CANNABINOID STOCK FOR FORMULATION PRODUCTS

Abstract

Transdermal cannabinoid formulations including a versatile cannabinoid stock provided as a variety of cosmetic delivery systems providing enhanced cannabinoid absorption, and more controlled release into vascular and/or lymphatic systems for greater efficacy and a desirable subject experience. The cannabinoid stock is a substantially homogeneous concentrated stable cannabinoid emulsion characterized as a cannabinoid load capacity carrier that comprises emulsified particles of stabilized cannabinoid/lipid.

Claims

1. A cannabinoid stock comprising a stabilized cannabinoid/lipid particle emulsion, wherein the lipid and the cannabinoid are present in a ratio from about 5:1 to about 1:5.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0097] The above and other aspects, advantages, and features of this disclosure will become more apparent by describing in further detail exemplary embodiments thereof with reference to the accompanying drawings in which:

[0098] FIG. 1 shows release of cannabinoid from the sub dermal layer showing zero order release;

[0099] FIG. 2 shows release of cannabinoid from the sub dermal layer showing first order release;

[0100] FIG. 3 shows release of cannabinoid from the sub dermal layer showing loading and sustained release;

[0101] FIG. 4 shows release of cannabinoid from the sub dermal layer showing delayed and sustained release;

[0102] FIG. 5 shows release of cannabinoid from the sub dermal layer showing delayed and pulsatile release;

[0103] FIG. 6 shows release of cannabinoid from the sub dermal layer showing pulsatile release; and

[0104] FIG. 7 shows release of cannabinoid from the sub derma layer showing ascending release.

DETAILED DESCRIPTION

[0105] As used herein, the terms invention or present invention are non-limiting terms and not intended to refer to any single aspect of the particular invention but encompass all possible aspects as described in the specification and the claims.

[0106] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0107] In the case of conflict, the present specification, including definitions, will control.

[0108] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the subject matter herein belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0109] As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

[0110] It will be understood that any component defined herein as being included may be explicitly excluded from the claimed invention by way of proviso or negative limitation. In addition, all ranges given herein include the end of the ranges and also any intermediate range points, whether explicitly stated or not.

[0111] As used herein, the articles a and an preceding an element or component are intended to be non-restrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore, a or an should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

[0112] It will be further understood that the terms comprises and/or comprising, or includes, including and/or having and their inflections and conjugates denote when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.

It will be understood that any component defined herein as being included may be explicitly excluded from the claimed invention by way of proviso or negative limitation.

[0113] As used herein, the term about refers to variation in the numerical quantity. In one aspect, the term about means within 10% of the reported numerical value. In another aspect, the term about means within 5% of the reported numerical value. Yet, in another aspect, the term about means within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of the reported numerical value.

About, is equivalent to approximately, or substantially as used herein and inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity (i.e., the limitations of the measurement system). For example, about, approximately, or substantially can mean within one or more standard deviations, or within +30%, 20%, 10%, 5% of the stated value.

[0114] Should a range of values be recited, it is merely for convenience or brevity and includes all the possible sub-ranges as well as individual numerical values within and about the boundary of that range. Any numeric value, unless otherwise specified, includes also practical close values and integral values do not exclude fractional values. Sub-range values and practically close values should be considered as specifically disclosed values.

[0115] As will also be understood by one skilled in the art, all language such as up to, at least, greater than, less than, more than, or more, and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into subranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents.

[0116] As used herein the term may denotes an option or an effect which is either or not included and/or used and/or implemented and/or occurs, yet the option constitutes at least a part of some embodiments of the invention or consequence thereof, without limiting the scope of the invention.

[0117] The phrase and/or, as used herein in the specification and in the claims, should be understood to mean either or both of the elements so conjoined, e.g., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the and/or clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary.

[0118] As used herein, expressions such as at least one of, when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0119] The term transdermal patch as used herein means a skin patch to be applied to the mammals skin containing the pharmaceutical composition. The technology for constructing transdermal patches is well known in the pharmaceutical art. The terms backing layer and reservoir as used herein are components of the transdermal patch. Suitable materials and designs are well known in the transdermal drug delivery art. See for example D. Hsien, Multiple Lamination for Transdermal Patches, Controlled Release Systems Fabrication Technology, Vol. 1, pp. 167-188. 1988.

[0120] As used herein transdermal describes absorption through the skin or mucosal membranes for systemic distribution. As placed on the skin, the cannabinoid stock or transdermal cosmetic format is capable of delivering cannabinoid through the stratum corneum layer of the epidermis and through the dermis into the microvasculature. As placed on a mucous membrane that lines several passages and cavities of the body with openings exposed to the external environment, the cannabinoid stock or transdermal cosmetic format comprising the cannabinoid stock is capable of delivering cannabinoid through the mucous membrane into the microvasculature.

[0121] As used herein, the phrase transdermal delivery means administration of the cannabinoid stock or cosmetic formulation comprising the cannabinoid stock topically to the skin or mucosal surface wherein the active ingredient, the cannabinoid, will be percutaneously delivered in a therapeutically effective amount.

[0122] Combination or combining for the purposes of this invention means any method of putting two or more materials together. Such methods include, but are not limited to, mixing, blending, commingling, concocting, homogenizing, incorporating, intermingling, fusing, joining, shuffling, stirring, coalescing, integrating, confounding, joining, uniting, or the like.

[0123] The term pharmaceutically acceptable means that the compound or combination of compounds is compatible with the remaining ingredients of the formulation for pharmaceutical use, and that it is generally safe for administering to humans according to established governmental standards.

[0124] The term pharmaceutically acceptable carrier includes, but is not limited to solvents, dispersion media, coatings, antibacterial agents, antifungal agents, isotonic and/or absorption delaying agents and the like. The use of pharmaceutically acceptable carriers is well known.

[0125] An effective amount refers to an amount effective to treat to which this phrase refers, this can be a disease, disorder, and/or condition, or to bring about a recited effect. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term effective amount is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein for providing the recited effect to a subject. Thus, an effective amount generally means an amount that provides the desired effect.

[0126] As used herein cannabinoid is a class of chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain, the cannabinoid receptors including the endocannabinoids, phytocannabinoids, synthetic cannabinoids, and cannabidiol, or combinations thereof.

[0127] Cannabinoids as used herein refers to any cannabinoid (natural or synthetic) and include phytocannabinoids and most of these fall into the subclasses such as cannabigerol, cannabichromene, cannabidiol, cannabinol (including tetrahydrocannabinol, e.g., .sup.9-THC, .sup.8-THC). Other cannabinoids include cannabicyclol, cannabielsoin, cannabinoldiol, and cannabitriol. Cannabinoids useful for the present invention include cannabinols. In one embodiment, the invention includes tetrahydrocannabinols, including tetrahydrocannabinol (THC), dronobinol, cannabinol (CBN) and ()-trans-cannabidiol (CBD). Cannabinoids described herein are inclusive of their pharmaceutically acceptable salts.

