23, 1985; U.S. Patent 4,505,906, DeLuca, Schnoes, Sicinski and Tanaka, issued March 19, 1985; U.S. Patent 4,502,991, DeLuca, Ikekawa, Kobayashi and Tanaka, issued March 5, 1985; U.S. Patent 4,500,460, DeLuca, Ikekawa, Kobayashi and Tanaka, issued February 19, 1985; U.S. Patent 4,481,198, Chu, DeLuca, Kabakoff and Schnoes, issued November 6, 1984; U.S. Patent 4,461,766, DeLuca, Hart and Schnoes, issued July 24, 1984; U.S. Patent 4,448,726, DeLuca, Paaren, Schnoes and Smith, issued May 15, 1984; U.S. Patent 4,448,721, DeLuca, Morzycki and Schnoes, issued May 15, 1984; U.S. Patent 4,428,946, DeLuca, Jorgensen and Schnoes, issued January 31, 1984; U.S. Patent 4,411,833, DeLuca, Ikekawa, Kobayashi and Tanaka, issued October 25, 1983; U.S. Patent 4,367,177, DeLuca, Schnoes and Wichman, issued January 4, 1983; U.S. Patent 4,358,406, DeLuca, Ikekawa, Kobayashi and Tanaka, issued November 9, 1982; U.S. Patent 4,338,312, DeLuca,
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Jorgensen and Schnoes, issued July 6, 1982; U.S. Patent 4,338,250, DeLuca, Hamer, Paaren and Schnoes, issued July 6, 1982; U.S. Patent 4,336,193, DeLuca, Fivizzani, Paaren, Schnoes and Wichmann, issued June 22, 1982; U.S. Patent 4,313,942, DeLuca, Frank, Paaren and Schnoes, issued February 2, 1982; U.S. Patent 4,307,231, DeLuca, Paaren, Schnoes, Tanaka and Wichmann, issued December 22, 1981; U.S. Patent 4,307,025, DeLuca, Ikekawa, Morisaki, Oshida, Schnoes and Tanaka, issued December 22, 1981; U.S. Patent 4,305,880, DeLuca, Ikekawa, Kobayashi and Tanaka, issued December 15, 1981; U.S. Patent 4,297,289, DeLuca, Fivizzani, Paaren and Schnoes, issued October 27, 1981; U.S. Patent 4,292,250, DeLuca, Levan and Schnoes, issued September 29, 1981; U.S. Patent 4,265,822, DeLuca, Hamer, Paaren and Schnoes, issued May 5, 1981; U.S. Patent 4,264,513, DeLuca, Fivizzani, Napoli and Schnoes, issued April 28, 1981; U.S. Patent 4,263,214, DeLuca, Napoli, Onisko and Schnoes, issued April 21, 1981; U.S. Patent 4,260,804, DeLuca, Esvelt and Schnoes, issued April 7, 1981; U.S. Patent 4,260,549, DeLuca, Hamer, Paaren and Schnoes, issued April 7, 1981; U.S. Patent 4,254,045, DeLuca, Ikekawa, Morisaki, Oshida and Tanaka, issued March 3, 1981; U.S. Reissue Patent 30,538, DeLuca, Lam and Schnoes, issued March 3, 1981; U.S. Patent 4,248,791, DeLuca, Ikekawa, Kobayashi and Tanaka, issued February 3, 1981; U.S. Patent 4,234,495, DeLuca, Hamer, Paaren and Schnoes, issued November 18, 1980; U.S. Patent 4,230,627, DeLuca, Napoli, Onisko and Schnoes, issued October 28, 1980; U.S. Patent 4,229,359, Alper, DeLuca, Schnoes and Tanaka, issued October 21, 1980; U.S. Patent 4,229,358, DeLuca, Napoli, Onisko and Schnoes, issued October 21, 1980; U.S. Patent 4,229,357, DeLuca, Napoli, Onisko and Schnoes, issued October 21, 1980; U.S. Patent 4,226,788, DeLuca, Ikekawa, Kobayashi, Schnoes and Tanaka, issued October 7, 1980; U.S. Patent 4,226,787, DeLuca, Napoli, Onisko and Schnoes, issued October 7, 1980; U.S. Patent 4,224,231, Alper, DeLuca, Schnoes and Tanaka, issued September 23, 1980; U.S. Patent 4,224,230, DeLuca, Napoli, Onisko and Schnoes, issued September 23, 1980; U.S. Patent 4,223,131, DeLuca, Schnoes and Wichman, issued September 16, 1980; U.S. Patent 4,217,288, DeLuca, Onisko and Schnoes, issued August 12, 1980; U.S. Patent 4,209,634, DeLuca, Esvelt and Schnoes, issued June 24, 1980; U.S. Patent 4,202,829, DeLuca, Hamer, Paaren and Schnoes, issued May 13, 1980;
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U.S. Patent 4,201,881, DeLuca, Ikekawa, Kobayashi, Schnoes and Tanaka, issued May 6, 1980; U.S. Patent 4,196,133, DeLuca, Ikekawa, Kobayashi, Schnoes and Tanaka, issued April 1, 1980; U.S. Patent 4,195,027, DeLuca, Hamer, Paaren and Schnoes, issued March 25, 1980; U.S. Patent 4,188,345, DeLuca, Napoli, Oniski and Schnoes, issued February 12, 1980; and U.S. Patent 3,906,014, DeLuca, Lam and Schnoes, issued September 16, 1975. Additional Vitamin D compounds useful in the present invention and disclosed by these references include, but are not limited to, hydroxylated
24-homo-vitamin D; cyclopentano-vitamin D; hydroxylated 26-homo vitamin D; 1 a-hydroxyvitamin D; 1-hydroxyvitamin D; 1 a-hydroxy-vitamin D2; 1 a,25-dihydroxy-22Z-dehydroxyvitamin D; 26,26,26,-27,27-pentafluoro-l a-hydroxy-27-methoxyvitamin D3; 2 a-fluoro-vitamin D3; 1,24-dihydroxy-delta 22-vitamin D3; 23,23-difluoro-
-hydroxy-vitamin D3; l-hydroxy-3,5-cyclovitamin D; 23,23-di-fluoro-1 cr,25-dihydroxy-vitamin D3; 1,23-dihydroxyvitamin D; hydroxyvitamin D2; 23,23-difluoro-l a,25-dihydroxy-vitamin D3; 23,23-difluoro-25-hydroxy-vitamin D3; 26,26,26,27,27,27-hexa-fluoro-1 a, 25-dihydroxycholesterol; 23,25-dihydroxyvitamin D3; 26,26,26,27,27,27-hexafluoro-l a,25-dihydroxycholecalciferol; 1 or,25-dihydroxy-2 0-fluorovitamin D3; 24-fluoro-25-hydroxycholecal-ciferol; 5,6-trans-vitamin D; 1 a-hydroxy-25-keto-27-nor-chole-calciferol; fluorovitamin D; 1 a-hydroxy-2 ^-fluorocholecalciferol ; 3-deoxy-l o-hydroxycholecalciferol; 25-hydroxy-26,26,26,-27,27,27-hexafluorocholecaliferol; a-hydroxy-3,5-cyclovitamin D; 25-hydroxycholecalciferol; 24,24-difluoro-l a, 25-dihydroxychole-calciferol; 25-hydroxycholecalciferol; 25-hydroxycholecalciferol-
26.23-1actone; 24,24-di f1uoro-la,25-di hydroxycholecalci ferol;
24.24-difluoro-25-hydroxycholecalciferol; 3,5-cyclovitamin D; and 3-deoxy-a-hydroxycholecalciferol. Additional Vitamin D compounds useful in the present invention further include those disclosed in The Handbook of Vitamins. L. J. Machlin, Ed., Mercel Dekker, Inc. (1984), incorporated herein by reference. Vitamin D compounds useful in the present invention disclosed by this reference, include, bur are not limited to, 1,25-dihydroxy Vitamin D, 3-deoxy-l,25-dihydroxy Vitamin D, 27-nor-25-hydroxy Vitamin D3, 26,27-bis-nor-25-hydroxy Vitamin D3 24-nor-25-hydroxy Vitamin D3, 25-hydroxy Vitamin D, 1,25-dihydroxy Vitamin D, lcr-hydroxy Vitamin D3 and 25-fluoro-lcr-hydroxy Vitamin D3.
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A safe and effective amount of a Vitamin D compound is dosed in combination with at least one BMP or in combination with an osteoinductive extract comprising at least one BMP.
A preferred dose range for administration of the Vitamin D compound for systemic treatment is from about 1 ng to about 1 mg, preferably from about 10 ng to about 500 /xg, more preferably from about 20 ng to about 10 n9-
For purposes of regional treatment, the dose range of the Vitamin D compound is preferably from about 1 ng to about 1 mg, preferably from about 10 ng to about 500 ng, more preferably from about 10 ng to about 50 ng, most preferably from about 20 ng to about 30 ng.
Preferably, doses are administered over a 1 day to 6 month period, more preferably from about 1 week to about 1 month. Preferably doses are administered from about once per month to about 5 times per day, more preferably from about once per week to about once per day.
Bone Morphogenetic Proteins
In one embodiment of the present invention, a Vitamin D compound is administered in combination with one or more BMPs to generate new bone growth in a mammal. These BMPs are preferably selected from the group consisting of BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7.
A safe and effective amount of a BMP, preferably selected from the group consisting of BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7, is dosed in combination with a Vitamin D compound.
A preferred dose range for administration of the BMP for systemic treatment is from about 1 pg to about 100 pg, preferably from about 1 ng to about 10 M9> more preferably from about 10 ng to about 2.5 fig.
