Claims for Patent: 8,545,832

Summary for Patent: 8,545,832

Title:	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.
Inventor(s):	Thuresson Krister, Tiberg Fredrik, Johansson Markus, Harwigsson Ian, Joabsson Fredrik, Johnsson Markus
Assignee:	Camarus AB
Application Number:	US13537096
Patent Claims:	1. A pre-formulation comprising a low viscosity , non-liquid crystalline , mixture of:a) at least one diacyl glycerol and/or at least one tocopherol;b) at least one phosphatidylcholine;c) at least one biocompatible solvent comprising at least one amide;wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture, wherein the pre-formulation forms at least one liquid crystalline phase structure upon contact with an aqueous fluid and wherein the low viscosity, non-liquid crystalline, mixture has a viscosity of 0.1 to 5000 mPas at 20° C.2. A pre-formulation comprising a low viscosity , non-liquid crystalline , mixture of:a) at least one tocopherol and optionally at least one diacyl glycerol;b) at least one phosphatidylcholine;c) at least one biocompatible, oxygen containing, low viscosity organic solvent comprising at least one amide; wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture, wherein the pre-formulation forms at least one liquid crystalline phase structure upon contact with an aqueous fluid and wherein the low viscosity, non-liquid crystalline, mixture has a viscosity of 0.1 to 5000 mPas at 20° C.3. A pre-formulation as claimed in wherein said liquid crystalline phase structure is bioadhesive.4. A pre-formulation as claimed in wherein component a) consists essentially of diacyl glycerols.5. A pre-formulation as claimed in wherein said diacyl glycerols comprise glycerol dioleate (GDO).6. A pre-formulation as claimed in wherein component a) consists essentially of at least one tocopherol.7. A pre-formulation as claimed in wherein component a) consists essentially of a mixture of GDO and tocopherol.8. A pre-formulation as claimed in having a molecular solution claim 1 , Land/or Lphase structure.9. A pre-formulation as claimed in having a ratio of a) to b) of between 95:5 and 5:95 by weight.10. A pre-formulation as claimed in having 0.5 to 50% component e) by weight of components a)+b)+c).11. A pre-formulation as claimed in wherein component c) additionally comprises at least one solvent selected from alcohols claim 2 , ketones claim 2 , esters claim 2 , ethers claim 2 , sulphoxides and mixtures thereof.12. A pre-formulation as claimed in additionally comprising up to 10% by weight of a)+b) of a charged amphiphile.13. A pre-formulation as claimed in wherein said active agent is selected from the group consisting of drugs claim 1 , antigens claim 1 , nutrients claim 1 , cosmetics claim 1 , fragrances claim 1 , flavourings claim 1 , diagnostic agents claim 1 , vitamins claim 1 , dietary supplements and mixtures thereof.14. A pre-formulation as claimed in wherein said drugs is selected from hydrophilic drugs claim 13 , lipophilic drugs claim 13 , amphiphilic drugs claim 13 , peptides claim 13 , proteins claim 13 , oligonucleotides and mixtures thereof.15. A pre-formulation as claimed in wherein said drugs is selected from the group consisting of peptide somatostatin receptor agonists claim 13 , interferons claim 13 , glucagon-like peptides 1 and 2 claim 13 , GnRH agonists claim 13 , GnRH antagonists claim 13 , bisphosponates claim 13 , chlorhexidine and mixtures thereof.16. A pre-formulation as claimed in which is administrable by injection.17. A pre-formulation as claimed in which is administrable by spraying claim 1 , dipping claim 1 , rinsing claim 1 , application from a pad or ball roller claim 1 , painting claim 1 , dropping claim 1 , aerosol spraying or pump spraying.18. An injectable pre-formulation as claimed in which forms a depot providing continuous release of active agent for at least two weeks claim 1 , wherein said active agent comprises at least one selected from the group consisting of:octreotide;human growth hormone;interferon alpha; andleuprolide.19. An injectable pre-formulation as claimed in which forms a depot providing continuous release of active agent for at least two weeks claim 1 , wherein said active agent comprises at least one selected from the group consisting of:risperidone;oianzapine; andtestosterone undecanoate.20. A topical formulation as claimed in for intraoral administration which forms a bioadhesive claim 1 , controlled release product claim 1 , wherein said active agent comprises at least one selected from the group consisting of:benzydamine; andtramadol.21. A topical pre-formulation as claimed in suitable for intraoral administration for treatment of periodontal and topical infections claim 1 , wherein the active agent is chlorhexidine gluconate claim 1 , and where the pre-formulation is applied as a liquid product which forms a surface gel in situ between one second and five minutes after application.22. A non-parenteral