[0128] Cannabinoids for use in the present invention in an aspect are selected from CBN, CBDA, CBD, THC, THCA, and mixtures thereof. Mixtures of CBD and THC can be, for example, 1:1 w/w or any other mixture. Various ratios of the above-described cannabinoids can be used for the cannabinoid stock and transdermal formulation described herein. The ratios can be adjusted based on pharmacological effects required. Ratios of CBD:THC are for example, 1:1, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1:1.2, 1:1.5, 1:1.3, 1:1.5, 1:1.7, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 or 1:10 (all ratios given are w/w). In aspects, the cannabinoid stock comprises CBD and/or THC. In aspects, the cannabinoid stock comprises up to 50% by weight CBD and/or TI-IC.

[0129] Alleviate as used herein, is meant to include complete elimination as well as any clinically or quantitatively measurable reduction in the subject's symptoms and/or discomfort.

[0130] By pain as used herein is meant both acute and chronic. For example acute pain usually comes on suddenly and is caused by something specific. Acute pain usually does not last longer than six months. It goes away when there is no longer an underlying cause for the pain. Causes of acute pain include: surgery, broken bones, dental work, burns, cuts, strains, sprains, pain due to intercourse, menstruation and the like. Chronic pain is pain that is ongoing and usually lasts longer than six months. This type of pain can continue even after the injury or illness that caused it has healed or gone away. Pain signals remain active in the nervous system for weeks, months, or years. Some people suffer chronic pain even when there is no past injury or apparent body damage. Chronic pain is linked to conditions including but not limited to: headache, arthritis, cancer, nerve pain, scarring/scar tissue, back pain, fibromyalgia, bursitis, carpal tunnel syndrome, gout, tissue scarring and other muscular and joint aches and pains.

[0131] In aspects the cannabinoid stock can be applied to a patch (to form a cannabis transdermal delivery structure) that is constructed to have a backing layer selected from the group consisting of a patch, strip, bandage or covering, for example, the backing layer comprising the composition of the invention and optional other skin permeation enhancer(s) or other components. One of skill in the art would recognize that the composition described herein can be incorporated into a variety of patch formats such as for example but not limited to those disclosed in U.S. Pat. Nos. 6,113,940, 6,328,992 and 9,375,417 each of which are incorporated herein by reference in their entirety.

[0132] A general non-limiting overview of the invention and practising the invention is presented below. The overview outlines exemplary practice of embodiments/aspects of the invention, providing a constructive basis for variant and/or alternative and/or divergent aspects/embodiments, some of which are subsequently described.

Transdermal Formulations of Cannabinoid-Based Medicaments

[0133] Drug delivery through the skin to achieve a systemic effect of a drug is commonly known as transdermal drug delivery and differs from traditional topical drug delivery. Transdermal drug delivery systems (TDDS) are dosage forms involves drug transport to viable epidermal and or dermal tissues of the skin for local therapeutic effect while a very major fraction of drug is transported into the systemic blood circulation. The adhesive of the transdermal drug delivery system is critical to the safety, efficacy and quality of the product. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive methods of drug delivery. Several important advantages of transdermal drug delivery are limitation of hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. (International Journal of Pharmaceutical Sciences Review and Research, J. Ashok Kumar et al.).

[0134] Novel formulations are provided herein for carrying cannabis-based medicaments and cosmetic delivery systems containing cannabinoids and related compounds through the epidermis, through the dermis (containing at least lymph vessels) to the sub dermal lipid layer (i.e. the hypo dermis layer) that contains subcutaneous fat, such as the white adipose tissue (WDA) and blood vessels.

[0135] The transdermal delivery is achieved by topical application to any area of skin surface which carries the cannabinoid(s) through the epidermis to the dermal layer and then through to the sub dermal lipid layer where functional cannabinoid depots are formed. These functional cannabinoid depots comprise cannabinoid particles allowing precise controlled release of the cannabinoids into the vascular and/or lymphatic system of the subject. Administration of cannabinoids with multiple release times can be achieved by the carrier formulation components.

[0136] Transdermal delivery is also achieved by topical application to a mucosal surface (such as that lining the ears, inside the nose, inside the mouth, lip, vagina, the urethral opening and the anus) which carries the cannabinoid(s) through to the submucosa for cannabinoid delivery to the blood vessels. Administration of cannabinoids with multiple release times can be achieved by the cosmetic formulation components.

[0137] The invention relates to embodiments of a cannabinoid stock that is characterized as a cannabinoid load capacity carrier. The stock comprises emulsified particles of stabilized cannabinoid/lipid sized for enhanced absorption. The particles comprising desired ratios of lipid to cannabinoid. In an aspect of an embodiment, the cannabinoid stock is used to make a cosmetic delivery system for delivering the cannabinoid by topical application meaning the provision of a local effect, where the composition is applied directly where its action is desired. The term topical may be defined as application to a localized area of the body or to the surface of a body part, without necessarily involving a targeted effect of the substance, resulting in a systemic effect. Examples of topical administration/use includes, for example, transdermal and transmucosal delivery (e.g., by intravaginal administration, rectal, or intranasal). In aspects, there are also localized benefits from topical administration. For example, topically administered cannabinoids may find use in alleviating pain and other conditions originating near the surface of the skin. Transdermal includes application to any skin portion of the body.

[0138] Methods and systems for making the cannabinoid stock and the cosmetic delivery systems are within the scope of the invention.

[0139] The cannabinoid stock is generally made by combining a lipid phase containing the cannabinoid with a water phase which is then subjected to cycles of high pressure homogenization until the formation of a stable substantially homogeneous concentrated cannabinoid emulsion is formed in which the cannabinoid is entrapped within stable lipid particles of the emulsion resulting in the cannabinoid being less subject to degradation, hydrolysis and oxidation. The cannabinoid stock is suitable to use as an additive to formulate a cosmetic delivery system for topical use providing a release profile.

[0140] In one non-limiting aspect, the lipid phase is made by adding about 10% to about 30% by wgt of substantially pure CBD to a heated mixture of stabilizer and fatty acid (at a temperature of about 45 C. to about 55 C.) until well blended and then adding a water soluble antioxidant. This lipid phase is added to heated water (temperature of about 45 C. to about 50 C.) and subjected to about 1 to 6 cycles of high pressure homogenization at pressures of about 3,000 psi to about 20,000 psi. Each cycle being up to about 5 minutes. The final emulsion is stable and presents as smooth and uniform in consistency comprising cannabinoid particles that are liquid particles of a size of about 50 nm to about 300 nm, or micelles of a size of about 10 nm to about 300 nm.

