Topical bioadhesive formulations

Abstract

The present invention relates to topical bioadhesive formulations comprising low viscosity, non-liquid crystalline, mixtures of: a) at least one neutral diacyl lipid and/or at least one tocopherol; b) at least one phospholipid; c) at least one biocompatible, oxygen containing, low viscosity organic solvent; wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. The invention additionally relates to a method of delivery of an active agent comprising administration of a preformulation of the invention, a method of treatment comprising administration of a preformulation of the invention and the use of a preformulation of the invention in a method for the manufacture of a medicament.

1 . A pre-formulation comprising a low viscosity mixture of:
 a) at least one neutral diacyl lipid and/or a tocopherol;   b) at least one phospholipid;   c) at least one biocompatible, (preferably oxygen containing) organic solvent;   optionally including at least one bioactive agent is dissolved or dispersed in the low viscosity mixture, wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid and/or body surface.   
     
     
         2 . A pre-formulation as claimed in  claim 1  wherein said liquid crystalline phase structure is bioadhesive. 
     
     
         3 . A pre-formulation as claimed in  claim 1  or  claim 2  wherein component a) consists essentially of diacyl glycerols, especially glycerol dioleate. 
     
     
         4 . A pre-formulation as claimed in any of  claims 1  to  3  wherein component b) is phosphatidylcholine. 
     
     
         5 . A preformulation as claimed in any of  claims 1  to  4  having a viscosity of 0.1 to 5000 mPas. 
     
     
         6 . A preformulation as claimed in any of  claims 1  to  5  having a molecular solution, L 2  and/or L 3  phase structure. 
     
     
         7 . A preformulation as claimed in any of  claims 1  to  6  having 35 to 60% by weight a), 20 to 50% by weight b) and 10 to 20% by weight c). 
     
     
         8 . A preformulation as claimed in any of  claims 1  to  10  wherein component c) is an alcohol. 
     
     
         9 . A preformulation as claimed in any of  claims 1  to  8  additionally comprising up to 10% by weight of a)+b) of a charged amphiphile. 
     
     
         10 . A preformulation as claimed in any of  claims 1  to  9  wherein said active agent is selected from corticosteroids nonsteroidal anti-inflammatory compounds, local inhibitors of inflammatory pathways phospholipase inhibitors, antioxidants, antiinfectives, cytokines and cytokine inducers/supressors. 
     
     
         11 . A preformulation as claimed in any of  claims 1  to  10  which is administrable by rinsing, spraying, gargling, as a patch, by suppository or by enema. 
     
     
         12 . A preformulation as claimed in  claim 11  comprising bezydamine 
     
     
         13 . A topical formulation as claimed in any of  claims 1  to  11  for intraoral administration which forms a bioadhesive, controlled release product, wherein said active agent comprises at least one selected from; benzydamine, tramadol, Acetaminophen, Ibuprofen, Propoxyphene, Codeine, Dihydrocodein, Hydrocodone, Oxycodone, Nalbuphine, Meperidine, Leverorphanol, Hydromorphone, Oxymorphone, Alfentanil, Fentanyl and Sefentanil. 
     
     
         14 . A topical preformulation as claimed in any of  claims 1  to  11  suitable for intraoral administration for treatment of periodontal and topical infections, wherein the active agent is chlorhexidine gluconate, and where the preformulation is applied as a liquid product which forms a surface gel in situ between 1 second, and 5 min after application. 
     
     
         15 . A topical formulation as claimed in any of  claims 1  to  11  suitable for ocular administration, wherein said active agent comprises at least one selected from diclofenac, pilocarpine, levocabastine hydrochloride, ketotifen fumarate, timolol, betaxolol, carteolol, levobunolol, dorzolamide, brinzolamide, epinephrine, dipivefrin, clonidine, apraclonidine, brimonidine, pilocarpine, atanoprost, travoprost, bimatoprost, unoprostone, pilocarpine hydrochloride, dexamethasone, chloramphenicol, and indomethacin. 
     
     
         16 . A topical formulation as claimed in any of  claims 1  to  11  for dermatological administration which forms a bioadhesive, controlled release product, wherein the active agent is selected from cosmetic agents, fragrances, flavourings, essential oils UV absorbing agents and mixtures thereof. 
     
     
         17 . A method of delivery of a bioactive agent to a human or non-human animal (preferably mammalian) body, this method comprising administering a pre-formulation comprising a non-liquid crystalline, low viscosity mixture of:
 a) at least one neutral diacyl lipid and/or at least one tocopherol;   b) at least one phospholipid;   c) at least one biocompatible, oxygen containing, low viscosity organic solvent;   and at least one bioactive agent is dissolved or dispersed in the low viscosity mixture, whereby to form at least one liquid crystalline phase structure upon contact with an aqueous fluid in vivo following administration.   
     
     
         18 . A method as claimed in  claim 17  wherein said preformulation is a preformulation as claimed in any of  claims 1  to  16 . 
     
     
         19 . The use of a non-liquid crystalline, low viscosity mixture of:
 a) at least one neutral diacyl lipid and/or at least one tocopherol;   b) at least one phospholipid;   c) at least one biocompatible, oxygen containing, low viscosity organic solvent;   wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture in the manufacture of a pre-formulation for use in the sustained local administration of said active agent, wherein said pre-formulation is capable of forming at least one liquid crystalline phase structure upon contact with an aqueous fluid.   
     
     
         20 . The use as claimed in  claim 19  wherein said preformulation is a preformulation as claimed in any of  claims 1  to  16 . 
     
     
         21 . A method of treatment or prophylaxis of a human or non-human animal subject comprising administration of a preformulation as claimed in any of  claims 1  to  16 . 
     
     
         22 . A method for the treatment of a human or animal subject comprising administration of a preformulation as claimed in any of  claims 1  to  16 . 
     
     
         23 . A method as claimed in  claim 22  for the treatment of inflammation and/or irritation at a body surface and/or in a body cavity. 
     
     
         24 . The method as claimed in  claim 23  wherein said inflammation is caused by Crohn's disease, ulcerative collitus or oral mucositis. 
     
     
         25 . Use of a composition as claimed in any of  claims 1  to  16  in the manufacture of a medicament for the treatment of inflammation and/or irritation at a body surface and/or in a body cavity. 
     
     
         26 . Method for the treatment of oral mucositis in a human or animal subject comprising administration of a preformulation as claimed in  claim 1 , said composition comprising 40 to 60 wt % GDO, 20 to 35% PC, 5 to 25% ethanol, and 1 to 8% bezydamine, or a derivative thereof.