MXPA00002219A

MXPA00002219A - Reverse phase connective tissue repair composition

Info

Publication number: MXPA00002219A
Application number: MXPA/A/2000/002219A
Authority: MX
Inventors: Cameron M L Clokie
Original assignee: Gensci Orthobiologics Inc
Priority date: 1997-09-02
Filing date: 2000-03-02
Publication date: 2001-12-13

Abstract

A biocompatible connective tissue repair composition which comprises a therapeutic material and a carrier comprising a means for achieving reverse phase characteristics, and methods for using said composition. The therapeutic material can be demineralized bone powder, and the carrier can be a poloxamer such as poloxamer 407.

Description

COMPOSITION FOR RECONSTRUCTION OF REVERSE PHASE CONNECTIVE TISSUE FIELD OF THE INVENTION This invention relates to prosthetic materials. More particularly, it relates to a biocompatible material exhibiting reverse phase behavior.

TECHNICAL BACKGROUND Osteogenic materials for bone reconstruction are known in the art. These materials contain an osteogenic material, such as demineralized bone powder in a vehicle, such as glycerol (see, e.g., U.S. Patent 5,290,558, issued March 1, 1994 to O'Leary et al., And U.S. Patent 5,284,655, Issued on February 8, 1994 to Bogdansky et al. In the art, the vehicle of the bone material is a liquid having a viscosity generally somewhere between shifting to the form of a paste.The "loose" compositions for the reconstruction of bone They have the advantage of being relatively easy to apply and filling the bone defect, however, they are unfavorable because the material also tends to flow rapidly from the defect site, conversely, the compositions for bone reconstruction with a consistency "in the form of paste", are more difficult to apply to a defect, and yet tend to remain placed in it once applied. positions for the reconstruction of bone in the technique are placed in vivo and are heated, they become even less viscous; The decrease in viscosity is due to the addition of thermal energy to the composition. Accordingly, there is a need for a composition for bone reconstruction that is easy to apply to the site of a defect, and that remains positioned on the site once placed therein.

BRIEF DESCRIPTION OF THE INVENTION A biocompatible composition for facilitating the reconstruction of connective tissues is described. The composition may comprise demineralized bone powder and a vehicle comprising means for achieving reverse phase thermodynamic characteristics when mixed with the bone powder. The composition may be substantially liquid at 0 ° C, and substantially more viscous at 35 ° C, so that the composition has a consistency similar to that of floor paste wax or similar to that of solid shoe wax. The means for achieving reverse phase characteristics may comprise a block copolymer such as a block copolymer which poly (oxyalkylene), which may be a triple block copolymer of poly (oxyethylene) -poly (oxypropylene) -poly (oxyethylene) ). The triple block copolymer can be a compound of the formula: HO (CH2CH2O) 98 (CHCH2O) 67 (CH2CH2O) 98H I CH3 fc 5 The means for achieving the reverse phase characteristics comprise a poloxamer, such as poloxamer 407. The block copolymer can be a solid dissolved in a biocompatible solvent such as sterile water. Preferably, the composition comprises a vehicle of 25% by weight of a block copolymer dissolved in 75% by weight of a biocompatible solvent. To vary the consistency of the composition, the weight percentage of the demineralized bone powder or other solid can be varied with respect to the weight percentage of the vehicle in the composition. For example, one form of the paste composition comprises 50% by weight of bone powder and 50% by weight in a vehicle solution. One embodiment of the gel composition comprises 70% by weight of bone powder and 30% by weight of a vehicle solution. The bone powder of the composition may comprise particles with a mean length ratio: average thickness of about 1742: 1, an average length of 0.25-1 mm (250-1,000 microns), and an average thickness of about 0.5. mm (500 microns). A method for facilitating the development of bone tissue is also described, said method comprising: providing a biocompatible composition for the reconstruction of connective tissue comprising demineralized bone powder and a vehicle comprising means for achieving reverse phase thermodynamic characteristics when mixed with the bone powder; and placing the composition in a mammalian bone defect. A prosthetic object can also be placed in the bone defect. The method may also comprise coating a portion of the prosthetic object with the biocompatible composition, and in this embodiment the step of placing the composition and the step of placing a prosthetic object, may be contemporary.