formulation as claimed in for intranasal spray administration which forms a bioadhesive claim 1 , controlled release product claim 1 , wherein said active agent comprises at least one selected from the group consisting of:fentanyl; anddiazepam.23. A topical formulation as claimed in suitable for ocular administration claim 1 , wherein said active agent comprises at least one selected from the group consisting of diclofenac claim 1 , pilocarpine claim 1 , levocabastine hydrochloride claim 1 , ketotifen fumarate claim 1 , timolol claim 1 , betaxolol claim 1 , carteolol claim 1 , levobunolol claim 1 , dorzolamide claim 1 , brinzolamide claim 1 , epineplirine claim 1 , dipivefrin claim 1 , clonidine claim 1 , apraclonidine claim 1 , brimonidine claim 1 , pilocarpine claim 1 , atanoprost claim 1 , travoprost claim 1 , bimatoprost claim 1 , unoprostone claim 1 , pilocarpine hydrochloride claim 1 , dexamethasone claim 1 , chloramphenicol claim 1 , and indomethacin.24. A non-parenteral formulation as claimed in for dermatological administration which forms a bioadhesive claim 1 , controlled release product claim 1 , wherein the active agent is selected from the group consisting of:acyclovir; andtestosterone undecanoate.25. A topical formulation as claimed in for dermatological administration which forms a bioadhesive claim 1 , controlled release product claim 1 , wherein the active agent is selected from cosmetic agents claim 1 , fragrances claim 1 , flavourings claim 1 , essential oils claim 1 , UV absorbing agents and mixtures thereof.26. A method of delivery of a bioactive agent to a human or non-human animal body claim 1 , this method comprising administering a pre-formulation as claimed in claim 1 , 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 wherein said pre-formulation is administered by a method selected from subcutaneous injection claim 26 , intramuscular injection claim 26 , intra-cavity injection through tissue claim 26 , intra-cavity injection into an open cavity without tissue penetration claim 26 , spraying claim 26 , roiling claim 26 , wiping claim 26 , dabbing claim 26 , painting claim 26 , rinsing claim 26 , or dropping.28. A method for the preparation of a liquid crystalline composition comprising exposing a pre-formulation as claimed in to an aqueous fluid in vivo.29. A process for the formation of a pre-formulation suitable for the administration of a bioactive agent to a subject claim 1 , said process comprising forming a non-liquid crystalline claim 1 , low viscosity mixture as defined in and dissolving or dispersing at least one bioactive agent in the low viscosity mixture claim 1 , or in at least one of components a claim 1 , b or c prior to forming the low viscosity mixture claim 1 , wherein the low viscosity claim 1 , non-liquid crystalline claim 1 , mixture has a viscosity of 0.1 to 5000 mPas at 20° C.30. A process for the formation of a pre-formulation suitable for the administration of a bioactive agent to a subject claim 2 , said process comprising forming a non-liquid crystalline claim 2 , low viscosity mixture as defined in and dissolving or dispersing at least one bioactive agent in the low viscosity mixture claim 2 , or in at least one of components a claim 2 , b or c prior to forming the low viscosity mixture claim 2 , wherein the low viscosity claim 2 , non-liquid crystalline claim 2 , mixture has a viscosity of 0.1 to 5000 mPas at 20° C.31. A process as claimed in wherein said pre-formulation is a pre-formulation comprising a low viscosity claim 29 , non-liquid crystalline claim 29 , mixture of:a) at least one diacyl glycerol and/or at least one tocopherol;b) at least one phosphatidyicholine;c) at least one biocompatible solvent comprising at least one amide;wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture, wherein the pre-formulation forms at least one liquid crystalline phase structure upon contact with an aqueous fluid and wherein the low viscosity, non-liquid crystalline, mixture has a viscosity of 0.1 to 5000 mPas at 20° C.32. A method of treatment of a human or non-human animal subject comprising administration of a pre-formulation as claimed in for the treatment of a condition selected from bacterial infection claim 1 , fungal infection claim 1 , skin soreness claim 1 , eye conditions claim 1 , genital soreness claim 1 , infections and conditions for the finger and/or toe nails claim 1 , travel sickness claim 1 , addiction including nicotine addiction claim 1 , periodontal infection claim 1 , conjunctivitis claim 1 , glaucoma and hormone deficiency or imbalance.33. The method of against at least one condition selected from infection during surgery claim 32 , infection during implantation claim 32 , sunburn claim 32 , infection at the site of burns claim 32 , cuts or abrasions claim 32 , oral infections claim 32 , genital infections and infections resulting from activities resulting in exposure to infective agents.