Source: http://www.google.com/patents/US8057595?ie=ISO-8859-1
Timestamp: 2014-03-13 20:12:21
Document Index: 181825808

Matched Legal Cases: ['Application No. 60', 'Application No. 60', 'Application No. 2004273794', 'Application No. 2004273794', 'Application No. 2004273794', 'Application No. 200480032523', 'Application No. 200480032523', 'Application No. 200480032523', 'Application No. 2002', 'Application No. 2002']

Patent US8057595 - Bone cement compositions having fiber-reinforcement and/or increased flowability - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThe present invention relates in general to implantable compositions, and method for preparing same, containing a calcium salt-containing component, optionally demineralized bone, a plurality of discrete fibers, optionally a flow additive, and optionally continuous reinforcing fibers or an array of organized...http://www.google.com/patents/US8057595?utm_source=gb-gplus-sharePatent US8057595 - Bone cement compositions having fiber-reinforcement and/or increased flowabilityAdvanced Patent SearchPublication numberUS8057595 B2Publication typeGrantApplication numberUS 12/611,716Publication dateNov 15, 2011Filing dateNov 3, 2009Priority dateSep 5, 2003Also published asCA2539751A1, EP1663333A2, US7494950, US7628851, US20050208094, US20080226691, US20100048763, WO2005027988A2, WO2005027988A3Publication number12611716, 611716, US 8057595 B2, US 8057595B2, US-B2-8057595, US8057595 B2, US8057595B2InventorsBryan Monro Armitage, Ira Ison, Mark Fulmer, Sean Kerr, Michael Lehmicke, Patrick Leamy, William SchifferOriginal AssigneeSynthes Usa, LlcExport CitationBiBTeX, EndNote, RefManPatent Citations (61), Non-Patent Citations (37), Classifications (36) External Links: USPTO, USPTO Assignment, EspacenetBone cement compositions having fiber-reinforcement and/or increased flowabilityUS 8057595 B2Abstract The present invention relates in general to implantable compositions, and method for preparing same, containing a calcium salt-containing component, optionally demineralized bone, a plurality of discrete fibers, optionally a flow additive, and optionally continuous reinforcing fibers or an array of organized fibers in the form of mesh. Advantageously, the discrete fibers have a specific aspect ratio (length/diameter) from about 50:1 to about 1000:1. The addition of a small amount of discrete fibers and/or the continuous reinforcing fibers or fiber mesh can cause drastic increases in certain mechanical properties including flexural strength, flexural toughness, and/or screw pullout strength.
solid components including:
an alkaline earth salt-containing component
a plurality of γ-irradiated polymer fibers comprising at least about 15% by weight of L-lactide component repeat units and at least about 15% by weight of glycolide component repeat units, the fibers having an aspect ratio of about 50:1 to about 1000:1, the fibers having a modified surface configured to increase pullout resistance; and
2. The implantable composition of claim 1, wherein the alkaline earth salt-containing component is a calcium salt-containing component.
3. The implantable composition of claim 2, wherein the calcium salt-containing component is chosen from a list consisting of amorphous calcium phosphate, crystalline calcium phosphate, CaHPO4, CaHPO4.H2O, α�Ca3(PO4)2, α-bar-Ca3(PO4)2, β�Ca3(PO4)2, γ�Ca3(PO4)2, Ca5(PO4)3OH, Ca4O(PO4)2, CaP4O11, α�Ca2P2O7, β�Ca2P2O7, γ�Ca2P2O7, Ca(H2PO4)2.nH2O, where n is a real number from 0 to 5, Ca8H2(PO4)6.5H2O, Ca(SO4)2, α�Ca(SO4)2.1/2H2O, or β�Ca(SO4)2.1/2H2O; or any combination thereof.
4. The implantable composition of claim 1, wherein the alkaline earth salt-containing component includes a magnesium salt-containing component.
5. The implantable composition of claim 1, wherein the fibers have a fiber length of approximately 0.5 mm to 1.5 mm.
6. An implantable composition comprising:
an alkaline earth salt-containing component;
about 1% to about 5% by weight of γ-irradiated resorbable polymer fibers comprising at least about 15% by weight of L-lactide component repeat units and at least about 15% by weight of glycolide component repeat units, the fibers having an aspect ratio from about 50:1 to about 1000:1, the fibers having a modified surface configured to increase pullout resistance; and
7. The implantable composition of claim 6, wherein the alkaline earth salt-containing component is a calcium salt-containing component.
8. The implantable composition of claim 7, wherein the calcium salt-containing component is chosen from a list consisting of amorphous calcium phosphate, crystalline calcium phosphate, CaHPO4, CaHPO4.H2O, α�Ca3(PO4)2, α-bar-Ca3(PO4)2, β�Ca3(PO4)2, γ�Ca3(PO4)2, Ca5(PO4)3OH, Ca4O(PO4)2, CaP4O11, α�Ca2P2O7, β�Ca2P2O7, γ�Ca2P2O7, Ca(H2PO4)2.nH2O, where n is a real number from 0 to 5, Ca8H2(PO4)6.5H2O, Ca(SO4)2, α�Ca(SO4)2.1/2H2O, or β�Ca(SO4)2.1/2H2O\; or any combination thereof.
9. The implantable composition of claim 6, wherein the alkaline earth salt-containing component includes a magnesium salt-containing component.
