The invention provides a cosmetic or pharmaceutical composition in the form of an oil-in-glycerin emulsion, with mean droplet size below one micron, comprising a continuous glycerin phase, at least one vegetable oil comprising an internal phase, at least one emulsifying stabilizer, and at least one bioactive compount comprising at least one hydrophobic, moiety within its structure, wherein the composition facilitates stratum-corneum penetration and dermal penetration of said bioactive compound.

Description of the Invention

SUMMARY OF THE INVENTION

According to the present invention there is provided a cosmetic or pharmaceutical composition in the form of an oil-in-glycerin emulsion with mean droplet size below one micron, comprising a continuous glycerin phase at least one vegetable oil comprising an internal phase at least one emulsifying stabilizer and at least one bioactive compound comprising at least one hydrophobic moiety within its structure, wherein said composition facilitates stratum-corneum penetration and dermal penetration of said bioactive compound.

More specifically, the present invention provides a cosmetic or pharmaceutical composition in the form of an oil-in-glycerin emulsion, with mean droplet size below one micron, comprising: a) a continuous glycerin phase; b) at least one vegetable oil comprising an internal phase; c) at least one emulsifying stabilizer; and d) at least one bioactive compount comprising at least one hydrophobic, moiety within its structure, wherein the composition facilitates stratum-corneum penetration and dermal penetration of said bioactive compound.

As stated, the compositions of the present invention are especially preferred for trans-dermal, administration of bioactive compounds and intra-dermal administration of bioactive compounds.

In preferred embodiments of the present invention said bioactive compound is hydrophobic or amphiphilic and is predominantly associated with the oily internal phase droplets.

Preferably, in the compositions of the present invention, the mean droplet size is between 100 and 1,000 nanometers.

In preferred embodiments of the present invention the emulsifying stabilizer is made by condensation of at least one fatty acid or alcohol with a carbohydrate or poly-carbohydrate.

In the compositions of the present invention, preferably oil is present in an amount ranging from about 0.1-40 wt/wt % and most preferred are compositions wherein said oil is present in an amount ranging from about 1-20 wt/wt %.

In preferred embodiments said emulsifying stabilizer is preferably present in an amount ranging from about 0.1-10 wt/wt % and preferably said bioactive component is present in an amount ranging from about 0.1-20 wt/wt %.

In especially preferred embodiments of the present invention said continuous glycerin phase comprises at least 50% glycerin.

Preferably said emulsifying stabilizer is capable of forming liquid crystal lamellar phase.

In preferred embodiments of the present invention said emulsifying stabilizer is selected from the group consisting of cetearyl glucoside, sucrose esters and sorbitan esters.

In other preferred embodiments of the present invention said glycerin constitutes a continuous phase of said emulsion and a minor portion of water is included in said glycerin phase.

Preferably said oil-in-glycerin emulsion is self-preserving and free of microbial preservatives.

In preferred embodiments of the present invention the mean nanometer droplet size is obtained solely by a process of mechanical mixing or high shear homogenization.

Preferably said bioactive component is selected from the group consisting of a botanical extract, a drug, a peptide, a polypeptide, a nucleotide, and a glycolipid and preferably said vegetable oil is a vegetable tryglyceride of a regular or a medium chain triglyceride.

The present invention provides a stable oil-in-glycerin nanometer emulsion that can perform as an adequate storage and delivery vehicle bringing forth enhanced stratum-corneum and or skin penetration properties for bioactive ingredients having at least one hydrophobic moiety, including peptides, drugs, phytochemicals and oligonucleotides or liposacharides.

Thus, in one embodiment, this invention comprises an admixture of a pharmacologically active agent having at least one hydrophobic moiety formulated in a penetration enhancer oil in glycerin emulsion composition for the administration of therapeutically effective amounts of said active agent.

In another embodiment, the invention provides a method for enhancing the rate of penetration of a pharmacologically active agent having at least one hydrophobic moiety through the stratum-corneum, wherein the method comprises administering to the skin of the patient undergoing treatment a mixture of the pharmacologically active agent in the permeation enhancer composition as described herein.

In preferred embodiments of the present invention the emulsifying stabilizer is of vegetable origin made by condensation of at least one fatty acid or alcohol with a carbohydrate or poly-carbohydrate.

