阅读说明：本技术 用于治疗皮炎和炎性皮肤病的***素制剂 (Cannabinoid formulations for the treatment of dermatitis and inflammatory dermatoses ) 是由 E.库珀 M.卡拉汉 于 2018-01-24 设计创作，主要内容包括：本发明涉及一种包含大麻素和硅氧烷的药物组合物,其中大麻素溶解在组合物中。(The present invention relates to a pharmaceutical composition comprising a cannabinoid and a siloxane, wherein the cannabinoid is dissolved in the composition.)

1. a pharmaceutical composition comprises a cannabinoid and a siloxane, wherein the cannabinoid is dissolved in the composition.

2. The pharmaceutical composition of claim 1, wherein the cannabinoid is cannabidiol.

3. The pharmaceutical composition according to claim 1 or 2, wherein the composition is for topical application.

4. The pharmaceutical composition of any one of the preceding claims, wherein the ratio of silicone:

a) Containing 2 or 3 silicon atoms;

b) Has about the same level of volatility as isopropyl alcohol; and/or

c) Selected from: hexamethyldisiloxane, octamethyltrisiloxane, and combinations thereof.

5. The pharmaceutical composition of any one of the preceding claims, further comprising a residual solvent.

6. The pharmaceutical composition of claim 5, wherein the residual solvent is selected from the group consisting of: alkyl polypropylene glycol/polyethylene glycol ether (alkyl PEG/PPG ether) and/or fatty alcohols.

7. The pharmaceutical composition of claim 6, wherein the ratio of alkyl PEG/PPG ether:

a) An ether component having a PEG/PPG chain length of 10 to 50PG units and 2 to 20 carbons, wherein the sum of the carbons of the PG units and the ether component is 20 to 60;

b) Has low volatility so as to evaporate less than 5% within 24 hours at skin temperature;

c) Liquid at a temperature of about 30 ℃ or less; and/or

d) selected from: the polypropylene glycol ether of stearyl alcohol and the polypropylene glycol ether of butyl alcohol.

8. The pharmaceutical composition according to claim 6, wherein the relative amount of alkyl PEG/PPG ether is:

a) Selected from the group consisting of: at least 1% w/w, at least 2% w/w, at least 3% w/w, at least 4% w/w, and at least 5% w/w; and/or

b) The maximum concentration is 50% w/w; or

c) The maximum concentration was 80% w/w.

9. The pharmaceutical composition of claim 6, wherein the ratio of fatty alcohol:

a) Has low volatility so as to evaporate less than 5% within 24 hours at skin temperature;

b) Is a C12-22 fatty alcohol, and/or

Is liquid at a temperature of about 30 ℃ or less.

10. The pharmaceutical composition according to claim 9, wherein the fatty alcohol is selected from the group consisting of: oleyl alcohol, isostearyl alcohol, octyldodecanol, and 2-hexyldecanol.

11. The pharmaceutical composition of any one of the preceding claims, further comprising a low molecular weight alcohol.

12. The pharmaceutical composition of claim 11, wherein the ratio of low molecular weight alcohol:

a) Liquid at ambient temperature;

b) Has about the same level of volatility as isopropyl alcohol; and/or

c) Selected from: c2-6 alcohols and combinations thereof; or

d) Selected from: c2-4 alcohols and combinations thereof.

13. The pharmaceutical composition of claim 12, wherein the alcohol is selected from the group consisting of: ethanol, n-propanol, isopropanol, and combinations thereof.

14. Pharmaceutical composition according to any of the preceding claims, characterized in that the concentration of cannabinoid in the topical composition is selected from the group consisting of: at least 2% w/w, at least 3% w/w, at least 4% w/w, at least 5% w/w, at least 6% w/w, at least 7% w/w, at least 8% w/w, at least 9% w/w, at least 10% w/w, at least 11% w/w, at least 12% w/w, at least 13% w/w, at least 14% w/w and at least 15% w/w.

15. Pharmaceutical composition according to any of the preceding claims, characterized in that the concentration of cannabinoid in the topical composition is selected from the group consisting of: at least 20% w/w, at least 30% w/w, at least 40% w/w, at least 50% w/w, at least 60% w/w, at least 70% w/w, at least 80% w/w, at least 90% w/w, at least 95% w/w and at least 99% w/w.

16. A method of treating or preventing an inflammatory skin condition in a patient in need of such treatment, the method comprising topically administering a prophylactically or therapeutically effective amount of the pharmaceutical composition of any one of the preceding claims.

17. Use of a cannabinoid and a siloxane for the preparation of a pharmaceutical composition according to any one of the preceding claims for the treatment or prevention of an inflammatory skin disorder in a patient in need of such treatment.

18. Use of a pharmaceutical composition according to any one of the preceding claims for the prevention or treatment of an inflammatory skin condition.

Technical Field

The present invention relates to a pharmaceutical composition for the delivery of cannabinoids. The pharmaceutical compositions of the present invention are particularly suitable for use in the treatment of inflammatory skin conditions.

Background

The following discussion of the background art is intended to facilitate an understanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to was or was common general knowledge as at the priority date of the application.

Most mammalian skin, including human skin, comprises three layers: (i) the epidermal layer, which is composed mainly of keratinocytes, as well as a small number of melanocytes and langerhans cells (antigen presenting cells); (ii) the dermis layer, which contains nerve endings, sweat glands and oil (sebum) glands, hair follicles and blood vessels, and is composed mainly of fibroblasts; and (iii) deeper subcutaneous tissue layers of subcutaneous fat and connective tissue. The epidermis itself is composed of two layers, the outer stratum corneum and the inner epidermal basal layer.

Most skin conditions involve inflammation triggered by some skin injury. Keratinocytes respond rapidly to environmental stimuli (e.g., UV radiation (UVR), allergens, irritants, or physical damage) by producing a variety of inflammatory mediators, including cytokines (e.g., IL-1, TNF- α, and IL-6) and chemokines (e.g., IL-8). One of the most active inflammatory mediators is PGE-2 (prostaglandin E2), and of course, many topical dermatological agents are designed to reduce PGE-2 levels. Fibroblasts in the dermis also produce PGE-2 as well as various chemokines, cytokines, and matrix-disrupting enzymes (e.g., collagenase (MMP-1)).

eczema, also known as dermatitis, is a collective term for many types of skin disorders involving inflammation. Atopic dermatitis is the most common of many types of eczema. Several other forms have very similar symptoms. Some of the different types of eczema are listed and briefly described below.

Atopic dermatitis is a chronic skin disorder in which the skin becomes extremely itchy and inflamed, causing redness, swelling, cracking, exudation, scabbing, and desquamation. Atopic dermatitis most commonly affects infants and young children, but it can persist into adulthood or first onset later in life. Onset is less common after age 30 and often occurs after exposure of the skin to harsh conditions. In most cases, there is a period of disease progression called exacerbation or flare (flare) followed by a period of skin improvement or complete clearance called remission. The cause of atopic dermatitis is not clear, but the disease appears to be caused by a combination of genetic and environmental factors. Atopic dermatitis is very common, has the same effect on males and females, and accounts for 10 to 20 percent of the referral of dermatologists; over 1500 million people in the united states have symptoms of this disease. People living in urban areas and in climates with low humidity have an increased risk of atopic dermatitis.

Contact eczema is a local reaction, including redness, itching and burning, caused when the skin is exposed to allergens (substances causing allergy) or irritants (such as acids), detergents (soaps, shower gels) or other chemicals).

Allergic contact eczema is a red, itchy, exudative reaction when the skin comes into contact with substances that are considered foreign by the immune system, such as poison ivy or certain preservatives in creams and lotions.

Seborrheic eczema is an inflammation of the skin of unknown origin but associated with certain types of yeasts that live on the skin. Seborrheic eczema is characterized by yellowish, greasy, scaly patches (known as cradle cap in infants) of the skin on the scalp, face and other parts of the body that occasionally occur.

Nummular eczema is a coin-shaped plaque of irritated skin-most commonly found on the arms, back, buttocks and lower legs-which can scab, desquamate and be extremely itchy.

Neurodermatitis is a flaky spot of skin on the head, lower leg, wrist or forearm caused by local itching (e.g. insect bites), which becomes strongly irritated when scratched.

Stasis dermatitis is a skin irritation on the lower leg, often associated with circulatory problems.

pompholyx eczema is a skin irritation on the palms and soles and is characterized by itchy and burning large transparent blisters.

Radiation therapy has some undesirable side effects, including skin inflammation and radiodermatitis. The specific side effects of radiation therapy (both acute and chronic) depend on the body site being treated and the dose administered. In general, the first change is a reddening of the skin, similar to sunburn. In many patients, this is everything that is experienced. However, in most patients, burns can be severe and in many cases correspond to second degree burns. Like sunburn, the area involved is often sensitive to touch and even painful. Furthermore, the covered skin may break and the area may remain open after the irradiation process is completed for days to weeks. After the radiation treatment session is over, the redness will gradually disappear and any open areas will generally heal. However, the skin in this area is likely to develop the characteristics of aged skin, including significant wrinkling, thinning, stiffness and/or dryness of the skin, and possible changes in pigmentation.