[0141] The cannabinoid stock, as an additive, is admixed in a desired amount/ratio with a cosmetic formulation comprising components/ingredients that make a specific type of cosmetic delivery system such as a cream, lotion, gel, ointment, liquid, balm, oil and solid to provide an end product for a specific use with a desired amount/concentration of cannabinoid.

[0142] The cosmetic delivery system according to the present invention passively delivers cannabinoid and can release the cannabinoid for an extended time period by having long-term adhesion to the skin and by having a significantly improved skin penetration rate in comparison with other conventional formats. The judicious selection of lipid and cannabinoid and method to make the lipid/cannabinoid particle in the stabilized emulsion provides for increased absorption and thus better bioavailability of the cannabinoid. Without being bound by theory, the cosmetic delivery system comprising the cannabinoid stock penetrates the skin and the cannabinoid/lipid particles can penetrate into subdermal layers to form a depot within subcutaneous fat stores. This depot metabolizes over time releasing the cannabinoid into lymphatic and vasculature systems.

[0143] For transdermal delivery of the cannabinoid stock of the invention an amount of the cannabinoid stock is admixed with a desired cosmetic type formulation to provide a desired texture of a cosmetic delivery system comprising a lotion, cream, balm, gel, ointment, liquid, and solid. Contacting with the subject's skin is effective for at least one of the provided cannabinoids to penetrate into the skin and enter the bloodstream. The cannabinoid stock and cosmetic delivery systems incorporating the stock allow for significant transdermal delivery across skin and compromised skin.

[0144] A number of methods known in the art can be used to assess delivery across the skin. In one method, delivery may be assessed by measurement of the remaining cannabinoid in the composition after use. After the composition was present on the skin of a patient for at least 12 hours, for example, at least 0.1% of the cannabinoid can be delivered across the skin, at least 0.5% of the cannabinoid can be delivered across the skin, at least 1% of the cannabinoid can be delivered across the skin, at least 2% of the cannabinoid can be delivered across the skin, at least 3% of the cannabinoid can be delivered across the skin, at least 4% of the cannabinoid can be delivered across the skin, at least 5% of the cannabinoid can be delivered across the skin, at least 6% of the cannabinoid can be delivered across the skin, at least 7% of the cannabinoid can be delivered across the skin, at least 8% of the cannabinoid can be delivered across the skin, at least 9% of the cannabinoid can be delivered across the skin, at least 10% of the cannabinoid can be delivered across the skin, at least 11% of the cannabinoid can be delivered across the skin, at least 12% of the cannabinoid can be delivered across the skin, at least 14% of the cannabinoid can be delivered across the skin, at least 16% of the cannabinoid can be delivered across the skin, at least 18% of the cannabinoid can be delivered across the skin, at least 20% of the cannabinoid can be delivered across the skin, at least 25% of the cannabinoid can be delivered across the skin, at least 30% of the cannabinoid can be delivered across the skin, at least 35% of the cannabinoid can be delivered across the skin, at least 40% of the cannabinoid can be delivered across the skin, at least 45% of the cannabinoid can be delivered across the skin, at least 50% of the cannabinoid can be delivered across the skin, at least 55% of the cannabinoid can be delivered across the skin, at least 60% of the cannabinoid can be delivered across the skin, at least 65% of the cannabinoid can be delivered across the skin, at least 70% of the cannabinoid can be delivered across the skin, at least 75% of the cannabinoid can be delivered across the skin, at least 80% of the cannabinoid can be delivered across the skin, at least 85% of the cannabinoid can be delivered across the skin, at least 90% of the cannabinoid, at least 90% of the cannabinoid can be delivered across the skin, and at least 95% of the cannabinoid can be delivered across the skin.

Cosmetic Delivery Systems

[0145] The cosmetic delivery systems described herein will typically include the cannabinoid stock and one or more other ingredients to provide different cosmetic formulations.

[0146] For topical administration, it will generally be desirable to administer the cosmetic delivery system directly to the skin/mucosal surface or can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto a desired area using a pump-type or aerosol sprayer.

[0147] For topical application the cosmetic delivery system may comprise generally ingredients inclusive but not limited to lipid thickeners (e.g. Cetyl Alcohol, Stearyl Alcohol, Carnauba Wax, and Stearic acid), naturally derived thickeners (cellulose derivatives such as hydroxyethylcellulose, guar gum, xanthan gum and gelatin), mineral thickeners (e.g. Silica, Bentonite, and Magnesium Aluminum Silicate), synthetic thickeners (e.g. carbomer thickeners), alcohols, absorption promotors, fragrances, natural ingredients (e.g. aloe vera, cocoa butter, and coconut oil), scents (peppermint, cinnamon, menthol, jasmine), camphor, shea butter, gelling agents, emollients, synthetic preservatives (e.g. organohalogens, aldehydes, glycol ethers, parabens), natural preservatives (benzoic acid, sorbic acid, salicyclic acid and alcohol), synthetic antioxidants (e.g. butylated hydroxytoluene (BHT) and butylated hydroxyanidole (BHA)), natural antioxidants (e.g. tocopherol (Vitamin E), ascorbic acid (Vitamin C), polyphenols, and flavonoids).

[0148] More specifically, cosmetic formulation ingredients may include a carrier that is physiologically compatible with the skin or mucosal tissue of a human or animal to which it is topically administered. Typically the carrier is substantially inactive, with the exception of its intrinsic surfactant properties which may aid in the production of a solution or suspension of the active ingredients. In some embodiments, the carriers can be liquid or gel-based materials for use in liquid or gel formulations. Suitable carrier materials include any carrier or vehicle commonly used as a base for solutions, dispersions, emulsions, gels, creams, ointment, lotions, pastes, or foams, for topical administration. Examples include emulsifying agents, inert carriers including hydrocarbon bases, emulsifying bases, non-toxic solvents or water-soluble bases.

