WO2018148787A1 - Formulations de cannabinoïdes pour le traitement du psoriasis - Google Patents

Formulations de cannabinoïdes pour le traitement du psoriasis Download PDF

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Publication number
WO2018148787A1
WO2018148787A1 PCT/AU2018/050047 AU2018050047W WO2018148787A1 WO 2018148787 A1 WO2018148787 A1 WO 2018148787A1 AU 2018050047 W AU2018050047 W AU 2018050047W WO 2018148787 A1 WO2018148787 A1 WO 2018148787A1
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WO
WIPO (PCT)
Prior art keywords
cbd
pharmaceutical composition
alcohol
skin
cannabinoid
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PCT/AU2018/050047
Other languages
English (en)
Inventor
Eugene Cooper
Matthew CALLAHAN
Original Assignee
Botanix Pharmaceuticals Ltd
Botanix Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2017900494A external-priority patent/AU2017900494A0/en
Application filed by Botanix Pharmaceuticals Ltd, Botanix Pharmaceuticals, Inc. filed Critical Botanix Pharmaceuticals Ltd
Priority to JP2019544844A priority Critical patent/JP2020508991A/ja
Priority to EP18754611.4A priority patent/EP3582769A4/fr
Priority to AU2018221882A priority patent/AU2018221882A1/en
Priority to BR112019017011A priority patent/BR112019017011A2/pt
Priority to US16/486,297 priority patent/US20220313621A1/en
Priority to CN201880023266.4A priority patent/CN110520123A/zh
Priority to CA3053505A priority patent/CA3053505A1/fr
Publication of WO2018148787A1 publication Critical patent/WO2018148787A1/fr
Priority to IL26873319A priority patent/IL268733A/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • the present invention relates to a pharmaceutical composition for the delivery of a cannabinoid, such as cannabidiol.
  • the pharmaceutical composition of the present invention is particularly suited for the treatment of psoriasis.
  • Most mammalian skin comprises three layers: (i) an epidermis layer, which is predominantly composed of keratinocytes and a small number of melanocytes and Langerhans cells (antigen presenting cells); (ii) a dermis layer, which contains nerve endings, sweat glands and oil (sebaceous) glands, hair follicles, and blood vessels and which is primarily composed of fibroblasts; and (iii) a hypodermis layer of deeper subcutaneous fat and connective tissue.
  • the epidermis itself is made up of two layers, the outer stratum corneum and the inner epidermal basal layer.
  • Psoriasis is a long-lasting autoimmune disease which is characterized by patches of abnormal skin. These skin patches are typically red, itchy, and scaly. They may vary in severity from small and localized to complete body coverage. Damage to the skin can trigger psoriatic skin changes at that spot, which is known as Koebner phenomenon.
  • Plaque psoriasis also known as psoriasis vulgaris, makes up about 90% of cases. It typically presents with red patches with white scales on top. Areas of the body most commonly affected are the back of the forearms, shins, around the navel, and the scalp. Guttate psoriasis has drop-shaped lesions. Pustular psoriasis presents with small non-infectious pus- filled blisters. Inverse psoriasis forms red patches in skin folds.
  • Erythrodermic psoriasis occurs when the rash becomes very widespread, and can develop from any of the other types. Fingernails and toenails are affected in most people at some point in time. This may include pits in the nails or changes in nail colour.
  • Psoriasis is generally thought to be a genetic disease which is triggered by environmental factors. Symptoms often worsen during winter and with certain medications such as beta blockers or NSAIDs, and infections and psychological stress may also play a role. The underlying mechanism involves the immune system reacting to skin cells.
  • Pustular psoriasis appears as raised bumps filled with non-infectious pus (pustules). The skin under and surrounding the pustule is red and tender. Pustular psoriasis can be localized, commonly to the hands and feet (palmoplantar pustulosis), or generalized with widespread patches occurring randomly on any part of the body.
  • Acrodermatitis continua is a form of localized psoriasis limited to the fingers and toes that may spread to the hands and feet.
  • Pustulosis palmaris et plantaris is another form of localized pustular psoriasis similar to acrodermatitis continua with pustules erupting from red, tender, scaly skin found on the palms of the hands and the soles of the feet.
  • Generalized pustular psoriasis (pustular psoriasis of von Zumbusch), also known as impetigo herpetiformis during pregnancy, is a rare and severe form of psoriasis that may require hospitalization.
  • the development of generalized pustular psoriasis is often caused by an infection, abrupt withdrawal of topical corticosteroid treatment, pregnancy, hypocalcemia, medications, or following an irritating topical treatment for plaque psoriasis.
  • This form of psoriasis is characterized by an acute onset of numerous pustules on top of tender red skin. This skin eruption is often accompanied by a fever, muscle aches, nausea, and an elevated white blood cell count.