In especially preferred embodiments of the present invention there is provided a systemic pharmaceutical composition in the form of an oil-in-glycerin emulsion with mean droplet size below one micron for trans-dermal administration, comprising: a) a continuous glycerin phase, b) at least one vegetable oil comprising an internal phase, c) at least one emulsifying stabilizer wherein said emulsifying stabilizer is capable of forming a liquid crystal lamellar phase and the emulsifying stabilizer is made by condensation of at least one fatty acid or alcohol with a hydrophilic molecule, d) at least one bioactive pharmaceutical compound comprising at least one hydrophobic moiety within its structure, and low water solubility or hydrophobic properties, wherein said composition facilitates stratum corneum penetration and dermal penetration of said bioactive pharmaceutical compound.

DETAILED DESCRIPTION OF THE INVENTION

"Penetration enhancement" or "permeation enhancement" as used herein relates to an increase in the permeability of skin to a pharmacologically active agent, having at least one hydrophobic moiety or increase in the rate at which the agent permeates into and through the skin.

The term "transdermal" drug delivery as used herein is intended to denote the term in its conventional sense, i.e., to indicate delivery of a drug by passage through the skin and into the blood stream. "Topical" drug delivery is used to mean local administration of a topical drug as in, for example, the treatment of various skin disorders.

The terms, vegetable or botanical are interchangeable and are aimed to describe non-animal origin in respect to the origin of the oil-in-glycerin emulsion ingredients.

The term HLB is an arbitrary scale from 0 to 40 depicting the Hydrophilic/Lipophilic Balance of a surfactant. Products with low HLB are more oil soluble. High HLB represents good water solubility. Note that HLB is a numerically calculated number based on the surfactants molecular structure. It is not a measured parameter.

It has been unexpectedly found that such bioactive agents incorporated in the present homogenized nanometer oil-in-glycerin penetration enhancer composition as formed from components A, B and C above of mean droplets size of below 1 micron, better penetrates into and through the skin to obtain significant dermal or transdermal activity. Even peptides of MW larger then 1,000 or with 20 or more amino acids, have been unexpectedly found to pass the stratum-corneum into the skin inner layers and also sub-dermal.

It has also been unexpectedly found that it is possible to obtain nanometer oil-in-glycerin emulsion by plain high shear homogenization in contrast to the common art, where a high-pressure homogenization is required to reduce emulsions droplet to below one micron. Moreover, single pass in high pressure homogenization is enough to further reduce particles size. Also, oil-in-glycerin emulsion show lower distribution of sizes around mean in comparison to regular oil-in-water emulsions, especially less energy, time and pressure is required to obtain uniform particle size.

In preferred embodiments of the present invention the following quantities are preferable:

a) said vegetable oil is present in an amount ranging from about 1-30 wt/wt %, or from 2-20 wt/wt %;

b) said emulsifying stabilizer is present in an amount ranging from about 0.1-20 wt/wt %, or from about 0.1-5 wt/wt %; and

c) said bioactive component is present in an amount ranging from about 0.1-20 wt/wt %.

In a most preferred embodiment said emulsifying stabilizer is biodegradable (i.e., degradable in the human body and the environment) and is substantially free of polyoxyethylene or propylene glycols and is preferably of botanical origin.

A hydrophobic moiety in the bioactive agent may be a benzene or cyclic ring or heterocyclic backbone or hydrocarbon side chain, etc.

In an even further preferred embodiment of the present invention said glycerin constitutes a continuous phase of said emulsion and a minor portion of water is included in said glycerin phase.

Example of vegetable oils are: isopropyl miristate, jojoba oil, almond oil, avocado oil, coconut oil, capric-caprylic tryglyceride of fractionated coconut oil, nutmeg oil, castor oil, olive oil and oleic acid, soybean oil etc. The oil may be saponifiable or unsaponifiable and liquid or solid at room temperature.

In a preferred embodiment there is provided a composition of matter comprising oil-in-glycerin emulsion and bioactive agent, wherein the bioactive component is selected from the group consisting of a phytochemical (plant origin or plant extract) or drug or a peptide or nucleotide or glycolipid or cosmeceutics anti-histamines, anti-inflammatory agents, analgesics, anesthetics, antiperspirants, anti-dandruffs, anti-microbial agents, astringents, counter-irritants, depigmenting agents, bleaching agents, and steroids.

In a preferred embodiment of this invention said emulsifying stabilizer is selected from the group consisting of at least one fatty acid or fatty alcohol condensation with natural hydrophilic molecule to form an amphiphilic and surface active agent with HLB of 5 to 16, that is the emulsifying stabilizer. The hydrophilic molecule may be selected from carbohydrates or amino acids or amine containing carbohydrate molecules prevailing in the vegetable kingdom. The carbohydrate may be a saccharide or an acid such as tartaric or citric acid and the like. The amine carbohydrate molecule is one having a natural carbohydrate backbone and at least one nitrogen atom such as amine or tertiary amine or amide and at least one alcohol or carboxylic acid moiety, for example: betain or choline.