[0149] Suitable liquid or gel-based carriers are may include water, physiological salt solutions, alcohols (e.g., methanol, ethanol, propanol, or butanol), glycerol, glycols (e.g., ethylene glycol, propylene glycol, or ethoxy diglycol), polyethylene glycol (e.g., MW 400 to 20,000), water-alcohol/glycol blends, and the like. Suitable carriers further include aqueous and oleaginous carriers such as, for example, white petrolatum, isopropyl myristate, lanolin or lanolin alcohols, mineral oil, fragrant or essential oil, nasturtium extract oil, sorbitan mono-oleate, cetostearyl alcohol (together or in various combinations), and detergents (e.g., polysorbates (Tweens) such as polysorbate 20, 40, 60, or 80; polyoxyl stearate; or sodium lauryl sulfate). One or more carrier materials can be mixed with water to form a lotion, gel, cream, semi-solid composition, or the like. Other suitable carriers include water-in-oil or oil-in-water emulsions and mixtures of emulsifiers and emollients with solvents such as sucrose stearate, sucrose cocoate, sucrose distearate, mineral oil, propylene glycol, 2-ethyl-1,3-hexanediol, polyoxypropylene-15-stearyl ether, water, or combinations thereof. For example, emulsions containing water, glycerol stearate. glycerin, mineral oil, synthetic spermaceti, cetyl alcohol, or combinations thereof, may be used. Preservatives may also be included in the carrier, such as one or more of butylparaben, methylparaben, propylparaben, benzyl alcohol, and ethylene diamine tetraacetate salts. The composition of the carrier can be varied so long as it does not interfere significantly with the stability of the emulsified cannabinoid/lipid particles.

[0150] In one embodiment, the carrier can be a PLO gel (pluronic lecithin organogel). PLO gel contains isopropyl palmitate (a non-oleaginous emollient), soy lecithin (mixture of phospholipids), water, and Pluronic F127.

[0151] The cosmetic formulation components/ingredients may comprise gelling agents and thickening agents to increase the viscosity of the cosmetic delivery system. Examples of gelling agents and thickening agents, include, but are not limited to, fatty acids, fatty acid salts and esters, fatty alcohols, synthetic polymers, modified celluloses, xanthan gum, or combinations thereof. Examples of suitable synthetic polymers include polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), various Pluronics (poloxamers), or carbomers (e.g., Carbomer 940 or Carbomer 934). Examples of suitable modified celluloses include methylcellulose, carboxymethylcellulose (CMC), hydroxyethylcellulose (HEC), hydroxymethyl cellulose (HMC), hydroxypropyl cellulose (HPC), hydroxypropyl-methylcellulose (HPMC), or other cellulose-based gelling agents.

[0152] A variety of gelling agents is commercially available and can be obtained in many suitable molecular weights and ranges. For example, the molecular weights of the gelling agent can be about 1 kDa to about 1,000 kDa, about 10 kDa to about 1,000 kDa, about 100 kDa to about 1,000 kDa, or about 50 kDa to about 500 kDa.

[0153] Examples of thickening agents include lanolin, hard paraffin, liquid paraffin, white petrolatum, soft yellow paraffin or soft white paraffin, white beeswax, yellow beeswax, propolis (propoleum), cetostearyl alcohol, cetyl alcohol, dimethicones, emulsifying waxes, microcrystalline wax, oleyl alcohol and stearyl alcohol.

[0154] One or more gelling agents or thickening agents may be included in a single cosmetic delivery system and further used to form spreadable gels, pastes, ointments and the like, for application directly to the skin of the user.

[0155] Solutions and dispersions of cosmetic delivery systems of the invention can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or in a pharmaceutically acceptable oil or mixtures thereof. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, emu oil, nontoxic glyceryl esters, and suitable mixtures thereof. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thiomersal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the cosmetic delivery system can be brought about by agents delaying absorption, for example, aluminum monostearate and/or gelatin.

[0156] Solutions can be prepared by incorporating the cannabinoid stock in a desired amount in the appropriate solvent or oil with various other ingredients described herein, as desired, followed by optional filter sterilization.

[0157] Gels are clear, sticky, jelly-like semisolids or solids prepared from high molecular weight polymers in an aqueous or alcoholic base. Alcoholic gels are often drying and cooling. Non-alcoholic gels are more lubricating. Gels or jellies can be produced using a suitable gelling agent including, but not limited to, gelatin, tragacanth, a carbomer, or a cellulose derivative and may include glycerol as a humectant, an emollient, and/or a preservative. In some embodiments, gel formulations will include the same or similar ingredients as a solution or dispersion, with the addition of a gelling agent.

[0158] The gel can include a nonionic copolymer gelling agent. In one embodiment, the gelling agent is a nonionic polyoxyethylene-polyoxypropylene copolymer gel, for example, a Pluronic gel such as Pluronic F-127 (BASF Corp.), to provide a pluronic gel-based formulation. This gel is a liquid at low temperatures but rapidly sets at physiological temperatures, which confines the release of the agent to the site of application or immediately adjacent that site. Other formulations can be carboxymethylcellulose (CMC)-based formulations, hydroxy methyl cellulose (HMC)-based formulations, hydroxypropyl cellulose (HPC)-based formulations, or hydroxypropylmethylcellulose (HPMC)-based formulations, and the like.

[0159] Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and comprise an oil phase, an emulsifier, and an aqueous-phase. Water-in-oil creams may be formulated by using a suitable emulsifying agent with properties similar, but not limited, to those of the fatty alcohols such as cetyl alcohol or cetostearyl alcohol and to emulsifying wax. Oil-in-water creams may be formulated using an emulsifying agent such as cetomacrogol emulsifying wax. Suitable properties include the ability to modify the viscosity of the emulsion and both physical and chemical stability over a wide range of pH. The water soluble or miscible cream base may contain a preservative system and may also be buffered to maintain an acceptable physiological pH.

[0160] The oil phase, also called the internal phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant (a substance, such as glycerin, sorbitol, or urea, that absorbs or helps another substance retain moisture).

[0161] The emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. Examples of emulsifiers include, but are not limited to, fatty alcohol polyoxyethylene ether (Peregal A-20), stearates such as polyoxylstearate (Softener SG), glyceryl stearate and pegylated forms of glyceryl stearate such as PEG-5 glyceryl stearate, cetyl alcohol, dithranol, or a combination thereof.

[0162] Oil-phase ingredients can include, but are not limited to, dimethicone, dimethiconol, cyclomethicone, diisopropyl adipate, cetyl alcohol, stearyl alcohol, paraffin, petrolatum, almond oil, stearic acid, or a combination thereof. In particular aspects, aqueous ingredients can include, but are not limited to, purified water, glycerol (glycerin), propylene glycol, ethyl paraben, a humectant, or a combination thereof. In some embodiments, the cream further comprises one or more film formers including but not limiting to polyglycerylmethacrylate, acrylates/Cio-Cso alkyl acrylate cross-polymers; antioxidant including but not limiting to tocopheryl acetate;

preservatives including but not limiting to phenoxyethanol, benzyl alcohol; other additives including but not limiting to dicaprylyl ether, disodium EDTA, sodium hydroxide, and lactic acid.