  • Annular pustular psoriasis (APP), a rare form of generalized pustular psoriasis, is the most common type seen during childhood. APP tends to occur in women more frequently than in men, and is usually less severe than other forms of generalized pustular psoriasis such as impetigo herpetiformis. This form of psoriasis is characterized by ring-shaped plaques with pustules around the edges and yellow crusting. APP most often affects the torso, neck, arms, and legs.
  • Additional types of psoriasis affecting the skin include inverse psoriasis, guttate psoriasis, oral psoriasis, and seborrheic-like psoriasis.
  • Inverse psoriasis also known as flexural psoriasis appears as smooth, inflamed patches of skin.
  • the patches frequently affect skin folds, particularly around the genitals (between the thigh and groin), the armpits, in the skin folds of an overweight abdomen (known as panniculus), between the buttocks in the intergluteal cleft, and under the breasts in the inframammary fold. Heat, trauma, and infection are thought to play a role in the development of this atypical form of psoriasis.
  • Napkin psoriasis is a subtype of psoriasis common in infants characterized by red papules with silver scale in the diaper area that may extend to the torso or limbs. Napkin psoriasis is often misdiagnosed as napkin dermatitis (diaper rash).
  • Guttate psoriasis is characterized by numerous small, scaly, red or pink, droplet-like lesions (papules). These numerous spots of psoriasis appear over large areas of the body, primarily the trunk, but also the limbs and scalp. Guttate psoriasis is often triggered by a streptococcal infection, typically streptococcal pharyngitis.
  • Oral psoriasis is very rare, in contrast to lichen planus, another common papulosquamous disorder that commonly involves both the skin and mouth.
  • psoriasis involves the oral mucosa (the lining of the mouth), it may be asymptomatic, but it may appear as white or grey-yellow plaques.
  • Fissured tongue is the most common finding in those with oral psoriasis and has been reported to occur in 6.5-20% of people with psoriasis affecting the skin.
  • Seborrheic-like psoriasis is a common form of psoriasis with clinical aspects of psoriasis and seborrheic dermatitis, and may be difficult to distinguish from the latter.
  • This form of psoriasis typically manifests as red plaques with greasy scales in areas of higher sebum production such as the scalp, forehead, skin folds next to the nose, skin surrounding the mouth, skin on the chest above the sternum, and in skin folds.
  • the present invention seeks to provide a composition and method to reduce the effects of psoriasis, or to provide the consumer with a useful or commercial choice.
  • a pharmaceutical composition comprising a solution of a cannabinoid and a siloxane wherein the cannabinoid is dissolved in the composition.
  • the cannabinoid is cannabidiol.
  • 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 most of the cannabinoids remain in that layer. Preferably some further penetrates to the dermis and hypodermal layer, to be absorbed systemically.
  • the skin to which the composition is delivered is preferably mammalian skin, more preferably human mammalian skin.
  • compositions of the invention may further contain (i) further 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 called the residual solvent as it may remain on the skin after evaporation of the siloxane (and the further volatile solvent if it is present)
  • additional volatile and residual solvent excipients may further enhance the capacity of the compositions of the invention to produce concentrated cannabinoid solutions in situ, and/or facilitate the delivery of the cannabinoid to the epidermis and the dermis for the treatment of psoriasis.
  • a method for treating or preventing psoriasis in a patient in need of such treatment comprising topically administering a prophylactically or therapeutically effective amount of pharmaceutical composition according to the invention.
  • the pharmaceutical composition is a topical composition.
  • Figure 1 Graphical representation of the data shown in Table 9 for delivered CBD. Data is shown in ⁇ g/cm 2 . A Dixon's Qtest with 95% confidence was first run on the data to identify and remove outliers.
  • Figure 2 Graphical representation of the data shown in Table 9 for delivered CBD. Data is shown in ⁇ g/cm 2 . A Dixon's Qtest with 95% confidence was first run on the data to identify and remove outliers.
  • FIG. 3 Graphical representation of the data shown in Table 10 for delivered CBD. Data is shown in percent delivery. A Dixon's Qtest with 95% confidence was first run on the data sets to identify and remove outliers.
  • FIG. 4 Graphical representation of the data shown in Table 10 for delivered CBD. Data is shown in percent delivery. A Dixon's Qtest with 95% confidence was first run on the data sets to identify and remove outliers.
  • Figure 5 Graphical representation of the data shown in Table 1 1 for delivered CBD. Data is shown in percent delivery. A Dixon's Qtest with 95% confidence was first run on the data sets to identify and remove outliers.
  • Figure 6 Graphical representation of data shown in Table 12 for CBD delivered into the skin. Data is shown in ⁇ g/g tissue. A Dixon's Qtest with 95% confidence was first run on the data to identify and remove outliers.
  • ECS Endocannabinoid System
  • Cannabinoids Cannabidiol
  • Psoriasis The Endocannabinoid System
  • Modulating the activity of the ECS holds therapeutic potential for a multitude of diseases and pathological conditions affecting humans, ranging from inflammatory, neurodegenerative, gastrointestinal, liver, cardiovascular disorders and obesity, to ischemia/reperfusion injury, cancer and pain.