10. The implantable composition of claim 6, wherein the fibers have a fiber length of approximately 0.5 mm to 1.5 mm.
11. The implantable composition of claim 6, wherein the solid components further include demineralized bone.
12. The implantable composition of claim 6, further comprising an anti-microbial agent.
13. The implantable composition of claim 1, wherein the ratio of liquid components to solid components is from 0.41 to 0.55.
14. An implantable composition comprising:
a magnesium salt-containing component;
about 1% to about 5% by weight of γ-irradiated resorbable polymer fibers comprising at least about 15% by weight of L-lactide component repeat units and at least about 15% by weight of glycolide component repeat units, the fibers having an aspect ratio from about 50:1 to about 1000:1, wherein the fibers have a geometry configured to increase pullout resistance; and
15. The implantable composition of claim 14, wherein the fibers include ends that are not substantially flat.
16. The implantable composition of claim 14, further including a flow additive comprising hyaluronic acid, a hyaluronate salt, a sodium phosphate salt, or a combination thereof.
17. The implantable composition of claim 16, wherein the flow additive includes sodium hyaluronate.
18. The implantable composition of claim 14, wherein the solid components further include demineralized bone.
19. An implantable composition comprising:
a plurality of γ-irradiated polymer fibers comprising at least about 15% by weight of L-lactide component repeat units and at least about 15% by weight of glycolide component repeat units, the fibers having an aspect ratio of about 50:1 to about 1000:1;
one or more liquid components; and
a flow additive, wherein the composition can be injected through a syringe needle having a gauge size of about 12 or greater with a maximum injection pressure of not more than about 40 pounds.
20. The implantable composition of claim 19, wherein the flow additive includes hyaluronic acid, a hyaluronate salt, a sodium phosphate salt, or a combination thereof.
21. The implantable composition of claim 19, wherein the flow additive includes sodium hyaluronate.
22. The implantable composition of claim 19, wherein the polymer fibers are present in an amount from about 1% to about 3% by weight of the composition.
23. The implantable composition of claim 19, wherein the polymer fibers are present in an amount from about 1% to about 2.5% by weight of the composition.
24. The implantable composition of claim 19, wherein the polymer fibers are present in an amount of about 2% by weight of the composition. Description
RELATED APPLICATIONS This application is a Continuation of U.S. patent application Ser. No. 12/130,287 filed May 30, 2008 now U.S. Pat. No. 7,628,851, and titled �BONE CEMENT COMPOSITIONS HAVING FIBER-REINFORCEMENT AND/OR INCREASED FLOWABILITY� which is a Continuation of U.S. patent application Ser. No. 10/936,188 filed on Sep. 7, 2004, and titled �BONE CEMENT COMPOSITIONS HAVING FIBER-REINFORCEMENT AND/OR INCREASED FLOWABILITY�, now issued as U.S. Pat. No. 7,494,950, which claims the benefit of U.S. Provisional Application No. 60/500,346, filed Sep. 5, 2003 and U.S. Provisional Application No. 60/574,532, filed May 25, 2004, the entire disclosure of each of the aforementioned applications being incorporated by reference herein in their entirety.
SUMMARY OF THE INVENTION One aspect of the invention relates to an implantable composition comprising: (a) a calcium salt-containing component, preferably a calcium phosphate containing component, including amorphous calcium phosphate, crystalline calcium phosphate, CaHPO4, CaHPO4.H2O, α�Ca3(PO4)2, α-bar-Ca3(PO4)2, β�Ca3(PO4)2, γ�Ca3(PO4)2, Ca5(PO4)3OH, Ca10(PO4)6(OH)2, Ca4O(PO4)2, CaP4O11, α�Ca2P2O7, β�Ca2P2O7, γ�Ca2P2O7, Ca(H2PO4)2.nH2O, where n is a real number from 0 to 5, Ca8H2(PO4)6.5H2O or calcium pyrophosphate; calcium sulfates including Ca(SO4)2, α�Ca(SO4)2.�H2O, β�Ca(SO4)2.�H2O; or any combination thereof; and (b) discrete fibers that are resorbable homopolymers or copolymers (particularly from about 1% to about 5% by weight) that have an aspect ratio from about 50:1 to about 1000:1 and that have a fiber length of about 15 mm or less. In one embodiment, the implantable composition further comprises demineralized bone. In another embodiment, the composition may include continuous reinforcing fibers. Advantageously, the composition according to the invention can further comprise a flow additive including, but not limited to, hyaluronic acid, a hyaluronate salt, a sodium phosphate salt, or a combination thereof (optionally also including continuous reinforcing fibers).
In another embodiment, the invention relates to an implantable composition comprising solid and liquid components in the form of the following: (a) a calcium salt-containing component comprising: amorphous calcium phosphate, crystalline calcium phosphate, CaHPO4, CaHPO4.H2O, α�Ca3(PO4)2, α-bar-Ca3(PO4)2, β�Ca3(PO4)2, γ�Ca3(PO4)2, Ca5(PO4)3OH, Ca10(PO4)6(OH)2, Ca4O(PO4)2, CaP4O11, α�Ca2P2O7, β�Ca2P2O7, γ�Ca2P2O7, Ca(H2PO4)2.nH2O, where n is a real number from 0 to 5, Ca8H2(PO4)6.5H2O or calcium pyrophosphate; calcium sulfates including Ca(SO4)2, α�Ca(SO4)2.�H2O, β�Ca(SO4)2.�H2O; or any combination thereof; and (b) a plurality of discrete resorbable homopolymer or copolymer fibers having a fiber length of not more than about 15 mm. In one embodiment, the implantable composition further comprises demineralized bone. Advantageously, the ratio of liquid components to solid components in the implantable composition can be from about 0.41 to about 0.55, and the implantable composition can exhibit increases over the calcium salt-containing component and the optional flow additive in flexural strength from about 50% to about 900%, in screw pullout strength from about 75% to about 800%, in flexural toughness of at least about 35-fold, or in some combination thereof.
