Process for preparing a cross-linked hyaluronic acid product

Abstract

Efficient cross-linking of hyaluronic acid (HA) is provided by a manufacturing process. In the process, HA is activated by an initial cross-linking in an aqueous solution. Unreacted cross-linking agent is removed from the activated HA. Cross-linking of the activated HA is finalized, without addition of any additional cross-linking agent, in a suspension of a liquid precipitating medium and the activated HA in precipitated form. The resulting cross-linked HA products exhibit high effective cross-linker ratio and other favorable properties, making the products useful as implants and in medical and cosmetic surgery.

1 - 11 . (canceled) 
     
     
         12 . A cross-linked HA product having an effective cross-linker ratio of 35% or higher. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . The cross-linked HA product according to  claim 12 , having an effective cross-linker ratio in the range of 35-80%. 
     
     
         17 . The cross-linked HA product according to  claim 12 , having a swelling degree of 4-500 mL per g HA. 
     
     
         18 . The cross-linked HA product according to  claim 17 , having a swelling degree of 15-300 mL per g HA. 
     
     
         19 . The cross-linked HA product according to  claim 12 , wherein the HA product has the shape of particles having a size of 0.1-5.0 mm. 
     
     
         20 . The cross-linked HA product according to  claim 12 , wherein the HA product has the shape of a string, a net, or a film. 
     
     
         21 . The cross-linked HA product according to 20, wherein the shape is a string and the string has a ratio between its length and its width of 5:1 or higher. 
     
     
         22 . The cross-linked HA product according to  claim 12 , wherein the HA product is in dried form. 
     
     
         23 . The cross-linked HA product according to  claim 12 , wherein the product is crosslinked with a crosslinking agent selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE), and diepoxyoctane. 
     
     
         24 . The cross-linked HA product according to  claim 12 , wherein the product is ether crosslinked with a crosslinking agent selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE), and diepoxyoctane. 
     
     
         25 . An aqueous composition comprising a cross-linked HA product according to  claim 12 , and optionally a buffering agent and/or a tonicity agent. 
     
     
         26 . The aqueous composition according to  claim 25 , further comprising one or more medical compound(s). 
     
     
         27 . The aqueous composition according to  claim 26 , wherein the medical compound(s) is selected from the group consisting of local anaesthetics, anti-inflammatory drugs, antibiotics, and bone growth factors. 
     
     
         28 . The aqueous composition according to  claim 27 , wherein the medical compound(s) comprises lidocaine hydrochloride. 
     
     
         29 . A method of treating a subject undergoing cosmetic or medical surgery, comprising administering to a subject in need thereof a cross-linked HA product according to  claim 12 . 
     
     
         30 . The method according to  claim 29 , wherein the cosmetic surgery comprises dermal filling, body contouring, and facial contouring, or the medical surgery comprises dermal filling, body contouring, prevention of tissue adhesion, formation of channels, incontinence treatment, and orthopaedic applications. 
     
     
         31 . The method according to  claim 29 , wherein the cosmetic surgery is facial contouring. 
     
     
         32 . A method of treating a subject undergoing cosmetic or medical surgery, comprising administering to a subject in need thereof an aqueous composition according to  claim 25 . 
     
     
         33 . The method according to  claim 32 , wherein the cosmetic surgery comprises dermal filling, body contouring, and facial contouring, or the medical surgery comprises dermal filling, body contouring, prevention of tissue adhesion, formation of channels, incontinence treatment, and orthopaedic applications. 
     
     
         34 . The method according to  claim 32 , wherein the cosmetic surgery is facial contouring.