  • endocannabinoids The most extensively studied endocannabinoids are anandamide (N arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG). Multiple pathways are involved in synthesis and cellular uptake of these lipid mediators. The most common degradation pathways for AEA and 2-AG are the fatty acid amid hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzyme.
  • FAC fatty acid amid hydrolase
  • MAGL monoacylglycerol lipase
  • Endocannabinoids similar to A 9 -tetrahydrocannabinol (THC; the main active ingredient of the plant Cannabis sativa), predominantly exert their physiological effects via two main G-protein-coupled cannabinoid receptors; however, numerous additional signalling mechanisms and receptor systems (e.g.
  • transient receptor potential cation channel subfamily V, member 1 ; TRPV1
  • TRPV1 transient receptor potential cation channel, subfamily V, member 1 ; TRPV1
  • CB1 -mediated effects were described centrally and CB1 receptors were thought to be restricted to the central nervous system, whereas CB2 was first identified at the periphery in immune cells.
  • CBD may play a beneficial role in decreasing unwanted skin cell growth and skin inflammation associated with many human inflammatory skin diseases.
  • CBD may:
  • CBD endocannabinoid system
  • cannabinoids such as cannabidiol are poorly absorbed through membranes such as the skin. Therefore, the success of administering therapeutically effective quantities of a cannabinoid such as cannabidiol to a mammal in need thereof within a reasonable time frame and over a suitable surface area has been substantially limited.
  • the present invention is based on the surprising discovery that a cannabinoid, such as cannabidiol, can be dissolved in a siloxane to form a pharmaceutical composition. Further, that pharmaceutical composition may be topically applied, after which at least some the siloxane evaporates to concentrate the cannabinoid in situ, facilitating permeation to the therapeutically relevant regions of the skin (preferably the epidermis and dermal layer) for the treatment of psoriasis.
  • a cannabinoid such as cannabidiol
  • a pharmaceutical composition comprising a cannabinoid and a siloxane wherein the cannabinoid is dissolved in the composition.
  • the cannabinoid is cannabidiol.
  • the pharmaceutical composition is a topical pharmaceutical composition.
  • the siloxane forms a volatile solvent for the cannabinoid.
  • 'psoriasis' means one or more of: pustular psoriasis (including palmoplantar pustulosis, acrodermatitis continua, pustulosis palmaris et plantaris, pustular psoriasis of von Zumbusch, annular pustular psoriasis), inverse psoriasis, napkin psoriasis, guttate psoriasis, oral psoriasis, and seborrheic-like psoriasis.
  • pustular psoriasis including palmoplantar pustulosis, acrodermatitis continua, pustulosis palmaris et plantaris, pustular psoriasis of von Zumbusch, annular pustular psoriasis
  • inverse psoriasis napkin psoriasis
  • guttate psoriasis guttate ps
  • High concentrations of dissolved cannabinoids are expected to be advantageous in terms of enhancing the relevant extent of delivery into the skin, particularly the epidermis (including the epidermal basal layer), with some penetration into the dermis. It is thought that the high concentration of dissolved cannabinoids on the outer surface of the skin causes a concentration gradient that enhances penetration of the cannabinoid into the skin, particularly the epidermis and the dermis.
  • the cannabinoid such as cannabidiol
  • the cannabidiol would concentrate mainly in the epidermis, thus maximizing its local effect.
  • the localized effect increase the potential therapeutic benefit, it potentially lessens the frequency and severity of any potential side-effects associated with systemic cannabinoid administration, because the amount of active compound circulating in the patient is reduced.
  • 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 surprising discovery that cannabinoids can be topically administered as (i) concentrated solutions of cannabinoid in siloxane, or (ii) suspensions of crystalline cannabinoids in concentrated solutions of cannabinoid in siloxane.
  • the preferred cannabinoid is cannabinol.
  • the compositions of the present invention may form a highly concentrated, non-crystalline, thin layer of a cannabinoid on the skin surface, after partial or complete evaporation of the volatile siloxane, and without crystallization of the cannabinoid.
  • the volatile solvent siloxane By using the volatile solvent siloxane, one can achieve much higher, non-crystalline (i.e., in solution), concentrations of cannabinoids.
  • the cannabinoids can be dissolved in much higher concentrations of the volatile solvent siloxane than many other less volatile solvents, and then once applied to the skin and the volatile siloxane has evaporated, the cannabinoids remain on the skin in high concentrations.
  • the cannabinoids are preferably kept in a non-crystalline form on the skin after evaporation of the siloxane by the addition of a less volatile solvent than siloxane.
  • This less volatile solvent is called the residual solvent, as it preferably remains on the skin after evaporation of the volatile solvent (siloxane and optionally another volatile solvent such as a low molecular weight alcohol) to keep the cannabinoid in a non-crystalline state after evaporation of the siloxane.
  • the residual solvent is an alkyl polypropylene glycol / polyethylene glycol ether and/or a fatty acid alcohol.
  • the residual solvent has a low volatility such that less than 5% would evaporate at skin temperature over 24 hours.
