Compositions of hyaluronic acid and methods of use

• US 20060094643A1
• Filed: 07/03/2003
• Published: 05/04/2006
• Est. Priority Date: 07/03/2002
• Status: Abandoned Application

• Current Assignee: Pericor Science, Inc.
• Original Assignee: Pericor Science, Inc.
• Inventors: Parsa, Ramine, Svirkin, Yuri, Zingerman, Dmitry
• Application Number:
  US10/519,329
• Publication Number:
  US 20060094643A1
• Time in Patent Office: Days
• US Class Current: 514/310
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/186 Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

The invention provides compositions for the treatment of disorders characterized by dryness including dry eye and dry mouth. The compositions commonly comprise a conjugate of hyaluronic acid and polylysine. These conjugates are attached to affected body tissues or surfaces using transglutaminase, and preferably endogenous transglutaminase.

Claims

1. A composition comprising a conjugate of hyaluronic acid and a linking molecule that is a substrate of transglutaminase, and free hyaluronic acid, wherein the free hyaluronic acid and the conjugate are present in a molar ratio of at least 2.

2-27. -27. (canceled)

28. A pharmaceutical composition comprising hyaluronic acid covalently linked to a linking molecule that is a substrate of transglutaminase, wherein the linking molecule is uncomplexed.

29-54. -54. (canceled)

55. A composition comprising a conjugate of hyaluronic acid and a linking molecule that is a substrate of transglutaminase, in an eye dropper bottle.

56-107. -107. (canceled)

108. A method for treating a subject comprising administering to an eye of a subject having or at risk of having dryness of the eye an effective amount of a conjugate of hyaluronic acid and a linking molecule that is a substrate of transglutaminase.

109. The method of claim 108, wherein the conjugate is provided in a form selected from the group consisting of an eye dropper, a contact lens solution, an ophthalmic ointment, an eye pack, and a contact lens.

115. The method of claim 108, wherein the effective amount is less than 0.05 μ

g/kg per day.

116. The method of claim 108, wherein the linking molecule has at least two contiguous aliphatic amines, at least three contiguous aliphatic amines, at least four contiguous aliphatic amines, at least five aliphatic amines, or at least six aliphatic amines.

117. The method of claim 108, wherein the linking molecule is native polylysine.

118. The method of claim 108, wherein polylysine is selected from the group consisting of poly-L-lysine, poly-D-lysine, and poly-DL-lysine.

119. The method of claim 108, wherein the linking molecule is a derivative of polylysine.

124. The method of claim 108, wherein the hyaluronic acid is native hyaluronic acid.

125. The method of claim 108, wherein the hyaluronic acid is a derivative of hyaluronic acid selected from the group consisting of a pharmaceutically acceptable salt of hyaluronic acid, a hyaluronic acid ester, and a sulfated hyaluronic acid.

126. The method of claim 108, wherein the hyaluronic acid has a molecular weight of at least 100,000.

127. The method of claim 108, wherein the conjugate has a negative charge to positive charge ratio of greater than 1.0.

128. The method of claim 108, wherein the conjugate is administered in a pharmaceutically acceptable carrier.

129. The method of claim 108, wherein the conjugate is administered in a pharmaceutically acceptable carrier that comprises an ophthalmic preservative.

130. The method of claim 129, wherein the ophthalmic preservative is selected from the group consisting of organic mercurials, quaternary ammonium compounds, parahydroxybenzoic acid esters, substituted alcohols and phenols.

131. The method of claim 129, wherein the organic mercurial is selected from the group consisting of phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, and thimerosal.

132. The method of claim 129, wherein the quaternary ammonium compound is selected from the group consisting of benzalkonium chloride, benzethonium chloride, cetyl pyridinium chloride, and polyquaternium-1 (POLYQUAD).

133. The method of claim 129, wherein the substituted alcohol and phenol is selected from the group consisting of chlorobutanol, and chlorobutanol/phenylethyl alcohol.

134. The method of claim 128, wherein the ophthalmic preservative is an antibiotic.

136. The method of claim 108, wherein the conjugate has a weight ratio selected from the group consisting of at least 90%, at least 95%, and at least 99%.

137. The method of claim 128, wherein the pharmaceutically acceptable carrier comprises arginine.

138. The method of claim 128, wherein the pharmaceutically acceptable carrier has a pH of at least 6.5.

139. The method of claim 128, wherein the pharmaceutically acceptable carrier has an osmolality of at least 280 mOsm.

110. A method of treating a subject comprising administering to an oral cavity of a subject having or at risk of having dryness of the oral cavity an effective amount of a conjugate of hyaluronic acid and a linking molecule that is a substrate of transglutaminase.

111-114. -114. (canceled)

120-123. -123. (canceled)

135. (canceled)