Lipid depot formulations

Abstract

The present invention relates to pre-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 preformulations are suitable for generating parenteral, non-parenteral and topical depot compositions for sustained release of active agents. 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, non-liquid crystalline, 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 and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid.   
     
     
         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  wherein component a) consists essentially of:
 diacyl glycerols, 
 at least one tocopherol, or 
 a mixture of GDO and tocopherol. 
 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . A pre-formulation as claimed in  claim 1  wherein component b) is selected from phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols and mixtures thereof. 
     
     
         7 . A preformulation as claimed in  claim 1  having a viscosity of 0.1 to 5000 mPas. 
     
     
         8 . A preformulation as claimed in  claim 1  having a molecular solution, L 2  and/or L 3  phase structure. 
     
     
         9 . A preformulation as claimed in  claim 1  having a ratio of a) to b) of between 95:5 and 5:95 by weight. 
     
     
         10 . A preformulation as claimed in  claim 1  having 0.5 to 50% component c) by weight of components a)+b)+c). 
     
     
         11 . A preformulation as claimed in  claim 1  wherein component c) is selected from alcohols, ketones, esters , ethers, amides, sulphoxides and mixtures thereof. 
     
     
         12 . A preformulation as claimed in  claim 1  additionally comprising up to 10% by weight of a)+b) of a charged amphiphile. 
     
     
         13 . A preformulation as claimed in  claim 1  wherein said active agent is selected from drugs, antigens, nutrients, cosmetics, fragrances, flavourings, diagnostic agents, vitamins, dietary supplements and mixtures thereof. 
     
     
         14 . A preformulation as claimed in  claim 13  wherein said drug is selected from hydrophilic small molecule drugs, lipophilic small molecule drugs, amphiphilic small molecule drugs, peptides, proteins, oligonucleotids and mixtures thereof. 
     
     
         15 . A preformulation as claimed in  claim 13  wherein said drug is selected from somatostatin related peptides, interferons, glucagon-like peptides 1 and 2, GnRH agonists, GnRH antagonists, bisphosponates, chlorhexidine and mixtures thereof. 
     
     
         16 . A preformulation as claimed in  claim 1  which is administrable by injection. 
     
     
         17 . A preformulation as claimed in  claim 1  which is administrable by spraying, dipping, rinsing, application from a pad or ball roller, painting, dropping, aerosol spraying or pump spraying. 
     
     
         18 . An injectable preformulation as claimed in  claim 1  which forms a depot providing continuous release of active agent for at least two weeks, wherein said active agent comprises at least one selected from
 i. octreotide 
 ii. human growth hormone 
 iii. interferon alpha 
 iv. leuprolide 
 
     
     
         19 . An injectable preformulation as claimed in  claim 1  which forms a depot providing continuous release of active agent for at least two weeks, wherein said active agent comprises at least one selected from
 i. risperidone 
 ii. olanzapine 
 iii. testosterone undecanoate 
 
     
     
         20 - 30 . (canceled) 
     
     
         31 . A process for the formation of a pre-formulation suitable for the administration of a bioactive agent to a (preferably mammalian) subject, said process comprising forming 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 dissolving or dispersing at least one bioactive agent in the low viscosity mixture, or in at least one of components a, b or c prior to forming the low viscosity mixture.   
     
     
         32 . A process as claimed in  claim 31  wherein said preformulation is a preformulation comprising a low viscosity, non-liquid crystalline, 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 and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. 
 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . A method of treatment or prophylaxis of a human or non-human animal subject comprising administration of a preformulation as claimed in  claim 1 . 
     
     
         36 . (canceled) 
     
     
         37 . (canceled)