For purposes of regional treatment, a preferred dose range for the BMP is from about 1 pg to about 100 /ig, more preferably from about 1.5 /ig to about 90 ng, preferably from about 1.8 /ig to about 75 ng, more preferably from about 2.0 ng to about 50 /ig, more preferably still from about 2.2 /ig to about 25 /ig, more preferably from about 2.3 ng to about 10 /ig, most preferably from about 2.5 ng to about 5 /ig. Preferably the dose range is at least about 2.5 ng-
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Preferably, doses are administered over a 1 day to 6 month period, more preferably from about 1 week to about 1 month. Preferably doses are administered from about once per month to about 5 times per day, more preferably from about once per week to about once per day.
As used herein, "BMP-1" means a peptide encoded by a DNA sequence comprising SEQ ID N0:1.
As used herein, "BMP-2" means a peptide encoded by a DNA sequence comprising SEQ ID NO:2.
As used herein, "BMP-3" means a peptide encoded by a DNA sequence comprising SEQ ID N0:3.
As used herein, "BMP-4" means a peptide encoded by a DNA sequence comprising SEQ ID N0:4.
As used herein, "BMP-5" means a peptide encoded by a DNA sequence comprising SEQ ID N0:5.
As used herein, "BMP-6" means a peptide encoded by a DNA sequence comprising SEQ ID NO: 6.
As used herein, "BMP-7" means a peptide encoded by a DNA sequence comprising SEQ ID NO: 7.
As used herein, "A", "T", "G", and "C" refer to the nucleotides containing adenine, thymine, guanine and cytosine respectively.
Osteoinductive Extract
Another component of the invention is an osteoinductive extract. As used herein, "osteoinductive extract" means a chemical extract of bone, comprising one or more various bone morphogenetic proteins, including, but not limited to, BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7, wherein each BMP has a molecular weight of from about 28,000 to about 40,000 daltons.
The 28,000 to 40,000 dalton molecular weight range is in reference to the BMP's dimer weight. Preferably, the molecular weight of the dimer is from about 30,000 to about 34,000 daltons.
The BMP dimer comprises two monomers, each having a molecular weight of from about 14,000 to about 20,000 daltons, preferably from about 15,000 to about 17,000 daltons.
A preferred method of obtaining the osteoinductive extract is as follows:
Snip the skin at the ankles of a 7-8 week old Long-Evans rat (Charles River laboratories, Wilmington, MA). Remove both tibiae
2L450 1g and place in cold water. Rinse the bone with distilled water to remove non-osseous tissue (tissue other than bone). Allow the bone to air dry. Grind the bones by placing in an Osterizer (Oster Commercial, Milwaukee, WI) blender with water and ice. With the blender set at "liquefy" speed, continue to add bone. Allow the blended material to settle for a few minutes. Decant the liquid layer. Place the solid layer on a stirring plate and add distilled water to wash. Continue washing until the distilled water washes clear. Once the distilled water is clear, add ice and stir. Add 1 ml of ImM of phenylmethylsulfonyl fluoride (PMSF). Wash for 1 hour adding ice frequently. Repeat with a second water wash. Place the sample in an ice water bath on a stirring plate. Defat with absolute ethanol, then defat twice with ethyl ether. Spread bone material onto glass petri dishes. Allow the bone chips to air dry overnight.
Weigh the bone chips following the overnight drying. Using a sieve (U.S.A. Standard Sieve Series, Newark Wire Cloth Co., Newark, N.J.; sieve #40 retains particles greater than 425 fun and sieve #170 retains particles greater than 90 /wn), isolate the bone particles in the 90-425um range. Grind any particles greater than 425/im in a MicroMill (Scienceware Bel-Art Products, Pequannock, NJ) for 1 minute adding dry ice to the bone particles to keep the material cold. Repeat the sieving and MicroMill grinding steps of the greater than 425/un particles until the amount of total recovery is greater than 2/3 of the initial weight of the bone. Store the particles at 4°C until the next step. Weigh the particles isolated thus far. For each gram of particles, add 25 ml of 0.6N HC1. Stir vigorously at 4*C for 2 hours. After 2 hours, stop stirring and allow the particles to settle. Decant the HC1. Add fresh 0.6N HC1 and stir again for 2 hours. Decant the HC1 and add fresh 0.6N HC1 a third time and stir for two hours. Decant the HC1 and rinse with distilled water. Using litmus paper, check the pH of the water for the presence of HC1. Continue rinsing with distilled water until the pH is between about 5 and 5.5. Rinse the bone particles with ethanol three times. Swirl, allow to settle, and remove the supernatant. Rinse the bone particles with ethyl ether three times as above. Dry overnight in glass plates. The dried bone particles are referred to as "acid demineralized bone particles".
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The acid demineralized bone particles are deproteinized as follows: Weigh the material following the overnight drying. For each gram of material, add a solution of 30 ml 4M guanidine-HCl,
lOmM Tris and l.OmM PMSF pH 6.4 to the bone material in a beaker.
Extract for 16 hours at 4* with vigorous stirring. Following the 16 hour extraction, cease stirring and allow the material to settle. Pour off the guanidine solution and save. Extract the material a second time for 6-7 hours using fresh guanidine-HCl solution. Following the extraction, pour off the solution and combine with the previously saved solution. The bone particles are now demineralized and deproteinized.
Dialyze the saved guanidine-HCl solution against distilled HjO at 4°C using 50 mm dialysis tubing (3500 molecular weight cutoff). Following dialysis, lyopholize the material and resolu-bilize the lyophilized material in 4M Urea-0.05M Tris-O.IM NaCl, pH 7.4. Mix the solubilized material in a conical centrifuge tube with Heparin-Agarose and mix overnight on a rotator at 4°C. Pour the Heparin-Agarose slurry into a column. Wash with 1 column volume 4M urea, 0.05M Tris, 0.1M NaCl, pH 7.4 buffer. Collect the fraction. Wash with 3 column volumes of 4M urea, 0.05M Tris, 0.2M NaCl, pH 7.4 buffer. Step off the material with 3 column volumes of 4M urea, 0.05M Tris, 0.75M NaCl, pH 7.4. Concentrate this sample in a 50 ml Amicon concentrator (Amicon Corp., Danvers, MA)
with filter (10,000 molecular weight cut off) to about 4-5ml.
Assay for protein concentration using BCA (bicinchoninic acid)
Protein Assay Reagent (Pierce, Rockford, IL) and dialyze (3500 molecular weight cutoff dialysis tubing) in 4M guanidine-0.01 M Tris pH 7.4. Load material on Sephacryl S-200 column and collect fractions. The fractions containing the major protein peak are dialyzed against 1M acetic acid and assayed for activity.
Active fractions from the gel filtration are combined and dialyzed against three changes of 6M urea, 25mH Na acetate, pH 4.6. The dialysate is loaded onto a column of carboxymethyl-sepharose (CM-Sepharose) equilibrated with the same buffer. The column is washed with 6M urea, 25mM Na acetate, pH 4.6 and activity eluted using a 0 - 0.5M NaCl gradient. Fractions are analyzed for protein concentration and sodium dodecyl sulfate gel electrophoresis. The activity located in the seven fractions before and after the beginning of the major protein peak are
24 3 0 | 3
pooled for further purification.
The pooled CM-Sepharose fractions are dialyzed three times for 24 hours each against IX acetic acid. The dialysate is lyophilized to dryness and the protein pellet dissolved into 30 ml of 6M urea, 0.5M NaCl, 25mM Na phosphate, pH 7.4. The sample is applied on a column of chelating Sepharose charged with zinc and equilibrated with the above buffer. The column is washed with the above buffer and then eluted with a gradient from 6M urea, 0.5M NaCl, 25mM Na phosphate, pH 7.4 to 6M urea, 0.5M NaCl, 25mM Na acetate, pH 4.6. Aliquots of each fraction are labeled with 1251 and analyzed by SDS gel electrophoresis. Aliquots (100 /il) of each fraction are combined with 400 pi of elution buffer, dialyzed against 1% acetic acid and assayed for activity. Highly purified molecular weight range (Mr) 25-40 kD peptides are assayed in the bone induction assay.
A safe and effective amount of osteoinductive extract is dosed in combination with a Vitamin D compound. For purposes of systemic treatment, the osteoinductive extract dosed preferably comprises at least one BMP in an amount from about 1 pg to about 100 /ig, preferably from about 1 ng to about 10 /ig, more preferably from about 10 ng to about 2.5 jug.
For purposes of regional treatment, the osteoinductive extract dosed preferably comprises at least one BMP in an amount from about 1 pg to about 100 /ig, more preferably from about 1.5 /ig to about 90 /ig, preferably from about 1.8 /ig to about 75 /ig, more preferably from about 2.0 /ig to about 50 /ig, more preferably still from about 2.2 fig to about 25 fig, more preferably from about 2.3 fig to about 10 fig, most preferably from about 2.5 fig to about 5 fig. Preferably the dose range is at least about 2.5 fig.
Preferably, doses are administered over a 1 day to 6 month period, more preferably from about 1 week to about 1 month. Preferably doses are administered from about once per month to about 5 times per day, more preferably from about once per week to about once per day.
Pharmaceutical!v Acceptable Carrier
The Vitamin D compound, osteoinductive extract, or BMP may be administered via a pharmaceutical^ acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one
2430 I S
or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the pharmaceutical compositions are capable of being commingled with the compound(s) of the subject invention, and with each other in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary usage situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to human or lower animal being treated.
Some examples of substances which can serve as pharmaceuti-cally-acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such a peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; sugar; alginic acid; pyrogen-free water; isotonic saline; phosphate buffer solutions; cocoa butter (suppository base); emulsifiers, such as the Tweens®; as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabilizers, antioxidants, and preservatives, can also be present. Other compatible pharmaceutical additives and actives (e.g., NSAI drugs; pain killers; muscle relaxants) may be included in the pharmaceutically-acceptable carrier for use in the compositions of the present invention. For example, art-known local anesthetics may be included in the pharmaceutically-acceptable carrier (e.g., benzyl alcohol; Novocaine®; lidocaine).
