Robust controlled-release formulations

A method of delivery of a bioactive agent to a human or non-human animal body, this method comprising administering a pre-formulation comprising a non-liquid crystalline, low viscosity mixture of:

• a. at least one diacyl glycerol and/or at least one tocopherol;
• b. at least one phospholipid component comprising phospholipids having
• i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and
• ii. two acyl chains each independently having 16 to 20 carbons wherein at least one acyl chain has at least one saturation in the carbon chain, and there are no more than four unsaturations over two carbon chains;
• 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 non-lamellar liquid crystalline phase structure upon contact with an aqueous fluid in vivo following administration.

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 diacyl glycerol and/or at least one tocopherol;
• b. at least one phospholipid component comprising phospholipids having
• i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and
• ii. two acyl chains each independently having 16 to 20 carbons wherein at least one acyl chain has at least one unsaturation in the carbon chain, and there are no more than four unsaturations over two carbon chains;
• c. at least 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.

A process for the formation of a pre-formulation suitable for the administration of a bioactive agent to a subject, said process comprising forming a non-liquid crystalline, low viscosity mixture of

• a. at least one diacyl glycerol and/or at least one tocopherol;
• b. at least one phospholipid component comprising phospholipids having
• i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and
• ii. two acyl chains each independently having 16 to 20 carbons wherein at least one acyl chain has at least one unsaturation in the carbon chain, and there are no more than four unsaturations over two carbon chains;
• 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.

A medicament comprising a non-liquid crystalline, low viscosity mixture of:

• a. at least one diacyl glycerol and/or at least one tocopherol;
• b. at least one phospholipid component comprising phospholipids having
• i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and
• ii. two acyl chains each independently having 16 to 20 carbons wherein at least one acyl chain has at least one unsaturation in the carbon chain, and there are no more than four unsaturations over two carbon chains;
• 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 in the manufacture of a pre-formulation for use in the sustained administration of said active agent, wherein said pre-formulation is capable of forming at least one non-lamellar liquid crystalline phase structure upon contact with an aqueous fluid.