Glucoside paucilamellar vesicles

Details Glucoside paucilamellar vesicles Glucoside paucilamellar vesicles

1998-10-02

2001-06-26

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C424S401000, C428S402200, C514S725000

Reexamination Certificate

active

06251425

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to formulations for lipid vesicles and methods of their manufacture. More particularly, the present invention discloses paucilamellar lipid vesicles designed of materials which have exceptional properties for cosmetic, edible, dermatological, and pharmaceutical use.
Lipid vesicles are substantially spherical structures made of amphiphiles, e.g., surfactants or phospholipids. The lipids of these spherical vesicles are generally organized in the form of lipid bilayers, e.g., multiple onion-like shells of lipid bilayers which encompass an aqueous volume between the bilayers. Paucilamellar lipid vesicles have 2-10 peripheral bilayers which surround a large, unstructured central cavity.
Until recently, liposome technology has been concerned mostly with vesicles composed of phospholipids. This is primarily because phospholipids are the principal structural components of natural membranes and, accordingly, lipid vesicles have been used as a model system for studying natural membranes. However, there are a number of problems associated with using phospholipids as synthetic membranes. Biological membranes are stabilized by membrane proteins and maintained by extensive enzymatic “support” systems that rapidly turn over, exchange or modify membrane lipids. Neither membrane proteins nor the requisite enzymatic support systems can be practically incorporated into the wall structure of liposomes, making the structures inherently less stable than natural membranes. In addition, the biological environment contains several potent phospholipases that rapidly break down free phospholipids. These phospholipids will attack liposomes and degrade the membrane. For these reasons, phospholipid liposomes are rapidly degraded in vivo.
Moreover, phospholipid liposome technology has other problems. Phospholipids are labile and expensive to purify or synthesize. In addition, classic phospholipid liposomes are in the form of multilamellar as opposed to paucilamellar vesicles and have poor carrying capacities, especially for lipophilic materials, and have poor shelf lives unless lyophilized in the dark with antioxidants. Finally, phospholipids degrade too rapidly in vivo for most pharmaceutical or vaccine applications. For these reasons, there is increasing interest in the art for paucilamellar lipid vesicles made of other amphiphilic compounds.
SUMMARY OF THE INVENTION
The present invention features lipid vesicles and a methods of their manufacture employing certain glucosides as primary wall formers. These vesicles feature materials with special usefulness for cosmetic and dermatological processes and products.
The vesicles in the invention generally have two to ten bilayers arranged in the form of substantially spherical shells separated by aqueous layers surrounding a large amorphous central cavity free of lipid bilayers. The lipid bilayers have as their primary wall components a mixture of a glucoside primary amphiphile, or wall former, and a steroid such as cholesterol. The glucoside primary amphiphile is not believed to form vesicles in the absence of the steroid. The vesicles may optionally comprise a minor amount of a secondary amphiphile, e.g., which improves the shelf life stability of the vesicles, such as C
12
-C
18
fatty alcohols, polyoxyethylene acyl alcohols, polyglycerols, sorbitan fatty acid esters, ethoxylated sorbitan fatty acid esters, C
12
-C
18
glycol monoesters, C
12
-C
18
glyceryl mono- and diesters, propylene glycol stearate, sucrose distearate, glyceryl dilaurate, and mixtures thereof.
In an embodiment the glucoside is a fatty glucoside, e.g., cocoyl glucoside, arachidyl behenyl glucoside, cetearyl glucoside, myristyl glucoside or mixtures thereof. In certain embodiments, the lipid bilayer may comprise a certain amount of the alcohol corresponding to the fatty acid portion of the glucoside, e.g., myristyl alcohol.
In an embodiment the steroid may be a sterol, such as cholesterol, cholesterol derivatives, hydrocortisone, phytosterol, and mixtures thereof. In other embodiments, other additives such as charge producing agents, and other lipid soluble materials may be incorporated into the vesicles.
DETAILED DESCRIPTION OF THE INVENTION
The present invention uses a blend of amphiphiles to form paucilamellar lipid vesicles. In particular, a glucoside such as a fatty glucoside is combined with at least one steroid such as cholesterol to form a lipid phase which can be hydrated to form vesicles. Minor amounts of other additives such as C
12
-C
18
fatty alcohols may also be blended with the lipid phase.
The lipid vesicles disclosed herein are paucilamellar lipid vesicles generally characterized as having two to ten lipid bilayers or shells with small aqueous volumes separating each substantially spherical lipid shell. The innermost lipid bilayer surrounds a large, substantially amorphous central cavity which may be filled with either an aqueous solution or a water-immiscible oily solution.
The lipid bilayers have as their primary wall components a mixture of a glucoside primary amphiphile (or wall former), and a steroid such as cholesterol. The glucoside primary amphiphile is not believed to form vesicles in the absence of the steroid. In a preferred embodiment, the glucoside primary amphiphile may be a fatty glucoside, e.g., where the fatty portion of the glucoside is derived from a C
10
to C
50
fatty acid. Exemplary glucoside primary amphiphiles include cocoyl glucoside, arachidyl behenyl glucoside, cetearyl glucoside and myristyl glucoside, and mixtures thereof. The lipid bilayers generally comprise up to 75% of glucoside primary amphiphile.
Preferred steroids include sterols including cholesterol, cholesterol derivatives, ethoxylated cholesterol, hydrocortisone, phytosterol, and mixtures thereof. The amount of sterol may depend up to some extent on whether it competes with any lipophilic material to be encapsulated. In an embodiment, the lipid bilayers generally comprise about 0-25% of a steroid such as a sterol.
The vesicles may optionally comprise a minor amount of a secondary amphiphile, e.g., which improves the shelf life stability of the vesicles likely by altering the phase transition of the vesicles. Also, in certain applications incorporation of the secondary amphiphile may modulate penetration of the encapsulated active molecule through skin. Exemplary secondary amphiphiles include C
12
-C
18
fatty alcohols, polyoxyethylene acyl alcohols, polyglycerols, sorbitan fatty acid esters, ethoxylated sorbitan fatty acid esters, C
12
-C
18
glycol monoesters, C
12
-C
18
glyceryl mono- and diesters, propylene glycol stearate, sucrose distearate, glyceryl dilaurate, and mixtures thereof.
The lipid bilayers may also comprise about 0-5% of a charge-producing agent such as dicetyl phosphate, quaternary ammonium salts, cetyl sulfate, sarcosinamides, phosphatidic acid, phosphatidyl serine, and fatty acids such as oleic acid or palmitic acid.
Examples of water-immiscible oily materials which can be encapsulated in the central cavity are mineral oils, soybean oil, paraffin waxes, petrolatum, triglyceride oils and fats, perfumes and fragrances, flavor oils, perfluorocarbon liquids, anthralin, retinoic acid, water insoluble vitamins, and water immiscible solvents. Avocado oil unsaponifiables can also be encapsulated in the central cavity and are particularly useful, as they may additionally be used as a source of phytosterol for stabilizing the vesicle bilayer(s).
Oil filled vesicles, e.g., vesicles having their amorphous central cavities filled with a water-immiscible oily solution, may be formed using either the “hot loading” technique disclosed in U.S. Pat. No. 4,911,928 or the “cold loading” technique described in U.S. Pat. No. 5,160,669, the disclosures of which are incorporated herein by reference. In either case, a lipid phase is formed by blending a glucoside primary amphiphile and the compatible amphiphile(s), along with any sterols or lipophilic materials to be incorporated into the lipid bilayers, to form a homogenous l

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