In another embodiment, the invention relates to an implantable composition comprising solid and liquid components in the form of the following: (a) a calcium salt-containing component comprising: amorphous calcium phosphate, crystalline calcium phosphate, CaHPO4, CaHPO4.H2O, α�Ca3(PO4)2, α-bar-Ca3(PO4)2, β�Ca3(PO4)2, γ�Ca3(PO4)2, Ca5(PO4)3OH, Ca10(PO4)6(OH)2, Ca4O(PO4)2, CaP4O11, α�Ca2P2O7, β�Ca2P2O7, γ�Ca2P2O7, Ca(H2PO4)2.nH2O, where n is a real number from 0 to 5, Ca8H2(PO4)6.5H2O or calcium pyrophosphate; calcium sulfates including Ca(SO4)2, α�Ca(SO4)2.�H2O, β�Ca(SO4)2.�H2O; or any combination thereof; (b) a plurality of discrete resorbable homopolymer or copolymer fibers; and (c) continuous reinforcing fibers comprising an array or mesh of resorbable homopolymer or copolymer fibers. In another embodiment, the implantable composition further comprises demineralized bone. Advantageously, the ratio of liquid components to solid components in the implantable composition can be from about 0.41 to about 0.55, and the implantable composition can exhibit increases over the implantable composition without the plurality of discrete fibers in flexural strength from about 50% to about 900%, in screw pullout strength from about 75% to about 800%, in flexural toughness of at least about 35-fold, or in some combination thereof.
Another aspect of the invention relates to an implantable composition comprising: (a) a calcium salt-containing component comprising: amorphous calcium phosphate, crystalline calcium phosphate, CaHPO4, CaHPO4.H2O, α�Ca3(PO4)2, α-bar-Ca3(PO4)2, β�Ca3(PO4)2, γ�Ca3(PO4)2, Ca5(PO4)3OH, Ca10(PO4)6(OH)2, Ca4O(PO4)2, CaP4O11, α�Ca2P2O7, β�Ca2P2O7, γ�Ca2P2O7, Ca(H2PO4)2.nH2O, where n is a real number from 0 to 5, Ca8H2(PO4)6.5H2O or calcium pyrophosphate; calcium sulfates including Ca(SO4)2, α�Ca(SO4)2.�H2O, β�Ca(SO4)2.�H2O; or any combination thereof; and (b) a plurality of discrete, resorbable, homopolymer or copolymer fibers that have an aspect ratio from about 50:1 to about 500:1, wherein the ends of the fibers have been modified to form beads, balls, dogbone shapes, or dumbbell shapes, the fibers have been textured to increase pullout resistance (e.g., kinking or crimping the fiber), or combinations thereof. In another embodiment, the implantable composition further comprises demineralized bone. Advantageously, the composition also includes continuous reinforcing fibers. In another embodiment, the composition according to the invention can further comprise a flow additive including hyaluronic acid, a hyaluronate salt, a sodium phosphate salt, or a combination thereof; and optionally continuous reinforcing fibers.
In an alternate embodiment, the calcium salt-containing component can comprise non-calcium phosphate-containing components, which include, but are not limited to, a calcium phosphite; a calcium carbonate; a calcium sulfate such as Ca(SO4)2, α�Ca(SO4)2.�H2O or β�Ca(SO4)2.�H2O; a calcium silicate; calcite; hydrocalcite; aragonite; or the like, or a combination thereof.
While acidic components are not always desired in bone cements, the calcium salt-containing component according to the invention can optionally contain a relatively small amount of an inorganic and/or an organic acid, preferably an organic acid. In such cases, any organic acid can be used, with specific examples thereof including, but not limited to, acetic acid, adipic acid, ascorbic acid, benzoic acid, butyric acid, citric acid, cinnamic acid, formic acid, fumaric acid, gallic acid, gluconic acid, glutamic acid, glutaric acid, glyceric acid, glycolic acid, glyconic acid, hydroxycimamic acid, isobutyric acid, isophthalic acid, lactic acid, malonic acid, maleic acid, malic acid, naphthoic acid, oxalic acid, phthalic acid, picolinic acid, propionic acid, salicylic acid, sebacic acid, succinic acid, tartaric acid, terephthalic acid, or the like, or combinations thereof. Preferred organic acids can include, but are not limited to, α-hydroxy acids such as glycolic acid, lactic acid, and the like, acetic acid, ascorbic acid, and combinations thereof. In one embodiment, the acidic component includes citric acid. In another embodiment, the acidic component does not include citric acid. Examples of inorganic acids that can be used alternately or in addition to organic acids include, but are not limited to, nitric acid, nitrous acid, hydrochloric acid, sulfuric acid, singly ionized sulfuric acids such as NaHSO4, KHSO4, Ca(HSO4)2, or the like, phosphoric acid, singly or doubly ionized phosphoric acids such as NaH2PO4, KH2PO4, LiH2PO4, Li2HPO4, Na2HPO4, K2HPO4, MgHPO4, or the like, phosphonic acids, ammoniated versions of the above acids (e.g., ammonium nitrate, ammonium chloride, diammonium sulfate, ammonium hydrogen sulfate, triammonium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, etc.), or the like, or combinations thereof. When present, the acid component in the bone cement is generally less than about 5% by weight, preferably less than about 4% by weight, e.g., from about 0.2% to about 1.5% by weight, from about 2% to about 4% by weight, from about 2.5% to about 3.5% by weight, or from about 0.1% to about 1% by weight, of the calcium salt-containing component or bone cement.
