WO1992021365A1 - Therapeutic compositions for osteoinduction - Google Patents
Therapeutic compositions for osteoinduction Download PDFInfo
- Publication number
- WO1992021365A1 WO1992021365A1 PCT/US1992/004356 US9204356W WO9221365A1 WO 1992021365 A1 WO1992021365 A1 WO 1992021365A1 US 9204356 W US9204356 W US 9204356W WO 9221365 A1 WO9221365 A1 WO 9221365A1
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- WIPO (PCT)
- Prior art keywords
- bmp
- vitamin
- issued
- compound
- deluca
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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
- A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
-
- 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
Definitions
- 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 orphogenetic proteins and a Vitamin D compound, resulting in synergistic bone growth.
- osteopor ⁇ osis is an abnormal loss of bony tissue often occurring in post- enopausal 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 treat ⁇ ments that go beyond the prevention of bone loss and promote bone formation and/or reverse bone loss.
- Various other bone morphogenetic proteins/factors, osteoin ⁇ ductive factors, osteogenic factors and other proteins/factors related to bone growth are disclosed in the following publica ⁇ tions: 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 4,294,753, 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 Applica ⁇ tion 145 155, Sen, published July 10, 1985; World Patent Applica- tion 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.
- 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 a BMP or osteoinductive extract comprising one or more
- BMPs BMPs
- a pharmaceutically-acceptable carrier BMPs
- the present invention comprises the administration to a mammal of a combination of a safe and effective amount of a Vitamin D compound amd a safe and effective amount of one or more BMPs or an osteoinducrtive extract comprising one or more BMPs. It has been determined that treatment with a Vitamin D compound, BMP or osteoinductive ex t ract alone increases bone growth. Surpris- ingly, it has been further determined that treatment with a Vitamin D compound, BMP or osteoinductive ex t ract alone increases bone growth. Surpris- ingly, it has been further determined that treatment with a Vitamin D compound, BMP or osteoinductive ex t ract alone increases bone growth. Surpris- ingly, it has been further determined that treatment with a Vitamin D compound, BMP or osteoinductive ex t ract alone increases bone growth. Surpris- ingly, it has been further determined that treatment with a Vitamin D compound, BMP or osteoinductive ex t ract alone increases bone growth. Surpris- ingly
- Vitamin D compound -m 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, osteoinducrrive extract or Vitamin D compound alone.
- Subjects in need o-r such treatment suffer from a variety of ailments which may ue treated via this procedure, including but not l imited to, borne fractures (closed and open) , non-union fractures, congenita " defects, as an adjunct in pl astic surgery, in treating oncological resections, all diseases cl assified as osteoporosis, rheum ⁇ etoid arthritis, osteoarthritis, septic arthritis, rickets, rtrganic incorporation of prosthetic joints and dental implants, pe.-iodcntal disease and defects, as well as osteopenic and osteo ⁇ alacic conditions and disease.
- safe and effective amount means an amount of compound or compicsition sufficient to significantly induce a positive modification, in the condition to be treated, but low enough to avoid seri ⁇ us side effects (at a reasonable benefit/risk ratio) , within the s.rope of sound medical judgment.
- the safe and effective amount of the expound or composition will vary with the particular condition beir-g treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the tre __tmer._ . the nature of concurrent therapy, the specific compound or composition employed, the particular pharma ⁇ ceutical ly-acceptabl •£ carrier util ized, and l ike factors within the knowledge and expertise of the attending physician.
- fracture reduction means the restoration of a bone fracture by 3urg-cal or manipulative means to its normal anatomical relation.
- q.s . means quantity sufficient.
- re onal treatment
- systemic treatment includes treating diseases classified as osteoporosis, rheumatoid arthritis, osteo- arthritis, septic arthritis, rickets, and osteopenic conditions and diseases.
- mineralized tissue means bone and teeth.
- Vitamin D compound includes Vitamin D, ergocalciferol (Vitamin D 2 ), cholecalciferol (Vitamin D 3 ) and their biologically active metabolites and precursors.