WAYS TO CARRY OUT THE INVENTION / Definitions "Reverse phase" or "reverse thermal behavior" means a material that exhibits the physical property of becoming more viscous or solidified after the addition of thermal energy. It is thought that solidification occurs by a mechanism different from that due to evaporation and loss of corresponding liquid. As used herein, the "ambient temperature" is 25 ° C, plus or minus 5 ° C. As used herein, the "body temperature" is 37 ° C, plus or minus 5 ° C. As used herein, a "bone defect" or "bone defect site" is the bony environment of a mammal that comprises some viable bone tissue. The defect can be congenital, caused by trauma or caused by illness. The "osteoinductive" materials cause the undifferentiated cells to differentiate into a line of compromised bone cells. "Osteoinductive" materials provide support for the cells of a lineage of bone cells, for example, by allowing the cells of a lineage of bone cells to grow along or through a matrix or crystal lattice.

PREFERRED MODALITIES OF THE INVENTION In a preferred embodiment, the composition of the present invention is a flowing liquid when applied to a bone defect, after which the composition solidifies increasingly or becomes more viscous as it is heated to room temperature, and solidifies further. as it warms to body temperature. After being heated to body temperature, a preferred composition of the invention is a highly viscous solid or fluid. The reverse phase compositions according to the invention are significantly different in principle from materials for bone reconstruction in the art, and do not work in the same way. The composition comprises a therapeutic material for treating one or more connective tissues, and a vehicle. The therapeutic material can be a material that facilitates the reconstruction of connective tissues, that is, a "material for the reconstruction of connective tissue". The vehicle achieves reverse phase characteristics when mixed with the therapeutic material. The therapeutic material may be a material that is osteoinductive or osteoconductive, or a material that is osteoinductive and osteoconductive. The therapeutic material can be xenogenic, allogenic or autogenous. The therapeutic material can be alloplastic. As will be appreciated by those skilled in the art, the therapeutic material may comprise combinations of various therapeutic materials. Examples of the osteoinductive material include, but are not limited to, bone powder (mineralized or demineralized), tissue growth beta factor (TGF-β) types 1 to 13, bone morphogenetic protein (BMP) types 1 to 15, or combinations thereof. Examples of therapeutic materials that are osteoinductive include, but are not limited to, xenogeneic bone (mineralized or demineralized); the xenogeneous bone can also be subjected to deproteinization. The currently preferred xenogenic sources are porcine and bovine. Therapeutic materials that are osteoinductive and osteoconductive include human allograft in particles, for example, demineralized bone. Examples of alloplastic materials include gypsum, coral hydroxyapatite, synthetic hydroxyapatite, calcium carbonate, calcium phosphate, calcium sulfate, biodegradable polymeric materials, or combinations thereof. A presently preferred composition comprises demineralized osteogenic bone powder in a vehicle; the composition can be applied to the site of a bone defect to induce new bone growth. The composition of the present invention comprises particles or granules of demineralized bone (referred to herein as "demineralized bone powder") in an inert biocompatible carrier. In a preferred embodiment, the particles / granules have a ratio of average length: average thickness of approximately 1742: 1, an average length of 0.25-1 mm (250-1,000 microns) and an average thickness of approximately 0.5 mm (500 microns). The presently preferred biocompatible carrier of the composition of the invention is a material that confers reverse phase thermodynamic properties to the composition. The use of PLURONIC® F127 as a component of a osseointegration promoting composition is described in the US patent. 5,503,558, issued on April 2, 1996 to the inventor of the present, Cameron C. L. Clokie; and in the PCT international publication No. WO 95/13099. In a currently preferred embodiment, the carrier comprises a polymer marketed by BASF (Parsipanny, New Jersey) as PLURONIC® F127. PLURONIC® F127 is a block copolymer of poly (oxyalkylene); more specifically, a triple block copolymer of poly (oxyethylene) -poly (oxypropylene) -poly (oxyethylene): is a member of the class of compounds called poloxamers (Schmolka, "A Review of Block Polymer Surfactants" J. Am. Oil Chemists Soc. 54: 110-116 (1977)). Several members of the poloxamer family exhibit reverse phase thermodynamic characteristics.