[0163] In one embodiment, the cream can include purified water, polyglycerylmethacrylate, propylene glycol, petrolatum, dicaprylyl ether, PEG-5 glyceryl stearate. glycerin, dimethicone, dimethiconol, cetyl alcohol, sweet almond oil, acrylates/C10-C30 alkyl acrylate cross-polymers, tocopheryl acetate, phenoxyethanol, benzyl alcohol, disodium EDT A, sodium hydroxide, lactic acid, or any combination thereof.

[0164] In another embodiment, the cream can include glycerol, light liquid paraffin, soft white paraffin, dimethicone, squalane, methyl hydroxybenzoate, dichlorobenzyl alcohol, or any combination thereof.

[0165] Ointments are semisolid preparations that include the cannabinoid base incorporated into a fatty, waxy, or synthetic base. Ointments are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for suitable cannabinoid delivery and other desired characteristics such as emolliency or the like. As with other carriers or vehicles, an ointment base is typically inert, stable, non-irritating and non-sensitizing.

[0166] Ointment bases may be generally grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases can include, for example, vegetable oils, fats obtained from animals such as emu oil, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and can include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum.

[0167] Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water O/W) emulsions, and the oil components can include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Water-soluble ointment bases can be prepared from polyethylene glycols of varying molecular weight.

[0168] Lotions are liquid or semiliquid preparations in which solid particles, including the active agent(s), are present in a water or alcohol base. Lotions are usually suspensions of solids, and can include a liquid oily emulsion of the oil-in-water type. Lotions are often desirable formulations because of the ease of applying a more fluid composition. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethyl-cellulose, or the like.

[0169] Pastes are semisolid dosage forms in which the cannabinoid stock is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel. The base in a fatty paste is generally petrolatum, hydrophilic petrolatum, or the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base.

[0170] Foam preparations may be formulated to be delivered from a pressurized aerosol canister, via a suitable applicator, using inert propellents. Suitable excipients for the formulation of the foam base include, but are not limited to, propylene glycol, emulsifying wax, cetyl alcohol, and glyceryl stearate. Potential preservatives include methylparaben and propylparaben.

Accordingly, the cosmetic delivery system described herein may be formulated for any desired form of topical or transdermal administration. Formulations may include known antioxidants (e.g., vitamin E); buffering agents; lubricants (e.g., synthetic or natural beeswax); sunscreens (e.g., para-aminobenzoic acid); and cosmetic agents (e.g., coloring agents, fragrances, essential oils, moisturizers, or drying agents).

[0171] Auxiliary agents such as casein, gelatin, albumin, or sodium alginate may also be included in various cosmetic formulations that make up the cosmetic delivery system. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. Examples of fragrances include Ylang-Ylang oil, lavender oil, powder scent, jasmine, gardenia oil, or green tea oil. In addition, substances such as wetting or emulsifying agents, stabilizing agents, or pH buffering agents, may also be included. When a water-based carrier is used, the composition is typically near a neutral pH(+/about 1 or 2, pH units).

[0172] Further examples of dermatological ingredients and compositions for delivering active agents to the skin are known to the art; for example, see U.S. Pat. No. 4,992,478 (Geria), U.S. Pat. No. 4,820,508 (Wortzman), U.S. Pat. No. 4,608,392 (Jacquet et al.), and U.S. Pat. No. 4,559,157 (Smith et al.).

[0173] The cannabinoid base is admixed into a desired amount of cosmetic formulation ingredients using principles of geometric dilution until a smooth and uniform suspension is formed that is combined with other ingredients to form a gel, a jelly, a cream, an ointment, a wax, a lotion, a paste, a foam, or an aerosol. The suspension, or a gel, jelly, cream, ointment, wax, lotion, or paste can also be incorporated into a patch, such as an occlusive patch, to further improve transdermal penetration.

[0174] As a cream or lotion the cosmetic delivery system can be formulated for dispensing in a variety of ways such as squeeze dispenser, pump dispenser, roll on dispenser, tube or jar.

[0175] As a liquid the cosmetic delivery system can be dispensed as a spray, aerosol spray or foam.

[0176] Gels can be formulated for use as a lubricant. Lubricants may be water-based, silicone based, a hybrid of water/silicone, oil based and organic.

[0177] Balms and ointments can be formulation for use dispensed via a pump dispenser or tube.

[0178] Solids can be formulated as salve or stick, or suppository.

[0179] The invention provides a system to make a cosmetic delivery system for topical use for transdermal administration of a cannabinoid in a passive delivery to alleviate/manage targeted pain and general pain, soreness and inflammatory pain.

[0180] In a further embodiment of the invention, formulations of the present invention are described below in a non-limiting manner. A formulation for application to the skin, the formulation comprising: (a) a biologically active agent and (b) a lipid. The biologically active agent is selected from the group comprising Dronabinol (2), Nabiximols, Nabilone, THC, CBD, Cannabidiol, Levonantradol Ajulemic acid, (CT3), ECP002A, Natural 9-THC, Cannabichromenes, Cannabichromene (CBC), Cannabichromenic acid (CBCA), Cannabichromevarin (CBCV), Cannabichromevarinic acid (CBCVA), Cannabidiol Cannabidiol (CBD), Cannabidiol monomethylether (CBDM), Cannabidiolic acid (CBDA), Cannabidiorcol (CBD-C1), Cannabidivarin (CBDV), Cannabidivarinic acid (CBDVA), Cannabielsoins, Cannabielsoic acid B (CBEA-B), Cannabielsoin (CBE), Cannabielsoin acid A (CBEA-A), Cannabigerols, Cannabigerol (CBG), Cannabigerol monomethylether (CBGM), Cannabigerolic acid (CBGA), Cannabigerolic acid monomethylether (CBGAM), Cannabigerovarin (CBGV), Cannabigerovarinic acid (CBGVA, Cannabinols and cannabinodiols, Cannabinodiol (CBND), Cannabinodivarin (CBVD), Cannabinol (CBN), Cannabinol methylether (CBNM), Cannabinol-C2 (CBN-C2), Cannabinol-C4 (CBN-C4), Cannabinolic acid (CBNA), Cannabiorcool (CBN-C1), Cannabivarin (CBV), Cannabitriols, 10-Ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol,8,9-Dihydroxy-delta-6a-tetrahydrocannabinol, Cannabitriol (CBT), Cannabitriolvarin (CBTV), Delta-8-tetrahydrocannabinols, Delta-8-tetrahydrocannabinol (.sup.8-THC), Delta-8-tetrahydrocannabinolic acid (.sup.8-THCA), Delta-9-tetrahydrocannabinols, Delta-9-tetrahydrocannabinol (THC), Delta-9-tetrahydrocannabinol-C4 (THC-C4), Delta-9-tetrahydrocannabinolic acid A (THCA-A), Delta-9-tetrahydrocannabinolic acid B (THCA-B), Delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), Delta-9-tetrahydrocannabiorcol (THC-C1), Delta-9-tetrahydrocannabiorcolic acid (THCA-C1), Delta-9-terahydrocannabivarin (THCV), Delta-9-tetrahydrocannabivarinic acid (THCVA) 10-Oxo-delta-6a-tetrahydrocannabinol (OTHC), Cannabichromanon (CBCF), Cannabifuran (CBF), Cannabiglendol, Cannabiripsol (CBR), Cannbicitran (CBT), Dehydrocannabifuran (DCBF), Delta-9-cis-tetrahydrocannabinol (cis-THC), Tryhydroxy-delta-9-tetrahydrocannabinol (triol-THC), 3,4,5,6-Tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol, or OH-iso-HHCV.