Most treatment options currently used for radiodermatitis involve the use of emollients or aloe vera gel in an attempt to keep the skin moist. However, while moisturizing helps dry skin, it does not reduce pain or redness caused by inflammation.

rosacea is a vascular inflammatory skin disease affecting about 5% of the population and is characterized by frequent episodes of facial redness or flushing due to overactive capillaries. Over time, this chronic state of skin inflammation causes various symptoms of rosacea. Rosacea is sometimes mischaracterized as adult acne because patients develop redness and acneiform symptoms on the face. However, individuals with such skin disorders may also continue to redden with pain and itching in areas such as the forehead, chin, nose, ears, chest and back. As the disease progresses, small blood vessels and tiny blisters (called papules or pustules) begin to appear on and around the reddened area. In severe cases, rosacea can affect the eyes (ocular rosacea) and cause nasal defects (rosacea). In addition to the physical symptoms associated with rosacea, patients suffer from serious psychological and social problems if left untreated.

The present invention aims to provide a composition and method for reducing the effects of the above-mentioned conditions, as well as other inflammatory skin conditions, or to provide the consumer with a useful or commercial choice.

Brief description of the invention

According to the present invention there is provided a pharmaceutical composition comprising a cannabinoid and a silicone, wherein the cannabinoid is dissolved in the composition. According to one embodiment, the cannabinoid is cannabidiol. According to another aspect of the invention, the pharmaceutical composition is a topical pharmaceutical composition. The siloxane forms a volatile solvent for the cannabinoid.

the cannabinoids delivered by the present invention preferably penetrate into the epidermis of the skin and the majority of the cannabinoids remain in this layer. Preferably some further penetrate into the dermis and some further cannabinoids penetrate into the subcutaneous tissue layer to be absorbed systemically. The skin to which the composition is delivered is preferably mammalian skin, more preferably human mammalian skin.

the compositions of the present invention may further comprise (i) other volatile solvents, such as low molecular weight alcohols, and/or (ii) less volatile solvents, such as fatty alcohols and/or alkyl polypropylene glycol/polyethylene glycol ethers (alkyl PEG/PPG ethers). The less volatile solvent is referred to as residual solvent because it remains on the skin after the silicone evaporates (and when other volatile solvents, if present, evaporate). These other volatile solvents and residual solvent excipients can further enhance the ability of the compositions of the present invention to generate concentrated cannabinoid solutions in situ, and/or facilitate the delivery of cannabinoids to the epidermis and dermis to treat inflammatory skin conditions.

According to the present invention there is provided a method of treating or preventing an inflammatory skin condition in a patient in need of such treatment, said method comprising topically administering a prophylactically or therapeutically effective amount of a pharmaceutical composition according to the present invention.

According to the present invention, there is provided a method of using cannabinoids and silicones for the preparation of a pharmaceutical composition for use in the prevention or treatment of an inflammatory skin condition in a patient in need thereof.

According to the present invention, there is provided a method of preventing or treating inflammatory skin conditions using a topical composition according to the present invention.

In one embodiment, the pharmaceutical composition is a topical composition.

Brief Description of Drawings

FIG. 1: the figure represents the data for the delivered CBD shown in table 10. Data are shown in μ g/cm 2. Data are shown in μ g/cm 2. A Dixon test (Dixon's Qtest) with 95% confidence is first run on the data to identify and remove outliers.

FIG. 2: the figure represents the data for the delivered CBD shown in table 10. Data are shown in μ g/cm 2. A dixon test with 95% confidence is first run on the data to identify and remove outliers.

FIG. 3: the figure represents the data for the delivered CBD shown in table 11. Data are shown as percent delivered. A dixon test with 95% confidence is first run on the data to identify and remove outliers.

FIG. 4: the figure represents the data for the delivered CBD shown in table 11. Data are shown as percent delivered. A dixon test with 95% confidence is first run on the data to identify and remove outliers.

FIG. 5: the figure represents the data for the delivered CBD shown in table 12. Data are shown as percent delivered. A dixon test with 95% confidence is first run against the data set to identify and remove outliers.

FIG. 6: the figure represents the data for CBD delivered into the skin shown in table 13. Data are shown in μ g/g tissue. A dixon test with 95% confidence is first run on the data to identify and remove outliers.

Detailed Description

Endocannabinoid system (ECS), cannabinoids, cannabidiol and inflammatory skin conditions

The identification of the major cannabinoid receptors (CB1 and CB2), their endogenous lipid ligands (endocannabinoids), biosynthetic pathways and metabolic enzymes (collectively referred to as ECS) and the discovery and/or rational design of exogenous ligands for many CB receptors has led to an exponential growth of research to explore the ever-increasing regulatory function of this newly discovered physiological system in health and disease.

Modulating the activity of ECS has therapeutic potential for a variety of diseases and pathological conditions affecting humans, ranging from inflammation, neurodegeneration, gastrointestinal tract, liver, cardiovascular disease and obesity to ischemia/reperfusion injury, cancer and pain.

The most widely studied endocannabinoids are anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoyl glycerol (2-AG). Various pathways are involved in the synthesis and cellular uptake of these lipid mediators. The most common degradation pathways for AEA and 2-AG are Fatty Acid Amide Hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Endocannabinoids, like Δ 9-tetrahydrocannabinol (THC; the main active ingredient of the plant Cannabis sativa), exert their physiological effects mainly via two main G-protein coupled cannabinoid receptors; however, many other signaling mechanisms and receptor systems may also be involved (e.g., transient receptor potential cation channels, subfamily V, members 1; TRPV 1). Initially, CB 1-mediated effects were described centrally, and CB1 receptors were thought to be localized to the central nervous system, whereas CB2 was first recognized in the periphery of immune cells.

The classical steps of AD pathology are as follows:

The entry of skin barrier defects or skin irritants triggers keratinocytes to release IL-25, IL-33 and Thymic Stromal Lymphopoietin (TSLP), which activates dendritic cells (antigen presenting cells in the skin) and langerhans cells.

In the "acute phase" of onset, dendritic cells cause an excessive cellular activation of Th2, T-helper 22(Th22), and T-helper 17(Th17) (note that these changes persist into the "chronic phase" of the disease).

Th2 cells produce IL-4, IL-13 and IL-31, which subsequently induce changes in keratinocyte gene expression, disrupt skin barrier function, and trigger itching symptoms. IL-4 and IL-14 increase keratinocyte release of additional TSLP, which leads to further Th2 cell activation.

Activated Th22 cells release IL-22, which promotes keratinocyte proliferation, down-regulates keratinocyte differentiation, and induces the pro-inflammatory S100 gene in synergy with IL-17.

Activated Th17 cells release IL-17, which regulates S100 protein and gene expression.

In the chronic phase (beginning on day 3), dendritic cells recruit the T-helper 1(Th1) cell population via IL-12 and continue to recruit Th22 and Th17 cells. Th1 cells release interferon-gamma (IFN- γ), which may reduce the role of Th2 cells in disease. Th1, Th22, and Th17 cells induce responses that continue to attract additional immune cells into the epidermis, alter keratinocyte differentiation, and induce epidermal thickening.

It is estimated that Th2 cell responses predominate in-80% of AD cases (exogenous AD), but in other cases (endogenous AD), a shift to more pronounced Th22 and Th17 responses. A recent study of [ D' erm 2017] showed that IL-17 may be more dominant in AD than was thought in the classical model [ Tan 2017 ]:

IL-17 protein levels are elevated in AD skin lesions compared to healthy children, but not in sera of children with AD, indicating a local effect of IL-17.

The effect of 2, 4-dinitrochlorobenzene (DNCB; for inducing a mouse AD model) was evaluated in IL-17 knockout and wild-type C57Bl/6 mice. DNCB is capable of inducing AD-like lesions in two types of mice; however, the thickness of the epidermis and dermis of the lesions was significantly reduced in IL-17 knockout mice compared to that observed in wild type mice.

A reduction in skin mRNA levels of the Th2 cytokines IL-4 and IL-13 in IL-17 knockout mice compared to wild type mice; however, there was no difference in the expression level of IFN-. gamma.skin mRNA. Splenocytes isolated from naive IL-17 knockout mice released less IL-4 following concanavalin a (cona) stimulation (T cell activation model) than splenocytes from treated wild type mice.

IL-17 has been shown to trigger a pro-inflammatory response in cell lines of immortalized human keratinocytes (HaCaT cells). The addition of IL-17 increases the release of pro-inflammatory IL-6 and IL-8, but not IL-1 β. This suggests that IL-17 may have an important role in the immune response associated with AD.

CBD may have beneficial effects in reducing unwanted skin cell growth and skin inflammation associated with many inflammatory skin diseases.

It is believed that CBD can:

Inhibition of keratinocyte hyperproliferation;

Exert a general anti-inflammatory effect, such as:

-reducing activated T cell activity and also inhibiting subsequent B cell responses;

-inhibiting multiple T cell populations and inhibiting general T cell activation;

-reducing the concentration of pro-inflammatory mediators and also increasing the release of anti-inflammatory cytokines;

-inhibiting the action and/or reducing the level of IFN- γ;

-inhibiting migration, proliferation and cell maturation processes involved in Th17, Th1 and Th2 immune responses; and

Has a direct antioxidant effect.