PLURONIC® F127 is also known as "poloxamer 407" (Schmolka, "A Comparison of Block Polymer Surfactant Gels" J. Am Oil Chemist Soc. 68: 206-209 (1991)). PLURONIC® F127 has an average molecular weight of about 12,500 (Schmolka, "A Comparison of Block Polymer Surfactant Gels" J. Am Oil Chemist Soc. 68: 206-209 (1991)). The following shows the polymer structure PLURONIC® F127: HO (CH2CH2O) 98 (CHCH2O) 67 (CH2CH2O) 98H I CH3 In preferred embodiments of a composition of the present invention, the carrier is a liquid diluted in a solvent, or is a solid dissolved in a solvent. In one embodiment, PLURONIC® F127 is dissolved in a solvent such as sterile water. The PLURONIC® F127 vehicle is widely different in size, molecular weight and chemical structure from the vehicles in the art. The vehicle is also substantially different in terms of its functional properties than any vehicle of a material for bone reconstruction in the art. The proposed composition has a unique physical property, being flowable at refrigerated temperatures, and increasingly solidified at elevated temperatures, such as ambient temperature and body temperature. This property is referred to in the art as "reverse phase" or "reverse thermal behavior". Due to the reverse phase property of the proposed composition, the composition is generally manufactured at refrigerated temperatures, such as 5 ° C. The manufacture is carried out at refrigerated temperatures to improve the mixing of the components of the composition, since the proposed composition comprising an aqueous solution of PLURONIC® F127 begins to be more viscous at room temperature, and is increasingly viscous and solidified at body temperature. Generally, a composition of the invention will be twice as viscous at 35 ° C, as Is is at 0 ° C. For example, the preferred vehicle PLURONIC® F127 in the composition of the present invention (when dissolved in an appropriate amount of sterile water), has the unique property of being a liquid at room temperature and of solidifying more and more, and then solid at room temperature, without the effects of evaporation and concomitant water loss. This property is called "reverse phase" or "reverse thermal behavior", since it is the exact opposite of the thermodynamic properties exhibited by standard vehicles. It is thought that the reverse phase property is due, at least in part, to the fact that PLURONIC® F127 is formed of defined blocks of hydrophilic (i.e., oxyethylene) and hydrophobic (i.e., oxypropylene) sub-units (cf. , for example, Schmolka, "A Comparison of Block Polymer Surfactant Gels" J. Am Oil Chemist Soc. 68: 206-209 (1991)). In contrast, standard vehicles, as well as all liquids, manifest the typical physical property of becoming more flowing after the addition of thermal energy, such as occurs when the liquid is heated to body temperature. However, the preferred vehicle in a composition of the present invention becomes less flowing as energy is added to it either by heating or by stirring. The unique reverse phase thermodynamic properties of the composition of the present invention allow the product to function substantially / differently and preferably from other flowing products for bone reconstruction. When the composition is applied to the site of a bone defect, the reverse phase property of the preferred vehicle provides support characteristics for the composition, which are substantially different from the characteristics of standard vehicles. The improved support is provided by the composition of the invention. The preferred PLURONIC® F127 vehicle of the composition of the present invention, helps to provide support features which are different from those of any standard vehicle. This is because the composition is free flowing at room temperature, and can thus easily be applied to the site of a bone defect, but becomes increasingly viscous and solidified once it is heated at the site. The solidification of the composition of the present invention achieves several beneficial effects. When solidified, the composition does not drain from the defect site, and the solidified product immediately increases and facilitates structural support in the defect. In the same way, since the osteogenic composition of the invention is initially liquid, it quickly covers a defect, and then solidifies and achieves improved osteogenesis. Furthermore, in the case of preferred compositions of the invention comprising a sterile aqueous solution of PLURONIC® F127 as vehicle and demineralized bone powder, the vehicle will be reabsorbed or dissolved after approximately 3 days, leaving the osteogenic bone powder on the site. of the bone defect. It is thought to be advantageous for the vehicle to dissolve, since this then allows for improved new growth of connective or vascular tissues. In a composition of the invention, the percentages by weight of the therapeutic material and the vehicle can be varied. For example, the weight percentage of the therapeutic material can vary between about 20 to 80% by weight of the composition, and the weight percentage of the vehicle can vary between about 20 to 80% by weight of the composition. In addition, one or more additional components may be present in a composition of the invention, such as antibiotics, analgesics, anti-inflammatory agents or agents to promote tissue development of the circulatory or connective systems.