Additional examples of carriers include collagen, demineralized bone particles, ceramic and metallic implant materials, collagen membrane and bone grafts (isogenic or allogenic).
The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the compounds of the present invention is
2.430 1 8
determined by the way the compound is to be administered. The preferred modes of administering the compounds of the present invention are by injection, oral administration, topical-oral administration, and nasopharyngeal administration or a combination of modes (i.e., osteoinductive extract via injection and Vitamin D compound via oral administration). If the compound is to be injected, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline. Suitable pharmaceutically-acceptable carriers for oral administration include those suited for tablets, and capsules. Suitable pharmaceutically-acceptable carriers for topical-oral administration include those suited for pastes, gels, and liquids. Suitable pharmaceutically-acceptable carriers for nasopharyngeal administration include those suited for drops, sprays, mists and powders.
A separate pharmaceutically-acceptable carrier may be used in conjunction with each active component of the present invention or a single pharmaceutically-acceptable carrier may be employed in conjunction with a mixture of the active components of the present invention. In either case, the pharmaceutically-acceptable carrier is used at a concentration sufficient to provide a practical size to dosage relationship. The pharmaceutically-acceptable carriers, in total, may comprise from about 0.1% to about 99.99999% by weight of the pharmaceutical compositions of the present invention, preferably from about 50% to about 99.999%, and most preferably from about 75% to about 99.9%.
Specific oral and injectable carriers useful in this invention are described in the following U.S. Patents, all incorporated by reference herein: U.S. Patent No. 4,401,663, Buckwalter, et al, issued August 30, 1983; U.S. Patent No. 4,424,205, LaHann, et al, issued January 31, 1984; U.S. Patent No. 4,443,473, Buckwalter, et al, issued April 12, 1984; U.S. Patent No. 4,493,848, LaHann, et al, issued January 15, 1984. Representative pharmaceutical compositions of the present invention are provided in the Examples hereinafter.
Pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration, topical-oral administration, nasopharyngeal administration and injection are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and/or shelf stability,
2430 | Z
which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art. Pharmaceutically-acceptable carriers useful in the compositions of the present invention are described more fully hereinafter.
A. Oral Dose Forms:
Preferably, the vitanrn D compound is administered via an oral dose form. Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules, bulk powders and microcapsules of the drug. These oral forms comprise a safe and effective amount, usually at least about .5%, and preferably from about 1% to about 10% of t.ne compound of the present invention. Tablets can be compressed, enteric-coated, sugar-coated or film-coated containing suitable rinders, lubricants, surfactants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents, and flavoring agents. Preferred carriers for oral administration include gelatin and propylene glycol. Specific examples of pharmaceutically-accept-able carriers and excipient^ that may be used in formulating oral dosage forms containing compounds of the present invention are described in U.S. Patent 2,903,297, Robert, issued September 2, 1975, incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics. Vol. 7. (Banker and Rhodes, editors), 359-427 (1979), incorporated herein by reference. Techniques and compositions for making tablets (compressed, formulas and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980), incorporated herein by reference.
B. Topical-oral Dose Forms
"Topical-oral carrier", as used herein, denotes a carrier for the component of interest which results in a composition which is administered topically to the oral cavity, held therein for a period of time, and then is largely expectorated rather than being
3L43&1S
swallowed. Such compositions include toothpastes, tooth gels,
tooth powders, mouthwashes, mouthsprays, prophylaxis pastes,
dental treatment solutions, biogels or other sustained release products, and the like.
Components of the topical-oral carrier are suitable for administration to the oral cavity of a human or lower animal and are compatible with one another and the other components, especially the Vitamin D compound and osteoinductive extract or BMP,
used in an oral composition of the subject invention. Preferred topical-oral carriers thus provide the desired characteristics for toothpastes, tooth gels, tooth powders, mouthwashes, mouthsprays, prophylaxis pastes, dental treatment solutions, and the like. The topical-oral carriers of the subject invention comprise components typically used in such compositions which are well known to a skilled practitioner. Such components include, but are not limited to anticaries agents, antiplaque agents, anticalculus agents, dental abrasives, surfactants, flavoring agents, sweetening agents, binders, humectants, thickening agents, buffering agents, preservatives, coloring agents and pigments,
ethanol, and water.
Preferred compositions of the subject invention are in the form of toothpastes. Components of such toothpastes generally include a dental abrasive (from about 10% to about 50%), a surfactant (from about 0.5% to about 10%), a thickening agent (from about 0.1% to about 5%) a humectant (from about 10% to about 55%), a flavoring agent (from about 0.04% to about 2%), a sweetening agent (from about 0.1% to about 3%), a coloring agent (from about 0.01% to about 0.5%) and water (from about 2% to about 45%). Such toothpastes may also include one or more of an anticaries agent (from about 0.05% to about 0.3% as fluoride ion), an anticalculus agent (from about 0.1% to about 13%), and an antiplaque agent (from about 0.1% to about 5%).
Other preferred compositions of the subject invention are mouthwashes and mouthsprays. Components of such mouthwashes and mouthsprays include water (from about 45% to about 95%), ethanol (from about 0% to about 25%), a humectant (from about 0% to about 50%), a surfactant agent (from about 0.01% to about 7%), a flavoring agent (from about 0.04% to about 2%), a sweetening agent (from about 0.1% to about 3%), and a coloring agent (from about
243 5 1
0.001% to about 0.5%). Such mouthwashes and mouthsprays may also include one or more of an anticaries agent (from about 0.05% to about 0.3% as fluoride ion), an anticalculus agent (from about 0.01% to about 3%), and an antiplaque agent (from about 0.1% to about 5%).
Other preferred compositions of the subject invention are dental solutions. Components of such dental solutions generally include water (from about 90% to about 99%), preservative (from about 0.01% to about 0.5%), thickening agent (from about 0% to about 5%), flavoring agent (from about 0.04% to about 2%), sweetening agent (from about 0.1% to about 3%), and surfactant (from 0% to about 5%).
"Topical-oral carrier" as used herein, also denotes fibers, strips or tubes which can be impregnated with the active components of the present invention and inserted or implanted into a periodontal pocket. Such compositions of the subject invention can readily be achieved by one of ordinary skill in the art using the teachings disclosed hereinbefore, the following references, incorporated herein by reference, and related well-known technologies: U.S. Patent No. 4,666,897 issued to Golub, McNamara & Ramamurthy on May 19, 1987; European Patent Application No. 244,118 Al in the name of Baker, published on November 4, 1987; European Patent Application No. 286,802 A2 in the name of Kametaka, Miyazaki, Hayashi, Handa & Kameda, published October 19, 1988; Addy, M., L. Rawle, R. Handley, H. Newman & J. Coventry, "The development and in vitro evaluation of acrylic strips and dialysis tubing for local drug delivery", Journal of Periodontology, Vol. 53 (1982), pp. 693-698; Goodson, J.M., A.D. Haffajee & S.S. Socransky, "Periodontal therapy by local delivery of tetracycline, Journal of Clinical Periodontology. Vol. 6 (1979), pp. 83-92; Goodson, J., D. Holborow, R. Dunn, P. Hogan & S. Dunham, "Monolithic tetracycline containing fibers for controlled delivery to periodontal pockets", Journal of Periodontology. Vol. 54 (1983), pp. 575-579; Dunn, R., J. Gibson, B. Perkins, J. Goodson & L. Laufe, "Fibrous delivery systems for antimicrobial agents", Polymer Science and Technology. Vol. 32 (1985), pp. 47-59; Dunn, R., J. Gibson, B. Perkins, J. Goodson & L. Laufe, "Fibrous delivery systems for antimicrobial agents", Polvmer Material Science Engineering. Vol. 51 (1984), pp. 28-31; Olanoff,
2.430 U
L. & J. Anderson, "Controlled release of tetracycline - III: A physiological pharmacokinetic model of the pregnant rat", Journal of Pharmacokinetics and Biopharmaceutics. Vol. 8 (1980), pp. 599-620; Elkayam, R., M. Friedman, A. Stabholz, A. Soskolne, M.
Sela & L. Golub, "Sustained release device containing minocycline for local treatment of periodontal disease", Journal of Controlled Release. Vol. 7 (1988), pp. 231-236; and Goodson, J., "Multi-center evaluation of tetracycline fiber therapy. I. Experimental Design", Journal of Dental Research. Vol. 68 (1989), p. 197; and references cited therein.
C. Injectable Dose Forms:
The active components of the present invention are also useful when injected. The dosage of the active components of the present invention which is both safe and effective to provide bone growth activity will vary with the particular condition being treated, the severity of the condition, the duration of treatment, the specific mixture of compounds employed and its usage concentration, and like factors within the specific knowledge and expertise of the attending physician and commensurate with a reasonable benefit/risk ratio associated with the use of any drug compound. In addition, lower dosages will be utilized when only local or minor bone growth is desired, whereas higher dosages will be utilized when general or major bone growth is desired.
Methods and materials for manufacturing injectables can be found in Remington's Pharmaceutical Sciences. 17ed., 1985, Chapter 85, p. 1518, the disclosures of which are incorporated herein by reference in their entirety. Preferably, the injectable composition is an aqueous solution.
The aqueous solutions preferably consist of water (preferably from about 80% to about 99.999%), a suitable solubilizer, various types of acids, and an antimicrobial agent. Several solubilizers are known. Examples of such solubilizers are as follows: urea compounds (e.g., urea; urethan); surfactants (e.g., Tweens; Spans;
sodium deoxycholate and Pluronics); cellulosic agents (e.g., carboxymethylcellulose); carbohydrates (e.g., sorbitol; mannitol); B vitamins (e.g., nicotinamide); xanthine derivatives; and alcohols (e.g., benzyl alcohol). Examples of acids to be used include the following: glucuronic; galacturonic; fumaric; gentisic;
acetic; citric and lactobionic. Types of antimicrobial agents
2.430 1 8
that can be used are the following: phenyl mercuric nitrate; thimerosal; benzethonium chloride; benzalkonium chloride; phenol; cresol; and chlorobutanol. An art-known local anesthetic (e.g., benzyl alcohol; Novocaine*; lidocaine) may also be included.