  • the residual solvent has a chain structure that has a hydrophobic end and a hydrophilic end.
  • the residual solvent is a liquid at or below 32 e C.
  • the residual solvent dissolves siloxane.
  • the residual solvent maintains the cannabinoid in non-crystalline form in concentrations of 20% up to 70% cannabinoid.
  • the total amount of the volatile solvent (siloxane and optionally another volatile solvent such as a low molecular weight alcohol), and the residual solvent if present, required is sufficient to keep the cannabinoid non-crystalline at room temperature for between about 2-8 hours once the composition is applied to the skin.
  • Such administration is expected to result in enhanced delivery of a cannabinoid, such as cannabidiol, to the epidermis and dermis of the skin, which is expected to be effective in significantly reducing, and therefore, treating psoriasis in patients in need of such treatment.
  • a cannabinoid such as cannabidiol
  • the present invention may allow larger doses of cannabinoids, such as cannabidiol, to be applied without having to have a thick layer of residue that would be rubbed off or be unacceptable to the user.
  • cannabinoids such as cannabidiol
  • the topical pharmaceutical compositions of the present invention allow more rapid delivery of the cannabinoid due to the metastable high driving force or supersaturation of the composition.
  • the high concentration of dissolved cannabinoids on the outer surface of the skin causes a concentration gradient that enhances penetration of the cannabinoid into the epidermis and dermis.
  • the present invention comprises a topical composition comprising a solution of a cannabinoid in a siloxane.
  • the cannabinoid is cannabidiol.
  • CBD cannabidiol
  • IPA isopropyl alcohol
  • MO occlusive mineral oil (a viscous liquid petrolatum)
  • HDS hexylmethyldisiloxane
  • PMS polymethylsiloxane 10 6 cSt
  • HDA 2-hexyldecyl alcohol
  • PG propylene glycol
  • OA oleyl alcohol
  • EtOH ethanol
  • ODDA octyldodecyl alcohol
  • AE arlamol E
  • IPA isopropyl alcohol
  • Klucel MF hydroxypropylcellulose (brand name Klucel® MF from Ashland, Inc.).
  • the preferred ratio of cannabinoid to siloxane to residual solvent is selected from the range consisting of (w/w%): 0.5-20% cannabinoid, between 1 -99% siloxane and between 0.1 - 99% residual solvent; between 5-20% cannabinoid, between 4-70% siloxane and between 1 %- 70% residual solvent; between 1 -15% cannabinoid, between 20-95% siloxane and between 1 - 15% residual solvent.
  • composition is selected from the group consisting of (w/w%):
  • composition is selected from the group consisting of:
  • the following formulations are solutions: 5%CBD/10%OA/10%PG/10%HDS/65%IPA, 14%CBD/9%OA/9%PG/9%HDS/59%IPA and 14%CBD/4.5%OA/13.5%PG/4.5%HDS/63.5%IPA, 5%CBD/2%AE/1 %P MS/92% HDS.
  • these formulations are gelled with 1 % Klucel.
  • 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 does not contain water, i.e. it is non-aqueous.
  • Siloxanes do not burn, sting or have an odour, and thus are highly advantageous for topical application for the treatment of psoriasis. Importantly for the compositions of the present invention, siloxanes, due to their low molecular weight, are highly volatile.
  • the siloxane contains two or three silicon atoms.
  • the siloxanes may have between one and eight methyl groups.
  • the siloxane is selected from the group consisting of: hexamethyldisiloxane, octamethyltrisiloxane and combinations thereof. These are the most volatile siloxanes, and are thus the most advantageous.
  • the level of volatility of the siloxane is about the same as that of isopropyl alcohol.
  • the siloxane contains 4 or 5 silicon atoms, and is, for example, decamethyltetrasiloxane or dodecamethylpentasiloxane.
  • the siloxane is a cyclical 4 or 5 silicon atom compound such octamethylcyclotetrasiloxane (CAS# 556-67-2) or decamethylcyclopentasiloxane (CAS# 541 -02-6).
  • further improvements in the solubility and crystallinity characteristics of the cannabinoid in the siloxane may be achieved by the addition of a further volatile solvent in the form of an alcohol, including a low molecular weight alcohol.
  • An improvement in the solubility and crystallinity characteristics of the cannabinoid in the siloxane may also be achieved by the addition of an alkyl PEG/PPG ether and/or a fatty alcohol.
  • Alkyl polypropylene glycol / polyethylene glycol ethers [0056] In certain embodiments, further improvements in the solubility characteristics of the cannabinoid, such as cannabidiol, in the siloxane may be achieved by the addition of alkyl polypropylene glycol / polyethylene glycol ethers (alkyl PEG/PPG ethers).
  • alkyl PEG/PPG ethers as well as suitable alkyl PEG/PPG ethers that can be used in accordance with this invention, are discussed in the Cosmetic Ingredient Review (CIR) Expert Panel 2013 "Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics” Report (www.cir-safety.org/sites/default/files/PEGPPG062013tent.pdf; accessed 21 Dec 2016) and the contents of that document are incorporated herein.