EXAMPLES EXAMPLE 1 To obtain a composition having a consistency in the form of a gel, the composition comprised 70% by weight of a solution of PLURONIC® F127 and 30% by weight of bone powder. In this example, the vehicle comprised 25% by weight of PLURONIC® F127 powder dissolved in 75% by weight of sterile water. A composition of the invention is available as a gel DynaGraft ™ (GenSci Regeneration Laboratories, Inc., Irvine, CA); this product is a composition comprising demineralized allograft bone from a single donor, mixed with an inert preservative and a biocompatible carrier. The composition has a "gel" consistency, and is provided in a single sterile package for use by the patient. The tissues used in the composition for bone reconstruction are recovered by tissue banks of the United States, from carefully selected donors, according to standards established by the American Association of Tissue Banks. All tissues meet strict specifications during donor selection, and laboratory tests to reduce the risk of transmitting an infectious disease. For example, each donor is tested and found to be negative (to a minimum) for: hepatitis B surface antigen, human immunodeficiency virus antibodies 1 and 2, HTLV-1 antibody, hepatitis virus antibody C, and syphilis. The tests were carried out by a laboratory approved by CLIA using test equipment authorized by the FDA. The donor's medical and social history revealed no risk factors for, or clinical evidence of, HIV infection or hepatitis. This biocompatible composition according to the invention was produced under controlled conditions from the environmental point of view using strict cleaning, preservation and sterilization procedures. All steps are rigorously controlled in terms of quality, in accordance with accepted methodologies in the technique. DyrvaGraft ™ gel is indicated for use in surgical procedures in which osteogenesis, calcification or bone fusion is required to achieve or improve the quality of the final result. Accordingly, the DynaGraft ™ gel can be used in a variety of orthopedic, reconstructive and dental bone grafting procedures. The DynaGraft ™ gel can be used alone or as a bone graft in cases where the graft is not intended to provide weight support support or dimensional integrity to the graft site. If the graft is intended to support the weight, the composition should be used with proper fixation. The DynaGraft ™ gel, therefore, can be used as an adjunct to musculoskeletal implants, such as joint replacement prostheses, intra-oral implants and internal and external fixation devices for procedures in which demineralized bone allografts dehydrated by freezing. The composition is sterilized by a directed electron beam irradiation of 2.5 megarrads as a terminal sterilization. When the composition is implanted, a sterile technique must be maintained to minimize the risk of postoperative complications. The use of the composition is contraindicated when there is active or latent infection, in or near the surgical site. The composition should be stored long term in a clean and dry place at room temperature. It should be kept away from direct sunlight, and should not be frozen. DynaGraft ™ gel does not require rehydration before use. The packaging of all DynaGraft ™ implant compositions has been specially designed to provide ease of use within the surgical field. For example, the composition can be packed into syringes that are kept sterile within containers of one or more metal sheets. DynaGraft ™ gel is provided in 1.0 cm3 syringes, 5 cm3 and 10 cm3. To use the composition packaged in syringes within metal sheet containers, the package is opened by detaching the outer metal sheet and, using a sterile technique, transferring the entire inner package to the sterile field. The inner packing is then opened and the syringe removed. Immediately before use, a protective cap covering the tip of the syringe is removed. The composition is then extruded by pressing the plunger of the syringe to supply the desired volume. Proper placement and / or fixation are critical factors in the prevention of potentially adverse effects on the product's useful life. Therefore, the DynaGraft ™ gel is bacteriologically sterile during the shelf life established in an unopened and undamaged package. The product must be used before the expiration date. The unused product must be disposed of properly.