[0181] The formulation comprises the lipid and biologically active agent in a ratio from about 5:1 to about 1:5. It is further herein acknowledged that in some embodiments of the present invention the formulation comprises the lipid and biologically active agent in a ratio from about 3:1 to about 1:3.

[0182] It is further herein acknowledged that in some embodiments of the present invention the formulation comprises a stabilizer, said stabilizer having at least one surfactant selected from the group consisting of non-ionic, anionic, cationic, and amphiphilic.

[0183] It is further herein acknowledged that in some embodiments of the present invention the formulation the non-ionic surfactant is selected from the group consisting of a polyethylene glycol derivative and a glycerol derivative.

[0184] It is further herein acknowledged that in some embodiments of the present invention the polyethylene glycol derivative is selected from the group consisting of alpha-Hydro-omega0hydroxypoly-(oxy-1,2-ethanediyl), Polyethylene glycol mono[4-(1,1,3,3-tetramethylbutyl) phenyl]ether, O-3-Amino-3-deoxy-D-glucopyranosyl-(14)-O-[2,6,diamino-2,3,6-trideoxy-D-ribo-hexopyransol-(16)]-2-deoxy-L-streptamine, alpha-hydro-omega-hydroxpoly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymers, Polyethylene glycol fatty alcohol ethers, Sorbitan fatty acid esters, poloxamer, and polyethylene glycol esters of fatty acids.

[0185] It is further herein acknowledged that in some embodiments of the present invention the glycerol derivative is selected from the group consisting of alpha-hydro-omega-hydroxypoly(oxy-1,2-ethanediyl) and polyalkylglyceride.

[0186] It is further herein acknowledged that in some embodiments of the present invention the anionic surfactant is selected from the group consisting of carboxylate, alkyl sulfonate, aryl sulfonate and phosphate.

[0187] It is further herein acknowledged that in some embodiments of the present invention the cationic surfactant is selected from the group consisting of alkyl pyridinium salt and tetraalkylammonium salt.

[0188] It is further herein acknowledged that in some embodiments of the present invention the amphiphilic surfactant is selected from the group consisting of alkyl betaine derivative, cocoamphodiacetate derivative, trimyristin, trilaurin, tripalmitin, tristearin, and phosphatidylglycerol.

[0189] It is further herein acknowledged that in some embodiments of the present invention the at least one lipid additive is selected from the group consisting of triglyceride, alkyl ester, cholesterol, octadecenoic acid 1,2,3-propanetriyl ester, edible oil, tetradecanoic acid 1-methylethyl ester, and methyl ester beta-Cholest-5-en-3-ol.

[0190] It is further herein acknowledged that in some embodiments of the present invention the formulation further comprises at least one additive selected from the group consisting of flavor, aroma modifier, sweetener, color, and antioxidant.

[0191] It is further herein acknowledged that in some embodiments of the present invention the lipid is in a colloidal dispersion of micelles, mixed micelles, and micellar aggregates, the lipid having a particle size of from about 10 to about 300 nm inclusive of any integer within this range. It is further herein acknowledged that in some embodiments of the present invention the lipid is in the form of a dispersion having liquid particles of size in the range of from about 50 to 300 nm.

[0192] In some embodiments of the formulation the biologically active agent is further characterized by having systemic activity, said activity being suitable for treatment of at least one condition selected from the group consisting of inflammation, irritation, dryness, and microbial infection, nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, Tourette syndrome, neuropathic pain (central, peripheral, or not specified), cancer pain, diabetic peripheral neuropathy, fibromyalgia, refractory pain due to MS or other neurological conditions, rheumatoid arthritis, non-cancer pain (nociceptive and neuropathic), central musculoskeletal problems, and chemotherapy-induced pain.

[0193] The formulations comprise nano-sized lipid based high cannabinoid load capacity carrier. These formulations include an amphiphilic lipid carrier in the form of a colloidal composition which can include a micellar aggregate or mixed micelles dispersed in a continuous aqueous phase, or lipid droplets suspended in a continuous lipid phase (emulsions), and an active agent which is a cannabis derived product or cannabinoids. The formulations provide trans-dermal systemic delivery of a large amount of the cannabinoids at a controlled and prolonged manner.

[0194] It is herein acknowledged that the present invention provides novel formulations for release of predetermined release of cannabinoids from the sub dermal lipid layer in zero order (FIG. 1), first order (FIG. 2), loading and sustained (FIG. 3), delayed and sustained (FIG. 4), delayed (FIG. 5), pulsatile (FIG. 6) and ascending (FIG. 7) manner, or any combination thereof.

[0195] It is herein acknowledged that formulations of the present invention provide trans-dermal systemic delivery of cannabinoids from the sub dermal lipid layer in a zero order (FIG. 1) release manner such that a constant amount of drug is eliminated per unit time independent of the total drug concentration in the plasma. Zero order kinetics are rare yet it is within the scope of the present invention to provide such formulations.

[0196] It is herein acknowledged that formulations of the present invention provide trans-dermal systemic delivery of cannabinoids from the sub dermal lipid layer in a first order (FIG. 2) release manner such that a constant amount of drug is eliminated per unit time dependent of the total drug concentration in the plasma,

[0197] It is herein acknowledged that formulations of the present invention provide trans-dermal systemic delivery of cannabinoids from the sub dermal lipid layer in a loading and sustained (FIG. 3) release manner after cannabinoids have been deposited in depots of the WDA to a predetermined loading concentration and then released in a sustained manner such that a constant amount of drug is eliminated per unit time dependent of the total drug concentration in the plasma.