Without being bound by any theory, we believe that the mode of action of CBD on inflammatory skin diseases involves inhibition of inflammatory response mediators. The endocannabinoid system (ECS) has a physiological regulatory function in the proliferation, differentiation, apoptosis and cytokine, mediator and hormone production of various cell types of the skin and appendages (e.g., hair follicles, sebaceous glands).

In vitro studies showed that CBD stimulated human vanilloid receptor type 1 (VR1) with maximal effect similar in potency to capsaicin when using HEK-hVR1 transfected cells, and inhibited arachidonic acid ethanolamine, an endogenous CBD neurotransmitter, when using rat basophilic leukemia cells [ Bisogno 2001, Mechoulam 2002 ]. These findings suggest a mode of action for the anti-inflammatory properties of CBD. In vivo studies with intravenous (i.v.) administration of CBD (1mg/kg) attenuated ovalbumin-induced airway obstruction in sensitized guinea pigs, indicating the potential role of CBD in reducing immune-induced inflammatory responses [ Dud sov a 2013 ]. Similarly, CBD (5mg/kg, intravenous) administration to rats for 4 weeks once daily attenuated cardiac inflammation produced by doxorubicin [ Fouada 2013 ].

Unfortunately, cannabinoids (such as cannabidiol) are difficult to absorb through membranes (such as the skin) due to their highly lipophilic nature. Thus, the successful administration of therapeutically effective amounts of cannabinoids (e.g., cannabidiol) to a mammal in need thereof within a reasonable time frame and over a suitable surface area has been severely limited.

Composition comprising a metal oxide and a metal oxide

The present invention is based on the following surprising findings: the cannabinoid is soluble in the siloxane to form the pharmaceutical composition. Optionally, the cannabinoid is cannabidiol. The pharmaceutical composition can be administered topically, after which at least some of the silicone evaporates to concentrate the cannabinoid in situ, facilitating penetration into therapeutically relevant areas of the skin (preferably the epidermal and dermal layers) to treat inflammatory skin conditions.

accordingly, there is provided a pharmaceutical composition comprising a cannabinoid and a siloxane, wherein the cannabinoid is dissolved in the composition. According to one embodiment, the cannabinoid is cannabidiol. According to another aspect of the invention, the pharmaceutical composition is a topical pharmaceutical composition. Siloxanes form volatile solvents for cannabinoids.

Inflammatory skin disorders are the most common problem in dermatology. They take many forms, ranging from occasional rashes with itching and redness to chronic diseases such as dermatitis (eczema), rosacea, seborrheic dermatitis and psoriasis. However, they are linked by a common factor, inflammation. Inflammatory markers (cytokines) produced by skin and immune cells have been found to be essential for the development of inflammatory responses such as atopic dermatitis and radiodermatitis. The present invention includes active agents in the form of cannabinoids that inhibit the production of various inflammatory responses in cultured skin cells (keratinocytes and fibroblasts) and immune cells (monocytes and T lymphocytes) as well as intact living skin. Because of blocking these inflammatory processes in the skin, the Cannabinoid-form compounds of the present invention are effective in reducing or eliminating various inflammatory symptoms associated with common skin problems (see Kupczyk et al (2009) Cannabinoid systems in the skin-a accessible target for future therapeutics in dermatology Exp Dermatol.18(8): 669-79).

High concentrations of dissolved cannabinoids (including cannabidiol) (as opposed to solid cannabinoids) are expected to be advantageous in enhancing the relevant degree of delivery into the skin, particularly the epidermis (including the basal layer of the epidermis), and some penetration into the dermis. It is believed that a high concentration of dissolved cannabinoid at the outer surface of the skin causes a concentration gradient that enhances the penetration of the cannabinoid into the skin, in particular the epidermis and dermis.

To achieve local distribution for the treatment of inflammatory skin conditions, it is advantageous that most cannabinoids (such as cannabidiol) penetrate into the epidermis and preferably remain there, and some cannabinoids further penetrate into the dermis and subcutaneous tissue layers and are absorbed systemically. In this case, cannabidiol will be concentrated mainly in the epidermis, thereby maximizing its local effect. Not only does the local effect enhance the potential therapeutic benefit, it potentially reduces the frequency and severity of any possible side effects associated with systemic cannabinoid administration as the amount of active compound circulating in the patient is reduced.

In a preferred embodiment, the composition is non-aqueous. In another preferred embodiment, the composition does not comprise a preservative.

The present invention is based, at least in part, on the following surprising findings: cannabinoids may be administered topically as: (i) a concentrated solution of cannabinoid in siloxane, or (ii) a suspension of crystalline cannabinoid in a concentrated solution of cannabinoid in siloxane. In either case, the preferred cannabinoid is cannabinol. The compositions of the present invention form a highly concentrated, amorphous thin layer of cannabinoid on the skin surface after partial or complete evaporation of the volatile siloxane and without crystallization of the cannabinoid.

By using a volatile solvent siloxane, a higher, non-crystalline (i.e., in solution) concentration of cannabinoid can be obtained. Cannabinoids can be dissolved in volatile solvent silicones in higher concentrations than many other less volatile solvents, and then remain in high concentrations on the skin after application to the skin and evaporation of the volatile silicone.

By adding a solvent which is less volatile than the silicone, the cannabinoid is preferably left in amorphous form on the skin after evaporation of the silicone. This non-volatile solvent is referred to as residual solvent because it can preferably remain on the skin after evaporation of the volatile solvent (the silicone and optionally another volatile solvent, such as a low molecular weight alcohol) in order to keep the cannabinoids in a non-crystalline state after evaporation of the silicone. Preferably, the residual solvent is an alkyl polypropylene glycol/polyethylene glycol ether and/or a fatty acid alcohol. Preferably, the residual solvent has a low volatility such that it evaporates less than 5% within 24 hours at skin temperature. Preferably, the residual solvent has a chain structure with a hydrophobic end and a hydrophilic end. Preferably, the residual solvent is liquid at a temperature of 32 ℃ or less. Preferably, the residual solvent is soluble in the siloxane. Preferably, the residual solvent maintains the cannabinoid in an amorphous form at a concentration of 20% to 70% cannabinoid.

The total amount of volatile solvent (silicone and optionally another volatile solvent, such as a low molecular weight alcohol) and residual solvent (if present) required is sufficient to keep the cannabinoid non-crystalline within about 2-8 hours after application of the composition to the skin at room temperature.

Table 1: exemplary concentrations of CBD on skin after volatile solvent evaporation

such administration is expected to result in enhanced delivery of cannabinoids (such as cannabidiol) to the epidermis and dermis of the skin, which is expected to be effective in significantly reducing and thus treating inflammatory skin conditions in patients in need of such treatment.

in addition to enhanced delivery, the present invention may allow for the use of larger doses of cannabinoids (such as cannabidiol) without having to employ a thick residual layer that may be wiped off or otherwise unacceptable to the user. The topical pharmaceutical compositions of the present invention allow for more rapid delivery of cannabinoids, which may be attributed to the metastable high driving force or supersaturation of the composition. In summary, it is believed that a high concentration of dissolved cannabinoid at the outer surface of the skin causes a concentration gradient that enhances the penetration of the cannabinoid into the epidermis and dermis.

Thus, in one aspect, the invention includes a topical composition comprising a solution of cannabinoid in silicone. In one embodiment, the cannabinoid is cannabidiol.

Defining: CBD: cannabidiol (CPD), IPA: isopropanol, MO: occlusive mineral oil (a viscous liquid paraffin), HDS: hexamethyldisiloxane, PMS: polymethylsiloxane 106cSt, HDA: 2-hexyldecanol, PG: propylene glycol, OA: oleyl alcohol, EtOH: ethanol, ODDA: octyldodecanol, AE: arlamol E, and Klucel MF: hydroxypropyl cellulose (trade name MF, from Ashland, Inc.).