- Preferred Vitamin D compounds include, but are not limited to, Vitamin D 2 (Sigma, St. Louis, MO), Vitamin D 3 (Sigma, St.
- the Vitamin D compound is selected from 25-hydroxy Vitamin D 2 , 25-hydroxy Vitamin D 3 , 1,25-dihydroxy Vitamin D 2 , 24,25-dihydroxy Vitamin D 2 , 24,25-dihy ⁇ droxy Vitamin D 3 , and 1,25-dihydroxy Vitamin D 3 , more preferably 1,25-dihydroxy Vitamin D 3 .
- 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 4,313,942 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 4,224,230 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; 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.
- 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 ⁇ -hydroxy- vitamin D 2 ; 1 ⁇ ,25-dihydroxy-22Z-dehydroxyvitamin D; 26,26,26,- 27,27-pentafluoro-l ⁇ -hydroxy-27-methoxyvitamin D 3 ; 2 ⁇ -fluoro- vitamin D 3 ; 1,24-dihydroxy-delta 22-vitamin D 3 ; 23,23-difluoro- 25-hydroxy-vitamin D 3 ; l-hydroxy-3,5-cyclovitamin D; 23,23-di- fluoro-1 ⁇ ,25-dihydroxy-vitamin D 3 ; 1,23-dihydroxyvitamin D; hydroxyvitamin D 2 ; 23,23-difluoro-l ⁇ ,25-d
- 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-1,25-dihydroxy Vitamin D, 27- ⁇ or-25-hydroxy Vitamin D 3 , 26,27-bis-nor-25-hydroxy Vitamin D 3 24-no.-25-hyd.oxy Vitamin D 3 , 25-hydroxy Vitamin D, 1,25-dihydroxy Vitamin D, l ⁇ -hydroxy Vitamin D 3 and 25-fluoro-la-hydroxy Vitamin D 3 . - 9 -
- 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 ⁇ g, more preferably from about 20 ng to about 10 ⁇ g.
- 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.
- doses are administered over a 1 day to 6 month period, more preferably from about 1 week to about 1 month.
- 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.
- a Vitamin D compound is administered in combination with one or more BMPs to generate new bone growth in a mammal.
- BMPs are preferably selected from the group consisting of BMP-1, BMP-2, BMP-3, BMP-4,
- 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 ⁇ g, preferably from about 1 ng to about 10 ⁇ g, more preferably from about 10 ng to about 2.5 ⁇ g.
- a preferred dose range for the BMP is from about 1 pg to about 100 ⁇ g, more preferably from about 1.5 ⁇ g to about 90 ⁇ g, preferably from about 1.8 ⁇ g to about 75 ⁇ g, more preferably from about 2.0 ⁇ g to about 50 ⁇ g, more preferably still from about 2.2 ⁇ g to about 25 ⁇ g, more preferably from about 2.3 ⁇ g to about 10 ⁇ g, most preferably from about 2.5 ⁇ g to about 5 ⁇ g.
- the dose range is at least about 2.5 ⁇ g. 56
- doses are administered over a 1 day to 6 month period, more preferably from about 1 week to about 1 month.
- 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.
- BMP-1 means a peptide encoded by a DNA sequence comprising SEQ ID N0:1.
- BMP-2 means a peptide encoded by a DNA sequence comprising SEQ ID NO:2.
- BMP-3 means a peptide encoded by a DNA sequence comprising SEQ ID NO:3.
- BMP-4" means a peptide encoded by a DNA sequence comprising SEQ ID NO:4.
- BMP-5" means a peptide encoded by a DNA sequence comprising SEQ ID NO:5.
- BMP-6 means a peptide encoded by a DNA' sequence comprising SEQ ID NO: 6.
- BMP-7 means a peptide encoded by a DNA sequence comprising SEQ ID NO: 7.
- A”, “T”, “G”, and “C” refer to the nucleo ⁇ tides containing adenine, thymine, guanine and cytosine respectively.
- 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.
