Liposomal systems comprising sphingomyelin

Abstract

The present disclosure provides a liposomal system comprising an aqueous medium having dispersed therein liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the aqueous medium being in iso-osmotic equilibrium with said intraliposomal aqueous compartment, the liposomes having a membrane comprising a liposome forming lipids, at least one of which being sphingomyelin (SPM), the liposomal system having increased stability as compared to the same liposomes free of SPM, and in one embodiment being stable during long-term storage, said stability being characterized in that no more than 30% of the at least one active agent is present in the aqueous medium after said storage. Further provided by the present disclosure are a method for storage of liposomes making use of the liposomal system; use of the liposomal system for the treatment of a medical condition or for the diagnostic of a medical condition; a pharmaceutical or diagnostic composition comprising the liposomal system, and a method of treating or diagnosing of a medical condition comprising administering to a subject an amount of the liposomal system.

Description

FIELD OF THE INVENTION[0001]This invention relates to the field of liposome technology.BACKGROUND OF THE INVENTION[0002]Among other applications, liposomes are used as carriers of drugs for delivery via a plurality of mechanisms. To this end, various types of liposomes are used, from small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), multilamellar vesicles (MLV), multivesicular vesicles (MVV), large multivesicular vesicles (LMVV, also referred to, at times, by the term giant multivesicular vesicles, “GMV”), oligolamellar vesicles (OLV), and others. It is appreciated by those versed in the art that LMVV are somewhat different from unilamellar vesicles of various sizes and of the “onion like” MLV structure. In LMVV the amount of aqueous medium forming the aqueous phase per the amount of lipid is greater than that in MLV, this potentially allowing higher amount of drug to be loaded into the aqueous phase, namely, higher drug to lipid mole ratio in the LMVV when compare...

AI Technical Summary

Benefits of technology

[0004]The present disclosure is based on the finding that large multivesicular vesicles (LMVV) loaded with high amount of an amphipathic drug (bupivacaine, BUP) can be stabilized, in terms of reduced BUP leakage, if the liposomes' membranes comprise sphingomyelin and the LMVV are within an aqueous medium being in an iso-osmotic equilibrium with the intraliposomal aqueous medium.

[0005]Thus, the present disclosure provides, in accordance with a first of its aspects a liposomal system comprising an aqueous medium having dispersed therein liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the aqueous medium being in iso-osmotic equilibrium with said intraliposomal aqueous compartment, the liposomes having a membrane comprising a liposome forming lipids, at least one of which being sphingomyelin (SPM), the liposomal system having increased stability as compared to the same liposomes free of SPM (namely, where there is no SPM in the liposome forming membrane). In one embodiment, the liposomal system is stable during long-term storage, said stability being characterized in that no more than 30% of the at least one active agent is present in the aqueous medium after said storage.

[0006]The present disclosure also provides, in accordance with a second of its aspects, a method for storage of liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a membrane comprising liposome forming lipids, at least one liposome forming lipid being sphingomyelin (SPM), the method comprising forming a liposomal system where said liposomes are dispersed in an aqueous medium being in an iso-osmotic equilibrium with the intraliposomal aqueous compartment of said liposomes and storing said liposomal system, the liposomal system having increased stability as compared to the same liposomes free of SPM.

Problems solved by technology

However a phenomenon that still remains unresolved with these LMVV relates to leakage of bupivacaine from the LMVV during storage at 4° C. or room temperature.

Thus, after time, free drug is contained in the system (the amount being above drug MTD) and the administration of the liposomal system containing such free drug may result in toxicity and unwanted side effects (from exposure high amounts of free drug), unfavorable pharmacokinetics and shorter duration of the therapeutic effect.

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