[0198] It is herein acknowledged that formulations of the present invention provide trans-dermal systemic delivery of cannabinoids from depots in the sub dermal lipid layer in a delayed and sustained (FIG. 4) release manner such that, after a predetermined latent period of the cannabinoid formulation residing in the depots of the WDA a predetermined amount of drug is released into the patient vascular or lymphatic system, and a constant amount of drug is eliminated per unit time dependent of the total drug concentration in the plasma over a sustained period of time.

[0199] It is herein acknowledged that formulations of the present invention provide trans-dermal systemic delivery of cannabinoids from the sub dermal lipid layer depots in a delayed (FIG. 5) manner such that a constant amount of drug is released per unit time into the patient vascular or lymphatic system.

[0200] It is herein acknowledged that formulations of the present invention provide trans-dermal systemic delivery of cannabinoids from the sub dermal lipid layer in a pulsatile (FIG. 6) release manner such that several pulses of a constant amount of drug is released per unit time into the patient vascular or lymphatic system, with different pulse characteristics over time as illustrated in the graph.

[0201] It is herein acknowledged that formulations of the present invention provide trans-dermal systemic delivery of cannabinoids in an (FIG. 7) ascending manner from the sub dermal lipid layer depots of the WDA such that an increasing amount of drug is released such that a constant amount of drug is eliminated per unit time dependent of the total drug concentration in the plasma.

[0202] FIGS. 1-7 illustrate plasma concentration v. time achieved by various formulations of the present invention. Cannabinoids were measured in whole blood and/or plasma samples by conventional cannabinoid measuring techniques such as those reported in Intra-and Intersubject Whole Blood/Plasma Cannabinoid Ratios Determined by 2-Dimensional, Electron Impact GC-MS with Cryofocusing, Clin Chem. PMC 2011 Oct. 18, Clin Chem. 2009 June; 55(6): 1188-1195.

[0203] Further embodiments of the formulation of the invention comprise a transdermal patch in combination with cannabinoid formulations for carrying cannabis-based medicaments and products containing cannabis-derived products and/or cannabinoids and related compounds through the epidermis to the sub dermal lipid layer, such as the white adipose tissue (WDA).

It is herein acknowledged that embodiments of the present invention comprise a combination product, as classified by the US Food and Drug Administration. Combination products of the present invention consist of a medical device combined with formulations of cannabinoids that the device is designed to deliver.

[0204] In embodiments of the invention is a medicated cream containing cannabinoids is provided which, when applied to the skin, is able to deliver a specific dose of cannabinoids through the skin and into the bloodstream.

[0205] In embodiments of the present invention is a medicated gel containing cannabinoids is provided which, when applied to the skin, is able to deliver a specific dose of cannabinoids through the skin and into the bloodstream.

Transdermal Patch

[0206] It is herein acknowledged that in embodiments of the present invention transdermal patch is a medicated cannabinoid dispensing adhesive patch that is placed on the skin to deliver a specific dose of cannabinoids through the skin and into the bloodstream.

[0207] It is herein acknowledged that an advantage of a transdermal drug deliver), route over other types of medication delivery such as oral, topical, intravenous, intramuscular, etc. is that the patch provides a controlled release of the cannabinoid formulations into the patient.

[0208] It is herein acknowledged that the aforementioned cannabinoid formulations are made available for topical administration via transdermal patches through a porous membrane covering a reservoir of medication or through body heat melting thin layers of cannabinoid formulation embedded in the adhesive of the transdermal patch. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective harrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered by this method.

[0209] It is herein acknowledged that components to a transdermal patch of the present invention may comprise: [0210] LinerProtects the patch during storage. The liner is removed prior to use. [0211] Cannabinoid based formulationDrug solution in direct contact with release liner. [0212] AdhesiveServes to adhere the components of the patch together along with adhering the patch to the skin [0213] MembraneControls the release of the cannabinoids based formulation from the reservoir and multi-layer patches [0214] BackingProtects the patch from the outer environment [0215] Permeation EnhancerThese are permeation promoters for drugs, which increases delivery of drug, in the case of the present invention, the drug comprises Cannabinoids based formulation. [0216] Matrix FillerIt provides bulk to matrix as well as some of fillers acts as matrix stiffening agent.

Single Layer Drug Adhesive Patch

[0217] Embodiments of the present invention may comprise cannabinoid based formulations included in the adhesive layer of a transdermal patch. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing.

Multi-Layer Drug-in-Adhesive Patch

[0218] It is herein acknowledged that embodiments of the present invention may comprise Cannabinoids based formulation of the present invention included in a multi-layer drug-in-adhesive patch similar to the single-layer system; the multi-layer system is different, however, in that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). One of the layers is for immediate release of the drug and other layer is for control release of drug from the reservoir. This patch also has a temporary liner-layer and a permanent backing. The drug release from this depends on membrane permeability and diffusion of drug molecules.

Reservoir Patch

[0219] It is herein acknowledged that embodiments of the present invention may comprise a cannabinoid based formulation/stock of the present invention included in a reservoir transdermal system. Unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. The drug reservoir is totally encapsulated in a shallow compartment molded from a drug-impermeable metallic plastic laminate, with a rate-controlling membrane made of a polymer like vinyl acetate on one surface. This patch is also backed by the backing layer. In this type of system the rate of release is zero order.

Matrix Patch

[0220] It is herein acknowledged that embodiments of the present invention may comprise cannabinoid based formulation of the present invention included in a matrix. The matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer, partially overlaying it. Also known as a monolithic device.

[0221] The descriptions of the various embodiments and/or examples of the present invention have been presented for purposes of illustration but are not intended to be exhaustive or limited to the embodiments and/or examples disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein was chosen to best explain the principles of the embodiments, the practical application, or to enable further understanding of the embodiments disclosed herein.

[0222] The present invention will now be described in more detail with the following non-limiting Examples:

WORKING EXAMPLES

Example 1Non-medicated Colloidal Composition for Evaluation of Bioadhesive Behavior on the Skin of the Upper Arm Under a Dressing

[0223] 315 mg of pure phosphatidylcholine and 80 mg of polyoxyethylated sorbitan monolaurate (Tween-20) were dissolved in 2 ml of ethyl alcohol to form a solution. The solution was diluted with purified water to a final volume of 100 ml and then passed through a 0.22 micron PTFE membrane filter. The resultant colloidal carrier had a mean droplet size of about 185 nm.

