Aggregates with increased deformability, comprising at least three amphipats, for improved transport through semi-permeable barriers and for the non-invasive drug application in vivo, especially through the skin

Abstract

The invention describes combinations of at least three amphipatic substances forming aggregate suspensions in a polar liquid. Judicious choice of system components, which differ at least 2-times to 10-times in solubility, ensures said aggregates to have extended, unusually adaptable surfaces. This is probably due to simultaneous action on said aggregates of at least two more soluble substances amongst said three system components, at least one of which is an active ingredient and preferably a drug; the third component, alternatively, can take the role of a drug. The patent further deals with the use of said combinations in pharmaceutical preparations capable of transporting drugs into the body of warm blood creatures. This is made possible by the drug loading capability of said aggregates with the highly flexible and deformable coating, which renders the resulting drug carriers highly adaptable. The patent finally reveals suitable methods and favourable conditions for carrier manufacturing and application.

Description

[0001] The present application claims the benefit of U.S. provisional application No. 60 / 417,847 filed on Oct. 11, 2002, incorporated herein by reference in its entirety.[0002] The invention relates to aggregates with extended surface (extended-surface aggregates, ESAs) with increased deformability and improved barrier penetration capability, said ESAs being suspendable in a suitable liquid medium and comprising at least three amphipats (amphipatic components) and being capable to improve the transport of actives through semi-permeable barriers, such as the skin, especially for the non-invasive drug application in vivo by means of barrier penetration by such aggregates. The three amphipats include at least one membrane forming compound (MFC), which can form the membrane of said ESAs, and at least two membrane destabilising compounds (MDC.sub.1 and MDC.sub.2) differentiated by their capability of forming smaller aggregates (with no extended surfaces) by either themselves or else in c...

AI Technical Summary

Benefits of technology

[0019] A further aspect of the invention is to provide suspensions of extended surface aggregates in a liquid medium comprising: at least one first membrane forming component (MFC); at least one second membrane destabilising component (MDC); at least one third membrane destabilising component (MDC), the third component typically being a drug, such that said complex extended surface aggregates (ESAs) can penetrate intact mammalian skin and thus increase drug concentration in the skin and / or increase the reach of drug distribution below the skin, in comparison with the result of the same drug application in a solution on the skin. In a special version of said suspensions, said extended surface aggregates are membrane-enclosed, liquid-filled vesicles, said first component is a membrane-forming lipid, and said second and third components are membrane-destabilising components.

[0047] Non-destructing passage of ultradeformable, mixed lipid aggregates through narrow pores in a semi-permeable barrier is thus diagnostic of high aggregate adaptability. If pore radius is two times smaller than the average aggregate radius the aggregate must change its shape and surface-to-volume ratio at least 100% to pass without fragmentation through the barrier. An easy and reversible change in aggregate shape inevitably implies high aggregate deformability and requires large surface-to-volume ratio adaptation. A change in surface-to-volume ratio per se implies: a) high volume compressibility, e.g. in the case of compact droplets containing material other than, and immiscible with, the suspending fluid; b) high aggregate membrane permeability, e.g. in the case of vesicles that are free to exchange fluid between inner and outer vesicle volume.

[0081] FIG. 4: Molecular redistribution in an aggregate-enshrining lipid bilayer during aggregate deformation and pore crossing, which lowers the activation energy for transbarrier transport.

Problems solved by technology

Administration of active ingredients frequently is limited by natural barriers, such as the skin, which prevent adequate absorption of the active molecules due to the low barrier permeability for such ingredients.

None of these, however, solves the problem of active ingredient transport through the skin or mucous barrier to general satisfaction.

Epidermal use of one or several amphipatic substances in the form of a suspension or an O / W or W / O emulsion, has also brought about too little improvement.

However, the ability of the active ingredient to permeate the skin was not appreciably increased.

However, such vesicles are not used on the skin or for transport through semi-permeable barriers.

Further, such vesicles are not used for transport of drugs through a semi-permeable barrier.

However, the reports demonstrate no liposome-mediated drug transport through the skin.

Further, Foldvari's formulations evidently were not optimised for adaptability but rather for best drug retention / release.

However, all the tested suspensions were reported by Planas et al. to be unstable.

Further, Planas et al. failed to disclose how a stable drug formulation could be prepared, which would be suitable for transdermal drug delivery.

However, such vesicles do not simultaneously include both a MFC and a MDC, and are unsatisfactory.

An easy and reversible change in aggregate shape inevitably implies high aggregate deformability and requires large surface-to-volume ratio adaptation.

Introduction of membrane stiffening agents (including cholesterol and other sterols, little polar long chain lipids, etc., as quasi-MFC) into bilayers also lowers the adaptability of the resulting mixed aggregates.

Such detailed analysis is not necessary for optimising aggregate suspensions for transbarrier transport, however, and therefore is not used in the present application.

Images