- 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:
- the acid demineral zed 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. 5 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 10 combine with the previously saved solution. The bone particles are now demineralized and deproteinized.
- Active fractions from the gel filtration are combined and dialyzed against three changes of 6M urea, 25mM Na acetate, pH 4.6.
- the dialysate is loaded onto a column of carboxymethyl- sepharose (CM-Sepharose) equilibrated with the same buffer.
- CM-Sepharose carboxymethyl- sepharose
- the 35 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 13 - pooled for further purification.
- the pooled CM-Sepharose fractions are dialyzed three times for 24 hours each against 1% 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.
- a safe and effective amount of osteoinductive extract is dosed in combination with a Vitamin D compound.
- the osteoinductive extract dosed preferably comprises at least one BMP in an amount from about 1 pg to about 100 ⁇ g, preferably from about 1 ng to about 10 ⁇ g, more preferably from about 10 ng to about 2.5 ⁇ g.
- the osteoinductive extract dosed preferably comprises at least one BMP in an amount from about 1 pg to about 100 ⁇ g, more preferably from about 1.5 ⁇ g to about 90 ⁇ g, preferably from about 1.8 ⁇ g to about 75 ⁇ g, more preferably from about 2.0 ⁇ g to about 50 ⁇ g, more preferably still from about 2.2 ⁇ g to about 25 ⁇ g, more preferably from about 2.3 ⁇ g to about 10 ⁇ g, most preferably from about 2.5 ⁇ g to about 5 ⁇ g.
- the dose range is at least about 2.5 ⁇ g.
- doses are administered over a 1 day to 6 month period, more preferably from about 1 week to about 1 month.
- 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.
- Pharmaceutically Acceptable Carrier are administered over a 1 day to 6 month period, more preferably from about 1 week to about 1 month.
- the Vitamin D compound, osteoinductive extract, or BMP may be administered via a pharmaceutically acceptable carrier.
- pharmaceutically-acceptable carrier means one - 14 - or more compatible solid or liquid filler diluents or encapsu ⁇ lating substances which are suitable for administration to a human or lower animal.
- compatible 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.
- substances which can ssr ⁇ e 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, ethylcellulose, 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 formulation
- 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
- NSAI drugs e.g., NSAI drugs; pain killers; muscle relaxants
- art-known local anesthetics may be included in the pharmaceutically-accept ⁇ able carrier (e.g., benzyl alcohol; Novocaine*; lidocaine).
- Additional examples of carriers include collagen, deminer ⁇ alized bone particles, ceramic and metallic implant materials, collagen membrane and bone grafts (isogenic or allogenic).
- a pharmaceutically-acceptable carrier to be used in conjunction with the compounds of the present invention is - 15 - 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).
- 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%.
- compositions of the present invention are described more fully hereinafter.
- Oral Dose Forms are described more fully hereinafter.
- the vita ⁇ rn D compound is administered via an oral dose form.
- 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 .ne compound of the present invention. Tablets can be compressed, enteric-coated, sugar-coated or film- coated containing suitable tinders, lubricants, surfactants, dilu ⁇ ents, 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 or ⁇ l administration include gelatin and propylene glycol.
- Specific examples of pharmaceutically-accept ⁇ able carriers and excipient.5 that may be used in formulating oral dosage forms containing compounds of the present invention are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, incorporated by reference herein.
- Topical-oral carrier 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 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, espe ⁇ cially 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.
- 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 sur ⁇ factant (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%).
- a dental abrasive from about 10% to about 50%
- a sur ⁇ factant 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
- 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%).
- an anticaries agent from about 0.05% to about 0.3% as fluoride ion
- an anticalculus agent from about 0.1% to about 13%)
- an antiplaque agent from about 0.1% to about 5%
- 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 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%).
- an anticaries agent from about 0.05% to about 0.3% as fluoride ion
- an anticalculus agent from about 0.01% to about 3%
- an antiplaque agent from about 0.1% to about 5%
- 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 technol- ogies: 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.
- 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 concen ⁇ tration, 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.
- 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.
- the injectable compo ⁇ sition 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.
