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 - 37 . (canceled) 
     
     
         38 . A pre-formulation comprising a low viscosity, non-liquid crystalline, mixture of:
 a) at least one neutral lipid component comprising a polar head group linked to at least one non-polar tail group by an ester;   b) at least one phospholipid;   c) 2 to 30% of at least one biocompatible, oxygen containing, low viscosity organic solvent selected from the group consisting of an alcohol, an amide, a sulfoxide, and a mixture thereof;   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.   
     
     
         39 . The method of  claim 38  wherein said at least one neutral lipid component further comprises at least one tocopherol. 
     
     
         40 . The pre-formulation as claimed in  claim 38  wherein said polar head group is a polyol. 
     
     
         41 . The pre-formulation as claimed in  claim 40  wherein the polyol is selected from the group consisting of glycerol, diglycerol and a sugar moiety. 
     
     
         42 . The pre-formulation as claimed in  claim 41  wherein the sugar moiety is selected from the group consisting of an inositol based moiety and a glucosyl based moiety. 
     
     
         43 . The pre-formulation as claimed in  claim 38  wherein the polar head group is an esterified polyol. 
     
     
         44 . The pre-formulation of  claim 43  wherein the esterified polyol is an acetate ester of a polyol or a succinate ester of a polyol. 
     
     
         45 . The pre-formulation as claimed in  claim 38  wherein the neutral lipid component comprises a fatty acid ester of a polyol. 
     
     
         46 . The pre-formulation as claimed in  claim 38  wherein the neutral lipid component comprises a fatty acid ester of a sugar. 
     
     
         47 . The pre-formulation as claimed in  claim 38  wherein the neutral lipid component a) comprises at least one of a C6 to C32 alkyl group, or an alkenyl group. 
     
     
         48 . The pre-formulation as claimed in  claim 38  wherein the neutral lipid component comprises at least one non-polar tail group selected from the group consisting of: a caproyl (C6:0) group, a capryloyl (C8:0) group, a capryl (C10:0) group, a lauroyl (C12:0) group, a myristoyl (C14:0) group, a palmitoyl (C16:0) group, a phytanoly (C16:0) group, a palmitoleoyl (C16:1) group, a stearoyl (C18:0) group, an oleoyl (C18:1) group, an elaidoyl (C18:1) group, a linoleoyl (C18:2) group, a linolenoyl (C18:3) group, an arachidonoyl (C20:4) group, a behenoyl (C22:0) group, and a lignoceroyl (C24:9) group. 
     
     
         49 . The pre-formulation as claimed in  claim 38  wherein the neutral lipid component comprises a sugar head group, and at least one fatty acid tail group selected from the group consisting of: a caproyl (C6:0) group, a capryloyl (C8:0) group, a capryl (C10:0) group, a lauroyl (C12:0) group, a myristoyl (C14:0) group, a palmitoyl (C16:0) group, a phytanoly (C16:0) group, a palmitoleoyl (C16:1) group, a stearoyl (C18:0) group, an oleoyl (C18:1) group, an elaidoyl (C18:1) group, an linoleoyl (C18:2), and a linolenoyl (C18:3) group. 
     
     
         50 . The pre-formulation as claimed in  claim 38  wherein the neutral lipid component comprises a sugar head group, and at least one fatty acid tail group selected from the group consisting of a palmitoyl (C16:0) group, a phytanoly (C16:0) group, a palmitoleoyl (C16:1) group, a stearoyl (C18:0) group, an oleoyl (C18:1) group, an elaidoyl (C18:1) group, a linoleoyl (C18:2) group, and a linolenoyl (C18:3) group. 
     
     
         51 . The pre-formulation as claimed in  claim 38  wherein component a) comprises two apolar tail groups. 
     
     
         52 . The pre-formulation as claimed in  claim 38  further comprising a drug agent which acts on a part of a patient selected from the group consisting of cell, receptor, peripheral nerve, adrenergic receptor, cholinergic receptor, skeletal muscle, cardiovascular system, smooth muscle, blood circulation system, endocrine system, hormone system, blood circulatory system, synoptic site, neuroeffector junctional site, immunological system, reproductive system, skeletal system, autacoid system, alimentary system, excretory systems, histamine system, and central nervous system. 
     
     
         53 . The pre-formulation as claimed in  claim 38  wherein said tocopherol is present and is selected from the group consisting of vitamin E, a salt of vitamin E, and an analogue s thereof. 
     
     
         54 . The pre-formulation as claimed in  claim 38  wherein component b) is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and a mixture thereof. 
     
     
         55 . The pre-formulation as claimed in  claim 38 , wherein said pre-formulation has a viscosity of 0.1 to 5000 mPas. 
     
     
         56 . The pre-formulation as claimed in  claim 38  having a molecular solution, L 2  and/or L 3  phase structure. 
     
     
         57 . The pre-formulation as claimed in  claim 38  having a ratio of a) to b) of between 85:15 and 30:70 by weight. 
     
     
         58 . The pre-formulation as claimed in  claim 38  having 5 to 20% component c) by weight of components a)+b)+c). 
     
     
         59 . The pre-formulation as claimed in  claim 38  wherein component c) is selected from the group consisting of ethanol, dimethylacetamide, N-methyl pyrrolidone and dimethylsulfoxide. 
     