In a preferred embodiment of this invention said emulsifying stabilizer is selected from the group consisting of at least one fatty acid condensation with a carbohydrate or with a polycarbohdrate, wherein said carbohydrate is a saccharide, a disaccharide or a polysaccharide, said surfactant and stabilizer is a liquid crystal lyothropic lamellar forming amphiphil, and said liquid-crystal-forming surfactant and stabilizer is a sucrose ester or cetearyl glucoside.

In a preferred aspect of the invention, the combination of an oil-in-glycerin emulsion and a bioactive agent facilitates the dispersion of a water insoluble bioactive component in a biocompatible, safe and convenient dosage form, while avoiding the disadvantages associated with classical vehicles comprising ionic or polymeric and synthetic surfactants or alcohols or preservatives.

Practically there is no need to include anti-microbial preservatives in oil-in-glycerin emulsions, since oil-in-glycerin emulsions are self preserving and passing the preservative efficacy test also named challenge test as specified in USP or BP or CTFA guidance.

The oil-in-glycerin emulsions are pleasant for use on the skin and on mucous membranes such as the oral cavity, ears and scalp and are also ingestable when prepared from food grade ingredients. Additionally, the emulsions of the present invention are well accepted organoleptically and physiologically, hence, offering good patient compliance. Stable oil-in-glycerin emulsions offering water free surrounding with potential for stabilizing bioactive agents that are sensitive to water and that are rapidly degrading in aqueous medium.

As will be realized, the present invention provides an emulsion which may be produced alcohol and/or water free, has a prolonged shelf life and improved heat stability for withstanding elevated temperatures during a long period of time. Furthermore, the oil-in-emulsion resists sub-zero temperatures, it is stable upon freezing and does not break at minus 20.degree. C. Thaw of oil-in-glycerin emulsions is simple and does not affect original properties.

Oil-in-glycerin emulsions are easily prepared. It is possible to produce coarse oil-in-glycerin emulsions of 5 to 10 microns droplet size with simple stirring and without resort to the use of high shear mixers. It is also easy to control droplet size by the utilization of appropriate mixing equipment and energy input. Fine oil-in-glycerin emulsions, having a mean droplet size of 1 to 5 micron, are achieved with a conventional "Silverson" type mixer at moderate speed and a short duration of mixing. High shear homogenizer mixing is sufficient to obtain emulsions containing 0.5 to 1 microns mean droplets size, consequent high pressure homogenization produces 0.5 to 0.1 mean particle size.

Typical oil-in-glycerin emulsions are characterized by having viscosity of 5,000 to 25,000 centipoise and newtonian flow. Viscosity may be reduced by the addition of water. The oil-in-glycerin emulsion viscosity may be controlled by addition of viscosity forming agents, such as, carbomers, carbopol, cellulose derivatives or natural gums, such as xanthan gum or colloidal fumed silica. Also, the same additives easily achieve non-neutinian characteristics.

Oil-in-glycerin emulsions are suitable for use in humans and animals, on skin, scalp, mucous membrane, ear instillation, oral rinse, and f. Buccal transmucosal applications

The oil-in-glycerin emulsions are basically newtonian and flow easily out of any commercial consumer product orifice opening or dropper. Oil-in-glycerin emulsions may be packaged in glass, aluminum or plastic containers or designed into patch device.

A bioactive agent may be a phytochemical, drug, cosmeceutical, peptide, oligonucleotide or liposaccharide or combinations thereof.

The botanical extract of the present invention may have anti-inflammatory, anti-allergic, anti-bacterial, anti-parasitic, anti-viral, immunity modulation and/or anti-oxidant, anti-psoriatic, sun-protecting, anti-aging, rejuvenating, anti-wrinkle or anti-cancer properties.

Example of botanical bioactive agents, are: polyphenols, isoflavones, resveratrol, soy isoflavones, grape seed extract polyphenols, curcumin, epigenin. Anti-inflammatory plant extracts such as aloe vera, echinacea and chamomile hammamekis extracts, anti-psoriatic such as chinese zizipus jujuba. Astringents such as hammamelis anti bacterial such as artemisia, chamomile, golden seal. Immune modulators such as echinacea, anti-aging or anti-cancer or anti-photo damage, anti-inflammatory such as feverfew parthenolides, rejuvenation agents, carotenoids, beta-carotene, lycopene, tocopheryl and retinol.