Preferred cannabinoid silicone to residual solvent ratios are selected from the following ranges (w/w%): 0.5-20% cannabinoid, 1-99% siloxane, and 0.1-99% residual solvent; 5-20% cannabinoid, 4-70% siloxane, and 1% -70% residual solvent; 1-15% cannabinoid, 20-95% siloxane, and 1-15% residual solvent. In a preferred embodiment, the composition is selected from the following (w/w%):

·5％CBD/10％OA/10％PG/10％HDS/65％IPA

·14％CBD/9％OA/9％PG/9％HDS/59％IPA

·14％CBD/4.5％OA/13.5％PG/4.5％HDS/63.5％IPA

·15％CBD/5％PMS/10％OA/70％HDS

15% CBD/10% argan oil/10% HDS/65% IPA

10% CBD/7% argan oil/7% ISA/9% PMS/67% HDS

·15％CBD/13％IPA/7％PMS/66％HDS

·15％CBD/12.5％HDA/6％PMS/66.5％HDS

·15％CBD/12.5％ODDA/6％PMS/66.5％HDS

·15％CBD/10％HDA/40％IPA/35％HDS

·15％CBD/10％ODDA/40％IPA/35％HDS

·7.2％CBD/6.3％PMS/1.4％MO/1.8％IPA/83.3％HDS

·20％CBD/10％ODDA/70％IPA

·9.5％CBD/4.8％ODDA/57.1％EtOH/28.6％HDS

·10％CBD/12.5％PMS/4.5％IPA/72％HDS

·5％CBD/2.5％HDA/50％IPA/41％HDS/1％Klucel MF

·5％CBD/3.33％HDA/50％IPA/40.67％HDS/1％Klucel MF

·5％CBD/3.33％HDA/75％IPA/15.67％HDS/1％Klucel MF

·10％CBD/6.67％HDA/75％IPA/7.33％HDS/1％Klucel MF

·15％CBD/10％HDA/70％IPA/4％HDS/1％Klucel MF

·15％CBD/7.5％HDA/70％IPA/6％HDS/1.5％Klucel MF

·5％CBD/2.5％HDA/1％PMS/91.5％HDS

·10％CBD/5％HDA/1％PMS/84％HDS

·15％CBD/7.5％HDA/1％PMS/1％IPA/1％D5/74.5％HDS

·5％CBD/2％AE/1％PMS/92％HDS

·10％CBD/4％AE/1％PMS/1％IPA/84％HDS

·5％CBD/2.5％HDA/1％PMS/91.5％HDS

·5％CBD/1.7％HDA/1.2％PMS/92.1％HDS

·5.25％CBD/1.15％PMS/1.22％IPA/92.38％HDS

·5％CBD/2.5％AE/1％PMS/91.5％HDS

·5％CBD/1％AE/1％PMS/93％HDS

·5％CBD/2.5％IPM/1％PMS/1％IPA/90.5％HDS

·10％CBD/4％AE/1％PMS/1％IPA/84％HDS

·5％CBD/2％AE/1％PMS/92％HDS

·5％CBD/2.5％HDA/5％PMS/87.5％HDS

·10％CBD/6.67％HDA/5％PMS/78.33％HDS

·15％CBD/7.5％HDA/5％PMS/1％IPA/71.5％HDS

·15％CBD/7.5％HDA/10％PMS/1％IPA/66.5％HDS

In a further preferred embodiment, the composition is selected from the group consisting of:

·5％CBD/3.33％HDA/50％IPA/40.67％HDS/1％Klucel MF

·5％CBD/3.33％HDA/75％IPA/15.67％HDS/1％Klucel MF

·10％CBD/6.67％HDA/75％IPA/7.33％HDS/1％Klucel MF

·15％CBD/10％HDA/70％IPA/4％HDS/1％Klucel MF

·15％CBD/7.5％HDA/70％IPA/6％HDS/1.5％Klucel MF

·5％CBD/2％AE/1％PMS/92％HDS

·10％CBD/4％AE/1％PMS/1％IPA/84％HDS

·5％CBD/2.5％HDA/1％PMS/91.5％HDS

·10％CBD/5％HDA/1％PMS/84％HDS

·15％CBD/7.5％HDA/1％PMS/1％IPA/1％D5/74.5％HDS

·5％CBD/1.7％HDA/1.2％PMS/92.1％HDS

·5.25％CBD/1.15％PMS/1.22％IPA/92.38％HDS

In a preferred embodiment, the following formulation is a solution: 5% CBD/10% OA/10% PG/10% HDS/65% IPA, 14% CBD/9% OA/9% PG/9% HDS/59% IPA, 14% CBD/4.5% OA/13.5% PG/4.5% HDS/63.5% IPA, and 5% CBD/2% AE/1% PMS/92% HDS. In another preferred embodiment, these formulations are gelled with 1% Klucel.

In a preferred form, the composition is a gel. In another preferred form, the composition is a spray. The composition may or may not contain water. Preferably, the composition is free of water, i.e. it is anhydrous.

Siloxanes

silicones do not burn, irritate or smell and are therefore very advantageous for topical application to treat inflammatory skin conditions. It is important for the compositions of the present invention that the silicones are highly volatile due to their low molecular weight.

In one embodiment, the siloxane comprises two or three silicon atoms. The siloxane may have 1-8 methyl groups. In one embodiment, the siloxane is selected from the group consisting of: hexamethyldisiloxane, octamethyltrisiloxane, and combinations thereof. These are the most volatile siloxanes and are therefore most advantageous. Preferably, the siloxane has about the same level of volatility as isopropyl alcohol.

In another embodiment, the siloxane contains 4 or 5 silicon atoms and is, for example, decamethyltetrasiloxane or dodecamethylpentasiloxane. In another embodiment, the siloxane is a cyclic 4 or 5 silicon atom compound, such as octamethylcyclotetrasiloxane (CAS #556-67-2) or decamethylcyclopentasiloxane (CAS # 541-02-6).

In some embodiments, the improvement in the solubility and crystallization characteristics of cannabinoids in silicones can be achieved by the addition of other volatile solvents in the form of alcohols (including low molecular weight alcohols). Improvements in the solubility and crystallization properties of cannabinoids in silicones can also be achieved by the addition of alkyl PEG/PPG ethers and/or fatty alcohols.

Alkyl polypropylene glycol/polyethylene glycol ether

www.cir-safety.org/sites/default/files/PEGPPG062013tent.pdfIn some embodiments, further improvement of the dissolution characteristics of cannabinoids (such as cannabidiol) in silicones may be achieved by the addition of alkyl polypropylene glycol/polyethylene glycol ether (alkyl PEG/PPG ethers). The nature of Alkyl PEG/PPG ethers and suitable Alkyl PEG/PPG ethers that can be Used in accordance with the present invention are discussed in the Cosmetic Ingredient Review (CIR) Expert Panel 2013 "Security Association of Alkyl PEG/PPG Ether as Used in Cosmetics" Report (www.cir-safety. org/sites/default/files/PEGPPG062013. pdf; access 21Dec 2016), the contents of which are incorporated herein.

The alkyl PEG/PPG ether also acts as a residual solvent to help keep the cannabinoids in a non-crystalline state after some or all of the siloxane and optional low molecular weight alcohol have evaporated.

Advantageously, in some embodiments, the composition further comprises one or more alkyl PEG/PPG ethers. Alkyl PEG/PPG ethers are the reaction products of alkyl alcohols with one or more equivalents of each of ethylene oxide and propylene oxide (forming polyethylene glycol (PEG) and polypropylene glycol (PPG) repeat units, respectively).

The inventors have found that the addition of alkyl PEG/PPG ethers (including the polypropylene glycol ether of stearyl alcohol and the polypropylene glycol ether of butanol) can improve the solubility of cannabinoids (such as cannabidiol) in silicone solvents. This ability to increase the concentration of cannabinoids in the initial composition and in the final composition on the skin after application and evaporation allows high residual concentrations of cannabinoids to be achieved on the skin. The alkyl PEG/PPG ethers provide a residual solvent that is able to retain the cannabinoids in solution at exceptionally high concentrations after the volatile solvent or solvent mixture has evaporated.

Advantageously, in some embodiments, the alkyl PEG/PPG ether is a liquid at ambient temperature. Preferably, the alkyl PEG/PPG ether is a liquid at about 30 ℃ or less or at about 25 ℃.

Advantageously, in some embodiments, the alkyl PEG/PPG ethers have a low volatility, such that less than 5% evaporates within 24 hours at skin temperature.

www.cir- safety.org/sites/default/files/PEGPPG062013tent.pdfAdvantageously, in some embodiments, the alkyl PEG/PPG ether has a PEG/PPG chain length of 10-50PG units and an ether component of 2-20 carbons, where the sum of the carbons of the PG units and the ether component is preferably 20-60. Various alkyl PEG/PPG ethers are discussed in the following documents: the content of the Cosmetic Ingredient Review (CIR) Expert Panel 2013, "Safety Association of Alkyl PEG/PPG Ether as Used in Cosmetics" Report (www.cir-Safety. org/sites/default/files/PEGPPG062013ten. pdf; access 21Dec 2016), the contents of which (including the listed Alkyl PEG/PPG ethers) are incorporated herein.

Advantageously, in some embodiments, the alkyl PEG/PPG ethers are selected from the group consisting of: a polyoxypropylene ether of stearyl alcohol or a polyoxypropylene ether of butyl alcohol, and combinations thereof.

In a specific embodiment, the alkyl PEG/PPG stearyl ether or butyl ether is selected from: polypropylene Glycol (PPG) stearyl ether and polypropylene glycol butyl ether, such as PPG-15 stearyl ether and PPG-40 butyl ether, and combinations thereof.

In particular embodiments, the relative amount of alkyl PEG/PPG ether is selected from; at least 1% w/w, at least 2% w/w, at least 3% w/w, at least 4% w/w, at least 5% w/w. In a specific embodiment, the alkyl PEG/PPG ether is present at a maximum concentration of 50% w/w. In a specific embodiment, the alkyl PEG/PPG ether is present at a maximum concentration of 80% w/w.

Preferably, the amount of alkyl PEG/PPG ether is sufficient to allow the cannabinoid to remain in a non-crystalline form on the skin after evaporation of a portion or all of the one or more volatile solvents.