  • CIR Cosmetic Ingredient Review
  • the alkyl PEG/PPG ethers also act as a residual solvent to assist in maintaining the cannabinoid in a non-crystalline state after evaporation of some or all of the siloxane and the optional low molecular weight alcohol.
  • the composition also comprises one or more alkyl PEG/PPG ethers.
  • Alkyl PEG/PPG ethers are the reaction products of an alkyl alcohol and one or more equivalents each of ethylene oxide and propylene oxide (forming repeats of polyethylene glycol (PEG) and polypropylene glycol (PPG), respectively).
  • alkyl PEG/PPG ethers including polypropylene glycol ethers of stearyl alcohol and butyl alcohol, can improve the solubility of cannabinoids, such as cannabidiol, in siloxane solvents.
  • cannabinoids such as cannabidiol
  • siloxane solvents This ability to increase the concentration of the cannabinoid in the initial composition and in the final composition on the skin after application and evaporation makes it possible to achieve high residual concentrations of cannabinoids on the skin.
  • the alkyl PEG/PPG ethers provide a residual solvent that can retain the cannabinoid in solution at an exceptionally high concentration after evaporation of the volatile solvent or solvent mixture.
  • the alkyl PEG/PPG ethers are liquids at ambient temperatures.
  • the alkyl PEG/PPG ethers are liquids at about 30°C, or less, or at about 25°C.
  • the alkyl PEG/PPG ethers have a low volatility such that less than 5% would evaporate at skin temperature over 24 hours.
  • the alkyl PEG/PPG ether has a PEG/PPG chain length of between 10-50 PG units and an ether component of between 2-20 carbons, wherein the sum of the PG units and the carbons of the ether component is preferably between 20 and 60.
  • a range of alkyl PEG/PPG ethers are discussed in the Cosmetic Ingredient Review (CIR) Expert Panel 2013 "Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics" Report (www.cir-safety.org/sites/default/files/PEGPPG062013tent.pdf; accessed 21 Dec 2016) and the contents of that document are incorporated herein.
  • the alkyl PEG/PPG ether is selected from the group consisting of: polypropylene glycol ethers of stearyl alcohol or butyl alcohol and combinations thereof.
  • the alkyl PEG/PPG stearyl ether or butyl ether is selected from the group consisting of: polypropylene glycol (PPG) stearyl ethers and polypropylene glycol butyl ethers such as PPG-15 stearyl ether and PPG-40 butyl ether and combinations thereof.
  • the relative amount of alkyl PEG/PPG ether is selected from the following group; 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.
  • the maximum concentration of the alkyl PEG/PPG ether is 50% w/w. In specific embodiments, the maximum concentration of the alkyl PEG/PPG ether is 80% w/w.
  • the amount of alkyl PEG/PPG ether is sufficient to keep the cannabinoid is a non-crystalline form on the skin after partial or complete evaporation of the more volatile solvent or solvents.
  • the topical composition also comprises a low molecular weight alcohol.
  • a low molecular weight alcohol may improve the solubility of cannabinoids, such as cannabidiol, in siloxane solvents.
  • This ability to increase the concentration of the cannabinoid in the initial composition makes it possible to achieve high residual concentrations of cannabinoids on the skin after application.
  • the low molecular weight alcohol forms a further volatile solvent in addition to the siloxane.
  • the level of volatility of the low molecular weight alcohol is about the same as that of isopropyl alcohol.
  • the addition of a further volatile solvent such as a low molecular weight alcohol may be of particular advantage if the concentration of cannabinoid in the initial composition is very high.
  • the low molecular weight alcohol is a liquid at ambient temperatures.
  • the low molecular weight alcohol is liquid at about 30°C, or less, or at about 25°C.
  • the level of volatility of the low molecular weight alcohol is about the same as that of isopropyl alcohol.
  • the low molecular weight alcohol is selected from the group consisting of: C 2 - 6 alcohols, and combinations thereof.
  • the low molecular weight alcohol is selected from the group consisting of: C 2 - 4 alcohols, and combinations thereof.
  • the low molecular weight alcohol is selected from the group consisting of: ethyl alcohol (or ethanol), n-propanol, isopropyl alcohol, butanol and combinations thereof.
  • the relative amount of low molecular weight alcohol selected from the following group: 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, 1 1 %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.
  • the maximum concentration of the low molecular weight alcohol is 50% w/w.
  • the maximum concentration of the 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.
  • the topical composition is further characterised in that the composition comprises a fatty alcohol.
  • the purpose of the fatty alcohol is to act as a solvent for the cannabinoid once the volatile components, such as the siloxane and, optionally, the low molecular weight alcohol, have evaporated.
  • the fatty alcohol is a C 1 2 -22 fatty alcohol.
  • the fatty alcohol is a C 16 . 22 fatty alcohol.
