Liposomal formulations of lipophilic compounds
AssigneeMediGene AG
InventorsHeinrich Haas, Ursula Fattler
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Abstract
The present invention relates to the preparation of liposomes with enhanced loading capacity for pharmaceutically and/or diagnostically active agents and/or cosmetic agents which are substantially solubilized by the liposomal membranes, to liposome dispersions with enhanced stability with respect to release of the active agent and/or cosmetic agent from the liposomes obtainable by the process, and to pharmaceutical or cosmetic compositions comprising said stabilized liposome dispersions. The preparation may involve dehydration and rehydration steps of liposome dispersions which may be carried out by spray drying.
Claims42
A process for the manufacture of a liposomal preparation comprising:
- a) providing a first liposomal preparation comprising a suspension of liposomes in an aqueous phase, wherein the liposomes comprise at least one membrane, wherein the membrane encloses a liposomally encapsulated volume of the aqueous phase and the aqueous phase comprises at least one osmotically active substance and has an initial overall osmolarity, O1, wherein the first liposomal preparation comprises at least one active agent or cosmetic agent in the liposomal membrane,
- b) thereafter generating an osmolar gradient in the aqueous phase of said preparation wherein the osmolarity of the aqueous phase outside the liposomally encapsulated volume, Oout, is lower than the osmolarity of the aqueous phase inside the liposomally encapsulated volume, Oin, to yield a second liposomal preparation, and wherein at least one active agent or cosmetic agent is incorporated into the liposomal membrane of the second liposomal preparation,
- c) optionally dehydrating the second liposomal preparation to obtain a dehydrated preparation, and
- d) optionally rehydrating the dehydrated preparation.
A process for the manufacture of a liposomal preparation comprising at least one lipophilic active agent or cosmetic agent, comprising:
- i) providing a stressed liposomal preparation,
- ii) incubating said stressed liposomal preparation with at least one lipophilic active agent or cosmetic agent, optionally in an unsolubilised form, thereby obtaining a stressed liposomal preparation with at least one lipophilic active agent or cosmetic agent incorporated into the liposomal membrane, and
- iii) optionally separating unsolubilised compound from the liposomal preparation, preferably by filtration or centrifugation.
A liposomal preparation comprising a suspension of liposomes in an aqueous phase, wherein the liposomes comprise at least one membrane, wherein at least one active agent or cosmetic agent is present in the liposomal membrane and at least one osmotically active substance is present in the aqueous phase, wherein the osmolarity of the aqueous phase inside the liposomes, Oin, is higher than the osmolarity of the aqueous phase outside of the liposomes, Oout.
A liposomal preparation comprising a suspension of liposomes in an aqueous phase, wherein the liposomes comprise at least one membrane, wherein at least one active agent or cosmetic agent is present in the liposomal membranes and at least one osmotically active substance is present in the aqueous phase, wherein the aqueous phase inside the liposomally encapsulated volume has a higher density than the aqueous phase outside the liposomally encapsulated volume.
A liposomal preparation comprising a suspension of liposomes in an aqueous phase, wherein the liposomes comprise at least one membrane, wherein at least one active agent or cosmetic agent is present in the liposomal membranes and at least one osmotically active substance is present in the aqueous phase, wherein the liposomal membrane is under tensile stress.
A liposomal preparation comprising a suspension of liposomes in an aqueous solution obtained by rehydration of a dehydrated liposomal preparation, characterised by an average diameter (Zaverage) which differs by less than a factor of 1.5 and a polydispersity index (PI) which differs by less than a factor of two from the liposomal preparation subjected to dehydration to obtain said dehydrated liposomal preparation.
A liposomal preparation comprising a suspension of liposomes in an aqueous phase obtained by rehydration of a dehydrated liposomal preparation, characterised by changes of the average diameter (Zaverage) by not more than a factor of about 1.5, preferably not more than 1.25, and changes of the polydispersity index (PI) by not more that a factor of about 2, preferably not more than about 1.5, most preferably not more than about 1.25 over 24 hours at 25° C.
A liposomal suspension comprising liposomes comprising DOTAP, DOPC, and paclitaxel at a total lipid concentration of about 10 mM, and trehalose, suspended in an aqueous phase comprising about 10 mg/ml, especially 9.79 mg/ml trehalose, wherein said liposomes are characterised by an anhydrous density of at least about 1.1 g/ml.
Dependencies are inferred from the claim text.