In another embodiment, the implantable composition can further comprise a radioopaque agent to provide a radioopaque cement. Non-limiting examples of radioopaque agents include barium sulfate, barium apatite, and iodine. In one embodiment, the implantable composition comprises barium sulfate.
In another embodiment, the resorbable fibers can comprise homopolymers or copolymers of monomers selected from the group consisting of L-lactide; L-lactic acid; D-lactide; D-lactic acid; D,L-lactide; glycolide; α-hydroxybutyric acid; α-hydroxyvaleric acid; α-hydroxyacetic acid; α-hydroxycaproic acid; α-hydroxyheptanoic acid; α-hydroxydecanoic acid; α-hydroxymyristic acid; α-hydroxyoctanoic acid; α-hydroxystearic acid; hydroxybutyrate; hydroxyvalerate; β-propiolactide; β-propiolactic acid; γ-caprolactone; β-caprolactone; γ-butyrolactone; pivalolactone; tetramethylglycolide; tetramethylglycolic acid; dimethylglycolic acid; trimethylene carbonate; dioxanone; those monomers that form liquid crystal (co)polymers; those monomers that form cellulose; those monomers that form cellulose acetate; those monomers that form carboxymethylcellulose; those monomers that form hydroxypropylmethyl-cellulose; polyurethane precursors comprising macrodiols selected from the group consisting of polycaprolactone, poly(ethylene oxide), poly(ethylene glycol), poly(ethylene adipate), poly(butylene oxide), and a mixture thereof, isocyanate-functional compounds selected from the group consisting of hexamethylene diisocyanate, isophorone diisocyanate, cyclohexane diisocyanate, hydrogenated methylene diphenylene diisocyanate, and a mixture thereof, and chain extenders selected from the group consisting of ethylenediamine, 1,4-butanediol, 1,2-butanediol, 2-amino-1-butanol, thiodiethylene diol, 2-mercaptoethyl ether, 3-hexyne-2,5-diol, citric acid, and a mixture thereof; collagen, alginates (e.g., sodium or calcium alginate), polysaccarides such as chitin and chitosan, poly(propylene fumarate); and any mixture thereof.
In still another embodiment, the resorbable fibers comprise a poly(L-lactide) (co)polymer, a poly(D,L-lactide) (co)polymer, a polyglycolide (co)polymer, a polycaprolactone (co)polymer, a poly(tetramethylglycolic acid) (co)polymer, a polydioxanone (co) polymer, a polyhydroxybutyrate (co)polymer, a polyhydroxyvalerate (co)polymer, a poly(L-lactide-co-glycolide) copolymer, a poly(glycolide-co-trimethylene carbonate) copolymer, a poly(glycolide-co-caprolactone) copolymer, a poly(glycolide-codioxanone-co-trimethylene carbonate) copolymer, a poly(tetramethylglycolic acid-co-dioxanone-co-trimethylene carbonate) copolymer, a poly(glycolide-co-caprolactone-co-L-lactide-co-trimethylene carbonate) copolymer, a poly(hydroxybutyrate-co-hydroxyvalerate) copolymer, a liquid crystal (co)polymer, a combination thereof, or a copolymer thereof. Preferably, the resorbable fibers comprise a poly(L-lactide-co-glycolide) copolymer.
When poly(L-lactide-co-glycolide) copolymer fibers are used in the composition according to the invention, it is preferable that the copolymers contain at least 11% of each of the L-lactide and glycolide component repeat units, preferably at least about 13%, more preferably at least about 15%, for example at least about 17%. Thus, preferred poly(L-lactide-co-glycolide) copolymer fibers according to the invention can contain from 11% to 89% L-lactide repeat units and from 89% to 11% glycolide units, preferably from about 13% to about 87% L-lactide repeat units and from about 87% to about 13% glycolide units, more preferably from about 15% to about 85% L-lactide repeat units and from about 85% to about 15% glycolide units, for example from about 17% to about 83% L-lactide repeat units and from about 83% to about 17% glycolide units. In one embodiment, the aforementioned percentage represent weight percentages of the component repeat units. In another embodiment, the aforementioned percentages represent mole percentages of the component repeat units. In a preferred embodiment, the poly(L-lactide-co-glycolide) copolymer fibers contain about 82% by weight of the lactide component and about 18% by weight of the glycolide component
In an alternate embodiment, a third type of repeat unit can be present in the poly(L-lactide-co-glycolide) copolymers according to the present invention, e.g., D-lactide dimer, D,L-lactide (or meso-lactide) dimer, the ring-opened structure of ε-caprolactone (or pentamethylene carboxylate ester) monomer, or D-lactic acid monomer, again depending upon the polymerization process used to form these copolymers.