  • the fatty alcohol is selected from the group consisting of: oleyl alcohol, isostearyl alcohol, octyldodecyl alcohol, 2-hexyl decyl alcohol.
  • the relative amount of fatty alcohol selected from the following group; at least 2% w/w, at least 3% w/w, at least 4% w/w, at least 5%w/w.
  • the maximum concentration of the fatty alcohol is 50% w/w. In specific embodiments, the maximum concentration of the fatty alcohol is 80% w/w.
  • the amount of fatty alcohol is sufficient to keep the cannabinoid is a noncrystalline form on the skin after partial or complete evaporation of the more volatile solvent or solvents.
  • the cannabinoid is cannabinol.
  • the cannabinoid is any compound that interacts with the cannabinoid receptor.
  • This may include various cannabinoid mimetics, such as certain tetrahydropyran analogs (e.g., A9-tetrahydrocannabinol, ⁇ 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, 10a-hexahydro-1 -hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9- one, (-) -(3S,4S)- 7-hydroxy-A6-tetrahydrocannabinol-1 ,1 -dimethylheptyl,(+)-(3S,4S)- 7-hydroxy-
  • the concentration of cannabinoid in the topical composition of the invention may be 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 1 1 % w/w, at least 12% w/w, at least 13% w/w, at least 14% w/w, and at least 15% w/w.
  • the concentration of cannabinoid in the topical composition may be 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 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.
  • concentrations may be achieved after at least partial evaporation of the volatile siloxane and, optionally, low molecular weight alcohol components.
  • the concentration of cannabinoid in the topical composition may be within a range with a lower limit selected from the group consisting of: 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, 1 1 % w/w, 12% w/w, 13% w/w, 14% w/w, and 15% w/w;
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within 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, 1 1 % 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.
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the concentration of the cannabinoid in the topical composition may be within a range selected from the group consisting of:
  • the cannabinoid could be incorporated into a composition with an additional active moiety that is capable of improving the appearance and/or hydration of the skin.
  • composition of the present invention can be used in conjunction with other topically applied analgesic and/or systemically available agents for the treatment of psoriasis.
  • Examples of such analgesic agents include, but are not limited to: morphine, cyclazocine, piperidine, piperazine, pyrrolidine, morphiceptin, meperidine, trifluadom, benzeneacetamine, diacylacetamide, benzomorphan, alkaloids, peptides, phenantrene and pharmaceutically acceptable salts, prodrugs or derivatives thereof.
  • compounds contemplated by as suitable in the present invention include, but are not limited to morphine, heroin, hydromorphone, oxymorphone, levophanol, methadone, meperidine, fentanyl, codeine, hydrocodone, oxycodone, propoxyphene, buprenorphine, butorphanol, pentazocine and nalbuphine.
  • pharmaceutically acceptable salts, prodrugs and derivatives refers to derivatives of the opioid analgesic compounds that are modified by, e.g., making acid or base salts thereof, or by modifying functional groups present on the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to produce the analgesically active parent compound.
  • examples include but are not limited to mineral or organic salts of acidic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, acetate, formate, sulfate, tartrate and benzoate derivatives, etc.
  • Suitable opioid analgesic agents including those specifically mentioned above, are also described in Goodman and Gilman, ibid, chapter 28, pp. 521 -555.
  • retinoids such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol
  • salicylic acid such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol
  • salicylic acid such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol
  • salicylic acid such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol
  • salicylic acid such as tretin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and reti
  • composition of the present invention may include other active agents, e.g., topically-effective anaesthetics such as xylocaine, cocaine, lidocaine, benzocaine, etc., which may provide a more immediate, if less effective in the long run, level of pain relief until the analgesic agent becomes fully effective.
  • anaesthetics such as xylocaine, cocaine, lidocaine, benzocaine, etc.
  • Still other agents can also be administered, preferably topically, to potentiate the effects of the topically-administered cannabidiol.
  • dextromethorphan a non-addictive opioid compound
  • parenteral administration is also effective, to enhance the effectiveness of the topically administered agent.
  • dextromethorphan has previously unappreciated analgesic properties in peripheral nerves.
  • Suitable concentrations of dextromethorphan are routinely ascertainable by the skilled worker, and include the normal therapeutic amounts administered parenterally for conventional purposes, e.g., as a cough suppressant, or less, and routinely determinable amounts for topical administration; for example, 1 g of dextromethorphan can be added to a composition disclosed herein to provide additional treatment for psoriasis.
  • the pharmaceutical composition of the present invention further comprises one or more of the following agents for the treatment of psoriasis: retinoids such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol; salicylic acid; resorcinol; sulfacetamide; urea; imidazoles such as ketoconazole and elubiol; essential oils; alpha-bisabolol; dipotassium glycyrrhizinate; camphor; beta.-glucan; allantoin; feverfew; flavonoids such as soy isoflavones; saw palmetto; chelating agents such as EDTA; lipase inhibitors such as silver and copper ions; hydrolyzed vegetable proteins; inorganic ions of chloride, iodide, fluoride, and their nonionic derivatives chlorine,
  • retinoids such as
  • the topical application of cannabinoid, such as cannabidiol, by way of the compositions of the present invention is expected to reduce the incidence and/or severity of psoriasis.