The term "drug" or "pharmacologically active agent" as used herein is intended to mean a compound or composition of matter which, when administered to an organism (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action. In general, the terms include the therapeutic or prophylactic agents in all major therapeutic or prophylactic areas of medicine. Examples of drugs useful in conjunction with the present invention include: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticholinergic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents, antimigraine preparations; anti-motion sickness drugs; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; steroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers. For purposes of the aforementioned definition, "drugs" as used herein also include locally administered topical medicaments such as antibacterial agents, antifungals, antimicrobials, cutaneous growth enhancers, antipsoriatics, anti-acne medicaments, and the like.

The invention is thus, in one embodiment, a method for enhancing the rate of penetration of a pharmacologically active agent into and/or through the skin, wherein the method involves co-administration of the agent through a predetermined area of intact skin, and for a predetermined period of time, of the selected agent in a permeation enhancer composition comprising oil in glycerin emulsion.

A transdermal delivery system for the administration of drug and enhancer composition as described herein may take the form of a depot-type device, matrix or laminate-type device, bandages, or the like. A preferred transdermal delivery system for use herein is a laminated composite that contains one or more drug/permeation enhancer reservoirs, a backing layer and, optionally, one or more other layers, e.g., additional drug and/or enhancer reservoirs, release rate controlling membranes, or the like (as those skilled in the art of transdermal delivery will readily appreciate).

In these composites, the backing layer will function as the primary structural element of the device and provide the device with much of its flexibility. This layer also serves as a protective covering to prevent loss of drug and enhancer via transmission through the upper surface of the device. The backing layer may also be used to impart the device with a desirable or necessary degree of occlusivity, which in turn causes the area of skin on which the device is placed to become hydrated. The backing is preferably made of a sheet or film of a flexible elastomeric material. Suitable, flexible elastomeric materials include polyether block amide copolymers, polyurethanes, silicone elastomers, rubber-based polyisobutylene, styrene, polyethylene, polypropylene, polyesters, or the like. The preferred polymer used for the backing will depend primarily on the particular pharmacologically active agent incorporated into the device.

Prior to use, the laminated composite also includes a release liner layer. Just prior to use, this layer is removed from the device to expose the basal surface of the device. The release liner will normally be made from a drug/enhancer impermeable material that is inherently "strippable" or rendered so by techniques such as silicone or fluorocarbon treatment.

Preferred daily dosages obtained with the present methods and systems will, similarly, vary with the drug administered. The targeted daily dosage will depend on the individual being treated, the indication addressed, the length of time the individual has been on the drug, and the like.

In still another embodiment, the invention comprises a drug delivery device in the form of a patch administering a pharmacologically active agent through a selected area of skin. The device is preferably in the form of a laminated composite that includes a drug reservoir layer containing both the agent to be administered and the permeation enhancer composition of the invention.

Oil-in-glycerin emulsion may comprise also known in the art additives, such as anti-oxidants, coloring, flavoring and fragrance.

While the invention will now be described in connection with certain preferred embodiments in the following examples so that aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of formulation procedures as well as of the principles and conceptual aspects of the invention.
 

Claim 1 of 13 Claims

1. A method for facilitating stratum corneum and dermal penetration of at least one bioactive agent having at least one hydrophobic moiety, the method comprising administering a topical cosmetic or pharmaceutical composition in the form of an oil-in-glycerin emulsion to a subject in need or desirous thereof, wherein said topical cosmetic or pharmaceutical composition comprises: a continuous glycerin phase, wherein the continuous glycerin phase comprises at least 50% glycerin; at least one oil comprising an internal phase, wherein the oil is present in an amount ranging from about 0.1-40 wt/wt %; at least one emulsifying stabilizer, selected from the group consisting of saccharide esters or ethers, alkyl glucoside, sucrose esters, and sorbitan esters, wherein the emulsifying stabilizer is present in an amount ranging from about 0.1-10 wt/wt %; and the at least one bioactive agent comprising at least one hydrophobic moiety within its structure, wherein the at least one bioactive agent is present in an amount ranging from about 0.1-20 wt/wt %; wherein the emulsion has a mean droplet size below one micron; and said topical cosmetic or pharmaceutical composition facilitates stratum-corneum and dermal penetration of said at least one bioactive agent.

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