The (co)polymer fibers according to the present invention can also exhibit a wide range of degrees of crystalline perfection (or crystalline imperfection), again with preferable values depending upon the desired application for which they are to be used. The degree of crystalline perfection or imperfection can be measured, for example, by DSC or another well-known experimental technique and can be referred to herein in terms of a heat of fusion (ΔHf), which represents the relative perfection or imperfection of the crystals of the copolymer in terms of the amount of energy per unit of material (e.g., in Joules per gram, J/g, or milliJoules per milligram, mJ/mg) required to melt, or de-crystallize, the crystals of the copolymer. In one embodiment, the fibers of the invention are semicrystalline and can exhibit a heat of fusion of less than about 50 J/g, for example less than about 30 J/g or less than about 25 J/g. In another embodiment, the fibers of the invention can exhibit a heat of fusion from about 50 J/g to about 70 J/g. In alternate embodiments, the fibers of the invention can exhibit a heat of fusion of from about 0.5 J/g to about 15 J/g, from about 0.1 J/g to about 10 J/g, from about 15 J/g to about 25 J/g, or can exhibit substantially no heat of fusion (i.e., less than about 0.1 J/g, or at any rate not quantitatively detectable by one or more experimental methods).
about 3 to about 14
about 100 to about 200
about 5 to about 9
about 50 to about 175
about 90 to about 175
Single or multiple doses to these means of sterilization can be performed on the copolymers, articles, or devices according to the invention in an amount, or in amounts, sufficient to prevent, inhibit, or curtail in vivo response. In one preferred embodiment, the sterilization includes a single dose exposure to 7-radiation or ethylene oxide. In another preferred embodiment, the sterilization includes a single dose exposure of the poly(L-lactide-co-glycolide) copolymers or devices according to the invention to γ-radiation of 25 kGy.
When the fiber ends have been altered or have a shape other than substantially flat and/or featureless (as is typical of most chopped fibers), the aspect ratio constraints mentioned above can be relaxed, particularly on the low end of the ratio. Therefore, where the fiber ends have been altered or have a shape other than substantially flat and/or featureless, the aspect ratio range can remain the same or advantageously change to be from about 50:1 to about 500:1, for example from about 75:1 to about 500:1, such as from about 100:1 to about 250:1. In cases where the fiber ends have been altered or have a shape other than substantially flat and/or featureless, the aspect ratio can be calculated using the diameter or width of the fibers away from the ends.
The flow additive, when used, is typically present in an amount from about 0.05% to about 5%, from about 0.1% to about 2.5%, or from about 0.25% to about 1% by weight of solid components of the composition. In one embodiment, the flow additive, when used, is present in amount of about 0.22% by weight of solid components and liquid components of the composition
Suitable examples of flow additives can include, but are in no way limited to, hyaluronic acid; hyaluronate salts such as sodium, potassium, lithium, or the like, or a combination thereof; alginate salts such as sodium, potassium, lithium, or the like; starch compounds, which can be present in its natural form (e.g., as extracted from one or more plants, or as purified by any method), in a destructured form, or in any number of chemically modified derivative forms (e.g., alkyoxylated derivatives, esterified derivatives, ionically modified starches, oxidized starches, grafted starches, crosslinked starches, or the like, or mixtures thereof); saturated, monounsaturated, and/or polyunsaturated oils, such as those extracted or isolated from plant and/or animal sources, e.g., including, but not limited to, sunflower, safflower, peanut, castor bean, sesame, coconut, soybean, corn, canola, olive, vegetable, palmitins, stearins, oleins, and the like, or derivatives or combinations thereof, as naturally extracted, as synthesized, or as modified or processed in some way, e.g., partially or fully hydrogenated, partially or fully dehydrogenated, partially or fully saponified, partially or fully acidified, partially halogenated, or the like; a wax including, but not limited to, hydrocarbon waxes (e.g., polyolefin waxes, such as polyethylene wax, polypropylene wax, and the like, or copolymers thereof), oligoester waxes, monoester waxes, oligoether waxes, monoether waxes, and the like, or combinations thereof, as naturally extracted, as synthesized, or as modified or processed in some way, e.g., partially or fully hydrogenated, partially or fully dehydrogenated, partially or fully saponified, partially or fully acidified, partially halogenated, or the like; cellulosic compounds, e.g., including, but not limited to, native or synthetic cellulose, cotton, regenerated cellulose (e.g., rayon, cellophane, or the like), cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate-propionate, cellulose acetate-butyrate, cellulose propionate-butyrate, cellulose nitrate, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, cellulose salts, and combinations or copolymers thereof, as naturally extracted, as synthesized, or as modified or processed in some way, e.g., partially or fully esterified, partially or fully nitrated, partially or fully regenerated, partially or fully etherified, partially or fully acidified, partially or fully acid-neutralized, or the like, or combinations thereof; surface-active biomolecules or (co)polymers; poly(ethylene glycol) and/or poly(ethylene oxide) oligomers, homopolymers, or copolymers; autologous substances such as autologous bone marrow aspirates, autologous blood substances, or the like, or a combination thereof; heterologous substances such as allogeneic bone marrow aspirates, xenogenic bone marrow aspirates, allogeneic blood substances, xenogenic blood substances, or the like, or a combination thereof; or the like, or combinations thereof. In a preferred embodiment, the flow additive comprises hyaluronic acid and/or a hyaluronate salt. In another preferred embodiment, the flow additive comprises sodium hyaluronate. In an alternate embodiment, the flow additive can include chondroitin, glucosamine, hyaluronic acid, a salt thereof, or a mixture thereof.