  • Therapeutic effects of the present invention include, but are not limited to, reduction in redness, itch, pain or irritation, a reduction in pimples, papules, blisters or pustules, a reduction in infection, a reduction of swelling, cracking, weeping, crusting, and scaling and/or a general decrease in inflammation.
  • the topical application of cannabinoid, such as cannabidiol, by way of the compositions of the present invention is expected to improve the symptoms of psoriasis.
  • the term "improve” is used to convey that the present invention changes either the appearance, form, characteristics and/or the physical attributes of the tissue to which it is being provided, applied or administered.
  • the change in form may be demonstrated by any of the following alone or in combination: enhanced appearance of the skin; decreased inflammation of the skin, prevention of inflammation or blisters, decreased spread of blisters, decreased ulceration of the skin, decreased redness, reduction of scarring, reduction in lesions, healing of blisters, reduced skin thickening, closure of wounds and lesions, a reduction in symptoms including, but not limited to, pain, inflammation, itching, milia or other symptoms associated with inflammatory conditions or the like.
  • a primary advantage of the present invention is expected to be the improvement in the condition of the skin without the typical side effects of conventional therapies.
  • the potential for the present invention is widespread, and the topical application of cannabinoids shows promise as an exciting new method of psoriasis treatment.
  • treatment of psoriasis in accordance with embodiments of the present invention results in improved healing of the skin.
  • swollen, cracked or scaled skin is which is treated is expected to heal more quickly and/or completely, compared to when left untreated.
  • treatment When administered in accordance with the present invention, treatment is expected to result in one or more therapeutic effects.
  • Therapeutic effects in the affected area include, but are not limited to, reduction in redness, itch, pain or irritation, the number and severity of the psoriasis lesions, a reduction in infection, a reduction of swelling, cracking, weeping, crusting, and scaling and/or a general decrease in inflammation.
  • One or more of these therapeutic effects are expected to be observed when treatment in accordance with the present invention is made to any of the suitable conditions.
  • the present invention further provides a method for treating or preventing psoriasis 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 further provides the use of a cannabinoid and a siloxane for the manufacture of a topical composition, as described herein, for the prevention or treatment of psoriasis in a patient in need thereof.
  • the present invention further provides the use of a topical composition, as described herein, for the prevention or treatment of psoriasis.
  • the present invention is directed to methods of treating psoriasis using topical cannabinoids, including cannabidiol.
  • a topical composition of the invention containing cannabinoids such as cannabidiol is preferably applied topically to an area which is affected by psoriasis.
  • the application of cannabinoid in accordance with certain embodiments results in reduction in redness, itch, pain or irritation, a reduction in pimples, papules, blisters or pustules, a reduction in infection, less breakdown and loss of collagen and elastin in the skin, a reduction of swelling, cracking, weeping, crusting, and scaling and/or a general decrease in inflammation.
  • compositions of the present invention comprise any topically acceptable non-transdermally effective carrier vehicle.
  • Preferred topically acceptable vehicles include but are not limited to gels, ointments, and liquids. Administration of the preferred embodiment is performed in accordance with that mode which is most amenable to the topically acceptable form chosen. For example, gels, lotions, creams and ointments are preferably administered by spreading.
  • the dilution of the cannabinoid in the topical composition can be an important consideration.
  • the cannabinoid concentration in the composition should be high enough that the patient does not need to wait an excessively long time for the composition to dry.
  • the cannabinoid concentration should be dilute enough that a patient can achieve effective coverage of the affected area.
  • the composition could include a component which polymerizes in response to exposure to air or ultraviolet radiation.
  • the amount of composition to be applied will vary depending on the choice of siloxane, low molecular weight alcohol, fatty alcohol, and/or alkyl PEG/PPG ether as well.
  • the cannabinoid such as cannabidiol
  • the total volume in a single dose may be as low as 0.1 ml.
  • the cannabinoid such as cannabidiol
  • the total volume may be as high as 3 ml.
  • psoriasis comprises scattered lesions, the volume applied to each lesion may be smaller.
  • the carrier selected, and its manner of application are preferably chosen in consideration of the needs of the patient and the preferences of the administering physician.
  • the composition comprises a gel which is preferably administered by spreading the gel onto the affected area.
  • the composition comprises a liquid, which can be administered by spraying or otherwise applying the liquid onto the affected area.
  • [001 1 1 ] The quantities of the applied cannabinoid, such as cannabidiol, described herein in the Examples are illustrative only and it is to be appreciated that lesser and greater quantities may be used, which can be routinely optimized by the skilled worker. In general, amounts therapeutically equivalent to 0.1 to 200 mg of cannabinoid, such as cannabidiol, applied to an area of 5 - 100cm 2 , are preferred. However, the quantity of cannabinoid used in the topical application of the present invention is typically a small fraction of the typical dosage used in other methods of treatment using these agents, e.g., epilepsy.