Low molecular weight alcohols

Advantageously, in some embodiments, the topical composition further comprises a low molecular weight alcohol. The inventors have found that small amounts of low molecular weight alcohols can improve the solubility of cannabinoids (such as cannabidiol) in silicone solvents. This ability to increase the concentration of cannabinoids in the initial composition allows for a high residual concentration of cannabinoids on the skin after application. Preferably, the low molecular weight alcohol forms another volatile solvent in addition to the siloxane. Preferably, the low molecular weight alcohol has a volatility level about the same as isopropanol. The addition of another volatile solvent (such as a low molecular weight alcohol) can be of particular advantage if the concentration of cannabinoid in the initial composition is very high.

Advantageously, in some embodiments, the low molecular weight alcohol is a liquid at ambient temperature. Preferably, the low molecular weight alcohol is a liquid at a temperature of about 30 ℃ or less or at about 25 ℃. Preferably, the low molecular weight alcohol has a volatility level about the same as isopropanol.

advantageously, in some embodiments, the low molecular weight alcohol is selected from the group consisting of C2-6 alcohols and combinations thereof. Advantageously, in some embodiments, the low molecular weight alcohol is selected from the group consisting of C2-4 alcohols and combinations thereof.

In a specific embodiment, the low molecular weight alcohol is selected from the group consisting of: ethanol (or alcohols), n-propanol, isopropanol, butanol, and combinations thereof.

In particular embodiments, the relative amount of low molecular weight alcohol is selected from the group consisting of: at least 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w, 11% w/w, 12% w/w, 13% w/w, 14% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w. In a specific embodiment, the maximum concentration of low molecular weight alcohol is 50% w/w. In a specific embodiment, the maximum concentration of low molecular weight alcohol is 60% w/w, 70% w/w, 80% w/w. The amount of low molecular weight alcohol may be between 1% w/w and 50% w/w, 1% w/w and 40%, 1% w/w and 30% w/w, 1% w/w and 20% w/w, 1% w/w and 10% w/w.

Fatty alcohols

Advantageously, in some embodiments, the topical composition is further characterized in that the composition comprises a fatty alcohol. The purpose of the fatty alcohol is to act as a solvent for the cannabinoid after evaporation of the volatile components (such as the siloxane and optionally the low molecular weight alcohol). In a specific embodiment, the fatty alcohol is a C12-22 fatty alcohol. In a specific embodiment, the fatty alcohol is a C16-22 fatty alcohol. In particular embodiments, the fatty alcohol is selected from the group consisting of: oleyl alcohol, isostearyl alcohol, octyldodecanol, 2-hexyldecanol.

In particular embodiments, the relative amount of fatty alcohol is selected from the group consisting of: at least 2% w/w, at least 3% w/w, at least 4% w/w, at least 5% w/w. In a specific embodiment, the maximum concentration of fatty alcohol is 50% w/w. In a specific embodiment, the maximum concentration of fatty alcohol is 80% w/w.

Preferably, the amount of fatty alcohol is sufficient to retain the cannabinoid in a non-crystalline form on the skin after partial or complete evaporation of the more volatile solvent or solvents.

Cannabinoid

Preferably, the cannabinoid is cannabinol. Alternatively, a cannabinoid is any compound that interacts with a cannabinoid receptor. This may include a variety of cannabinoids, such as some tetrahydropyran analogs (e.g., Δ 9-tetrahydrocannabinol, Δ 8-tetrahydro-cannabinol, 6,6, 9-trimethyl-3-pentyl-6H-dibenzo [ b, d ] pyran-1-ol, 3- (1, 1-dimethylheptyl) -6,6a,7,8,10,10 a-hexahydro-1-hydroxy-6, 6-dimethyl-9H-dibenzo [ b, d ] pyran-9-one, (-) - (3S,4S) -7-hydroxy- Δ 6-tetrahydrocannabinol-1, 1-dimethylheptyl, (+) - (3S,4S) -7-hydroxy- Δ 6-tetrahydrocannabinol-1, 1-dimethylheptyl, 11-hydroxy- Δ 9-tetrahydrocannabinol, and Δ 8-tetrahydrocannabinol-11-oic acid)); some piperidine analogs (e.g., (-) - (6S,6aR,9R,10aR) -5,6,6a,7,8,9,10,10 a-octahydro-6-methyl-3- [ (R) -1-methyl-4-phenylbutoxy ] -1, 9-phenanthridine diol-1-acetate)); some aminoalkyl indole analogs (e.g., (R) - (+) - [2, 3-dihydro-5-methyl-3- (-4-morpholinylmethyl) -pyrrolo [1,2,3-de ] -1, 4-benzoxazin-6-yl ] -1-naphthyl-methanone); some ring-opened pyran analogs (e.g., 2- [ 3-methyl-6- (1-methylvinyl) -2-cyclohexen-1-yl ] -5-pentyl-1, 3-benzenediol and 4- (1, 1-dimethylheptyl) -2,3 '-hydroxy-6' alpha- (3-hydroxypropyl) -1',2',3',4',5',6' -hexahydrobiphenyl); cannabinol; cannabigerol (cannbigerol); tetrahydrocannabinol; cannabidivarin (cammabidvarin); cannabichromene; and include synthetic cannabinoids such as cannabilone (nabilone), rimonabant (rimonabant), JWH-018, JWH-073, CP-55940, dimethylheptylpyran (dimethylheptylpryan), HU-210, HU-331, SR144528, WIN 55,212-2, JWH-133, L-vandol (Levonardol), and AM-2201, as well as salts and analogues thereof.

In some embodiments, the concentration of cannabinoid in the topical composition of the invention may be selected from: at least 2% w/w, at least 3% w/w, at least 4% w/w, at least 5% w/w, at least 6% w/w, at least 7% w/w, at least 8% w/w, at least 9% w/w, at least 10% w/w, at least 11% w/w, at least 12% w/w, at least 13% w/w, at least 14% w/w, and at least 15% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition may be selected from: at least 20% w/w, at least 30% w/w at least 40% w/w, at least 50% w/w, at least 60% w/w, at least 65% w/w, at least 70% w/w, at least 80% w/w, at least 90% w/w, at least 95% w/w and at least 99% w/w. Such concentrations may be achieved after at least partial evaporation of the volatile siloxane and optionally the low molecular weight alcohol component.

In some embodiments, the concentration of cannabinoid in the topical composition may be in a range having a lower limit selected from 1% w/w, 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w, 11% w/w, 12% w/w, 13% w/w, 14% w/w and 15% w/w and an upper limit selected from 20% w/w, 30% w/w, 40% w/w, 50% w/w, 60% w/w, 65% w/w, 70% w/w, 80% w/w, 90% w/w, 95% w/w and 99% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 99% w/w, 3% w/w to 70% w/w, 4% w/w to 70% w/w, 5% w/w to 70% w/w, 6% w/w to 70% w/w, 7% w/w to 70% w/w, 8% w/w to 99% w/w, 9% w/w to 99% w/w, 10% w/w to 99% w/w, 11% w/w to 99% w/w, 12% w/w to 99% w/w, 13% w/w to 99% w/w, 14% w/w to 99% w/w, and 15% w/w to 99% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 95% w/w, 3% w/w to 95% w/w, 4% w/w to 95% w/w, 5% w/w to 95% w/w, 6% w/w to 95% w/w, 7% w/w to 95% w/w, 8% w/w to 95% w/w, 9% w/w to 95% w/w, 10% w/w to 95% w/w, 11% w/w to 95% w/w, 12% w/w to 95% w/w, 13% w/w to 95% w/w, 14% w/w to 95% w/w, and 15% w/w to 95% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 90% w/w, 3% w/w to 90% w/w, 4% w/w to 90% w/w, 5% w/w to 90% w/w, 6% w/w to 90% w/w, 7% w/w to 90% w/w, 8% w/w to 90% w/w, 9% w/w to 90% w/w, 10% w/w to 90% w/w, 11% w/w to 90% w/w, 12% w/w to 90% w/w, 13% w/w to 90% w/w, 14% w/w to 90% w/w, and 15% w/w to 90% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 80% w/w, 3% w/w to 80% w/w, 4% w/w to 80% w/w, 5% w/w to 80% w/w, 6% w/w to 80% w/w, 7% w/w to 80% w/w, 8% w/w to 80% w/w, 9% w/w to 80% w/w, 10% w/w to 80% w/w, 11% w/w to 80% w/w, 12% w/w to 80% w/w, 13% w/w to 80% w/w, 14% w/w to 80% w/w, and 15% w/w to 80% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 70% w/w, 3% w/w to 70% w/w, 4% w/w to 70% w/w, 5% w/w to 70% w/w, 6% w/w to 70% w/w, 7% w/w to 70% w/w, 8% w/w to 70% w/w, 9% w/w to 70% w/w, 10% w/w to 70% w/w, 11% w/w to 70% w/w, 12% w/w to 70% w/w, 13% w/w to 70% w/w, 14% w/w to 70% w/w, and 15% w/w to 70% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 65% w/w, 3% w/w to 65% w/w, 4% w/w to 65% w/w, 5% w/w to 65% w/w, 6% w/w to 65% w/w, 7% w/w to 65% w/w, 8% w/w to 65% w/w, 9% w/w to 65% w/w, 10% w/w to 65% w/w, 11% w/w to 65% w/w, 12% w/w to 65% w/w, 13% w/w to 65% w/w, 14% w/w to 65% w/w, and 15% w/w to 65% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 60% w/w, 3% w/w to 60% w/w, 4% w/w to 60% w/w, 5% w/w to 60% w/w, 6% w/w to 60% w/w, 7% w/w to 60% w/w, 8% w/w to 60% w/w, 9% w/w to 60% w/w, 10% w/w to 60% w/w, 11% w/w to 60% w/w, 12% w/w to 60% w/w, 13% w/w to 60% w/w, 14% w/w to 60% w/w, and 15% w/w to 60% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 50% w/w, 3% w/w to 50% w/w, 4% w/w to 50% w/w, 5% w/w to 50% w/w, 6% w/w to 50% w/w, 7% w/w to 50% w/w, 8% w/w to 50% w/w, 9% w/w to 50% w/w, 10% w/w to 50% w/w, 11% w/w to 50% w/w, 12% w/w to 50% w/w, 13% w/w to 50% w/w, 14% w/w to 50% w/w, and 15% w/w to 50% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 40% w/w, 3% w/w to 40% w/w, 4% w/w to 40% w/w, 5% w/w to 40% w/w, 6% w/w to 40% w/w, 7% w/w to 40% w/w, 8% w/w to 40% w/w, 9% w/w to 40% w/w, 10% w/w to 40% w/w, 11% w/w to 40% w/w, 12% w/w to 40% w/w, 13% w/w to 40% w/w, 14% w/w to 40% w/w, and 15% w/w to 40% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 30% w/w, 3% w/w to 30% w/w, 4% w/w to 30% w/w, 5% w/w to 30% w/w, 6% w/w to 30% w/w, 7% w/w to 30% w/w, 8% w/w to 30% w/w, 9% w/w to 30% w/w, 10% w/w to 30% w/w, 11% w/w to 30% w/w, 12% w/w to 30% w/w, 13% w/w to 30% w/w, 14% w/w to 30% w/w, and 15% w/w to 30% w/w.