EXAMPLE 2 To obtain a composition having a paste-like consistency, the composition comprised 50% by weight of a solution of PLURONIC® F127 and 50% by weight of bone powder. In this example, the vehicle comprised 25% by weight of PLURONIC® F127 powder dissolved in 75% by weight of sterile water. A composition of the invention is available as DynaGraft ™ putty (GenSci Regeneration Laboratories, Inc., Irvine, CA); This product is a composition comprising demineralized bone from a single donor, mixed with an inert preservative and a biocompatible carrier. The composition has a "putty" consistency, and is provided in a single sterile package for use by the patient.

The tissues used in the composition for bone reconstruction are recovered by tissue banks of the United States, from carefully selected donors, according to standards established by the American Association of Tissue Banks. All tissues meet strict specifications during donor selection, and laboratory tests to reduce the risk of transmitting an infectious disease. For example, each donor is tested and found to be negative (to a minimum) for: hepatitis B surface antigen, human immunodeficiency virus antibodies 1 and 2, HTLV-1 antibody, hepatitis virus antibody C, and syphilis. The tests were carried out by a laboratory approved by CLIA using test equipment authorized by the FDA. The donor's medical and social history revealed no risk factors for, or clinical evidence of, HIV infection or hepatitis. This biocompatible composition according to the invention was produced under controlled conditions from the environmental point of view using strict cleaning, preservation and sterilization procedures. All steps are rigorously controlled in terms of quality, in accordance with accepted methodologies in the technique. DynaGraft ™ putty is indicated for use in surgical procedures in which osteogenesis, calcification or bone fusion is required to achieve or improve the quality of the final result. Therefore, DynaGraft ™ putty can be used in a variety of orthopedic, reconstructive and dental bone grafting procedures. DynaGraft ™ putty can be used alone or as a bone graft in cases where the graft is not intended to provide weight support support or dimensional integrity to the graft site. If the fc 5 graft is intended to support the weight, the composition should be used with proper fixation. DynaGraft ™ putty, therefore, can be used as an adjunct to musculoskeletal implants, such as joint replacement prostheses, intraoral implants, and internal and external fixation devices for procedures in which bone allografts would be used demineralized dehydrated by freezing. The composition is sterilized by a directed electron beam irradiation of 2.5 megarrads as a terminal sterilization. When the composition is implanted, a sterile technique must be maintained to minimize the risk of postoperative complications. The use of The composition is contraindicated when there is active or latent infection in or near the surgical site. The composition should be stored long term in a clean and dry place at room temperature. It should be kept away from direct sunlight, and should not be frozen. DynaGraft ™ putty does not require rehydration before use. The packaging of all DynaGraft ™ implant compositions has been specially designed to provide ease of use within the surgical field. For example, the composition can be packaged within containers that are kept sterile within containers of one or more metal sheets. DynaGraft ™ putty is provided in 2.5 cm3 containers, 5 cm3 and 10 cm3. To use the composition packaged in containers in sheet metal containers, the package is opened by detaching the outer metal sheet and, using a sterile technique, transferring the entire inner package to the sterile field. The inner packing is then opened, and the container and a spatula are removed. The lid of the container is opened in sterile form, and the putty of the composition is removed with the spatula or other instrument held by hand. Proper placement and / or fixation of the composition are critical factors in the prevention of potentially adverse effects on the product's useful life. Therefore, DynaGraft ™ putty is bacteriologically sterile during the shelf life established in an unopened and undamaged package. The product must be used before the expiration date. The unused product must be disposed of properly.

Conclusion It should be noted that as used herein and in the appended claims, the singular forms "a" "and" and "the" include plural references, unless the context clearly dictates otherwise.

Thus, for example, the reference to "a formulation" includes mixtures of different formulations, and the reference to "the treatment method" includes references to equivalent steps and methods known to those skilled in the art, etc. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. Although methods and materials similar to, or equivalent to, those described herein may be used in the practice or testing of the invention, preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A biocompatible composition for the reconstruction of connective tissue, characterized in that it comprises: demineralized bone powder and a vehicle comprising a liquid poloxamer solution or a solid poloxamer dissolved in a solvent, whereby said vehicle achieves reversed phase characteristics when mix with the demineralized bone powder.

