Claims for Patent: 5,516,673

Summary for Patent: 5,516,673

Title:	Bioactive conjugates of cellulose with amino compounds
Abstract:	Polymers containing a plurality of free hydroxy groups, such as cellulose, agarose or polyvinyl alcohol, are contacted in absence of reactants for hydroxy groups, with at least one N-heterocyclic compound, e.g. pyridine, pyrrole, pyridazine, their partially or fully hydrogenated analogs and any of these which may be substituted, in a pre-activation step prior to reaction with reactant for free hydroxy groups in the polymer, the polymer-bound residue of which reactant may be thereafter reacted in turn with amino compounds containing at least one unsubstituted N-attached hydrogen atom, e.g. proteins, thereby to form amine-polymer conjugates. The invention further relates to a powder, bandage, patch or like cover for application to wounds which has been manufactured from polymer containing a plurality of hydroxy groups by a process which includes the step of providing an amine conjugated to the polymer; the amine may be, e.g., trypsin, chymotrypsin, lysozyme, collagenase, albumin and hyaluronidase.
Inventor(s):	Margel; Shlomo (Rehovot, IL), Sturchak; Sophia (Tel Aviv, IL)
Assignee:	Bar Ilan University (Ramat Gan, IL)
Application Number:	08/196,390
Patent Claims:	1. In a process for making conjugates of at least one amino compound containing at least one unsubstituted N-attached hydrogen atom, with at least one polymer which is selected from the group consisting of cellulose, polysaccharides other than cellulose and polyvinyl alcohol and its copolymers, and which contain a plurality of free hydroxy groups, which process comprises at least steps (a) and (b) of the following steps (a), (b) and (c), namely: (a) derivatizing the at least one polymer by reaction with at least one reactant for free hydroxy groups in said polymer, such reactant being selected from the group consisting of cyanogen halides, carbonate esters, halogenated s-triazines, haloformates, sulfonyl halides and N-heterocyclic compounds containing nuclear-bound active halogen atoms, (b) reacting the thus-derivatized polymer with at least one amino compound, and optionally (c) reconverting to hydroxy groups any polymer-bound groups which are the product of reacting polymer-bound hydroxy groups with such reactant; the improvement which comprises effecting a preactivation step prior to step (a) in order to increase the capacity of the at least one polymer for reaction with such at least one reactant, wherein said preactivation step consists of contacting said at least one polymer in absence of reactants for hydroxy groups, for a period of time sufficient to increase the capacity of the at least one polymer for reaction with such at least one reactant, with at least one N-heterocyclic compound selected from the group consisting of pyridine, pyrrole and pyridazine, partially hydrogenated analogs thereof, fully hydrogenated analogs thereof, and any of the foregoing which contain at least one substituent selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, fluorine, chlorine, bromine and trifluoromethyl. 2. In a process for making conjugates of at least one amino function in a protein, with at least one polymer which is selected from the group consisting of cellulose, polysaccharides other than cellulose and polyvinyl alcohol and its copolymers, and which contain a plurality of free hydroxy groups, which process comprises at least steps (a) and (b) of the following steps (a), (b) and (c), namely: (a) derivatizing the at least one polymer by reaction with at least one reactant for free hydroxy groups in said polymer, such reactant being selected from the group consisting of cyanogen halides, carbonate esters, halogenated s-triazines, haloformates, sulfonyl halides and N-heterocyclic compounds containing nuclear-bound active halogen atoms, (b) reacting the thus-derivatized polymer with at least one amino function, and optionally (c) reconverting to hydroxy groups any polymer-bound groups which are the product of reacting polymer-bound hydroxy groups with such reactant; the improvement which comprises effecting a preactivation step prior to step (a) in order to increase the capacity of the at least one polymer for reaction with such at least one reactant, wherein said preactivation step consists of contacting said at least one polymer in absence of reactants for hydroxy groups, for a period of time sufficient to increase the capacity of the at least One polymer for reaction with such at least one reactant, with at least one N-heterocyclic compound selected from the group consisting of pyridine, pyrrole and pyridazine, partially hydrogenated analogs thereof, fully hydrogenated analogs thereof, and any of the foregoing which contain at least one substituent selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, fluorine, chlorine, bromine and trifluoromethyl. 3. A process according to claim 2, wherein said at least one protein is selected from the group consisting of trypsin, chymotrypsin, lysozyme, collagenase, albumin and hyaluronidase. 4. A process according to claim 2, wherein said at least one polymer is in the form of a textile web which is adapted for use as a bandage, patch or like wound cover. 5. A process according to claim 4, wherein said at least one protein is selected from the group consisting of trypsin, chymotrypsin, lysozyme, collagenase, albumin and hyaluronidase.

Details for Patent 5,516,673

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	05/05/2004		2013-05-14
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	12/02/2004		2013-05-14
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	10/26/2004		2013-05-14
Akorn, Inc.	HYDASE	hyaluronidase	Injection	021716	10/25/2005		2013-05-14