- 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 alco ⁇ hols (e.g., benzyl alcohol).
- urea compounds e.g., urea; urethan
- surfactants e.g., Tweens; Spans; sodium deoxycholate and Pluronics
- cellulosic agents e.g., carb
- acids to be used include the following: glucuronic; galacturonic; fumaric; gentisic; acetic; citric and lactobionic.
- Types of antimicrobial agents that can be used are the following: phenyl mercuric nitrate; thi erosal ; benzethoniu chloride; benzal konium chl oride; phenol ; cresol ; and chlorobutanol .
- An art-known local anesthetic e.g. , benzyl alcohol ; Novocaine*; l idocaine may al so be included.
- the osteoinductive extract and the BMP's are administered via an injectable dose form.
- An injectable composition comprising • the osteoinductive- extract and an oral composition comprising 1,25-dihydroxy Vitami.n D 3 for bone fracture repair is prepared by combining the following components utilizing conventional mixing techniques.
- BMP composition comprising • the osteoinductive- extract and an oral composition comprising 1,25-dihydroxy Vitami.n D 3 for bone fracture repair is prepared by combining the following components utilizing conventional mixing techniques.
- composition 1.25-dihvdroxy Vitamin D, composition
- Component of Composition 1,25-dihydroxy Vitamin D 3 0.01 Corn starch 18.49 Lactose 63.00 Talc 18.00 Stearic acid 0.50
- 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 ⁇ g of the 1,25-dihydroxy Vitamin D 3 composition is orally administered 24 hours before fracture reduction and once daily thereafter.
- the BMP and 1,25-dihydroxy Vitamin D 3 are adminis- tered until desired repair is achieved, perferably over a seven day period.
- EXAMPLE II An injectable composition for bone fracture repair is prepared by combining the following components utilizing conven ⁇ tional mixing techniques.
- 100.00 0.1 cc of the composition is injected into the fracture site at the time of fracture reduction and once daily thereafter until desired repair is achieved.
- EXAMPLE III A composition for inducing bone growth following reconstruc ⁇ tive surgery is prepared by combining the following components utilizing conventional mixing techniques.
- 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- tional mixing techniques.
- a topical oral carrier composition for periodontal therapy is 0 prepared by combining the following components utilizing conven ⁇ tional mixing techniques.
- An injectable composition comprising the BMPs 2, 3, 4 and 5 and an oral composition comprising 1,25-dihydroxy Vitamin D 3 for treatment of osteoporosis is prepared by combining the follow i ng components utilizing conventional mixing techn i ques.
- Component of Composition 1,25-dihydroxy Vitamin D 3 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-dihydroxy Vitamin D 3 composition is orally administered within one hour of the osteoinductive extract injection and once daily thereafter.
- the osteoinductive extract and 1,25-dihydroxy Vitamin D are administered over a 7-day period.
- non-union fracture means a fracture that has failed to heal normally.
- Acid demineralized bone particles 90.000 NaCl 0.900 Sterile water for injection q.s.
