WO2001041706A2

WO2001041706A2 - Lipid nanotubules for topical delivery

Info

Publication number: WO2001041706A2
Application number: PCT/US2000/042361
Authority: WO
Inventors: Vitthal S. Kulkarni
Original assignee: The Collaborative Group, Ltd.
Priority date: 1999-11-29
Filing date: 2000-11-29
Publication date: 2001-06-14
Also published as: WO2001041706A3; AU4508101A

Abstract

The present invention relates to novel methods and compositions for the delivery of active agents. More specifically, the invention provides lipid nanotubules comprising a sphingolipid and at least one phospholipid. Preferably, the sphingolipid is a Ceramide and the phospholipid is soy lecithin. The lipid nanotubules can also comprise cholesterol. The lipid nanotubules of the invention are suitable for topical delivery of pharmaceutical or cosmaceutical agents.

Description

Lipid Nanotubules For Topical Delivery

This patent application claims the priority of U.S. provisional patent application No. 60/167,832, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to methods for preparing lipid nanotubules, containing sphingolipids, for topical delivery of bioactive material. More specifically, the invention relates to a new type of lipid vesicle having unique properties that confer special advantages for topical delivery of agents to the skin in comparison to other delivery vehicles, such as increased stability and skin penetrability. The delivery system of the invention is capable of transporting a multitude of active ingredients, including drugs, genetic material or cosmaceuticals deep into the skin.

BACKGROUND OF THE INVENTION

Oral delivery of dermatological products to target cells within the layers of the skin is hampered by variable rates of adsorption and metabolism of the products. A large majority of dermatological conditions have thus been traditionally treated by topical administration of drug and skin treatment agents. Transdermal drug delivery treatments have been limited, however, by adsorption of the product into the blood stream or failure of the product to be absorbed at all. The skin's surface provides a natural barrier to these agents, often making effective topical delivery difficult. Skin is an excretory organ that makes it challenging for pharmacological or cosmetic agents to penetrate against the natural excretory forces. In addition, the skin surface is enriched with sweat, bacteria, and cells that have been damaged or killed by ultraviolet light, creating a harsh environment for drug molecules and making them susceptible to degradation before reaching their target. Topical administration is nevertheless often preferred to oral administration of drugs and other agents for the treatment of dermatologic problems because substantially less agent enters the blood stream and systemic side effects can be eliminated or significantly reduced. In topical delivery systems, an active ingredient can penetrate the skin by several mechanisms, including through skin pores, sweat glands, and hair follicles. Various topical drug delivery systems are known in the art. These delivery systems generally fall into one of several major categories. The first category consists of traditional formulating agents such as, for example, ethanol, propylene glycol, various fatty compounds, and surfactants. Under certain conditions, these agents can function as penetration enhancers, but they generally do not provide for prolonged duration of action of drugs or skin care agents. These agents are frequently not very effective unless used in doses that may cause skin irritation or other adverse side effects, or that may produce excessive and poorly controlled absorption, in particular, into the vascular system.

A second category of skin care delivery systems are those that utilize specialized delivery technologies. These include, for example, liposomes, microspheres, transdermal patches and iontophoresis. The drug or skin care agent is encapsulated in liposomes (a liquid encapsulation system) and microspheres (a solid entrapment system). Transdermal patches and iontophoresis can be used to treat dermatologic disorders, but these technologies may be impractical to use at multiple skin sites or on certain areas, such as the face. A third major category of known topical drug delivery systems includes non- invasive, long-lasting liquid reservoirs for holding and depositing therapeutic or cosmetic agents in and on the stratum corneum and epidermis. An example of this type of topical delivery system is polyolprepolymers, which are hydroxy-terminated polyalkylene glycol- based polyurethane polymers that are capable of forming reservoirs in the upper layers of the skin, and which can be used to hold and deposit therapeutic or cosmetic agents in an on the stratum corneum and epidermis. U.S. Pat. Nos. 4,971,800, 5,045,317 and 5,051,260, all to Chess et al, relate to these compositions and methods. These polymeric agents, however, tend to be viscous materials that are difficult to spread onto the skin, and exhibit considerable drag, oily feel, and tackiness.

In selecting a topical drug delivery system it is essential that adverse systemic effects and irreversible damage to the skin structure be avoided. It is also desirable that the compound itself not cause irritation or allergic response and that the delivery system is resistant to accidental removal and remains on and in the upper layers of the skin for an extended period of time. The delivery systems should also provide acceptable feel and spreadability. It is also desirable that the polymeric drug delivery system be compatible with a wide range of active agents and formulation ingredients.

