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 optionally dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, at least one liquid crystalline phase structure upon contact with an aqueous fluid.   
     
     
         2 . The pre-formulation as claimed in  claim 1  wherein said liquid crystalline phase structure is bioadhesive. 
     
     
         3 . The pre-formulation as claimed in  claim 1  wherein component a) consists essentially of diacyl glycerols, especially glycerol dioleate. 
     
     
         4 . The pre-formulation as claimed in  claim 1  wherein component a) consists essentially of at least one tocopherol. 
     
     
         5 . The pre-formulation as claimed in  claim 1  wherein component a) consists essentially of a mixture of GDO and tocopherol. 
     
     
         6 . The pre-formulation as claimed in  claim 1  wherein component b) is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and a mixture thereof. 
     
     
         7 . The preformulation as claimed in  claim 1  having a viscosity of 0.1 to 5000 mPas. 
     
     
         8 . The preformulation as claimed in  claim 1  having a molecular solution, L 2  and/or L 3  phase structure. 
     
     
         9 . The preformulation as claimed in  claim 1  having a ratio of a) to b) of between 95:5 and 5:95 by weight. 
     
     
         10 . The preformulation as claimed in  claim 1  having 0.5 to 50% component c) by weight of components a)+b)+c). 
     
     
         11 . The preformulation as claimed in  claim 1  wherein component c) is selected from the group consisting of alcohol, ketone, ester, ether, amide, sulphoxide and a mixture thereof. 
     
     
         12 . The preformulation as claimed in  claim 1  additionally comprising up to 10% by weight of a)+b) of a charged amphiphile. 
     
     
         13 . The preformulation as claimed in  claim 1  wherein said active agent is present and is selected from the group consisting of drug, antigen, nutrient, cosmetic, fragrance, flavouring, diagnostic agent, vitamin, dietary supplement and a mixture thereof. 
     
     
         14 . The preformulation as claimed in  claim 13  wherein said drug is selected from the group consisting of hydrophilic small molecule drug, lipophilic small molecule drug, amphiphilic small molecule drug, peptide, protein, oligonucleotide and a mixture thereof. 
     
     
         15 . The preformulation as claimed in  claim 13  wherein said drug is selected from the group consisting of somatostatin related peptide, interferon, glucagon-like peptide 1, glucagon-like peptide 2, GnRH agonist, GnRH antagonist, bisphosphonates bisphosphonate, chlorhexidine and a mixture thereof. 
     
     
         16 . The preformulation as claimed in  claim 1  which is administrable by injection. 
     
     
         17 . The 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 is present and comprises at least one selected from the group consisting of
 i. octreotide, 
 ii. human growth hormone, 
 iii. interferon alpha, 
 iv. leuprolide, and 
 v. a mixture thereof. 
 
     
     
         19 . The preformulation as claimed in  claim 1  which is injectable and which forms a depot providing continuous release of active agent for at least two weeks, wherein said active agent is present and comprises at least one selected from the group consisting of
 i. risperidone 
 ii. olanzapine 
 iii. testosterone undecanoate and 
 iv. a mixture thereof. 
 
     
     
         20 . The formulation as claimed in  claim 1  for topical intraoral administration which forms a bioadhesive, controlled release product, wherein said active agent is present and comprises at least one selected from the group consisting of
 i. benzydamine, 
 ii. tramadol and 
 iii. a mixture thereof. 
 
     
     
         21 . The preformulation as claimed in  claim 1  for topical intraoral administration for treatment of periodontal and topical infections, wherein the active agent is present and 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. 
     
     
         22 . The formulation as claimed in  claim 1  for topical intranasal spray administration which forms a bioadhesive, controlled release product, wherein said active agent is present and comprises at least one selected from the group consisting of
 i. fentanyl 
 ii. diazepam, and 
 iii. a mixture thereof. 
 
     
     
         23 . The formulation as claimed in  claim 1  for ocular administration, wherein said active agent is present and comprises at least one selected from the group consisting of 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, indomethacin and a mixture thereof. 
     
     
         24 . The formulation as claimed in  claim 1  for non-parenteral dermatological administration which forms a bioadhesive, controlled release product, wherein the active agent is present and is selected from the group consisting of
 i. acyclovir 
 ii. testosterone undecanoate, and 
 iii. a mixture thereof. 
 
     
     
         25 . The formulation as claimed in  claim 1  for topical dermatological administration which forms a bioadhesive, controlled release product, wherein the active agent is present and is selected from the group consisting of cosmetic agent, fragrance, flavouring, essential oil, UV absorbing agent and a mixture thereof. 
     
     
         26 . A method of delivery of a bioactive agent to a human or non-human animal body, this method comprising administering to said mammalian body 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 . The method as claimed in  claim 26  wherein said preformulation is a preformulation as claimed in  claim 1 . 
     
     
         28 . The method as claimed in  claim 26  wherein said pre-formulation is administered by a method selected the group consisting of 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, dropping and a combination thereof. 
     
     
         29 . A method for the preparation of a liquid crystalline composition comprising exposing 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 optionally at least one bioactive agent dissolved or dispersed in the low viscosity mixture, to an aqueous fluid in vivo.   
     
     
         30 ) The method as claimed in  claim 29  wherein said preformulation is a preformulation as claimed in  claim 1 . 
     
     
         31 ) A process for the formation of a pre-formulation suitable for the administration of a bioactive agent to a 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 ) The process as claimed in  claim 31  wherein said preformulation is a preformulation as claimed in  claim 1 . 
     
     
         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 the group consisting of bacterial infection, fungal infection, skin soreness, eye condition, genital soreness, infection and condition for the finger and/or toe nails, travel sickness, addiction including nicotine addiction, periodontal infection, conjunctivitis, glaucoma, hormone deficiency and hormone imbalance. 
     
     
         37 ) The method of  claim 35  for prophylaxis against at least one condition selected from the group consisting of infection during surgery, infection during implantation, sunburn, infection at the site of burns, cuts, abrasions, oral infection, genital infection and infection resulting from activities resulting in exposure to infective agent. 
     
     
         38 . The method of  claim 35  for the treatment or prophylaxis of damaged, sensitized and/or infected mucosa. 
     
     
         39 . The method of  claim 38  comprising administration of the preformulation of  claim 20 .