- GCATCTCTGT CACACCCGGG GAGAAGATCA TCCTGAACTT CACGTCCCTG GACCTGTACC 114
- CTGCGGTCTC CTAAAGGTCG ACCATGGTGG CCGGGACCCG CTGTCTTCTA GCGTTGCTGC
- GAAACCAAAG TCAACTCCTT GGCCATCTGT CAGTGGATAT GGCCAAATCT CATCGAGATA 9
- ATAGCCACAT CAGAGCTGCC CTTTCCATTG AGCGGAGGAA GAAGCGCTCT ACTGGGGTCT 12
- CCAGCATGTC AGGATTAGCC GATCGTTACC TCAAGGGAGT GGGAATTGGG CCCAGCTCCG 120
- ACCAGGCTAC CAGGCCTTCT ACTGCCATGG GGACTGCCCC TTTCCACTGG CTGACCACCT 144
- CAACTCAACC AACCATGCCA TTGTGCAGAC CCTGGTCAAT TCTGTCAATT CCAGTATCCC 150
- CTCCTCCCCC AAAAACCCAC CAAAATTAGT TTTAGCTGTA GATCAAGCTA TTTGGGGTGT 2040 TTGTTAGTAA ATAGGGAAAA TAATCTCAAA GGAGTTAAAT GTATTCTTGG CTAAAGGATC 21
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
RU93058532A RU2107512C1 (en) | 1991-06-05 | 1992-05-26 | Pharmaceutical composition for osteoinduction and method for generation of a new bone |
JP5500485A JPH06508140A (en) | 1991-06-05 | 1992-05-26 | Therapeutic composition for bone induction |
CS932624A CZ282231B6 (en) | 1991-06-05 | 1992-05-26 | Pharmaceutical preparation for generating new growth of a bone in a mammal |
AU21454/92A AU667815B2 (en) | 1991-06-05 | 1992-05-26 | Therapeutic compositions for osteoinduction |
BR9206110A BR9206110A (en) | 1991-06-05 | 1992-05-26 | Therapeutic compositions for osteoinduction |
SK1366-93A SK136693A3 (en) | 1991-06-05 | 1992-05-26 | Therapeutic compositions for osteoinduction |
NO934381A NO934381L (en) | 1991-06-05 | 1993-12-02 | Therapeutic compositions for osteoinduction |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US70962191A | 1991-06-05 | 1991-06-05 | |
US709,621 | 1991-06-05 | ||
US85611092A | 1992-03-27 | 1992-03-27 | |
US856,110 | 1992-03-27 |
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WO1992021365A1 true WO1992021365A1 (en) | 1992-12-10 |
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PCT/US1992/004356 WO1992021365A1 (en) | 1991-06-05 | 1992-05-26 | Therapeutic compositions for osteoinduction |
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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) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993005751A3 (en) * | 1991-08-30 | 1993-05-13 | Creative Biomolecules Inc | Osteogenic proteins in the treatment of bone deseases |
WO1995033831A1 (en) * | 1994-06-07 | 1995-12-14 | Creative Biomolecules, Inc. | Methods and compositions for modulating morphogenic protein expression |
US5533836A (en) * | 1993-03-29 | 1996-07-09 | Zymogenetics, Inc. | Compositions and methods for stimulating the growth of osteoblasts |
WO1997021447A1 (en) * | 1995-12-12 | 1997-06-19 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
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 |
US6071695A (en) * | 1992-02-21 | 2000-06-06 | Creative Biomolecules, Inc. | Methods and products for identification of modulators of osteogenic protein-1 gene expression |
US6492508B1 (en) | 1996-06-03 | 2002-12-10 | United States Surgical Corp. A Division Of Tyco Healthcare Group | Nucleic acids encoding extracellular matrix proteins |
JP2005518788A (en) * | 2001-10-31 | 2005-06-30 | アルコン,インコーポレイテッド | Bone morphogenetic protein (BMP), BMP receptor and BMP binding protein and their use in the diagnosis and treatment of glaucoma |
US7026292B1 (en) | 1995-12-12 | 2006-04-11 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
US7056882B2 (en) | 1991-03-11 | 2006-06-06 | Curis, Inc. | Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases |
EP2332564A1 (en) * | 1997-02-07 | 2011-06-15 | Stryker Corporation | Matrix-free osteogenic devices, implants and methods thereof |
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RU2146928C1 (en) * | 1998-07-02 | 2000-03-27 | Белых Сергей Иванович | Composition for stimulation of osseous tissue regeneration |
AU2004273658A1 (en) * | 2003-09-19 | 2005-03-31 | Wisconsin Alumni Research Foundation (Warf) | Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and an estrogen agonist/antagonist |
PL2148684T3 (en) * | 2007-04-25 | 2013-06-28 | Cytochroma Inc | Method of treating vitamin d insufficiency and deficiency |