One of the main disadvantages of the topical delivery of pharmacological or cosmetic agents, however, is the low penetrability of drug substances through the skin. Several techniques have been employed in an attempt to increase the drug penetration rate across skin, including the use of penetration enhancers and liposomes.

Liposomes

Liposomes were first discovered in the 1960s by Bangham et al. (Adv. Lipid Res. 1963; 1 : 65-104). Since then, liposomes have been used as model membranes to study transport of molecules across bilayers, lipid-protein interactions, and physiochemical properties of amphipatic molecules. Liposomes have also been used in dermo- pharmacotherapy.

Liposomes are self-assembling structures comprising one or more lipid bilayers, each of which surrounds an aqueous compartment and comprises two opposing monolayers of amphipathic lipid molecules. These comprise a polar (hydrophilic) headgroup region covalently linked to one or two non-polar (hydrophobic) acyl chains. Energetically unfavorable contacts between the hydrophobic acyl chains and the aqueous medium are generally believed to induce lipid molecules to rearrange such that their polar headgroups are oriented towards the aqueous medium while the acyl chains reorient towards the interior of the bilayer. An energetically stable structure is formed in which the acyl chains are effectively shielded from coming into contact with the aqueous medium.

Liposomal bilayers can comprise a variety of amphipathic lipids, including those that are saturated or unsaturated, and that typically have acyl chains of from 10 to 24 carbons. Suitable polar groups include phosphorylcholine, phosphorylethanolamine, phosphorylserine, phosphorylglycerol and phosphorylinositiol. Suitable acyl chains include laurate, myristate, palmitate, stearate and oleate chains. Liposomal bilayers can further comprise sterols, such as cholesterol. Liposomes may also contain nonphospholipids such as ceramide, cerebroside, glycosphingolipld. sphingolipid, free fatty acids, eicosanoids, and lipid vitamins.

Stability, rigidity, and permeability of the liposome is altered by changes in lipid composition. Membrane fluidity is generally controlled by the fatty acyl chains of the lipid.

The fatty acyl chain can exist in an ordered, rigid state or in a relatively disordered fluid state. Factors affecting rigidity include chain length, the degree of saturation of the fatty acyl chains and temperature. Longer chains interact more strongly with each other and fluidity is thus greater with short chains; saturated fatty acyl chains are more flexible than unsaturated fatty acyl chains. Transition of the membrane from the rigid to the fluid state occurs as the temperature is raised above the melting temperature. The melting temperature is dependent upon the length and degree of saturation of the fatty acyl chain.

Liposomes may be multilamellar or unilamellar. Multilamellar vesicles contain concentric membranes with numerous enclosed aqueous compartments. Large and small unilamellar vesicles contain one single bilayer and one enclosed aqueous compartment.

Liposomes can be loaded with one or more biologically active agents by solubilizing the agent in the lipid or aqueous phase used to prepare the liposomes. Alternatively, ionizable bioactive agents can be loaded into liposomes by first forming the liposomes, establishing an electrochemical potential, e.g., by way of a pH gradient, across the outermost liposomal bilayer, and then adding the ionizable agent to the aqueous medium external to the liposome (Bally et al. U.S. Pat. No. 5.077,056 and WO086/01102).

In topical delivery systems, liposomes have been reported to target hair follicles (Hoffman, J. Drug Transport 1997;5:67-74). However, the environment on the skin surface is fairly harsh due to the presence of sweat and dead skin, and stratum corneum, the uppermost layer of the skin, consists of highly structured lipids with minimum water content. For these reasons, the stability of liposomes on the skin surface, and their ability to penetrate an intact stratum corneum, is very limited (Schreier & Bouwstra, J. Controlled Release 1984; 2: 61-65). Other major drawbacks in the use of conventional liposomes for the topical delivery of pharmacological agents include their instability to storage, low reproducibility of manufacture, low entrapment efficiency, and the leakage of drugs. Lipid Tubules

Lipid tubules comprise a self-organizing system in which lipids crystalize into tightly packed bilayers that spontaneously form hollow cylinders less than 1 μm in diameter. (Schnur et α/., Thin Solid Films 1987;152: 181-296); U.S. Pat. Nos. 4,877,501 and 4,990,291). The basic subunit of the tubule is a helical ribbon of lipid bilayer and, in some cases, open helical structures of the same diameter could be seen. An efficient synthesis of lipid tubules is described in U.S. Pat. No. 4,867,917.