     
         60 . The pre-formulation as claimed  claim 38  wherein said at least one bioactive agent is selected from the group consisting of drug, antigen, nutrient, cosmetic, fragrance, flavoring, diagnostic agent, vitamin, dietary supplement, and mixtures thereof. 
     
     
         61 . The pre-formulation as claimed in  claim 38  wherein the one bioactive agent is a UV absorbing agent. 
     
     
         62 . The pre-formulation as claimed in  claim 60  wherein said drug is selected from the group consisting of: peptide, protein, oligonucleotide, and mixtures thereof. 
     
     
         63 . The pre-formulation as claimed in  claim 60  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, and a mixture thereof. 
     
     
         64 . The pre-formulation as claimed in  claim 62  wherein said peptide or protein is selected from the group consisting of: antibody, antibody fragment, antigen, antigen fragment, bioadhesive peptide, cell surface receptor protein fragment, chemotactic peptide, enzyme inhibitor, immunostimulating peptide, immunostimulating polyaminoacid, gastrointestinal peptide, nuclear localization signal related peptide, neurotransmitter peptide, toxin, toxoid, functional peptide, anticancer peptide, antihypertension peptide, anti-blood clotting peptide, and antimicrobial peptide. 
     
     
         65 . The pre-formulation as claimed in  claim 62  wherein said peptide or protein is selected from the group consisting of: adrenocorticotropic hormone (ACTH), adrenocorticotropic hormone (ACTH) fragment, angiotensin, angiotensin related peptide, atrial natriuretic peptide, bradykinin, bradykinin related peptide, calcitonin, calcitonin related peptide, cyclosporin, cytokine, dynorphin, dynorphin related peptide, endorphin, P-lidotropin fragment, enkephalin, enkephalin related protein, fibronectin fragment, fibronectin related peptide, gonadotrophin-releasing hormone (GnRH), gonadotrophin-releasing hormone (GnRH) agonists, gonadotrophin-releasing hormone (GnRH) antagonist, glucagon like peptide, growth hormone releasing peptide, insulin, insulin-like growth factor, interleukin, luthenizing hormone releasing hormone (LHRH), luthenizing hormone releasing hormone (LHRH) related peptide, melanocyte stimulating hormone, melanocyte stimulating hormone related peptides, neurotensin, neurotensin related peptide, opioid peptide, oxytocin, vasopressin, vasopressin related peptides, parathyroid hormone, parathyroid hormone fragments, protein kinase, protein kinase related peptide, somatostatin, somatostatin related peptide, substance P, substance P related peptide, transforming growth factors (TGF), transforming growth factors (TGF) related peptide, tumor necrosis factor fragment, angiostatin, immunoglobulin, angiogenin, bone morphogenic protein, chemokine, colony stimulating factors (CSF), cytokine, growth factor, interferon (Type I), interferon (Type II), interleukin, leptin, leukaemia inhibitory factors, stem cell factor, transforming growth factor, and tumor necrosis factor. 
     
     
         66 . The pre-formulation as claimed in  claim 38  to which is administrable by injection. 
     
     
         67 . An injectable pre-formulation as claimed in  claim 38  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 the group consisting of
 i. octreotide, 
 ii. human growth hormone, 
 iii. interferon alpha, 
 iv. leuprolide, and 
 v. testosterone undecanoate. 
 
     
     
         68 . A method of delivery of a bioactive agent to a human or non-human animal body, this method comprising administering a pre-formulation as claimed in  claim 38  to said human or non-human animal body. 
     
     
         69 . The method of  claim 68  wherein said non-human animal is a mammal. 
     
     
         70 . The method of  claim 68  wherein said pre-formulation is administered by a method selected from the group consisting of: 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, and dropping. 
     
     
         71 . A method for the preparation of a liquid crystalline composition comprising exposing a pre-formulation as claimed in  claim 38  to an aqueous fluid in vivo. 
     
     
         72 . 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 lipid component comprising a polar head group linked to at least one non-polar tail group by an ester, and optionally at least one tocopherol;   b) at least one phospholipid;   c) 2 to 30% of at least one biocompatible, oxygen containing, low viscosity organic solvent selected from the group consisting of alcohol, amide, sulfoxide and a mixture thereof;   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.   
     
     
         73 . A process as claimed in  claim 72  wherein said pre-formulation is a pre-formulation comprising a low viscosity, non-liquid crystalline, mixture of:
 a) at least one neutral lipid component comprising a polar head group linked to at least one non-polar tail group by an ester; 
 b) at least one phospholipid; 
 c) 2 to 30% of at least one biocompatible, oxygen containing, low viscosity organic solvent selected from the group consisting of an alcohol, an amide, a sulfoxide, and a mixture thereof; 
 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. 
 
     
     
         74 . A method of treatment or prophylaxis of a human or non-human animal subject comprising administration of a pre-formulation as claimed in  claim 72 . 
     
     
         75 . The method of  claim 74  for the treatment of a condition selected from the group consisting of bacterial infection, fungal infection, skin soreness, eye condition, genital soreness, infection, conditions for the finger nail, conditions for the toe nail, travel sickness, addiction, nicotine addiction, periodontal infection, conjunctivitis, glaucoma, hormone deficiency, imbalance, and a combination thereof. 
     
     
         76 . The method of  claim 74  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, abrasion, oral infection, genital infection, and infection resulting from activities resulting in exposure to infective agent.