In some embodiments, the concentration of cannabinoid in the topical composition can be in a range selected from the group consisting of: 1% w/w, 2% w/w to 20% w/w, 3% w/w to 20% w/w, 4% w/w to 20% w/w, 5% w/w to 20% w/w, 6% w/w to 20% w/w, 7% w/w to 20% w/w, 8% w/w to 20% w/w, 9% w/w to 20% w/w, 10% w/w to 20% w/w, 11% w/w to 20% w/w, 12% w/w to 20% w/w, 13% w/w to 20% w/w, 14% w/w to 20% w/w, and 15% w/w to 20% w/w.

Other drugs

Cannabinoids may be added to compositions having other active ingredients that improve the appearance and/or hydration of the skin.

In addition, the compositions of the present invention may be used in combination with other topically applied analgesics and/or systemically available agents for the treatment of inflammatory skin conditions.

Examples of such analgesics include, but are not limited to: morphine, ciclovir, piperidine, piperazine, pyrrolidine, morphinan, pethidine, teflonica (trifluodom), phenylacetamide, diacylacetamide, benzomorphan, alkaloid, peptide, phenanthrene (phenantrene) and pharmaceutically acceptable salts, prodrugs or derivatives thereof. Specific examples of compounds suitable for use in the present invention include, but are not limited to: morphine, heroin, hydromorphone, oxymorphone, levorphanol, methadone, meperidine, fentanyl, codeine, hydrocodone, oxycodone, dextropropoxyphene, buprenorphine, butorphanol, pentazocine, and nalbuphine. As used herein in the context of opioids, "pharmaceutically acceptable salts, prodrugs and derivatives thereof" refer to derivatives of opioid analgesic compounds that are modified, for example, by making acid or base salts thereof or by modifying functional groups present on the compound, in the following manner: such that the modification dissociates in a conventional manner or in vivo to yield the parent compound having analgesic activity. Examples include, but are not limited to, mineral or organic salts of acidic residues, such as amine, alkali metal or organic salts of acidic residues, e.g., carboxylic acids, acetate, formate, sulfate, tartrate and benzoate derivatives, and the like. Suitable opioid analgesics include those specifically mentioned above, which are also described in the following references: goodman and Gilman, supra, Chapter 28, page 521-.

Examples of systemically-available drugs for use in combination with the compositions of the present invention for the treatment of inflammatory skin conditions include, but are not limited to: retinoids such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid and retinol; salicylic acid; resorcinol; sulfacetamide; urea; imidazoles such as ketoconazole and neoconazole; essential oil; alpha-bisabolol; dipotassium glycyrrhizinate; camphor; beta-glucan; allantoin; camomile leaves; flavonoids, such as soy isoflavones; sawing palm; chelating agents such as EDTA; lipase inhibitors such as silver and copper ions; hydrolyzing the vegetable protein; inorganic ions such as chloride, iodide, fluoride and their non-ionic derivatives chloride, iodide, fluoride; synthetic and natural phospholipids; steroidal anti-inflammatory drugs such as hydrocortisone, hydroxytetralone, alpha-methyl dexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoximelasone, deoxycorticosterone acetate, dexamethasone, dichloropine, diflorasone diacetate, diflucortolone valerate, fluadronolone (fluadrenone), flurandrenolone ketal (flularolone acetate), fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinolone butylester, fluocortolone, fluprednide acetate (fluprednylidene), fludrolone acetonide, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, clobetasone, cortisone, cortolone, flutolone, fludrocortisone, diflucortolone diacetate, fludarcinolone acetonide, triamcinolone chloride, triamcinolone acetonide, triamcinolone aceton, Fluocinolone acetonide, flunisolide, fluoromethalone, fluperlone, flupredlone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortisone, methylprednisolone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, fluticasone monopropionate, fluticasone furoate, mometasone furoate, budesonide, ciclesonide, and salts or prodrugs thereof; non-steroidal anti-inflammatory drugs (NSAIDs), such as COX inhibitors, LOX inhibitors, p38 kinase inhibitors (including ibuprofen, naproxen, salicylic acid, ketoprofen, hetprofen, and diclofenac); analgesic active agents for the treatment of pain and itch, such as methyl salicylate, menthol, triethanolamine salicylate, capsaicin, lidocaine, benzocaine, pramoxine hydrochloride, and hydrocortisone; antibiotics, such as mupirocin, neomycin sulfate bacitracin, polymyxin B, 1-ofloxacin, clindamycin phosphate, gentamicin sulfate, metronidazole, hexylresorcinol, benzethonium chloride, phenol, quaternary ammonium compounds, tea tree oil, tetracycline, clindamycin, erythromycin; immunosuppressive agents, such as cyclosporine and cytokine synthesis inhibitors, tetracycline, minocycline, and doxycycline, or any combination thereof.

In addition, other active agents may be included in the compositions of the present invention, for example, locally effective analgesics such as celecoxib, ***e, lidocaine, benzocaine and the like, which if less effective in the long term will also provide at least a more immediate level of pain relief until the analgesic becomes fully effective.

Other drugs may also be administered (preferably topically) to potentiate the effects of the topically administered cannabidiol. For example, dextromethorphan, a non-addictive opioid, may be co-administered (preferably topically, but parenteral administration is also effective) to enhance the efficacy of the topically administered drug. Without wishing to be bound by theory, it is believed that dextromethorphan was not previously recognized to have analgesic properties in peripheral nerves. Suitable concentrations of dextromethorphan can be routinely determined by one of skill in the art and include normal therapeutic amounts or less for parenteral administration for routine purposes (e.g., as an antitussive), as well as routinely determinable amounts for topical administration; for example, 1g of dextromethorphan can be added to the compositions disclosed herein to provide additional treatment for inflammatory skin conditions.

