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 . (canceled) 
     
     
         3 . A pre-formulation as claimed in  claim 1  wherein component a) consists essentially of diacyl glycerols, especially glycerol dioleate; or wherein component a) consists essentially of at least one tocopherol; or wherein component a) consists essentially of a mixture of GDO and tocopherol. 
     
     
         4 - 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 . (canceled) 
     
     
         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) and/or wherein component c) is selected from alcohols, ketones, esters, ethers, amides, sulphoxides and mixtures thereof. 
     
     
         11 - 12 . (canceled) 
     
     
         13 . A preformulation as claimed  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, oligonucleotides and mixtures thereof; or
 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. 
 
     
     
         15 . (canceled) 
     
     
         16 . A preformulation as claimed in  claim 1  which is administrable by injection or which is administrable by spraying, dipping, rinsing, application from a pad or ball roller, painting, dropping, aerosol spraying or pump spraying. 
     
     
         17 . (canceled) 
     
     
         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; or 
 wherein said active agent comprises at least one selected from 
 i. risperidone 
 ii. olanzapine 
 iii. testosterone undecanoate 
 
     
     
         19 . (canceled) 
     
     
         20 . A topical formulation as claimed in  claim 1  for intraoral administration which forms a bioadhesive, controlled release product, wherein said active agent comprises at least one selected from
 i. benzydamine 
 ii. tramadol 
 
     
     
         21 . (canceled) 
     
     
         22 . A non-parenteral formulation as claimed  claim 1  for intranasal spray administration which forms a bioadhesive, controlled release product, wherein said active agent comprises at least one selected from
 i. fentanyl 
 ii. diazepam 
 
     
     
         23 . A topical formulation as claimed in  claim 1  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. 
     
     
         24 . A non-parenteral formulation as claimed in  claim 1  for dermatological administration which forms a bioadhesive, controlled release product, wherein the active agent is selected from;
 i. acyclovir 
 ii. testosterone undecanoate. 
 
     
     
         25 . (canceled) 
     
     
         26 . 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.   
     
     
         27 . A method as claimed in  claim 26  wherein said pre-formulation is administered by a method selected from subcutaneous injection, intramuscular injection, intra-cavity injection through tissue, intra-cavity injection into an open cavity without tissue penetration, spraying, rolling, wiping, dabbing, painting, rinsing, or dropping. 
     
     
         28 - 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 comprises 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 - 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 . The method of  claim 35  for the treatment of a condition selected from bacterial infection, fungal infection, skin soreness, eye conditions, genital soreness, infections and conditions for the finger and/or toe nails, travel sickness, addiction including nicotine addiction, periodontal infection, conjunctivitis, glaucoma and hormone deficiency or imbalance; or
 for prophylaxis against at least one condition selected from infection during surgery, infection during implantation, sunburn, infection at the site of burns, cuts or abrasions, oral infections, genital infections and infections resulting from activities resulting in exposure to infective agents. 
 
     
     
         37 . (canceled)