When the therapeutic substance is an antimicrobial agent, one, and usually no more than three, usually no more than two, antimicrobial agents can be present in the implant compositions. Non-limiting examples of useful antimicrobial agents include: Antiamebics, e.g. Arsthinol, Bialamicol, Carbarsone, Cephaeline, Chlorbetamide, Chloroquine, Chlorphenoxamide, Chlortetracycline, Dehydroemetine, Dibromopropamidine, Diloxanide, Diphetarsone. Emetine, Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo-5-quinoline-sulfonic Acid, Iodochlorhydroxyquin, Iodoquinol, Paromomycin, Phanquinone, Polybenzarsol, Propamidine, Quinfamide, Scenidazole, Sulfarside, Teclozan, Tetracycline, Thiocarbamizine, Thiocarbarsone, Tinidazole; Antibiotics, e.g. Aminoglycosides (such as Amikacin, Apramycin, Arbekacin, Bambermycins, Butirosin, Dibekacin, Dihydrostreptomycin, Fortimicin(s), Gentamicin, Isepamicin, Kaniamycin, Micronomicin, Neomycin, Neomycin Undecylenate, Netilmicin, Paromomycin, Ribostamycin, Sisomicin, Spectinomycin, Streptomycin, Tobramycin, Trospectomycin), Amphenicols (Azidamfenicol, Chloramphenicol, Florfenicol, Thiamphenicol), Ansamycins (Rifamide, Rifampin, Rifamycin, Rifapentine, Rifaximin), β-Lactams (Carbacephems, Loracarbef, Carbapenems (Biapenem, Imipenem, Meropenem, Panipenem), Cephalosporins (Cefaclor, Cefadroxil, Cefamandole, Cefatrizine, Cefazedone, Cefazolin, Cefcapene Povoxil, Cefclidin, Cefdinir, Cefditoren, Cefepime, Cefetamet, Cefixime, Cefinenoxine, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Cefozopran, Cefpimizole, Cefpiramide, Cefpirome, Cefpodoxime Proxetil, Cefprozil, Cefroxadine, Cefsulodin. Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam, Cephacetrile Sodium, Cephalexin, Cephaloglycin, Cephaloridine, Cephalosporin, Cephalothin, Cephapirin Sodium, Cephradine, Pivcefalexin), Cephamycins (Cefbuperazone, Cefinetazole, Cefminox, Cefotetan, Cefoxitin), Monobactams (Aztreonam, Carumonam, Tigemonam), Oxacephens (Flomoxef, Moxalactam), Penicillins (Amdinocillin, Amdinocillin Pivoxil, Amoxicillin, Ampicillin, Apalcillin, Aspoxicillin, Azidocillin, Azlocillin, Bacampicillin, Benzylpenicillic Acid, Benzylpenicillin Sodium, Carbenicillin, Carindacillin, Clometocillin, Cloxacillin, Cyclacillin, Dicloxacillin, Epicillin, Fenbenicillin, Floxacillin, Hetacillin, Lenampicillin, Metampicillin, Methicillin Sodium, Mezlocillin, Nafcillin Sodium, Oxacillin, Penamecillin, Penethamate Hydriodide, Penicillin G Benethamine, Penicillin G Benzathine, Penicillin G Benzhydrylamine, Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin G Potassium, Penicillin G Procaine, Penicillin N, Penicillin O, Penicillin V, Penicllin V Benzathine, Penicillin V Hydrabamine, Penimepicycline, Phenethicillin Potassium, Piperacillin, Pivampicillin, Propicillin, Quinacillin, Sulbenicillin, Sultamicillin, Talampicillin, Temocillin, Ticarcillin), Ritipenem), Lincosamides (Clindamycin, Lincomycin), Macrolides (Azithromycin, Carbomycin, Clarithromycin, Dirithromycin, Erythromycin, Erythromycin Acistrate, Erythromycin Estolate, Erythromycin Glucoheptonate, Erythromycin Lactobionate, Erythromycin Propionate, Erythromycin Stearate, Josamycin, Leucomycins, Midecamycins, Miokamycin, Oleandomycin, Primycin, Rokitamycin, Rosaramicin, Roxithromycin, Spiramycin, Troleandomycin), Polypeptides (Amphomycin, Bacitracin, Capreomycin, Colistin, Enduracidin, Enviomycin, Fusafungine, Gramicidin S, Gramicidin(s), Mikamycin, Polymyxin, Pristinamycin, Ristocetin, Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine, Tyrothricin, Vancomycin, Viomycin, Virginiamycin, Zinc Bacitracin), Tetracyclines (Apicycline, Chlortetracycline, Clomocycline, Demeclocycline, Doxycycline, Guamecycline, Lymecycline, Meclocycline, Methacycline, Minocycline, Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracycline, Sancycline, Tetracycline), Cycloserine, Mupirocin, Tuberin; synthetic antibacterial agents, e.g. 2,4-Diaminopyrimidines (Brodimoprim, Textroxoprim, Trimethoprim), Nitrofurans (Furaltadone, Furazolium Chloride, Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoinol, Nitrofurantoin), Quinolones and Analogs (Cinoxacin, Ciprofloxacin, Clinafloxacin, Difloxacin, Enoxacin, Fleroxacin, Flumequine, Grepafloxacin, Lomefloxacin, Miloxacin, Nadifloxacin, Nadilixic Acid, Norflaxacin, Ofloxacin, Oxolinic Acid, Pazufloxacin, Pefloxacin, Pipemidic Acid, Piromidic Acid, Rosoxacin, Rufloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin, Trovafloxacin), Sulfonamides (Acetyl Sulfamethoxpyrazine, Benzylsulfamide, Chloramine-B, Chloramine-T, Dichloramine