Preferably, the osteoinductive extract and the BMP's are administered via an injectable dose form.
The following examples further describe and demonstrate the preferred embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration, and are not to be construed as limitations of the present invention since many variations thereof are possible without departing from its spirit and scope.
EXAMPLE I
An injectable composition comprising the osteoinductive extract and an oral composition comprising 1,25-dihydroxy Vitamin D3 for bone fracture repair is prepared by combining the following components utilizing conventional mixing techniques.
BMP composition
Percent by Weight Component of Composition
BMP-1 0.04
NaCl 0.90
Sterile water o.s.
100.00
1.25-dihvdroxy Vitamin D* composition
Component 1,25-dihydroxy Vitamin D3 Corn starch Lactose Talc
Stearic acid .
100.00
0.1 cc of the BMP composition is injected into the fracture site at the time of fracture reduction and once daily thereafter. 100 M9 of the 1,25-dihydroxy Vitamin D3 composition is orally administered 24 hours before fracture reduction and once daily thereafter. The BMP and 1,25-dihydroxy Vitamin D3 are adminis-
Percent by Weight of Composition 0.01 18.49 63.00 18.00 0.50
2430 IS
tered until desired repair is achieved, perferably over a seven day period.
EXAMPLE II
An injectable composition for bone fracture repair is 5 prepared by combining the following components utilizing conven tional mixing techniques.
Percent by Weight
Component of Composition
BMP-2 0.04
25-hydroxy Vitamin 02 0.01
NaCl 0.09
Sterile water for injection a.s.
100.00
0.1 cc of the composition is injected into the fracture site 15 at the time of fracture reduction and once daily thereafter until desired repair is achieved.
EXAMPLE III
A composition for inducing bone growth following reconstructive surgery is prepared by combining the following components 20 utilizing conventional mixing techniques.
Percent by Weight
Component of Composition
BMP-3 0.04
1,25-dihydroxy Vitamin D2 0.01
NaCl 0.90
Sterile water o.s.
100.00
0.1 cc of the composition per cm2 of surface area of surgically reconstructed bone is deposited directly onto the bone 30 surface.
EXAMPLE IV
A composition for accelerating the healing and providing a stronger bond between natural bone and an artificial prosthesis is prepared by combining the following components utilizing conven-35 tional mixing techniques.
Percent by Weight
Component of Composition
BMP-1 0.04
BMP-2 0.04
2.430 1 8
BMP-4 0.04
24,25-dihydroxy Vitamin D3 0.01
NaCl 0.90
Sterile water q.s.
100.00
0.1 cc of the composition per cm2 surface area of natural bone proximate to the prosthesis is deposited directly onto the natural bone.
EXAMPLE V
A topical oral carrier composition for periodontal therapy is prepared by combining the following components utilizing conventional mixing techniques.
Percent by Weight
Component of Composition
BMP-2 0.04
NaCl 0.90
Sterile water q.s.
100.00
After the patient is prepared using conventional periodontal surgical therapy 0.1 cc of the composition per exposed tooth is deposited into the surgery site. Soft tissue flaps are then sutured to close the surgical site. This treatment is useful for restoring alveolar and supporting bone in the periodontium lost by disease.
EXAMPLE VI
An injectable composition comprising the BMPs 2, 3, 4 and 5 and an oral composition comprising 1,25-dihydroxy Vitamin D3 for treatment of osteoporosis is prepared by combining the following components utilizing conventional mixing techniques.
osteoinductive extract composition
Percent by Weight
Component of Composition
BMP-2 0.001
BMP-3 0.001
BMP-4 0.001
BMP-5 0.001
NaCl 0.900
Sterile water Q.s.
100.000
2.4 3 0 1 £
1.25-dihvdroxv Vitamin D» composition
Percent by Weight
Component of Composition
1,25-dihydroxy Vitamin D3 0.01
Corn starch 18.49
Lactose 63.00
Talc 18.00
Stearic acid 0.50
100.00
1 cc of the BMP composition is injected intravenously once per day. 50 mg of the 1,25-di hydroxy Vitamin D3 composition is orally administered within one hour of the osteoinductive extract injection and once daily thereafter. The osteoinductive extract and 1,25-dihydroxy Vitamin D3 are administered over a 7-day 15 period.
EXAMPLE VII
A composition for inducing bone growth of a non-union fracture is prepared by combining the following components utilizing conventional mixing techniques. As used herein, 20 "non-union fracture" means a fracture that has failed to heal normally.
Percent by Weight
Component of Composition
BMP-4 0.004
1,25-dihydroxy vitamin D3 0.01
Acid demineralized bone particles 90.000
NaCl 0.900
Sterile water for injection Q.s.
100.000
At the time of fracture reduction, a sufficient quantity of the above composition is deposited directly into the non-union site thereby filling in any bone deficit.
.35
2.430 18
- 24 -SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: STONE, ROGER L.
(ii) TITLE OF INVENTION: THERAPEUTIC FORMULAS FOR OSTEOINDUCTION (iii) NUMBER OF SEQUENCES: 7
(iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: The Procter & Gamble Company
(B) STREET: 11810 East Miami River Road
(C) CITY: Cincinnati
(D) STATE: Ohio
(E) COUNTRY: U.S.A.
(F) ZIP: 45239-8707
(v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk
(B) COMPUTER: IBM PC compatible
(C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentin Release #1.0, Version #1.25
(vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(C) CLASSIFICATION:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Corstanje, Brahm J.
(B) REGISTRATION NUMBER: 34,804
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 513-245-2858
(B) TELEFAX: 513-741-3012
2430 1 ?
(2) INFORMATION FOR SEQ ID N0:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2487 base pairs 5 (B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:1:
GCCGCTTCCC TCGCCGCCGC CCCGCCAGCA TGCCCGGCGT GGCCCGCCTG CCGCTGCTGC 60
TCGGGCTGCT GCTGCTCCCG CGTCCCGGCC GGCCGCTGGA CTTGGCCGAC TACACCTATG 120