2. The composition according to claim 1, further characterized / because the vehicle causes the composition to be substantially liquid at 0 ° C and substantially solid at 35 ° C.

3. The composition according to claim 1, further characterized in that it has a first viscosity at 0 ° C and a second viscosity at 35 ° C, wherein the second viscosity is at least twice as large as the first viscosity.

4. The composition according to claim 1, further characterized in that the vehicle comprises a solid poloxamer dissolved in a solvent, and the poloxamer is poloxamer 407.

5. The composition according to claim 4, further characterized in that the solvent It is sterile water.

6. The composition according to claim 5, further characterized in that 25% by weight of the poloxamer 407 is dissolved in 75% by weight of sterile water.

7. The composition according to claim 1, further characterized in that 30% by weight of the bone powder is dispersed in 70% by weight of the vehicle.

8. The composition according to claim 1, further characterized in that 50% by weight of the bone powder is dispersed in 50% by weight of the vehicle.

9. The composition according to claim 1, further characterized in that the bone powder comprises particles with a ratio of average length: average thickness of about 1742: 1, an average length of 0.25-1 mm (250-1,000) microns) and an average thickness of approximately 0.5 mm (500 microns).

10. The biocompatible composition for the reconstruction of connective tissue, further characterized in that it comprises: a therapeutic material and a vehicle comprising means to achieve reverse phase characteristics.

11. The composition according to claim 10, further characterized in that the therapeutic material is osteoinductive, osteoconductive, or osteoinductive and osteoconductive.

12. The composition according to claim 10, further characterized in that the therapeutic material is allo- plastic, xenogeneic, allogenic or autogenous.

13. The composition according to claim 10, further characterized in that the means for achieving reverse phase characteristics make the composition substantially liquid at 0 ° C and substantially solid at 35 ° C.

14. The composition according to claim 10, further characterized in that it has a first viscosity at 0 ° C and a second viscosity at 35 ° C, wherein the second viscosity is at least twice as large as the first viscosity.

15. The composition according to claim 10, further characterized in that the means for achieving reverse phase characteristics comprise a poloxamer.

16. The composition according to claim 15, further characterized in that the means for achieving reverse phase characteristics comprise poloxamer 407.

17. The composition according to claim 10, further characterized by the means to achieve reverse phase characteristics. they comprise a block copolymer.

18. The composition according to claim 17, further characterized in that the means for achieving reverse phase characteristics comprise a poly (oxyalkylene) block copolymer.

19. The composition according to claim 18, further characterized in that the means for achieving reverse phase characteristics comprise a triple block copolymer of poly (oxyethylene) -poly (oxypropylene) -poly (oxyethylene).

20. The composition according to claim 19, further characterized in that the triple block copolymer comprises the formula: / 5 HO (CH2CH2?) 98 (CHCH2O) 67 (CH2CH2O) 98H I CH3

21. The composition according to claim 17, further characterized in that the block copolymer is a solid and is dissolved in a biocompatible solvent.

22. The composition according to claim 21, further characterized in that the biocompatible solvent is sterile water.

23. The composition according to claim 21, further characterized in that 30% by weight of the therapeutic material is dispersed in 70% by weight of the vehicle.

24. The composition according to claim 21, further characterized in that 50% by weight of the therapeutic material is dispersed in 50% by weight of the vehicle.

25. The composition according to claim 10, 20 further characterized in that the therapeutic material comprises bone powder, and the bone powder comprises particles with a mean length ratio: mean thickness of about 1742: 1, an average length of

0. 25-1 mm (250-1,000 microns) and an average thickness of approximately 0.5 mm (500 microns).

26. A method for facilitating the development of bone tissue, said method comprising: providing the composition according to claim 10, and placing the composition in a bone defect of a mammal.

27. The method according to claim 26, further characterized in that it comprises placing a prosthetic object in the bone defect.

28. The method according to claim 27, further characterized in that the composition covers a portion of the prosthetic object, and the step of placing the composition and the step of placing a prosthetic object, are contemporary.