Polymerizable diacetylenic phosphatidylcholines were discovered by Yager and Schoen to form novel hollow tubular microstructures. (Yager et al, Mol. Cryst. Liq. Cryst. 1984; 106: 371-381). The diacetylenic lipid tubules were straight, rigid, about 0.75 μm in diameter, and could be made to range in length from a few μm to nearly 100 μm, depending upon the conditions used to form the micro structure. The walls of the tubules could be as thin as a single bilayer. The lumen (the open space in a tubular organ or device) was generally open, allowing free access by diffusion from the ends of the microstructures.

Helices and tubules of much smaller diameters ( ~300 A) were found by Yamada et al. to form synthetic two-chain amphiphiles with oligopeptides (such as 12-14-mers of glutamic and aspartic acid) as hydrophilic headgroups. (Yamada et al, Chem. Lett. 1984; 10: 1713-1716). Shimizu and Hato produced similar tubules and helices using similar lipids with polypeptide headgroups. Later studies by Yamada et al. demonstrated that both positive, negative, and neutral amino acids could be incorporated into block copolymers as headgroups for glutamate-based lipopeptides.

Helical and tubular structures, as well as rod-like cochelate cylinders, were found to be formed quantitatively from the N-fatty acyl and α-hydroxy fatty acyl fractions of bovine brain galactocerebrosides. (Yager et al, Biochem. 1992; 31 : 9045-9055). Tubular and helical structures have now been observed in samples of aged suspensions of saturated- chain phosphatidylcholines and as transient intermediates in the crystallization of cholesterol from mixed micellar suspensions. (Konikoff et al, J. Clin. Invest. 1992; 90: 1155-1160). Lipid tubules can be "decorated" with inorganic materials, including metals (U.S. Pat. Nos. 4,911,981 and 5,049,382) and salts (Yager et al, J. Mat. Sci. 1992; 11 : 633- 636). In addition, some work has been undertaken to use the lumen of diacetylenic lipid tubules as a reservoir for the encapsulation of drugs for delivery in wound dressings. (Cliff et al, Fourth World Biomaterials Conference. 1992). Price et al. have described the use of microtubules, which encapsulate a composition known to possess antimicrobial, herbicidal, or pesticidal properties, in the preparation of coating compositions for the protection of surfaces. (U.S. Pat. Nos. 5,049,382; 5,492,696, and 5,705,191).

Yager et al. have recently described the use of high axial ratio microstructures, including tubules, for the delivery of therapeutic compounds that are covalently attached to molecules assembled into the microstructures (U.S. Pat. No. 5,851,536). However, no sufficiently efficient lipid tubule composition for topical delivery of certain drugs has been developed so far.

There is thus a need in the art for stable delivery vehicles, and methods of use thereof, for transporting drug substances more effectively across the stratum corneum and into deeper skin layers.

SUMMARY OF THE INVENTION

This invention provides lipid nanotubules comprised of lipid bilayers in the form of hollow cylindrical microstructures. The nanotubules are preferably comprised of at least one sphingolipid and at least one phospholipid. The invention further provides methods of preparation of the lipid nanotubules.

In another aspect, the invention provides lipid nanotubules in which a pharmacologically active agent or cosmetic agent is incorporated therein, and preparation thereof. In yet another aspect, the invention provides a pharmaceutical or cosmetic formulation comprising said lipid nanotubules and an appropriate topical carrier or carriers.

In yet another aspect, the invention provides a method of administering lipid nanotubules to a human or animal comprising topical administration of an effective amount of said pharmaceutical or cosmetic formulation. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1: Transmission electron micrographs of different preparations of lipid nanotubules (A-C).

FIGURE 2: Recovery of retinol palmitate from skin after application via a SanSurf formulation or nanotubule formulation. Each data point indicates the average from four panelists.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to new and improved lipid vesicles comprising lipid nanotubules, and to methods of their production. The diameter of human skin pores has been estimated to about 40 nm (see, Aguiella V, et al, J Control Release 1994; 32: 249-

257). Unlike traditional liposomal systems, lipid nanotubules have a significant size population under 100 nanometers in diameter, while still carrying significant quantities of active ingredient. These lipid nanotubules are therefore particularly useful as topical drug delivery vehicles because their small size permits rapid dermal penetration. In addition, the tubular delivery system described herein consists of lipids compatible with lipids in stratum corneum, which further facilitates skin penetration. This invention can be applied in particular in the cosmetic or pharmaceutical sector, especially the dermatological sector.

