Claims for Patent: 8,236,292

Summary for Patent: 8,236,292

Title:	Liquid 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:	Camurus AB
Application Number:	US11628007
Patent Claims:	1. A non-liquid crystalline formulation precursor for the in vivo generation of a liquid crystalline lipid composition for the controlled release of at least one bioactive agent following parenteral administration , said formulation precursor comprising:i) a low-viscosity, non-liquid crystalline mixture having a viscosity of 1 to 1000 mPas at 20° C. and comprising:a) a minimum of 18 wt. % of a component consisting of at least one diacyl glycerol or at least one diacyl glycerol and at least one tocopherol;b) at least one phosphatidylcholine; andc) at least one biocompatible solvent comprising ethanol;ii) at least one bioactive agent dissolved or dispersed in the low viscosity mixture;wherein the formulation precursor forms at least one liquid crystalline phase structure in vivo upon contact with an aqueous fluid.2. A non-liquid crystalline formulation precursor for the in vivo generation of a liquid crystalline lipid composition for the controlled release of at least one bioactive agent following parenteral administration , said formulation comprising:i) a low-viscosity, non-liquid crystalline mixture having a viscosity of 1 to 1000 mPas at 20° C. and comprising:a) a minimum of 18 wt. % of a component consisting of at least one tocopherol and at least one diacyl glycerol;b) at least one phosphatidylcholine; andc) at least one biocompatible, oxygen containing, low viscosity organic solvent;ii) at least one bioactive agent dissolved or dispersed in the low viscosity mixture;wherein the formulation precursor forms at least one liquid crystalline phase structure in vivo upon contact with an aqueous fluid.3. The formulation precursor as claimed in wherein component a) consists essentially of diacyl glycerols.4. The formulation precursor as claimed in wherein said diacyl glycerols comprise glycerol dioleate.5. The formulation precursor as claimed in wherein component a) consists essentially of a mixture of glycerol dioleate (GDO) and tocopherol.6. The formulation precursor as claimed in having a molecular solution claim 1 , Land/or Lphase structure.7. The formulation precursor as claimed in having a ratio of a) to b) of between 95:5 and 5:95 by weight.8. The formulation precursor as claimed in having 0.5 to 50% component c) by weight of components a)+b)+c).9. The formulation precursor as claimed in additionally comprising up to 10% by weight of a)+b) of a charged amphiphile.10. The formulation precursor as claimed in wherein said active agent is selected from 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.11. The formulation precursor as claimed in wherein said drug is selected from hydrophilic small molecule drugs claim 10 , lipophilic small molecule drugs claim 10 , amphiphilic small molecule drugs claim 10 , peptides claim 10 , proteins claim 10 , oligonucleotides and mixtures thereof.12. The formulation precursor as claimed in wherein said drug is selected from somatostatin related peptides claim 10 , interferons claim 10 , glucagon-like peptides 1 and 2 claim 10 , GnRH agonists claim 10 , GnRH antagonists claim 10 , bisphosphonates claim 10 , chlorhexidine and mixtures thereof.13. The formulation precursor as claimed in which is administrable by injection.14. An injectable formulation precursor 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 fromi. octreotideii. human growth hormoneiii. interferon alphaiv. leuprolide.15. An injectable formulation precursor 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 fromi. risperidoneii. olanzapineiii. testosterone undecanoate.16. A method of delivery of a bioactive agent to a human or non-human animal (preferably mammalian) body claim 1 , this method comprising administering the formulation precursor as claimed in whereby to form at least one liquid crystalline phase structure upon contact with an aqueous fluid in vivo following administration.17. The method as claimed in wherein said formulation precursor is administered by a method selected from subcutaneous injection claim 16 , intramuscular injection claim 16 , intra-cavity injection through tissue claim 16 , intra-cavity injection into an open cavity without tissue penetration.18. A method for the preparation of a liquid crystalline composition comprising exposing the formulation precursor as claimed in to an aqueous fluid in vivo.19. A process for the formation of a formulation precursor for the administration of a bioactive agent to a mammalian subject claim 1 , said process comprising:i) forming a non-liquid crystalline, low viscosity mixture having a viscosity of 1 to 1000 mPas at 20° C. and comprising:a) a minimum of 18 wt. % of at least one neutral diacyl glycerol or at least one neutral diacyl glycerol and at least one tocopherol;b) at least one phosphatidylcholine;c) at least one biocompatible solvent having a viscosity of no more than 15 mPas at 20° C. comprising ethanol; andii) 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.20. A process for the formation of a formulation precursor for the administration of a bioactive agent to a mammalian subject claim 1 , said process comprising:i) forming a non-liquid crystalline, low viscosity mixture having a viscosity of 1 to 1000 mPas at 20° C. and comprising:a) a minimum of 18 wt. % of at least one tocopherol and least one diacyl glycerol;b) at least one phosphatidylcholine;c) at least one biocompatible, oxygen containing, low viscosity organic solvent; andii) 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.21. A process as claimed in wherein said formulation precursor is the formulation precursor as claimed in .22. A method of treatment or prophylaxis of a human or non human animal subject comprising parenteral administration of the formulation precursor as claimed in .23. The method of for the treatment of a condition selected from bacterial infection claim 22 , fungal infection claim 22 , skin soreness claim 22 , eye conditions claim 22 , genital soreness claim 22 , infections and conditions for the finger and/or toe nails claim 22 , travel sickness claim 22 , addiction including nicotine addiction claim 22 , periodontal infection claim 22 , conjunctivitis claim 22 , glaucoma and hormone deficiency or imbalance.24. The method of for prophylaxis against at least one condition selected from infection during surgery claim 22 , infection during implantation claim 22 , sunburn claim 22 , infection at the site of burns claim 22 , cuts or abrasions claim 22 , oral infections claim 22 , genital infections and infections resulting from activities resulting in exposure to infective agents.