ACCTGGCGGA GGAGGACGAC TCGGAGCCCC TCAACTACAA AGACCCCTGC AAGGCGGCTG 180
CCTTTCTTGG GGACATTGCC CTGGACGAAG AGGACCTGAG GGCCTTCCAG GTACAGCAGG 240
CTGTGGATCT CAGACGGCAC ACAGCTCGTA AGTCCTCCAT CAAAGCTGCA GTTCCAGGAA 300
ACACTTCTAC CCCCAGCTGC CAGAGCACCA ACGGGCAGCC TCAGAGGGGA GCCTGTGGGA 360
GATGGAGAGG TAGATCCCGT AGCCGGCGGG CGGCGACGTC CCGACCAGAG CGTGTGTGGC 420
CCGATGGGGT CATCCCCTTT GTCATTGGGG GAAACTTCAC TGGTAGCCAG AGGGCAGTCT 480
TCCGGCAGGC CATGAGGCAC TGGGAGAAGC ACACCTGTGT CACCTTCCTG GAGCGCACTG 540
ACGAGGACAG CTATATTGTG TTCACCTATC GACCTTGCGG GTGCTGCTCC TACGTGGGTC 600
GCCGCGGCGG GGGCCCCCAG GCCATCTCCA TCGGCAAGAA CTGTGACAAG TTCGGCATTG 660
TGGTCCACGA GCTGGGCCAC GTCGTCGGCT TCTGGCACGA ACACACTCGG CCAGACCGGG 720
ACCGCCACGT TTCCATCGTT CGTGAGAACA TCCAGCCAGG GCAGGAGTAT AACTTCCTGA 780
243 G> 1
AGATGGAGCC TCAGGAGGTG GAGTCCCTGG GGGAGACCTA TGACTTCGAC AGCATCATGC 840
ATTACGCTCG GAACACATTC TCCAGGGGCA TCTTCCTGGA TACCATTGTC CCCAAGTATG 900
AGGTGAACGG GGTGAAACCT CCCATTGGCC AAAGGACACG GCTCAGCAAG GGGGACATTG 960
CCCAAGCCCG CAAGCTTTAC AAGTGCCCAG CCTGTGGAGA GACCCTGCAA GACAGCACAG 1020
GCAACTTCTC CTCCCCTGAA TACCCCAATG GCTACTCTGC TCACATGCAC TGCGTGTGGC 1080
GCATCTCTGT CACACCCGGG GAGAAGATCA TCCTGAACTT CACGTCCCTG GACCTGTACC 1140
GCAGCCGCCT GTGCTGGTAC GACTATGTGG AGGTCCGAGA TGGCTTCTGG AGGAAGGCGC 1200
CCCTCCGAGG CCGCTTCTGC GGGTCCAAAC TCCCTGAGCC TATCGTCTCC ACTGACAGCC 1260
GCCTCTGGGT TGAATTCCGC AGCAGCAGCA ATTGGGTTGG AAAGGGCTTC TTTGCAGTCT 1320
ACGAAGCCAT CTGCGGGGGT GATGTGAAAA AGGACTATGG CCACATTCAA TCGCCCAACT 1380
ACCCAGACGA TTACCGGCCC AGCAAAGTCT GCATCTGGCG GATCCAGGTG TCTGAGGGCT 1440
TCCACGTGGG CCTCACATTC CAGTCCTTTG AGATTGAGCG CCACGACAGC TGTGCCTACG 1500
ACTATCTGGA GGTGCGCGAC GGGCACAGTG AGAGCAGCAC CCTCATCGGG CGCTACTGTG 1560
GCTATGAGAA GCCTGATGAC ATCAAGAGCA CGTCCAGCCG CCTCTGGCTC AAGTTCGTCT 1620
CTGACGGGTC CATTAACAAA GCGGGCTTTG CCGTCAACTT TTTCAAAGAG GTGGACGAGT 1680
GCTCTCGGCC CAACCGCGGG GGCTGTGAGC AGCGGTGCCT CAACACCCTG GGCAGCTACA 1740
AGTGCAGCTG TGACCCCGGG TACGAGCTGG CCCCAGACAA GCGCCGCTGT GAGGCTGCTT 1800
GTGGCGGATT CCTCACCAAG CTCAACGGCT CCATCACCAG CCCGGGCTGG CCCAAGGAGT 1860
ACCCCCCCAA CAAGAACTGC ATCTGGCAGC TGGTGGCCCC CACCCAGTAC CGCATCTCCC 1920
TGCAGTTTGA CTTCTTTGAG ACAGAGGGCA ATGATGTGTG CAAGTACGAC TTCGTGGAGG 1980
243 G>18
TGCGCAGTGG ACTCACAGCT GACTCCAAGC TGCATGGCAA GTTCTGTGGT TCTGAGAAGC 2040 CCGAGGTCAT CACCTCCCAG TACAACAACA TGCGCGTGGA GTTCAAGTCC GACAACACCG 2100 5 TGTCCAAAAA GGGCTTCAAG GCCCACTTCT TCTCAGAAAA GAGGCCAGCT CTGCAGCCCC 2160 CTCGGGGACG CCCCCACCAG CTCAAATTCC GAGTGCAGAA AAGAAACCGG ACCCCCCAGT 2220 GAGGCCTGCC AGGCCTCCCG GACCCCTTGT TACTCAGGAA CCTCACCTTG GACGGAATGG 2280
GATGGGGGCT TCGGTGCCCA CCAACCCCCC ACCTCCACTC TGCCATTCCG GCCCACCTCC 2340 CTCTGGCCGG ACAGAACTGG TGCTCTCTTC TCCCCACTGT GCCCGTCCGC GGACCGGGGA 2400 15 CCCTTCCCCG TGCCCTACCC CCTCCCATTT TGATGGTGTC TGTGACATTT CCTGTTGTGA 2460 AGTAAAAGAG GGACCCCTGC GTCCTGC 2487
(2) INFORMATION FOR SEQ ID NO:2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1547 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double 25 (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:
GGGGACTTCT TGAACTTGCA GGGAGAATAA CTTGCGCACC CCACTTTGCG CCGGTGCCTT 60
TGCCCCAGCG GAGCCTGCTT CGCCATCTCC GAGCCCCACC GCCCCTCCAC TCCTCGGCCT 120
TGCCCGACAC TGAGACGCTG TTCCCAGCGT GAAAAGAGAG ACTGCGCGGC CGGCACCCGG 180
GAGAAGGAGG AGGCAAAGAA AAGGAACGGA CATTCGGTCC TTGCGCCAGG TCCTTTGACC 240
24-30 1
AGAGTTTTTC CATGTGGACG CTCTTTCAAT GGACGTGTCC CCGCGTGCTT CTTAGACGGA 300
CTGCGGTCTC CTAAAGGTCG ACCATGGTGG CCGGGACCCG CTGTCTTCTA GCGTTGCTGC 360
TTCCCCAGGT CCTCCTGGGC GGCGCGGCTG GCCTCGTTCC GGAGCTGGGC CGCAGGAAGT 420
TCGCGGCGGC GTCGTCGGGC CGCCCCTCAT CCCAGCCCTC TGACGAGGTC CTGAGCGAGT 480
TCGAGTTGCG GCTGCTCAGC ATGTTCGGCC TGAAACAGAG ACCCACCCCC AGCAGGGACG 540
CCGTGGTGCC CCCCTACATG CTAGACCTGT ATCGCAGGCA CTCAGGTCAG CCGGGCTCAC 600
CCGCCCCAGA CCACCGGTTG GAGAGGGCAG CCAGCCGAGC CAACACTGTG CGCAGCTTCC 660
ACCATGAAGA ATCTTTGGAA GAACTACCAG AAACGAGTGG GAAAACAACC CGGAGATTCT 720
TCTTTAATTT AAGTTCTATC CCCACGGAGG AGTTTATCAC CTCAGCAGAG CTTCAGGTTT 780
TCCGAGAACA GATGCAAGAT GCTTTAGGAA ACAATAGCAG TTTCCATCAC CGAATTAATA 840
TTTATGAAAT CATAAAACCT GCAACAGCCA ACTCGAAATT CCCCGTGACC AGACTTTTGG 900
ACACCAGGTT GGTGAATCAG AATGCAAGCA GGTGGGAAAG TTTTGATGTC ACCCCCGCTG 960
TGATGCGGTG GACTGCACAG GGACACGCCA ACCATGGATT CGTGGTGGAA GTGGCCCACT 1020
TGGAGGAGAA ACAAGGTGTC TCCAAGAGAC ATGTTAGGAT AAGCAGGTCT TTGCACCAAG 1080
ATGAACACAG CTGGTCACAG ATAAGGCCAT TGCTAGTAAC TTTTGGCCAT GATGGAAAAG 1140
GGCATCCTCT CCACAAAAGA GAAAAACGTC AAGCCAAACA CAAACAGCGG AAACGCCTTA 1200
AGTCCAGCTG TAAGAGACAC CCTTTGTACG TGGACTTCAG TGACGTGGGG TGGAATGACT 1260
GGATTGTGGC TCCCCCGGGG TATCACGCCT TTTACTGCCA CGGAGAATGC CCTTTTCCTC 1320
TGGCTGATCA TCTGAACTCC ACTAATCATG CCATTGTTCA GACGTTGGTC AACTCTGTTA 1380
ACTCTAAGAT TCCTAAGGCA TGCTGTGTCC CGACAGAACT CAGTGCTATC TCGATGCTGT 1440
2450 1?
ACCTTGACGA GAATGAAAAG GTTGTATTAA AGAACTATCA GGACATGGTT GTGGAGGGTT 1500 GTGGGTGTCG CTAGTACAGC AAAATTAAAT ACATAAATAT ATATATA 1547
(2) INFORMATION FOR SEQ ID N0:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1774 base pairs
(B) TYPE: nucleic acid 10 (C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:3:
AGATCTTGAA AACACCCGGG CCACACACGC CGCGACCTAC AGCTCTTTCT CAGCGTTGGA 60
GTGGAGACGG CGCCCGCAGC GCCCTGCGCG GGTGAGGTCC GCGCAGCTGC TGGGGAAGAG 120
CCCACCTGTC AGGCTGCGCT GGGTCAGCGC AGCAAGTGGG GCTGGCCGCT ATCTCGCTGC 180
ACCCGGCCGC GTCCCGGGCT CCGTGCGCCC TCGCCCCAGC TGGTTTGGAG TTCAACCCTC 240
GGCTCCGCCG CCGGCTCCTT GCGCCTTCGG AGTGTCCCGC AGCGACGCCG GGAGCCGACG 300
CGCCGCGCGG GTACCTAGCC ATGGCTGGGG CGAGCAGGCT GCTCTTTCTG TGGCTGGGCT 360
GCTTCTGCGT GAGCCTGGCG CAGGGAGAGA GACCGAAGCC ACCTTTCCCG GAGCTCCGCA 420
AAGCTGTGCC AGGTGACCGC ACGGCAGGTG GTGGCCCGGA CTCCGAGCTG CAGCCGCAAG 480
ACAAGGTCTC TGAACACATG CTGCGGCTCT ATGACAGGTA CAGCACGGTC CAGGCGGCCC 540
GGACACCGGG CTCCCTGGAG GGAGGCTCGC AGCCCTGGCG CCCTCGGCTC CTGCGCGAAG 600
GCAACACGGT TCGCAGCTTT CGGGCGGCAG CAGCAGAAAC TCTTGAAAGA AAAGGACTGT 660
2.430 I S
ATATCTTCAA TCTGACATCG CTAACCAAGT CTGAAAACAT TTTGTCTGCC ACACTGTATT 720
TCTGTATTGG AGAGCTAGGA AACATCAGCC TGAGTTGTCC AGTGTCTGGA GGATGCTCCC 780
ATCATGCTCA GAGGAAACAC ATTCAGATTG ATCTTTCTGC ATGGACCCTC AAATTCAGCA 840