T, N2-Formylsulfisomide, N4-βD-Gluco sylsulfanilamide, Mafenide, 4′-(Methylsulfamoyl)sulfanilanilide, Noprylsulfamide, Phthalylsulfacetamide, Phthalylsulfathiazole, Salazosulfadimidine, Succinylsulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide, 4-Sulfanilamidosalicylic Acid, N4-Sulfanilylsulfanilamide, Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine, Sulfisoxazole), Sulfones (Acedapsone, Acediasulfone, Acetosulfone Sodium, Dapsone, Diathymosulfone, Glucosulfone Sodium, Solasulfone, Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzylamine, Sulfoxone Sodium, Thiazolsulfone), Clofoctol, Hexedine, Methenamine, Methenamine Anhydromethylenecitrate, Methenamine Hippurate, Methenamine Mandelate, Methenamine Sulfosalicylate, Nitroxoline, Taurolidine, Xibomol; leprostatic antibacterial agents, such as Acedapsone, Acetosulfone Sodium, Clofazimine, Dapsone, Diathymosulfone, Glucosulfone Sodium, Hydnocarpic Acid, Solasulfone, Succisulfone, Sulfoxone Sodium, antifungal agents, such as Allylamines Butenafine, Naftifine, Terbinafine, Imidazoles (e.g., Bifonazole, Butoconazole, Cholordantoin, Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole, Fenticonazole, Flutrimazole, Isoconazole, Ketoconazole, Lanoconazole, Miconazole, Omoconazole, Oxiconazole Nitrate, Sertaconazole, Sulconazole, Tioconazole), Thiocarbamates (Tolcilate, Tolindate, Tolnaftate), Triazoles (Fluconazole, Itraconazole, Saperconazole, Terconazole), Acrisorcin, Amorolfine, Biphenamine, Bromosalicylchloranilide, Buclosamide, Calcium Propionate, Chlorphenesin, Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole Dihydrochloride, Exalamide, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, Sodium Propionate, Sulbentine, Tenonitrozole, Triacetin, Ujothion, Undecylenic Acid, Zinc Propionate; and the like.
Other antimicrobial agents useful in the present invention include β-lactamase inhibitors (e.g. Clavulanic Acid, Sulbactam, Tazobactam); Chloramphenicols (e.g. Azidamphenicol, Chloramphenicol, Thiaphenicol); Fusidic Acid; synthetic agents such as Trimethoprim, optionally in combination with sulfonamides) and Nitroimidazoles (e.g., Metronidazole, Tinidazole, Nimorazole); Antimycobacterial agents (e.g. Capreomycin, Clofazimine, Dapsone, Ethambutol, Isoniazid, Pyrazinamide, Rifabutin, Rifampicin, Streptomycin, Thioamides); Antiviral agents (e.g. Acryclovir, Amantadine, Azidothymidine, Ganciclovir, Idoxuridine, Tribavirin, Trifluridine, Vidarabine); Interferons (e.g. Interferon α, Interferon β); and antiseptic agents (e.g., Chlorhexidine, Gentian violet, Octenidine, Povidone Iodine, Quaternary ammonium compounds, Silver sulfadiazine, Triclosan).
The therapeutic substance can further comprise a biological therapeutic substance, such as, e.g., a protein. Bone associated proteins can be added to modify the physical properties of the composition, enhance resorption, angiogenesis, cell entry and proliferation, mineralization, bone formation, growth of osteoclasts and/or osteoblasts, or the like. Proteins of particular interest are the different types of collagen, particularly Type I. Other proteins include osteonectin, bone sialoproteins (Bsp), alpha-2HS-glycoproteins, bone Gla-protein (Bgp), matrix Gla-protein, bone phosphoglycoprotein, bone phosphoprotein, bone proteoglycan, protolipids, bone morphogenic proteins (e.g., BMP-1, -2A, -2B, -3, -3b, -4, -5, -6, -7, -8, -8b, -9, -10, -11, -12, -13, -14, -15), cartilage induction factor, platelet derived growth factor (PDGF-, -2), endothelial cell growth factors ((ECGF-1, -2a, -2b), skeletal growth factor (SKF=IGF-2). insulin-like growth factors (IGF-1, IGF-2), fibroblast growth factor (ODGF-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23), colony stimulating factor, transforming growth factor ((e.g., TGF-β), vascular endothelial growth factors (VEGF), growth/differentiation factors (GDF-1, -3, -5, -6, -7, -8, -9, -9B, -10, -11, -15, -16), osteogenic proteins (OP-1=BMP-7, OP-2=BMP-8, OP-3=BMP-8b), brown growth hormone, parathyroid hormone (PTH), insulin, calcitonin, and the like. The proteins can also include proteins associated with cartilage, such as chondrocalcining protein; proteins associated with dentin, such as phosphosphoryn, glycoproteins and Gla proteins; or proteins associated with enamel, such as amelognin and enamelin. Structural proteins of interest include fibrin, fibrinogen, keratin, tubulin, elastin, and the like. Blood proteins can be employed, individually or together, in plasma or serum, e.g., serum albumin.