SG2014010680A (en) * | 2009-02-12 | 2014-04-28 | Stryker Corp | Peripheral administration of proteins including tgf-beta superfamily members for treatment of systemic disorders and disease |
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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 |
Citations (1)
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US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
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1992
- 1992-05-26 CZ CS932624A patent/CZ282231B6/en unknown
- 1992-05-26 WO PCT/US1992/004356 patent/WO1992021365A1/en not_active Application Discontinuation
- 1992-05-26 RU RU93058532A patent/RU2107512C1/en active
- 1992-05-26 CA CA002110410A patent/CA2110410C/en not_active Expired - Fee Related
- 1992-05-26 JP JP5500485A patent/JPH06508140A/en active Pending
- 1992-05-26 EP EP92913307A patent/EP0587751A1/en not_active Withdrawn
- 1992-05-26 BR BR9206110A patent/BR9206110A/en not_active Application Discontinuation
- 1992-05-26 AU AU21454/92A patent/AU667815B2/en not_active Ceased
- 1992-05-26 SK SK1366-93A patent/SK136693A3/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
-
1993
- 1993-12-02 NO NO934381A patent/NO934381L/en unknown
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US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
Non-Patent Citations (1)
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Nutrition Reviews, vol. 47, no. 11, November 1989, "Bone morphogenic proteins and vitamin D", pages 364-366, see whole article * |
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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 |
WO1993005751A3 (en) * | 1991-08-30 | 1993-05-13 | Creative Biomolecules Inc | Osteogenic proteins in the treatment of bone deseases |
EP1637156A1 (en) * | 1991-08-30 | 2006-03-22 | Curis, Inc. | Systemic administration of osteogenic proteins in the treatment of metabolic bone diseases |
US6071695A (en) * | 1992-02-21 | 2000-06-06 | Creative Biomolecules, Inc. | Methods and products for identification of modulators of osteogenic protein-1 gene expression |
US5533836A (en) * | 1993-03-29 | 1996-07-09 | Zymogenetics, Inc. | Compositions and methods for stimulating the growth of osteoblasts |
WO1995033831A1 (en) * | 1994-06-07 | 1995-12-14 | Creative Biomolecules, Inc. | Methods and compositions for modulating morphogenic protein expression |
US6048964A (en) * | 1995-12-12 | 2000-04-11 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
US5948428A (en) * | 1995-12-12 | 1999-09-07 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
AU719120B2 (en) * | 1995-12-12 | 2000-05-04 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
US5916870A (en) * | 1995-12-12 | 1999-06-29 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
US5854207A (en) * | 1995-12-12 | 1998-12-29 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
US7026292B1 (en) | 1995-12-12 | 2006-04-11 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
WO1997021447A1 (en) * | 1995-12-12 | 1997-06-19 | 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 |
US6958223B2 (en) | 1996-06-03 | 2005-10-25 | United States Surgical Corporation | Methods for producing extracellular matrix proteins |
EP2332564A1 (en) * | 1997-02-07 | 2011-06-15 | Stryker Corporation | Matrix-free osteogenic devices, implants and methods thereof |
JP2005518788A (en) * | 2001-10-31 | 2005-06-30 | アルコン,インコーポレイテッド | Bone morphogenetic protein (BMP), BMP receptor and BMP binding protein and their use in the diagnosis and treatment of glaucoma |
Also Published As
Publication number | Publication date |
---|---|
CA2110410C (en) | 1997-04-15 |
CZ262493A3 (en) | 1994-07-13 |
AU2145492A (en) | 1993-01-08 |
EP0587751A1 (en) | 1994-03-23 |
IE921812A1 (en) | 1992-12-16 |
SK136693A3 (en) | 1994-10-05 |
RU2107512C1 (en) | 1998-03-27 |
CZ282231B6 (en) | 1997-06-11 |
PT100567A (en) | 1994-01-31 |
NO934381D0 (en) | 1993-12-02 |
BR9206110A (en) | 1995-07-11 |
NZ243018A (en) | 1995-12-21 |
NO934381L (en) | 1994-01-31 |
JPH06508140A (en) | 1994-09-14 |
AU667815B2 (en) | 1996-04-18 |
CA2110410A1 (en) | 1992-12-10 |
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