GAAACCAAAG TCAACTCCTT GGCCATCTGT CAGTGGATAT GGCCAAATCT CATCGAGATA 900
TTATGTCCTG GCTGTCTAAA GATATCACTC AATTCTTGAG GAAGGCCAAA GAAAATGAAG 960
AGTTCCTCAT AGGATTTAAC ATTACGTCCA AGGGACGCCA GCTGCCAAAG AGGAGGTTAC 1020
CTTTTCCAGA GCCTTATATC TTGGTATATG CCAATGATGC CGCCATTTCT GAGCCAGAAA 1080
GTGTGGTATC AAGCTTACAG GGACACCGGA ATTTTCCCAC TGGAACTGTT CCCAAATGGG 1140
ATAGCCACAT CAGAGCTGCC CTTTCCATTG AGCGGAGGAA GAAGCGCTCT ACTGGGGTCT 1200
TGCTGCCTCT GCAGAACAAC GAGCTTCCTG GGGCAGAATA CCAGTATAAA AAGGATGAGG 1260
TGTGGGAGGA GAGAAAGCCT TACAAGACCC TTCAGGCTCA GGCCCCTGAA AAGAGTAAGA 1320
ATAAAAAGAA ACAGAGAAAG GGGCCTCATC GGAAGAGCCA GACGCTCCAA TTTGATGAGC 1380
AGACCCTGAA AAAGGCAAGG AGAAAGCAGT GGATTGAACC TCGGAATTGC GCCAGGAGAT 1440
ACCTCAAGGT AGACTTTGCA GATATTGGCT GGAGTGAATG GATTATCTCC CCCAAGTCCT 1500
TTGATGCCTA TTATTGCTCT GGAGCATGCC AGTTCCCCAT GCCAAAGTCT TTGAAGCCAT 1560
CAAATCATGC TACCATCCAG AGTATAGTGA GAGCTGTGGG GGTCGTTCCT GGGATTCCTG 1620
AGCCTTGCTG TGTACCAGAA AAGATGTCCT CACTCAGTAT TTTATTCTTT GATGAAAATA 1680
AGAATGTAGT GCTTAAAGTA TACCCTAACA TGACAGTAGA GTCTTGCGCT TGCAGATAAC 1740
CTGGCAAAGA ACTCATTTGA ATGCTTAATT CAAT 1774 (2) INFORMATION FOR SEQ ID N0:4:
'■1
60
120
180
240
300
360
420
480
540
600
660
720
780
840
243
(1) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1751 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(Xi) SEQUENCE DESCRIPTION: SEQ ID N0:4:
GGCAGAGGAG GAGGGAGGGA GGGAAGGAGC GCGGAGCCCG GCCCGGAAGC TAGGTGAGTG TGGCATCCGA GCTGAGGGAC GCGAGCCTGA GACGCCGCTG CTGCTCCGGC TGAGTATCTA GCTTGTCTCC CCGATGGGAT TCCCGTCCAA GCTATCTCGA GCCTGCAGCG CCACAGTCCC CGGCCCTCGC CCAGGTTCAC TGCAACCGTT CAGAGGTCCC CAGGAGCTGC TGCTGGCGAG CCCGCTACTG CAGGGACCTA TGGAGCCATT CCGTAGTGCC ATCCCGAGCA ACGCACTGCT GCAGCTTCCC TGAGCCTTTC CAGCAAGTTT GTTCAAGATT GGCTGTCAAG AATCATGGAC TGTTATTATA TGCCTTGTTT TCTGTCAAGA CACCATGATT CCTGGTAACC GAATGCTGAT GGTCGTTTTA TTATGCCAAG TCCTGCTAGG AGGCGCGAGC CATGCTAGTT TGATACCTGA GACGGGGAAG AAAAAAGTCG CCGAGATTCA GGGCCACGCG GGAGGACGCC GCTCAGGGCA GAGCCATGAG CTCCTGCGGG ACTTCGAGGC GACACTTCTG CAGATGTTTG GGCTGCGCCG CCGCCCGCAG CCTAGCAAGA GTGCCGTCAT TCCGGACTAC ATGCGGGATC TTTACCGGCT TCAGTCTGGG GAGGAGGAGG AAGAGCAGAT CCACAGCACT GGTCTTGAGT ATCCTGAGCG CCCGGCCAGC CGGGCCAACA CCGTGAGGAG CTTCCACCAC GAAGAACATC TGGAGAACAT CCCAGGGACC AGTGAAAACT CTGCTTTTCG TTTCCTCTTT AACCTCAGCA GCATCCCTGA
24J G> 11
GAACGAGGTG ATCTCCTCTG CAGAGCTTCG GCTCTTCCGG GAGCAGGTGG ACCAGGGCCC 900
TGATTGGGAA AGGGGCTTCC ACCGTATAAA CATTTATGAG GTTATGAAGC CCCCAGCAGA 960
AGTGGTGCCT GGGCACCTCA TCACACGACT ACTGGACACG AGACTGGTCC ACCACAATGT 1020
GACACGGTGG GAAACTTTTG ATGTGAGCCC TGCGGTCCTT CGCTGGACCC GGGAGAAGCA 1080
GCCAAACTAT GGGCTAGCCA TTGAGGTGAC TCACCTCCAT CAGACTCGGA CCCACCAGGG 1140
CCAGCATGTC AGGATTAGCC GATCGTTACC TCAAGGGAGT GGGAATTGGG CCCAGCTCCG 1200
GCCCCTCCTG GTCACCTTTG GCCATGATGG CCGGGGCCAT GCCTTGACCC GACGCCGGAG 1260
GGCCAAGCGT AGCCCTAAGC ATCACTCACA GCGGGCCAGG AAGAAGAATA AGAACTGCCG 1320
GCGCCACTCG CTCTATGTGG ACTTCAGCGA TGTGGGCTGG AATGACTGGA TTGTGGCCCC 1380
ACCAGGCTAC CAGGCCTTCT ACTGCCATGG GGACTGCCCC TTTCCACTGG CTGACCACCT 1440
CAACTCAACC AACCATGCCA TTGTGCAGAC CCTGGTCAAT TCTGTCAATT CCAGTATCCC 1500
CAAAGCCTGT TGTGTGCCCA CTGAACTGAG TGCCATCTCC ATGCTGTACC TGGATGAGTA 1560
TGATAAGGTG GTACTGAAAA ATTATCAGGA GATGGTAGTA GAGGGATGTG GGTGCCGCTG 1620
AGATCAGGCA GTCCTTGAGG ATAGACAGAT ATACACACCA CACACACACA CCACATACAC 1680
CACACACACA CGTTCCCATC CACTCACCCA CACACTACAC AGACTGCTTC CTTATAGCTG 1740
GACTTTTATT T 1751 (2) INFORMATION FOR SEQ ID NO:5:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2153 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear
Z43Dfg
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:
CTGGTATATT TGTGCCTGCT GGAGGTGGAA TTAACAGTAA GAAGGAGAAA GGGATTGAAT 60
GGACTTACAG GAAGGATTTC AAGTAAATTC AGGGAAACAC ATTTACTTGA ATAGTACAAC 120
CTAGAGTATT ATTTTACACT AAGACGACAC AAAAGATGTT AAAGTTATCA CCAAGCTGCC 180
GGACAGATAT ATATTCCAAC ACCAAGGTGC AGATCAGCAT AGATCTGTGA TTCAGAAATC 240
AGGATTTGTT TTGGAAAGAG CTCAAGGGTT GAGAAGAACT CAAAAGCAAG TGAAGATTAC 300
TTTGGGAACT ACAGTTTATC AGAAGATCAA CTTTTGCTAA TTCAAATACC AAAGGCCTGA 360
TTATCATAAA TTCATATAGG AATGCATAGG TCATCTGATC AAATAATATT AGCCGTCTTC 420
TGCTACATCA ATGCAGCAAA AACTCTTAAC AACTGTGGAT AATTGGAAAT CTGAGTTTCA 480
GCTTTCTTAG AAATAACTAC TCTTGACATA TTCCAAAATA TTTAAAATAG GACAGGAAAA 540
TCGGTGAGGA TGTTGTGCTC AGAAATGTCA CTGTCATGAA AAATAGGTAA ATTTGTTTTT 600
TCAGCTACTG GGAAACTGTA CCTCCTAGAA CCTTAGGTTT TTTTTTTTTT AAGAGGACAA 660
GAAGGACTAA AAATATCAAC TTTTGCTTTT GGACAAAAAT GCATCTGACT GTATTTTTAC 720
TTAAGGGTAT TGTGGGTTTC CTCTGGAGCT GCTGGGTTCT AGTGGGTTAT GCAAAAGGAG 780
GTTTGGGAGA CAATCATGTT CACTCCAGTT TTATTTATAG AAGACTACGG AACCACGAAA 840
GACGGGAAAT ACAAAGGGAA ATTCTCTCTA TCTTGGGTTT GCCTCACAGA CCCAGACCAT 900
TTTCACCTGG AAAACAAGCG TCCTCTGCAC CTCTCTTTAT GCTGGATCTC TACAATGCCA 960
TGACCAATGA AGAAAATCCT GAAGAGTCGG AGTACTCAGT AAGGGCATCC TTGGCAGAAG 1020
2430]8
AGACCAGAGG GGCAAGAAAG GGATACCCAG CCTCTCCCAA TGGGTATCCT CGTCGCATAC 1080
AGTTATCTCG GACGACTCCT CTGACCACCC AGAGTCCTCC TCTAGCCAGC CTCCATGATA 1140
CCAACTTTCT GAATGATGCT GACATGGTCA TGAGCTTTGT CAACTTAGTT GAAAGAGACA 1200
AGGATTTTTC TCACCAGCGA AGGCATTACA AAGAATTTCG ATTTGATCTT ACCCAAATTC 1260
CTCATGGAGA GGCAGTGACA GCAGCTGAAT TCCGGATATA CAAGGACCGG AGCAACAACC 1320
GATTTGAAAA TGAAACAATT AAGATTAGCA TATATCAAAT CATCAAGGAA TACACAAATA 1380
GGGATGCAGA TCTGTTCTTG TTAGACACAA GAAAGGCCCA AGCTTTAGAT GTGGGTTGGC 1440
TTGTCTTTGA TATCACTGTG ACCAGCAATC ATTGGGTGAT TAATCCCCAG AATAATTTGG 1500
GCTTACAGCT CTGTGCAGAA ACAGGGGATG GACGCAGTAT CAACGTAAAA TCTGCTGGTC 1560
TTGTGGGAAG ACAGGGACCT CAGTCAAAAC AACCATTCAT GGTGGCCTTC TTCAAGGCGA 1620
GTGAGGTACT TCTTCGATCC GTGAGAGCAG CCAACAAACG AAAAAATCAA AACCGCAATA 1680
AATCCAGCTC TCATCAGGAC TCCTCCAGAA TGTCCAGTGT TGGAGATTAT AACACAAGTG 1740
AGCAAAAACA AGCCTGTAAG AAGCACGAAC TCTATGTGAG CTTCCGGGAT CTGGGATGGC 1800
AGGACTGGAT TATAGCACCA GAAGGATACG CTGCATTTTA TTGTGATGGA GAATGTTCTT 1860
TTCCACTTAA CGCCCATATG AATGCCACCA ACCACGCTAT AGTTCAGACT CTGGTTCATC 1920
TGATGTTTCC TGACCACGTA CCAAAGCCTT GTTGTGCTCC AACCAAATTA AATGCCATCT 1980
CTGTTCTGTA CTTTGATGAC AGCTCCAATG TCATTTTGAA AAAATATAGA AATATGGTAG 2040