General Definitions

The term "delivery vehicle" or simply "vehicle" as used herein refers to carrier molecules used to deliver or deposit pharmacological or cosmetic agents into the skin.

The term "topical administration" or "dermal administration" as used herein refers to the local, non-systemic administration of a topical pharmacologically active agent or cosmetic agent on the skin, that is, without passage of the agent into the blood stream. The term "topical carriers" as used herein refers to vehicles suitable for topical application of drugs or cosmetics, and includes any such liquid or non-liquid solvent, diluent or like material known in the cosmetic and medical arts, for forming any liquid or semisolid gel, cream, ointment, emulsion, aerosol, foam, lotion, or the like, and that does not adversely affect living animal tissue or interact with other components of the composition in a deleterious manner. Topical carriers are used to provide the compositions of the invention in their preferred liquid form. Non-limiting examples of suitable topical carriers for use herein include water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrosylates, liquid alkylated protein hydroyslates, liquid lanolin and lanolin derivatives, and like materials, and mixtures thereof. The terms "pharmacologically active agent", "cosmetic agent", "cosmaceutical agent", "bioactive agent", or simply "active agent" as used herein refer to any chemical material or compound suitable for topical administration which produces any desired local effect. Non-limiting examples of such substances include antifungal agents, chemotherapeutic agents, antibiotics, anti-microbial agents, antiviral agents, hormones, cutaneous growth enhancers, including for the hair and nails, hair care agents, antipsoriatics, retinoids, anti-acne medicaments, antineoplastic agents, topical anesthesetics, phototherapeutic agents, sunscreens, cutaneous protection agents, alpha-hydroxy acids (including lactic acid and glycolic acid), insect repellants and the like.

The term "effective amount" of pharmacologically active agent or cosmetic agent refers to a nontoxic but sufficient amount of a compound to provide the desired local effect and performance at a reasonable benefit/risk ratio attending any medical treatment.

Lipid Nanotubules

The nanotubules of the present invention consist of lipid bilayers which form hollow cylindrical microstructures morphologically analogous to soda straws. The diameter of these "tubules" are preferably substantially within the range of about 30-100 nm, or even more preferably substantially within the range of about 40-100 nm, with an average length substantially within the range of about 1-2 μm. The lipid nanotubules are comprised of at least one sphingolipid, and at least one phospholipid. Preferred sphingolipids include, but are not limited to, Ceramide I- VI; galactosyl ceramides; glycosyl ceramides; lactosyl ceramides; and combinations thereof. Preferred phospholipids include, but are not limited to, soy lecithin; phospholipon 80, 90, and 90H; Varisolf preparations (Witco Corp., Dublin, OH); and combinations thereof. Optionally, the nanotubules further include cholesterol.

In one embodiment of the invention, the sphingolipid is Ceramide III and the phospholipid is soy lecithin. In another embodiment, the sphingolipid as a mixture between Ceramide I and IV. In a preferred embodiment, the amount of sphingolipid is in the range of about 0.01% to about 35% of the total amount of lipid (by weight).

In another preferred embodiment of the invention, the lipid content of the nanotubules include ceramide, phospholipid, and cholesterol in the approximate molar ratios of 10, 80, and 10, respectively.

In yet another embodiment of the invention, the lipids comprising the nanotubules consist of ceramide, phospholipid, and cholesterol, in the approximate molar ratios of 5, 85, and 10, respectively.

The lipid nanotubules can be used as carrier vehicles to deliver or deposit pharmacological or cosmetic agents into various depths of the skin; epidermis and dermis, as well as percutaneous. Depending on the chosen nanotubule composition, the amount of pharmaceutical or cosmetic active agent which can be incorporated into the nanotubules may range from about 0.1% to 25 % (by weight) of the preparation. The active agent may located within, or associated with, various regions of the nanotubule including the lipid bilayer, the inner aqueous spaces, the outer leaflet of the lipid bilayer, the surrounding solution, or any combination of these arrangements. Hydrophobic pharmaceutical or cosmetic agents are especially well suited for the type of delivery vehicles provided by the invention. Examples of preferred active agents include, but are not limited to, dipalmityl kojate, retinol palmitate, vitamin E acetate, vitamin E palmitate, and salicylic acid.