In one embodiment, the pharmaceutical composition of the invention further comprises one or more of the following drugs for treating inflammatory skin disorders: retinoids such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid and retinol; salicylic acid; resorcinol; sulfacetamide; urea; imidazoles such as ketoconazole and neoconazole; essential oil; alpha-bisabolol; dipotassium glycyrrhizinate; camphor; beta-glucan; allantoin; camomile leaves; flavonoids, such as soy isoflavones; sawing palm; chelating agents such as EDTA; lipase inhibitors such as silver and copper ions; hydrolyzing the vegetable protein; inorganic ions such as chloride, iodide and fluoride and their non-ionic derivatives chloride, iodide, fluoride; synthetic and natural phospholipids; steroidal anti-inflammatory drugs such as hydrocortisone, hydroxytryptasone, alpha-methyl dexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoximelasone, deoxycorticosterone acetate, dexamethasone, dichloropine, diflorasone diacetate, diflucortolone valerate, fluohydridol, fluohydridocosan ketal, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, fluoxetine butylester, fluocortolone, fluprednide (fluprednylene), fluocinolone acetonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortolone, fluocinonide, fludrocortisone, difluorodesonide, fluocinolone acetonide, medroxcinolone, amciferolone, amcinolone acetonide, fluocinolone acetonide, clobetamethasone acetate, fluocinolone chloride, fluocinolone acetonide, flunisolide, fluoromethalone, fluperlone, flupredlone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortisone hydrogen, methylprednisolone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, fluticasone monopropionate, fluticasone furoate, mometasone furoate, budesonide, ciclesonide or salts or prodrugs thereof; non-steroidal anti-inflammatory drugs (NSAIDs), such as COX inhibitors, LOX inhibitors, p38 kinase inhibitors (including ibuprofen, naproxen, salicylic acid, ketoprofen, hetprofen, and diclofenac); analgesic active agents for the treatment of pain and itch, such as methyl salicylate, menthol, triethanolamine salicylate, capsaicin, lidocaine, benzocaine, pramoxine hydrochloride, and hydrocortisone; antibiotics such as mupirocin, neomycin sulfate bacitracin, polymyxin B, 1-ofloxacin, clindamycin phosphate, gentamicin sulfate, metronidazole, hexylresorcinol, benzethonium chloride, phenol, quaternary ammonium compounds, tea tree oil, tetracycline, clindamycin, erythromycin; immunosuppressive agents, such as cyclosporine and cytokine synthesis inhibitors, tetracycline, minocycline, and doxycycline, or any combination thereof.

Treatment and therapy of inflammatory skin conditions

In some embodiments, topical application of cannabinoids (e.g., cannabidiol) by way of the compositions of the present invention is expected to reduce the incidence and/or severity of inflammatory skin conditions. Therapeutic effects of the present invention include, but are not limited to: reducing redness, itching, pain or irritation, reducing pimples, blisters or pustules, reducing infection, reducing dryness, cracking or wrinkling, reducing swelling, cracking, oozing, crusting and desquamation, and/or an overall reduction in inflammation.

In some embodiments, topical application of cannabinoids (such as cannabidiol) by way of the compositions of the present invention is expected to ameliorate the symptoms of inflammatory skin conditions.

The term "improve" means that the present invention alters the appearance, form, characteristics and/or physical attributes of the tissue to which it is provided, applied or applied. Changes in form can be evidenced by any one or combination of the following: improving the appearance of skin; reducing skin inflammation, preventing inflammation or blisters, reducing blister spreading, reducing skin ulceration, reducing redness, reducing scarring, reducing lesions, healing blisters, reducing skin thickening, closing wounds and lesions, alleviating symptoms (including but not limited to pain, inflammation, itch, miliaria or other symptoms associated with inflammatory conditions, etc.).

It is expected that the main advantage of the present invention is the improvement of skin condition without the common side effects of conventional treatments. The potential of the present invention is of general interest and the topical application of cannabinoids has shown promise as a new approach to the treatment of exciting inflammatory skin conditions.

Treatment of inflammatory skin conditions according to embodiments of the present invention is expected to promote skin healing. For example, when the present invention is used to treat inflammatory skin conditions, it is expected that the swollen, cracked, or desquamated skin being treated will heal more quickly and/or more completely than when untreated.

When administered according to the present invention, it is contemplated that the treatment results in one or more therapeutic effects. The therapeutic effect of the affected area includes, but is not limited to: reducing redness, itching, pain or irritation, reducing papules, pimples, blisters or pustules, reducing infection, reducing dryness, cracking and wrinkling, reducing breakdown and loss of collagen and elastin in the skin, reducing swelling, cracking, exudation, crusting and desquamation, and/or an overall reduction in inflammation. It is contemplated that one or more of these therapeutic effects will be observed when treatment according to the present invention is administered to any suitable condition.

Unless the context requires otherwise, the phrase "inflammatory skin conditions" encompasses skin diseases and skin disorders and denotes conditions that are accompanied by a series of clinical signs and symptoms (such as itching, edema, and abrasion) and are triggered by a variety of irritants that cause a series of skin inflammatory responses. In some aspects, the inflammatory skin condition may be characterized by ulceration, inflammation, or blistering of the skin. In some embodiments, the inflammatory skin disorder can be characterized by a genetic component, an autoimmune component, a circulatory component, or a combination thereof. In the present invention, the term "inflammatory skin condition" is used interchangeably with "inflammatory skin disease".

In one embodiment, the "inflammatory skin condition" is selected from the following: rosacea, dermatitis (including radiodermatitis, atopic dermatitis, allergic and irritant contact dermatitis, seborrheic dermatitis, stasis dermatitis (statis dermatitis), erythema (sunburn), actinic keratitis (including actinic cheilitis), scars, hyperpigmentation, lupus erythematosus, pemphigoid, urticaria, eczema, lichen planus, acrodermatitis, dermatomyositis, inflammatory skin conditions resulting from skin infections [ including tinea pedis and tinea versicolor, shingles, oral ulcers (including stomatitis, aphtha), diaper rash, ants, impetigo, cutaneous candidiasis ] or inflammation resulting from stings and stings (including bee stings, bites, wasp sting bites, tick bites, flea bites, scabies).

In one embodiment, the "inflammatory skin condition" is selected from the following: porphyria cutanea dermalis, scleroderma (scleroderma), epidermolysis bullosa (epidermolysis bullosa), decubitus ulcers, pressure ulcers, diabetic ulcers, venous stasis ulcers, sickle cell ulcers, burns-induced ulcers, urticaria, herpetiformis dermatitis, arthritis, gout, alopecia, cancer, miliaria, skin infections, post-operative care of incisions, post-operative skin care of any type of plastic surgery, skin care after radiation therapy, care of dry, cracked or aged skin and skin texture, and other conditions affecting the skin and having an inflammatory component, symptoms thereof, or combinations thereof. The symptoms treated may include pain, inflammation, redness, itching, scarring, skin thickening, miliaria, or combinations thereof.

In one embodiment, the "inflammatory skin condition" is selected from the following: skin pain, skin inflammation, bacterial skin infection, fungal skin infection, viral skin infection, parasitic skin infection, skin neoplasm, pruritus, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, skin abscess, necrotic subcutaneous tissue infection, scalded skin syndrome, folliculitis, furuncle, hidradenitis suppurativa, carbuncle, paronychia infection, rash, erythrasma, impetigo, acne, saccharogenic skin infection, wart, molluscum contagiosum, skin trauma or injury, post-operative or post-surgical skin conditions, pediculosis, prunus, pityriasis rosea, pityriasis rubra pilaris, edema, erythema multiforme, erythema nodosum, granuloma annulare, cutaneous necrotic slack, sunburn, photosensitivity, pemphigus, pemphigoid, dermatitis herpetiformis, keratosis pilaris, callosity, corn, ichthyosis, skin ulcers, avascular necrosis, miliaria, hyperhidrosis, moles, kaposi's sarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, poison-eared skin rash (poison ivy), poison oak dermatitis (poison oak), purpura, candidiasis (moniliasis), candidiasis (candidiasis), alopecia, androgenetic alopecia, behcet's syndrome, cholesteatoma, decamethylene, ectodermal dysplasia, gustatory sweating, menbal syndrome, telangiectasis, familial benign chronic pemphigus (Hailey-Hailey disease), chemical or thermal skin burn, scleroderma, skin aging, wrinkles, sunburn, necrotizing fasciitis, necrotizing myositis, gangrene, scars, and vitiligo.

In particular embodiments, unless otherwise required, the phrase "inflammatory skin condition" means rosacea, radiodermatitis, erythema (sunburn), atopic dermatitis, allergic and irritant contact dermatitis, actinic keratitis, acne, scars, hyperpigmentation, as well as seborrheic dermatitis or eczema, or other eczema, or and alopecia areata.

The present invention also provides a method of treating or preventing an inflammatory skin condition in a patient in need of such treatment, the method comprising topically administering a prophylactically or therapeutically effective amount of a topical composition as described herein.

The present invention also provides the use of a cannabinoid and a siloxane for the preparation of a topical composition as described herein for the prevention or treatment of an inflammatory skin disorder in a patient in need thereof.

The present invention also provides the use of a topical composition as described herein for the prevention or treatment of an inflammatory skin condition.

in one aspect, the invention relates to methods of treating inflammatory skin conditions using topical cannabinoids, including cannabidiol. According to some embodiments, the topical composition of the present invention comprising a cannabinoid, such as cannabidiol, is preferably applied topically to an area affected by an inflammatory skin condition. Preferably, according to some embodiments, the use of cannabinoids results in the following effects: reducing redness, itching, pain or irritation, reducing pimples, blisters or pustules, reducing infection, reducing redness, cracking and wrinkling, reducing the destruction and loss of collagen and elastin in the skin, reducing swelling, cracking, exudation, crusting and desquamation, and/or an overall reduction in inflammation.

Pharmaceutical composition

Some embodiments of the present invention include any topically acceptable non-transdermally effective carrier medium. Preferred topically acceptable media include, but are not limited to, gels, ointments, and liquids. Administration of the preferred embodiment is carried out in a manner most appropriate to the selected topically acceptable form. For example, gels, lotions, creams and ointments are preferably applied by spreading.

The composition may or may not contain water. Preferably, the composition is free of water, i.e., it is non-aqueous.