TACGCTCATG TGGCTGCCAC TAATATTAAA TAATATTGAT AATAACAAAA AGATCTGTAT 2100
TAAGGTTTAT GGCTGCAATA AAAAGCATAC TTTCAGACAA ACAGAAAAAA AAA 2153 (2) INFORMATION FOR SEQ ID N0:6:
2.430 18
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2923 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double 5 (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:6:
CGACCATGAG AGATAAGGAC TGAGGGCCAG GAAGGGGAAG CGAGCCCGCC GAGAGGTGGC 60
GGGGACTGCT CACGCCAAGG GCCACAGCGG CCGCGCTCCG GCCTCGCTCC GCCGCTCCAC 120
GCCTCGCGGG ATCCGCGGGG GCAGCCCGGC CGGGCGGGGA TGCCGGGGCT GGGGCGGAGG 180
GCGCAGTGGC TGTGCTGGTG GTGGGGGCTG CTGTGCAGCT GCTGCGGGCC CCCGCCGCTG 240
CGGCCGCCCT TGCCCGCTGC CGCGGCCGCC GCCGCCGGGG GGCAGCTGCT GGGGGACGGC 300
GGGAGCCCCG GCCGCACGGA GCAGCCGCCG CCGTCGCCGC AGTCCTCCTC GGGCTTCCTG 360
TACCGGCGGC TCAAGACGCA GGAGAAGCGG GAGATGCAGA AGGAGATCTT GTCGGTGCTG 420
GGGCTCCCGC ACCGGCCCCG GCCCCTGCAC GGCCTCCAAC AGCCGCAGCC CCCGGCGCTC 480
CGGCAGCAGG AGGAGCAGCA GCAGCAGCAG CAGCTGCCTC GCGGAGAGCC CCCTCCCGGG 540
CGACTGAAGT CCGCGCCCCT CTTCATGCTG GATCTGTACA ACGCCCTGTC CGCCGACAAC 600
GACGAGGACG GGGCGTCGGA GGGGGAGAGG CAGCAGTCCT GGCCCCACGA AGCAGCCAGC 660
TCGTCCCAGC GTCGGCAGCC GCCCCCGGGC GCCGCGCACC CGCTCAACCG CAAGAGCCTT 720
CTGGCCCCCG GATCTGGCAG CGGCGGCGCG TCCCCACTGA CCAGCGCGCA GGACAGCGCC 780
TTCCTCAACG ACGCGGACAT GGTCATGAGC TTTGTGAACC TGGTGGAGTA CGACAAGGAG 840
243© t
TTCTCCCCTC GTCAGCGACA CCACAAAGAG TTCAAGTTCA ACTTATCCCA GATTCCTGAG 900
GGTGAGGTGG TGACGGCTGC AGAATTCCGC ATCTACAAGG ACTGTGTTAT GGGGAGTTTT 960
AAAAACCAAA CTTTTCTTAT CAGCATTTAT CAAGTCTTAC AGGAGCATCA GCACAGAGAC 1020
TCTGACCTGT TTTTGTTGGA CACCCGTGTA GTATGGGCCT CAGAAGAAGG CTGGCTGGAA 1080
TTTGACATCA CGGCCACTAG CAATCTGTGG GTTGTGACTC CACAGCATAA CATGGGGCTT 1140
CAGCTGAGCG TGGTGACAAG GGATGGAGTC CACGTCCACC CCCGAGCCGC AGGCCTGGTG 1200
GGCAGAGACG GCCCTTACGA TAAGCAGCCC TTCATGGTGG CTTTCTTCAA AGTGAGTGAG 1260
GTCCACGTGC GCACCACCAG GTCAGCCTCC AGCCGGCGCC GACAACAGAG TCGTAATCGC 1320
TCTACCCAGT CCCAGGACGT GGCGCGGGTC TCCAGTGCTT CAGATTACAA CAGCAGTGAA 1380
TTGAAAACAG CCTGCAGGAA GCATGAGCTG TATGTGAGTT TCCAAGACCT GGGATGGCAG 1440
GACTGGATCA TTGCACCCAA GGGCTATGCT GCCAATTACT GTGATGGAGA ATGCTCCTTC 1500
CCACTCAACG CACACATGAA TGCAACCAAC CACGCGATTG TGCAGACCTT GGTTCACCTT 1560
ATGAACCCCG AGTATGTCCC CAAACCGTGC TGTGCGCCAA CTAAGCTAAA TGCCATCTCG 1620
GTTCTTTACT TTGATGACAA CTCCAATGTC ATTCTGAAAA AATACAGGAA TATGGTTGTA 1680
AGAGCTTGTG GATGCCACTA ACTCGAAACC AGATGCTGGG GACACACATT CTGCCTTGGA 1740
TTCCTAGATT ACATCTGCCT TAAAAAAACA CGGAAGCACA GTTGGAGGTG GGACGATGAG 1800
ACTTTGAAAC TATCTCATGC CAGTGCCTTA TTACCCAGGA AGATTTTAAA GGACCTCATT 1860
AATAATTTGC TCACTTGGTA AATGACGTGA GTAGTTGTTG GTCTGTAGCA AGCTGAGTTT 1920
GGATGTCTGT AGCATAAGGT CTGGTAACTG CAGAAACATA ACCGTGAAGC TCTTCCTACC 1980
CTCCTCCCCC AAAAACCCAC CAAAATTAGT TTTAGCTGTA GATCAAGCTA TTTGGGGTGT 2040
1430 18
TTGTTAGTAA ATAGGGAAAA TAATCTCAAA GGAGTTAAAT GTATTCTTGG CTAAAGGATC 2100
AGCTGGTTCA GTACTGTCTA TCAAAGGTAG ATTTTACAGA GAACAGAAAT CGGGGAAGTG 2160
GGGGGAACGC CTCTGTTCAG TTCATTCCCA GAAGTCCACA GGACGCACAG CCCAGGCCAC 2220
AGCCAGGGCT CCACGGGGCG CCCTTGTCTC AGTCATTGCT GTTGTATGTT CGTGCTGGAG 2280
TTTTGTTGGT GTGAAAATAC ACTTATTTCA GCCAAAACAT ACCATTTCTA CACCTCAATC 2340
CTCCATTTGC TGTACTCTTT GCTAGTACCA AAAGTAGACT GATTACACTG AGGTGAGGCT 2400
ACAAGGGGTG TGTAACCGTG TAACACGTGA AGGCAGTGCT CACCTCTTCT TTACCAGAAC 2460
GGTTCTTTGA CCAGCACATT AACTTCTGGA CTGCCGGCTC TAGTACCTTT TCAGTAAAGT 2520
GGTTCTCTGC CTTTTTACTA TACAGCATAC CACGCCACAG GGTTAGAACC AACGAAGAAA 2580
ATAAAATGAG GGTGCCCAGC TTATAAGAAT GGTGTTAGGG GGATGAGCAT GCTGTTTATG 2640
AACGGAAATC ATGATTTCCC TGTAGAAAGT GAGGCTCAGA TTAAATTTTA GAATATTTTC 2700
TAAATGTCTT TTTCACAATC ATGTGACTGG GAAGGCAATT TCATACTAAA CTGATTAAAT 2760
AATACATTTA TAATCTACAA CTGTTTGCAC TTACAGCTTT TTTTGTAAAT ATAAACTATA 2820
ATTTATTGTC TATTTTATAT CTGTTTTGCT GTGGCGTTGG GGGGGGGGCC GGGCTTTTGG 2880
GGGGGGGGGT TTGTTTGGGG GGTGTCGTGG TGTGGGCGGG CGG 2923
(2) INFORMATION FOR SEQ ID NO:7:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1448 base pairs 35 (B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
2430 18
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:7:
GTGACCGAGC GGCGCGGACG GCCGCCTGCC CCCTCTGCCA CCTGGGGCGG TGCGGGCCCG 60
GAGCCCGGAG CCCGGGTAGC GCGTAGAGCC GGCGCGATGC ACGTGCGCTC ACTGCGAGCT 120
GCGGCGCCGC ACAGCTTCGT GGCGCTCTGG GCACCCCTGT TCCTGCTGCG CTCCGCCCTG 180
GCCGACTTCA GCCTGGACAA CGAGGTGCAC TCGAGCTTCA TCCACCGGCG CCTCCGCAGC 240
CAGGAGCGGC GGGAGATGCA GCGCGAGATC CTCTCCATTT TGGGCTTGCC CCACCGCCCG 300
CGCCCGCACC TCCAGGGCAA GCACAACTCG GCACCCATGT TCATGCTGGA CCTGTACAAC 360
GCCATGGCGG TGGAGGAGGG CGGCGGGCCC GGCGGCCAGG GCTTCTCCTA CCCCTACAAG 420
GCCGTCTTCA GTACCCAGGG CCCCCCTCTG GCCAGCCTGC AAGATAGCCA TTTCCTCACC 480
GACGCCGACA TGGTCATGAG CTTCGTCAAC CTCGTGGAAC ATGACAAGGA ATTCTTCCAC 540
CCACGCTACC ACCATCGAGA GTTCCGGTTT GATCTTTCCA AGATCCCAGA AGGGGAAGCT 600
GTCACGGCAG CCGAATTCCG GATCTACAAG GACTACATCC GGGAACGCTT CGACAATGAG 660
ACGTTCCGGA TCAGCGTTTA TCAGGTGCTC CAGGAGCACT TGGGCAGGGA ATCGGATCTC 720
TTCCTGCTCG ACAGCCGTAC CCTCTGGGCC TCGGAGGAGG GCTGGCTGGT GTTTGACATC 780
ACAGCCACCA GCAACCACTG GGTGGTCAAT CCGCGGCACA ACCTGGGCCT GCAGCTCTCG 840
GTGGAGACGC TGGATGGGCA GAGCATCAAC CCCAAGTTGG CGGGCCTGAT TGGGCGGCAC 900
GGGCCCCAGA ACAAGCAGCC CTTCATGGTG GCTTTCTTCA AGGCCACGGA GGTCCACTTC 960
CGCAGCATCC GGTCCACGGG GAGCAAACAG CGCAGCCAGA ACCGCTCCAA GACGCCCAAG 1020
AACCAGGAAG CCCTGCGGAT GGCCAACGTG GCAGAGAACA GCAGCAGCGA CCAGAGGCAG 1080
GCCTGTAAGA AGCACGAGCT GTATGTCAGC TTCCGAGACC TGGGCTGGCA GGACTGGATC 1140
Z430H
ATCGCGCCTG AAGGCTACGC CGCCTACTAC TGTGAGGGGG AGTGTGCCTT CCCTCTGAAC 1200
TCCTACATGA ACGCCACCAA CCACGCCATC GTGCAGACGC TGGTCCACTT CATCAACCCG 1260
GAAACGGTGC CCAAGCCCTG CTGTGCGCCC ACGCAGCTCA ATGCCATCTC CGTCCTCTAC 1320
TTCGATGACA GCTCCAACGT CATCCTGAAG AAATACAGAA ACATGGTGGT CCGGGCCTGT 1380
GGCTGCCACT AGCTCCTCCG AGAATTCAGA CCCTTTGGGG CCAAGTTTTT CTGGATCCTC 1440
CATTGCTC 1448
The invention has been described herein with reference to certain preferred embodiments and examples. Obvious variations may 15 appear to those skilled in the art. Therefore, the invention is not to be considered limited thereto but only by the claims which follow.