Preparation of Lipid Nanotubules

Lipid nanotubules are prepared by heating a mixture of sphingolipid, phospholipid, and, if desired, cholesterol, above the phase transition temperature of the lipids (T.J. Preferably, the mixture should be heated to more than about 55 °C, but less than about 80 °C. Advantageously, the desired proportions of lipids are mixed in ethanol, and water heated to the same temperature is added to the ethanol phase to avoid separation of the ingredients in the ethanol phase. If the lipids are cooled rapidly to below 30 °C, small shards are formed. However, if the lipids are cooled slowly to approximately 37°C to 38 °C, hollow tubules are formed.

The nanotubules may be formed so as to contain selected pharmacologically active agents or cosmetic agents inserted in the lipid bilayer, in the inner aqueous spaces, associated with the outer leaflet of the lipid bilayer, in the surrounding solution, or in any combination of these arrangements. For example, the active agent can be added into the ethanol phase, or the water phase, or both, and the suspension processed by microfluidization. The lipid nanotubules may also be preformed, mixed with a pharmacological or cosmetic agent, and then reprocessed by microfluidization.

Formulations and Uses

The lipid nanotubules can be employed as an ingredient in a more complex pharmaceutical or cosmetic formulation. The pharmaceutical or cosmetic formulation may be prepared by mixing the nanotubules, in which a pharmacologically active agent or cosmetic agent is incorporated, with an appropriate topical carrier, including, but not limited to, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrosylates, liquid alkylated protein hydroyslates, liquid lanolin and lanolin derivatives, and other similar compounds, as well as mixtures thereof. The formulation may be topically applied in the form of an emulsion, gel, solution, suspension, or other forms known in the art. In most cases, water, or an aqueous phase, is the external media in which lipid nanotubules are contained.

Other pharmaceutically acceptable additives may also be incorporated into the pharmaceutical or cosmetic formulation including, for example, diluents, binders, stabilizers, preservatives, and colorings. The pharmaceutical or cosmetic formulation may be applied directly to the skin and allowed to dry, held in place with a dressing or patch or absorbent material, applied as an ointment, or otherwise held by a device, or sprayed onto the skin to maximize contact of the nanotubules with the skin. The formulation may also be applied in an absorbant dressing or gauze. The pharmaceutical or cosmetic formulation can be used in diversified applications involving topical administration of various compounds, either pharmaceutical or non- pharmaceutical. The formulation can be used for, but not limited to, the treatment of various skin conditions, including insect bites and stings or oral lesions; warts, corns, and calluses; bacterial skin infections such as piodermas furuncles, carbuncles, and folliculitis; localized inflammatory skin conditions; precancerous or cancerous lesions of the skin such -l ias keratoses and melanomas; localized viral-induced allergic reactions on the skin; and localized fungal infections of the skin.

EXAMPLES

The invention is further illustrated by the following non-limiting examples.

EXAMPLE 1:

Preparation of lipid nanotubules

Lipid nanotubules were prepared by heating a mixture of 0.15% (by weight) of Ceramide III (Centerchem, Inc., Stamford, CT), 0.55% (by weight) of Phospholipon 80 (American Lecithin Co., Oxford, CT), 0.041%> (by weight) of cholesterol (Spectrum), and 1.47% (by weight) of ethanol on a water bath to between 60 ^CC and 80 °C. Deonized water

(97.789%) by weight) was separately heated on a water bath to between 60 °C and 80 °C. The heated deionized water was quickly added to the heated Ceramide III, Phospholipon 80, cholesterol, and ethanol mixture. The mixture was then processed in a microfluidizer (Microfluidics, Newton, MA) using high pressure/high shear 5 times without the cooling loop on.

EXAMPLE 2: Preparation of lipid nanotubules

Lipid nanotubules were prepared by heating a mixture of 0.045%> (by weight) of Ceramide III, 0.64%> (by weight) of Phospholipon 80, 0.041% (by weight) of cholesterol, and 2.0%) (by weight) of ethanol on a water bath to between 60°C and 80^CC. Deonized water (97.274% by weight) was separately heated on a water bath to between 60°C and 80 °C. The heated deonized water was quickly added to the heated Ceramide III, Phospholipon 80, cholesterol, and ethanol mixture. The mixture was then processed in a microfluidizer (Microfluidics, Newton, MA) using high pressure/high shear 5 times without the cooling loop on.