[0224] The bioadhesive properties were examined according to the following method, using the radioactive Tc.sup.99 label, which is safe and approved for human use. The lipid colloidal particles were labeled with Tc.sup.99 by using potassium pertechnate-Tc.sup.99, after reduction by Sn.sup.2+ so that substantially all radioactivity was completely associated with lipid aggregates. A water solution of Tc.sup.99 complexed with DTPA (Diethylenetriamine pentaacetic acid), in which all radioactivity was in the aqueous phase, was used as a control. 10 ml of either the labeled colloidal composition or the control solution was administered to the upper arm of the volunteer human subject, and was then rinsed in a shower. More than 20% of the radioactive label associated with the colloidal carrier remained attached to the upper arm skin over 2.5 hours after the shower. By contrast, the radioactive label level for the control water solution dropped below 20% of its initial value after less than 20 minutes following rinse, and the remaining radioactivity detected was extremely low after this time.

[0225] Other methodologies for assessing transdermal penetration of an active are found in: Walters K A, Watkinson A C, Brain K R. In vitro skin permeation evaluation: the only realistic option. Int J Cosmet Sci. 1998; 20(5):307-316; Franz T J, Lehman P A, Raney S G. Use of excised human skin to assess the bioequivalence of topical products. Skin Pharmacol Physiol. 2009; 22(5):276-286; Yang Y, Manda P, Pavurala N, Khan M A, Krishnaiah Y S. Development and validation of in vitro-in vivo correlation (IVIVC) for estradiol transdermal drug delivery systems. J Control Release. 2015; 210:58-66; Sandby-Mller J, Poulsen T, Wulf H C; Kchler S, Strver K, Friess W. Reconstructed skin models as emerging tools for drug absorption studies. Expert Opin Drug Metab Toxicol. 2013; 9(10):1255-1263; and Cross S E, Roberts M S. Use of in vitro human skin membranes to model and predict the effect of changing blood flow on the flux and retention of topically applied solutes. J Pharm Sci. 2008; 97(8):3442-3450. (the disclosures of each are incorporated herein by reference in their entirety).

Example 2CBD Colloidal Self-Emulsifying Composition

[0226] The following was mixed together: 450 mg (0.6 mmol) of purified egg lecithin; 150 mg (0.25 mmol) of CBD; 150 mg of PEG-10 laurate; and 450 mg (0.5 mmol) of triolein, and heated to 60 C. for 20 minutes until dissolution. Water was then added to this solution with gentle stirring. Immediately, a fine oil-in-water emulsion was formed. Such emulsions were observed to be stable with final oil phase concentrations of 5%-25%. The resultant emulsion can be treated by sonication, extrusion or high-pressure homogenization to standardize the size of emulsion droplets.

Example 3CBD Colloidal Self-Emulsifying Composition

[0227] A self-emulsifying composition containing CBD was prepared as described except 150 mg of Tyloxapol was added instead of PEG-10 laurate. After formation of the emulsion, the mixture was treated by high-pressure homogenization (6 cycles, 800 bar), producing a stable emulsion.

[0228] It is herein acknowledged that in some embodiments of the present invention the droplets, particles or micelles comprising the cannabis derived product or cannabinoids are dispersed in a continuous phase, making up to 40% by weight of the total solution.

Example 4Cannabinoid Stock Formation

[0229]

TABLE-US-00001 LIPID PHASE A Grams CBD (>99% purity) 10.0 Phosphatidylcholine (Phospholipid 90H) 44.9 Propylene Glycol 44.9 Vitamin E Derivative (TPCG) 0.2 100.0
Process: Heat Propylene Glycol to 55 C., add Phospholipid 90H slowly with stirring, mix until dissolved, add the CBD slowly, mixing well and add the TPCG.

TABLE-US-00002 WATER PHASE B Grams Water 300 Process: Heat the water to about 45 to about 50 C.

Phase C

[0230] Process: Add Lipid phase A with water phase B using a high shear mixing followed by passing the mixture through a High Pressure homogenizer (e.g. Avestin EmulsiFlex-C-50) at pressures ranging from about 5,000 to about 20,000 psi. This process is repeated for several cycles until the emulsion to achieve a smooth and uniform emulsion system.

[0231] This emulsion is used as a base material to provide a fast and effective CBD and/or THC delivery system.

[0232] The emulsion was added in desired ratios to a cosmetic format that is a cream, balm, lotion, gel, ointment, liquid, oil or solid forming the product for topical use. Example: Topical cream/gel for pain relief, or for vaginal lubricant applications. Some products will be formulated for the specific applications as creams or spray. It is herein acknowledged that in some embodiments of the present invention the droplets, the non-lipid portion of the solution is a hydrogel.

Example 5Lubricant Cosmetic Format Formulation

[0233]

TABLE-US-00003 (%) Water 75.53 Natrosol 250HHR 0.8 Vanzan NF 0.15 Aloe Vera Gel 2.0 Zemea (Propanediol) 2.0 Hemp Extract 0.1 Sodium Hyaluronate 1% 1.0 Quinoa Seed Extract GL 0.1 Cannabinoid Stock - CBD 10% solution 16.0 Linseed Extract GL 0.1 Green Tea Extract GL 0.1 Shitake Mushroom Extract 0.1 Oat Kernel Extract GL 0.1 Citric Acid 20% solution 0.15 Geogard Ultra 1.0 Potassium Sorbate 0.3 NaOH 20% solution 0.37 Sodium Benzoate 0.1 (uric acid to pH to 5.0-5.5). 100.00

Example 6Pain Relief Gel 150 mg CBD

[0234]

TABLE-US-00004 (%) Water 67.6 Lecigel (Sodium acrylates copolymer and lecithin) 2.0 Glycerin 1.5 Allantoin 0.15 Sodium Hyaluronate 0.5 CBD Stock lipid 10% 16.0 Camphor 0.5 Allantoin 0.2 Menthol 10.0 Vitamin E Acetate (Tocopherol acetate) 0.25 Arnica Extract GL 0.10 Boswellia Extract GL 0.10 Aloe Veral Gel 10x (Ale Barbadensis Leaf Juice) 0.10 Euxyl PE 9010 1.0 100.0%

Example 7Cream 200 mg CBD

[0235]

TABLE-US-00005 CBD Stock lipid 10% 16.0 Water 67.6
One or more of Cetearyl Ethylhexanoate, Helianthus Annuus Seed Oil, Distarch Phosphate, Cetearyl Alcohol, Dimethicone, Cetearyl Glucoside, Parfum, Phenoxyethanol, Potassium Olivoyl Hydrolyzed Oat Protein, Glyceryl Stearate, Allantoin, Acrylates/C10-30 Alkyl Acrylate Crosspolymer, Cannabidiol, Glyceryl Oleate, Ethylhexylglycerin, Benzyl Alcohol, Potassium Sorbate, Sodium Benzoate, Alpha Isomethyl Ionone, and Benzyl Salicylate 17%.

[0236] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0237] It will be appreciated that the above descriptions are intended only to serve as examples, and that many other embodiments are possible within the spirit and the scope of the present invention.