Claims (9)
1. A composition for generating new bone growth^^^hMpjsfi in need of such treatment comprising: a. a safe and effective amount of a Vitamin D compound; b. a safe and effective amount of one or more BMPs (Bone Morphogenetic Proteins) or osteoinductive extract comprising one or more BMPs wherein the BMPs are selected from the group consisting of BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7; and c. a safe and effective amount of a pharmaceutically acceptable carrier.
2. The composition of Claim 1 wherein the safe and effective amount of the vitamin D compound is from 1 ng to 1 mg.
3. The composition of Claim 1 wherein the safe and effective amount of the Vitamin D compound is from 30 ng to 10 /vg.
4. The composition of any one of the preceding Claims wherein the safe and effective amount of the BMP is at least 2.5 /vg.
5. The composition of any one of the preceding Claims wherein the Vitamin D compound is selected from the group consisting of Vitamin D2, Vitamin D3, 1-a-hydroxy Vitamin 3D , 1-a-fluoro Vitamig D, 3-deoxy-l ,25-dihydroxy Vitamin D3, 25-hydroxy-5,6-trans Vitamin D3, 25-hydroxy Vitamin D2, 25-hydroxy Vitamin D3, 1,25-dihydroxy Vitamin D2, 24,25-dihydroxy Vitamin D2, 24,25-dihydroxy Vitamin D3, and 1,25-dihydroxy Vitamin D3.
6. The composition of Claim 5 wherein the Vitamin D compound is 1,25-di hydroxy Vitamin D3.
7. The composition of any one of the preceding Claims wherein the pharmaceutically-acceptable carrier is an injectable carrier.
8. The composition of any one of Claims 1-6 wherein the pharmaceutically-acceptable carrier is a topical-oral carrier. '243 01 -41-
9. A composition as claimed in Claim 1 substantially,, as herein described with reference to any embodiment disclosed. IV1 -TUl. Pfeckf r-Gec2^C$p(*J;By the authorised agents A J PARK & SO®;Per i . /, /;4*
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US70962191A | 1991-06-05 | 1991-06-05 | |
US85611092A | 1992-03-27 | 1992-03-27 |
Publications (1)
Publication Number | Publication Date |
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NZ243018A true NZ243018A (en) | 1995-12-21 |
Family
ID=27108286
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NZ243018A NZ243018A (en) | 1991-06-05 | 1992-06-04 | Bone-growth composition including "bone morphogenic proteins" and vitamin d derivatives |
Country Status (13)
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EP (1) | EP0587751A1 (en) |
JP (1) | JPH06508140A (en) |
AU (1) | AU667815B2 (en) |
BR (1) | BR9206110A (en) |
CA (1) | CA2110410C (en) |
CZ (1) | CZ282231B6 (en) |
IE (1) | IE921812A1 (en) |
NO (1) | NO934381L (en) |
NZ (1) | NZ243018A (en) |
PT (1) | PT100567A (en) |
RU (1) | RU2107512C1 (en) |
SK (1) | SK136693A3 (en) |
WO (1) | WO1992021365A1 (en) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7056882B2 (en) | 1991-03-11 | 2006-06-06 | Curis, Inc. | Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases |
US5674844A (en) * | 1991-03-11 | 1997-10-07 | Creative Biomolecules, Inc. | Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases |
ES2253736T3 (en) * | 1991-08-30 | 2006-06-01 | Curis, Inc. | TREATMENT TO PREVENT LOSS AND / OR INCREASE THE OSEA MASS IN BONE METABOLIC DISORDERS. |
US6071695A (en) * | 1992-02-21 | 2000-06-06 | Creative Biomolecules, Inc. | Methods and products for identification of modulators of osteogenic protein-1 gene expression |
KR960701648A (en) * | 1993-03-29 | 1996-03-28 | 마크 제이. 머레이 | Osteoblast growth composition containing PDGF and vitamin D (OESTEOBLAST GROWTH STIMULATING COMPOSTION CONTAINING PDGF AND VITAMIND) |
JPH10505223A (en) * | 1994-06-07 | 1998-05-26 | クリエイティブ バイオモレキュールズ, インコーポレイテッド | Methods and compositions for modulating morphogenic protein expression |
US7026292B1 (en) | 1995-12-12 | 2006-04-11 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
US6048964A (en) * | 1995-12-12 | 2000-04-11 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
US6492508B1 (en) | 1996-06-03 | 2002-12-10 | United States Surgical Corp. A Division Of Tyco Healthcare Group | Nucleic acids encoding extracellular matrix proteins |
WO1998034655A1 (en) * | 1997-02-07 | 1998-08-13 | Stryker Corporation | Matrix-free osteogenic devices, implants and methods of use thereof |
KR20110032003A (en) * | 2001-10-31 | 2011-03-29 | 알콘, 인코퍼레이티드 | Bone morphogenic proteins (bmp), bmp receptors and bmp binding proteins and their use in the diagnosis and treatment of glaucoma |
JP5444212B2 (en) * | 2007-04-25 | 2014-03-19 | シトクロマ インコーポレイテッド | Method for treating vitamin D deficiency and deficiency |
JP5819733B2 (en) * | 2009-02-12 | 2015-11-24 | ストライカー コーポレイションStryker Corporation | Peripheral administration of TGF-β superfamily member-containing protein for systemic treatment of disorders and diseases |
EP2396026A2 (en) * | 2009-02-12 | 2011-12-21 | Stryker Corporation | Compositions and methods for minimally-invasive systemic delivery of proteins including tgf- superfamily members |
RU2595804C1 (en) * | 2015-04-23 | 2016-08-27 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Саратовский государственный технический университет имени Гагарина Ю.А." (СГТУ имени Гагарина Ю.А.) | Composition for producing dental therapeutic film |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
-
1992
- 1992-05-26 JP JP5500485A patent/JPH06508140A/en active Pending
- 1992-05-26 SK SK1366-93A patent/SK136693A3/en unknown
- 1992-05-26 RU RU93058532A patent/RU2107512C1/en active
- 1992-05-26 EP EP92913307A patent/EP0587751A1/en not_active Withdrawn
- 1992-05-26 WO PCT/US1992/004356 patent/WO1992021365A1/en not_active Application Discontinuation
- 1992-05-26 AU AU21454/92A patent/AU667815B2/en not_active Ceased
- 1992-05-26 BR BR9206110A patent/BR9206110A/en not_active Application Discontinuation
- 1992-05-26 CA CA002110410A patent/CA2110410C/en not_active Expired - Fee Related
- 1992-05-26 CZ CS932624A patent/CZ282231B6/en unknown
- 1992-06-04 PT PT100567A patent/PT100567A/en not_active Application Discontinuation
- 1992-06-04 NZ NZ243018A patent/NZ243018A/en unknown
- 1992-07-01 IE IE181292A patent/IE921812A1/en not_active Application Discontinuation
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1993
- 1993-12-02 NO NO934381A patent/NO934381L/en unknown
Also Published As
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BR9206110A (en) | 1995-07-11 |
AU667815B2 (en) | 1996-04-18 |
IE921812A1 (en) | 1992-12-16 |
EP0587751A1 (en) | 1994-03-23 |
CZ282231B6 (en) | 1997-06-11 |
NO934381D0 (en) | 1993-12-02 |
AU2145492A (en) | 1993-01-08 |
RU2107512C1 (en) | 1998-03-27 |
NO934381L (en) | 1994-01-31 |
PT100567A (en) | 1994-01-31 |
CZ262493A3 (en) | 1994-07-13 |
CA2110410A1 (en) | 1992-12-10 |
WO1992021365A1 (en) | 1992-12-10 |
SK136693A3 (en) | 1994-10-05 |
JPH06508140A (en) | 1994-09-14 |
CA2110410C (en) | 1997-04-15 |
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