optionally grind the calcium salt-containing component, especially when relatively small particle sizes of this component are desirable; incorporate a flow additive described above to form a flowable calcium phosphate-containing composition, particularly for compositions processed using conventional viscoelastic-liquid forming or liquid-setting means (e.g., by flow through an aperture such as injection or by unrestrained flow such as pouring. molding by hand, or the like, or a combination thereof); optionally, incorporate demineralized bone (e.g., by hand, using a rotary mixer, or using a pneumatic mixer) to form a calcium salt/demineralized bone-containing component; optionally incorporate a plurality of discrete fibers (e.g., by hand, using a rotary mixer, or using a pneumatic mixer) described above; optionally pre-treat a void and/or defect (e.g., in a bone), and/or an in vivo area proximal thereto, for receiving the composition according to the invention; optionally position and/or anchor continuous reinforcing fibers near, around, and/or within the void and/or defect, particularly for compositions processed using conventional viscoelastic-liquid forming or liquid-setting means (e.g., by flow through an aperture such as injection or by unrestrained flow such as pouring, molding by hand, or the like, or a combination thereof); introduce the flowable calcium salt-containing component into, onto, and/or proximal to the void and/or defect in order to at least partially coat and/or fill the void and/or defect, thus forming an implantable composite material; and optionally post-treat the at least partially coated and/or filled void and/or defect containing the implantable composite material and/or the in vivo area proximal thereto to form a biocompatible and/or semi-permeable surface (e.g., by exposing the available surface to a catalytic and/or reactive compound to chemically alter the available surface; to set or to hasten the setting of the composition at the available surface; to protect the available surface, and optionally the entire implantable composite material, from undesired immune response; to induce at the available surface, and/or optionally within the entire implantable composite material, an increased immune response; to establish a semi-permeable layer through which and/or into which only certain desirable biological compounds may pass, while excluding certain other undesirable biological compounds; or the like; or some combination thereof). Another aspect of the present invention relates to a kit or packaging system for storing, preparing, mixing, and/or administering compositions according to the invention. Advantageously, the kit or packaging system can contain the composite components in at least two separate compartments. In this embodiment, the solid portion of the calcium salt-containing component according to the invention (e.g., bone cement) can be present in one compartment, which can optionally also contain the fiber component(s) to form a solid or �dry� components compartment, while the liquid portion of the calcium salt-containing component according to the invention (e.g., setting solution) can be present in another compartment, which can optionally also contain the flow additive component to form a liquid or �wet� components compartment. A non-limiting example of a two-compartment kit is described in U.S. Pat. No. 6,149,655, the entire content of which is hereby incorporated by express reference hereto.
0.075m,
Comparative Example 1A is adapted from a cement commercially available from Norian Corp. of Chester, Pa. under the tradename NORIAN SRS�. Comparative Example 1B is a radioopaque cement commercially available from Norian Corp. of West Chester, Pa. under the tradename NORIAN XR�. Comparative Example IC is adapted from a fast set cement commercially available from Norian Corp. of Chester, Pa. under the tradename NORIAN CRS�, by changing the Na2HPO4 content from about 0.15 m to about 0.075 m and by changing the L/S ratio from about 0.56 to about 0.52.
Resorbable Fibers
1% (3 mm � 16-20 μm) L6 fibers
2% (3 mm � 16-20 μm) L6 fibers
2% (6 mm � 16-20 μm) L6 fibers
1% (8 mm � 16-20 μm) L6 fibers
2% (8 mm � 16-20 μm) L6 fibers
2% (8 mm � 16-20 μm) L6
dogbone fibers
2% (3 mm long) LACTOMER 9-
L6 fibers are chopped copolymer fibers of 82% glycolide and 18% lactide (wt:wt) and are commercially available from U.S. Surgical of New Haven, CT.
L6 dogbone fibers have the fiber ends altered so that the fibers are in the shape of a dogbone or dumbbell.
LACTOMER fibers are glycolide-L-lactide copolymer fibers commercially available from U.S. Surgical of New Haven, CT.
LACTOMER 9-1 fibers are chopped multifilament (i.e., ≧5-fiber) spools.
Continuous fiber or
Calcium Phosphate Composition
Flow Additive1 Na2HPO4 sol'n
Flow Additive1 Resorbable Fibers2 4A
Calcium Phosphate Comp.
1% (3 mm � 16-20 μm) L6
2% (3 mm � 16-20 μm) L6
2% (6 mm � 16-20 μm) L6
1% (8 mm � 16-20 μm) L6
(L/S = 0.48)
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T., et al., "Bone-Shaped Short Fiber Composites�An Overview", Materials Science and Engineering: A, 326(2), (2002), 208-227.* Cited by examinerClassifications U.S. Classification106/690, 106/691, 106/775, 106/774, 106/35, 106/772, 106/776, 106/780International ClassificationC09K3/00, A61K33/06, C04B12/02, A61K31/74, A61K33/42, C04B28/14, A61L27/50, A61L24/00, A61L27/46, A61L27/42Cooperative ClassificationA61L24/0063, A61K33/06, A61L24/001, A61L24/0084, A61L27/50, A61L27/425, A61K33/42, A61L27/46, A61K31/74European ClassificationA61K33/42, A61K31/74, A61K33/06, A61L24/00R4E, A61L24/00R2E, A61L27/50, A61L24/00H, A61L27/42E, A61L27/46RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google