Formulations for nonsurgical exogenous crosslink therapy
AssigneeOrthopeutics, L.P.
InventorsPaul Slusarewicz, Thomas P. Hedman
Life of this patent
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Abstract
Improved methods and compositions for the treatment of native tissues with crosslinkers are provided. The methods and compositions will find particular use in increasing resistance to tearing, fissuring, rupturing, and/or delamination.
Claims40
A method of inducing methylglyoxal (MG)-mediated cross-linking in a native tissue having naturally-occurring collagen crosslinks within a living body comprising contacting said tissue with a concentration of MG of at least 5 mM up to a concentration such that there are 2400 micromoles of MG in a dose, in 25-250 mM of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) buffer and any combination of the following in a composition of about pH 8.0-10:
- (a) 25-500 mM phosphate ions;
- (b) sodium borohydride at about 1-5 mM;
- and/or
- (c) a surfactant.
A method of inducing genipin (GP)-mediated cross-linking in a native tissue having naturally-occurring collagen crosslinks within a living body comprising contacting said tissue with a concentration of GP of at least 5 mM up to a concentration such that there are 2400 micromoles of GP in a dose, in 25-250 mM EPPS buffer and any combination of the following in a composition of about pH 8.0-10:
- (a) 25-500 mM phosphate ions;
- (b) a surfactant;
- and/or
- (c) a water-miscible co-solvent.
A method of inducing genipin (GP)-mediated cross-linking in a native tissue having naturally-occurring collagen crosslinks within a living body comprising contacting said tissue with a concentration of GP of at least 5 mM up to a concentration such that there are 2400 micromoles of GP in a dose, in 25-250 mM of a buffer in combination with a water-soluble co-solvent in a composition of about pH 8.0-10, wherein the co-solvent is dimethyl sulfoxide (DMSO), methanol, ethanol, propanol or acetonitrile.
A method of inducing proanthrocyanidin (PA)-mediated cross-linking in a native tissue having naturally-occurring collagen crosslinks within a living body comprising contacting said tissue with a concentration of PA of at least 0.025% w/v up to a concentration such that there are 2400 micromoles of PA in a dose in 25-250 mM of EPPS buffer in a composition of about pH 9.
A method of inducing transglutaminase (TG)-mediated cross-linking in a native tissue having naturally-occurring collagen crosslinks within a living body comprising contacting said tissue with a composition comprising about 0.5-5 U/ml TG in 25-250 mM of Tris buffer at about pH 8.
A method of inducing 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC)-mediated cross-linking in a native tissue having naturally-occurring collagen cross-links within a living body comprising contacting said tissue with a concentration of EDC of at least 2 mM up to a concentration such that there are 2400 micromoles of EDC in a dose and a combination of the following in a composition of about pH 6.0:
- (a) 25-250 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffer;
- and
- (b) a surfactant.
A method of inducing L- or D-threose (LT or DT)-mediated cross-linking in a native tissue having naturally-occurring collagen cross-links within a living body comprising contacting said tissue with a concentration of LT or DT of at least 20 mM up to a concentration such that there are 2400 micromoles of LT or DT in a dose, in 25-250 mM EPPS buffer and any combination of the following in a composition of about pH 8-10:
- (a) 25-250 mM phosphate ions;
- (b) sodium borohydride at about 1-5 mM;
- and/or
- (c) a surfactant.
A method of inducing cross-linking in a native tissue having naturally-occurring collagen crosslinks within a living body comprising contacting said tissue with a cross-linking agent and an anionic surfactant, wherein said cross-linking agent is selected from the group consisting of genipin, methylglyoxal, proanthrocyanidin, L-threose, D-threose, ribose, glyoxal, lysyl oxidase, an epoxy, 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide and transglutaminase, and wherein said anionic surfactant is an alkyl sulfonate, sodium cholate, sodium deoxycholate, an alkyl benzene sulfonate, N-lauroylsarcosine, or a fatty acid salt.
A composition of matter comprising about 5-100 mM methylglyoxal (MG) and about 25-200 mM EPPS at about pH 8.0-10 and 25-200 mM phosphate ions.
A composition of matter comprising about 5-100 mM genipin (GP) and about 25-200 mM EPPS at about pH 8.0-10 and 25-200 mM phosphate ions.
A composition of matter comprising about 0.025-10% w/v of proanthrocyanidin (PA) and about 25-200 mM Tris at about pH 8.0-10.
A composition of matter comprising about 20-100 mM L- or D-threose (LT or DT) and about 25-200 mM EPPS at about pH 8.0-10 and phosphate ions at about 25-200 mM.
A method of inducing cross-linking in a native tissue having naturally-occurring collagen crosslinks within a living human body comprising contacting said tissue with any combination of methylglyoxal at about 5-500 mM, genipin at 5-500 mM, about 0.5-5 U/ml transglutaminase, about 2-500 mM 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC), or about 20-100 mM L- or D-threose, wherein the combination is at about pH 8.0-10.
A kit for treating a living human body with a genipin-containing crosslinking reagent comprising:
- (a) GP in a powdered form or in a non-aqueous, water miscible carrier selected from the group consisting of ethanol, methanol, propanol, chloroform, dichloromethane, acetonitrile and dimethy sulfoxide;
- and in a sealed vial having a sterile inner surface;
- and
- (b) an aqueous carrier in a sealed vial having a sterile inner surface, said carrier comprising 25-250 mM of EPPS buffer at about pH 8.0-10.
Dependencies are inferred from the claim text.