EXAMPLE 3: Active ingredients

Different active ingredients have been included in the tubular microstructures described herein, such as dipalmityl kojate, retinol palmitate, vitamin E acetate, and salicylic acid. Preliminary data showed that nanotubules containing said active ingredients were more stable than liposomes containing the same agents.

EXAMPLE 4: Skin test

Nanotubes were compared to lipid emulsion as delivery vehicles for retinol palmitate to skin. Lipid nanotubes were formed with a high pressure high shear technique. Retinol palmitate was incorporated into the tubes as an active ingredient. A SanSurf of retinol palmitate was also prepared via an established procedure.

A panel of five volunteers was chosen to test the products "Nanotubes retinol palmitate" and "SanSurf retinol palmitate" both at the same concentration (0.5%). Known amount of test product was applied to the forearm of volunteers at four different places. After a chosen length of time (See FIGURE 2), the spots were thoroughly cleaned with ethanol swabs to recover any unpenetrated retinyl palmitate. The retinol palmitate from skin washings was quantitatively analyzed via HPLC.

The results indicated that after 6 hrs of application about 50% of the retinol palmitate remained on the skin surface whereas after the same period of time, only 30% of the active agent remained on the skin after administering the nanotube formulation. The results indicated that the amount of retinol palmitate recovered from the nanotubular formulation was much less than that from the lipid emulsion, suggesting that retinol palmitate in nanotubular formulation was more rapidly absorbed into skin than retinol palmitate formulated in lipid emulsion.

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Patents, patent applications, and publications are cited throughout this application, the disclosures of which are incorporated herein by reference in their entireties.

Claims

WE CLAIM:

1. A lipid nanotubule comprising a lipid bilayer cylinder, wherein the diameter of the lipid bilayer cylinder is less than about 1 μm, and wherein the bilayer comprises at least one sphingolipid and at least one phospholipid.

2. The lipid nanotubule of claim 1, wherein the diameter is about 100 nm or less.

3. The nanotubule of claim 1 , wherein the lipid bilayer further comprises cholesterol.

4. The nanotubule of claim 1, wherein the sphingolipid is Ceramide III.

5. The nanotubule of claim 1, wherein the sphingolipid is selected from the group consisting of Ceramide I, Ceramide IV, and a mixture thereof

6. The nanotubule of claim 1, wherein the phospholipid is soy lecithin.

7. The nanotubule of claim 1, further comprising an active agent.

8. The lipid nanotubule of claim 1, wherein the bilayer comprises from about 0.01 % to about 35 % Ceramide III, from about 20 % to about 95 % soy lecithin, and from about 0 % to about 10 % cholesterol, by weight of the total lipid content.

9. A method of delivering an active agent to a human or animal comprising administering a lipid nanotubule comprising a lipid bilayer cylinder, wherein the diameter of the lipid bilayer cylinder is less than about 1 μm, and wherein the bilayer comprises at least one sphingolipid and at least one phospholipid. The method of claim 9, wherein the diameter is about 100 nm or less

The method of claim 9, wherein the lipid bilayer further comprises cholesterol

The method of claim 9, wherein the sphingolipid is Ceramide III

The method of claim 9, wherein the sphingolipid is selected from the group consisting of Ceramide I, Ceramide IV, and a mixture thereof

The method of claim 9. wherein the phospholipid is soy lecithin

The method of claim 9, wherein the lipid nanotubule further comprises an active agent

The method of claim 9, wherein the bilayer comprises from about 0 01 % to about 35 % Ceramide III, from about 20 % to about 95 % soy lecithin, and from about 0 % to about 10 % cholesterol, by weight of the total lipid content

The method of claim 9, wherein the active agent is delivered by topical administration

A method of delivering an active agent to a human or animal comprising topically administering a lipid nanotubule comprising a lipid bilayer cylinder comprising an effective amount of an active agent, wherein the diameter of the lipid bilayer cylinder is less than about 1 μm, and wherein the bilayer comprises at least one sphingolipid and at least one phospholipid. The method of claim 18, wherein the sphingolipid is selected from the group consisting of Ceramide I, Ceramide III, Ceramide IV, and a mixture thereof.