Dilution of cannabinoids in topical compositions may also be an important consideration. The concentration of cannabinoid in the composition should be sufficiently high so that the patient does not have to spend too long waiting for the composition to dry. On the other hand, the concentration of cannabinoids should be sufficiently dilute to enable the patient to achieve effective coverage of the affected area. Additionally, the composition may comprise a component that polymerizes in response to exposure to air or ultraviolet radiation.

The amount of composition applied will also vary depending on the choice of silicone, low molecular weight alcohol, fatty alcohol and/or alkyl PEG/PPG ether. For example, when cannabinoids (such as cannabidiol) are administered by spraying a pharmaceutical solution, the total volume of a single administration may be as low as 0.1 ml. When cannabinoids (such as cannabidiol) are administered as a gel or cream, the total volume may be up to 3 ml. Conversely, if the inflammatory skin condition comprises interspersed lesions, the volume applied to each lesion may be smaller. The choice of the selected carrier and its mode of application is preferably selected in consideration of patient needs and physician preference.

In a preferred embodiment, the composition comprises a gel, which is preferably applied by spreading the gel onto the affected area. In other preferred embodiments, the composition comprises a liquid, which may be applied by spraying or otherwise applying the liquid to the affected area.

The amounts of cannabinoids (such as cannabidiol) used herein in the examples are illustrative only and it will be appreciated that lesser and greater amounts may be used which may be routinely optimised by the skilled person. It is generally preferred to apply an amount therapeutically equivalent to 0.1 to 200mg of a cannabinoid, such as cannabidiol, to an area of 5-100cm 2. However, the amount of cannabinoid used in the topical application of the invention is typically a fraction of the conventional dose used in other therapeutic methods using these agents (e.g., epilepsy).

According to some embodiments, the composition is applied to the affected area periodically until remission is obtained. In a preferred embodiment, the composition is administered to the skin of a patient in need of such treatment using a dosing regimen selected from the group consisting of: hourly, every 2 hours, every 3 hours, once daily, twice daily, three times daily, four times daily, five times daily, once weekly, twice weekly, once biweekly and monthly. However, other administration schedules may also be used in accordance with the present invention.

In some embodiments, the compositions of the present invention may be provided in a form selected from, but not limited to, the group consisting of: liquid or gel, leave-on preparation, and cleaning preparation.

In one embodiment, the composition comprises impurities, wherein the amount of impurities, as a percentage of the total weight of the composition, is selected from the group consisting of: less than 20% impurities (based on the total weight of the composition); less than 15% impurities; less than 10% impurities; less than 8% impurities; less than 5% impurities; less than 4% impurities; less than 3% impurities; less than 2% impurities; less than 1% impurities: less than 0.5% impurities; less than 0.1% impurities. In one embodiment, the composition comprises microbial impurities or secondary metabolites, wherein the amount of microbial impurities, as a percentage of the total weight of the composition, is selected from the group consisting of: less than 5%; less than 4%; less than 3%; less than 2%; less than 1% s; less than 0.5%; less than 0.1%; less than 0.01%; less than 0.001%. In one embodiment, the composition is sterile and is stored in a sealed sterile container. In one embodiment, the composition is free of detectable levels of microbial contamination.

The foregoing embodiments are illustrative of applications in which the methods of using cannabinoids (e.g., cannabidiol) to treat inflammatory skin conditions according to the present invention may be used. One of ordinary skill in the art will readily appreciate that other modes of cannabinoid administration for the treatment of inflammatory skin disorders are also suitable and are in accordance with the present invention.

Definition of

The following definitions in this specification are intended to be interpreted in an illustrative and non-limiting sense. They are, therefore, to be construed as inclusive and not limited to the particular definitions set forth.

Antagonists: compounds that do not enhance or stimulate the functional properties of the receptor, but block these effects by agonists.

Bandage: a dressing for covering the affected area.

Cannabinoid: as used herein, it is intended to encompass compounds that interact with cannabinoid receptors and a variety of cannabinoid mimetics, such as some tetrahydropyran analogs (e.g., Δ 9-tetrahydrocannabinol, Δ 8-tetrahydrocannabinol, 6,6, 9-trimethyl-3-pentyl-6H-dibenzo [ b, d ] pyran-1-ol, 3- (1, 1-dimethylheptyl) -6,6a,7,8,10,10 a-hexahydro-1-hydroxy-6, 6-dimethyl-9H-dibenzo [ b, d ] pyran-9-one, (-) - (3S,4S) -7-hydroxy- Δ 6-tetrahydrocannabinol-1, 1-dimethylheptyl, (+) - (3S,4S) -7-hydroxy- Δ 6-tetrahydrocannabinol-1, 1-dimethylheptyl, 11-hydroxy- Δ 9-tetrahydrocannabinol, and Δ 8-tetrahydrocannabinol-11-acid)); some piperidine analogs (e.g., (-) - (6S,6aR,9R,10aR) -5,6,6a,7,8,9,10,10 a-octahydro-6-methyl-3- [ (R) -1-methyl-4-phenylbutoxy ] -1, 9-phenanthridine diol-1-acetate)); some aminoalkyl indole analogs (e.g., (R) - (+) - [2, 3-dihydro-5-methyl-3- (-4-morpholinylmethyl) -pyrrolo [1,2,3-de ] -1, 4-benzoxazin-6-yl ] -1-naphthyl-methanone); and some ring-opened pyran analogs (e.g., 2- [ 3-methyl-6- (1-methylvinyl) -2-cyclohexen-1-yl ] -5-pentyl-1, 3-benzenediol and 4- (1, 1-dimethylheptyl) -2,3 '-hydroxy-6' alpha- (3-hydroxypropyl) -1',2',3',4',5',6' -hexahydrobiphenyl). Other examples of "cannabinoids" include those compounds described in the references cited below.

Cannabidiol: as used herein, it means 2- [ 3-methyl-6- (1-methylvinyl) -2-cyclohexen-1-yl ] -5-pentyl-1, 3-benzenediol.

the synthesis of 2- [ 3-methyl-6- (1-methylvinyl) -2-cyclohexen-1-yl ] -5-pentyl-1, 3-benzenediol is described in the following: for example, Petilka et al, helv.chim.acta,52:1102(1969) and Mechoulam et al, j.am.chem.soc.,87:3273(1965), which are incorporated herein by reference.

Central nervous system: the brain and spinal cord.

Of the dermis: associated with the dermis.

Compound dressing: designed to provide warmth and protection to absorb large quantities of liquid that may be expelled from an incision or wound; it consists of a nonwoven fabric cover enclosing a fibrous product with or without an absorbent towel.

Inflammation: immune system mediated processes characterized by localized sites of redness, heat, swelling and pain.

Mammals: a vertebrate having hair, three middle ear bones, and a mammary gland. Mammals include humans.

Skin: outer coverings for animals. Mammalian skin comprises three layers: (i) the epidermal layer, which is composed mainly of keratinocytes, as well as a small number of melanocytes and lagrangian cells (antigen presenting cells); (ii) the dermis layer, which includes nerve endings, sweat and oil (sebum) glands, hair follicles and blood vessels, and which is composed mainly of fibroblasts; and (iii) deeper subcutaneous tissue layers of subcutaneous fat and connective tissue. The epidermis itself is composed of two layers, the outer stratum corneum and the inner epidermal basal layer, sometimes referred to as the basement membrane. The role of the stratum corneum is to form a barrier that protects the underlying tissue from infection, dehydration, chemicals and mechanical stress.

A therapeutically effective amount of: the amount necessary to bring about a therapeutic effect.

Transdermal: through the dermis.

Summary of the invention

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Other definitions for selected terms used herein may be found in the detailed description of the invention and throughout. Unless defined otherwise, all other scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Those skilled in the art will appreciate that variations and modifications may be made to the invention described herein, in addition to those specifically described. The present invention includes all such variations and modifications. The invention also includes all of the steps, features, formulations and compounds referred to or indicated in the specification, individually or collectively, and any and all combinations or any two or more of the steps or features thereof.

Each document, reference, patent application, or patent cited herein is expressly incorporated by reference in its entirety, which means that the reader should read and consider it as part of this document. The documents, references, patent applications or patents cited herein are not repeated herein for the sake of brevity only.

Manufacturer's instructions, descriptions, product specifications, and product pages for any of the products mentioned herein or described in any of the documents incorporated by reference herein are incorporated by reference herein and may be used in the practice of the invention.

The invention described herein may include one or more ranges of values (e.g., concentrations). A range of values is to be understood as encompassing all values within the range, including the values defining the range as well as values adjacent to the range that result in the same or substantially the same result as the value immediately adjacent to the value that bounds the range.

The following examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. These examples are for the purpose of illustrating the invention only. They are not to be construed as limitations on the broad overview, disclosure or description of the invention as described above. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. In the foregoing and following examples, all temperatures are shown uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.

Examples

Additional features of the invention will be described more fully in the following description of several non-limiting embodiments of the invention. This description is included solely for the purpose of illustrating the invention. It is not to be interpreted as limiting the broad overview, disclosure or description of the invention set forth above.