  • the composition is applied to the affected area regularly until relief is obtained.
  • the composition is administered to the skin of the patient in need of such treatment using a dosing regimen selected from the group consisting of: every hour, every 2 hours, every 3 hours, once daily, twice daily, three times daily, four times daily, five times daily, once weekly, twice weekly, once fortnightly and once monthly.
  • a dosing regimen selected from the group consisting of: every hour, every 2 hours, every 3 hours, once daily, twice daily, three times daily, four times daily, five times daily, once weekly, twice weekly, once fortnightly and once monthly.
  • other application schedules may be utilized in accordance with the present invention.
  • composition of the invention may be provided in a form selected from the group comprising, but not limited to a liquid or gel, a leave-on preparation, a wash-off preparation.
  • the composition comprises impurities, wherein the quantity of impurities as a percentage of the total weight of the composition is selected from the group consisting of: less than 20% impurities (by 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.
  • the composition comprises microbial impurities or secondary metabolites, wherein the quantity 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 %.
  • the composition is sterile and stored in a sealed and sterile container. In one embodiment, the composition contains no detectable level of microbial contamination.
  • Antagonist a compound that does not enhance or stimulate the functional properties of a receptor, yet block those actions by an agonist.
  • Bandage a dressing used to cover an afflicted area.
  • Cannabinoid as used herein, is meant to include compounds which interact with the cannabinoid receptor and various cannabinoid mimetics, such as certain tetrahydropyran analogs (e.g., A 9 -tetrahydrocannabinol, A 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, 10a-hexahydro-1 -hydroxy-6,6- dimethyl-9H-dibenzo[b,d]pyran-9-one, (-) -(3S,4S)- 7-hydroxy-A6-tetrahydrocannabinol-1 ,1 - dimethylheptyl,(+)-(3S,4S)-7-hydroxy-A6- tetrahydrocannabinol-1
  • Cannabidiol as used herein, is meant to refer to 2-[3-methyl-6-(1 -methylethenyl)- 2-cyclohexen-1 -yl]-5-pentyl-1 ,3-benzenediol.
  • Central nervous system the brain and spinal cord.
  • Dermal relating to the dermis.
  • Dressing combine: designed to provide warmth and protection to absorb large quantities of fluid that may drain from an incision or wound; consists of a nonwoven fabric cover enclosing fibre with or without absorbent tissue.
  • Inflammation an immune system-mediated process characterized by redness, heat, swelling, and pain at the local site.
  • Mammal vertebrates with hair, three middle ear bones and mammary glands. Mammals include humans.
  • Skin the outer covering of an animal body.
  • Mammalian skin comprises three layers: (i) an epidermis layer, which is predominantly composed of keratinocytes and a small number of melanocytes and Langerhans cells (antigen presenting cells); (ii) a dermis layer, which contains nerve endings, sweat glands and oil (sebaceous) glands, hair follicles, and blood vessels and which is primarily composed of fibroblasts; and (iii) a hypodermis layer of deeper subcutaneous fat and connective tissue.
  • the epidermis itself is made up of two layers, the outer stratum corneum and the inner epidermal basal layer, sometimes referred to as the basement membrane. The purpose of the stratum corneum is to form a barrier to protect underlying tissue from infection, dehydration, chemicals and mechanical stress.
  • Therapeutically-effective amount the amount necessary to bring about a therapeutic effect.
  • Transdermal passing through the dermis.
  • the invention described herein may include one or more range of values (e.g. concentration).
  • a range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range which lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.
  • Example techniques for ascertaining permeability of compositions containing cannabidiol are described in detail below.
  • the permeability of human skin has been studied for several decades.
  • the skin consists of two major layers, the outer epidermis and the inner dermis.
  • the stratum corneum (“SC") the outermost 10-20 ⁇ of the epidermis, is responsible for the skin's excellent diffusional resistance to the transdermal delivery of most drugs.
  • Most of the skin's enzymatic activity lies in the basal cell layer of the viable epidermis.
  • Fibrous collagen is the main structural component of the dermis.
  • the skin vasculature is supported by this collagen and lies a few microns underneath the epidermis. Basically, it is here that permeation ends and systemic uptake begins.
  • a high-pressure liquid chromatography (HPLC) assay can be used for the analysis of cannabidiol in samples.
  • An appropriate HPLC system may consist of a Waters 717 plus Autosampler, Waters 1525 Binary HPLC Pump and Waters 2487 Dual A Absorbance Detector with Waters Breeze software.
  • a Brown- lee C-18 reversed-phase Spheri-5 ⁇ column (220x4.6 mm) with a C-18 reversed phase 7 ⁇ guard column (15x3.2 mm) may be used with the UV detector set at a wavelength of 215 nm.
  • the mobile phase may comprise of acetonitrile: 25 mM phosphate buffer with 0.1 % triethylamine pH 3.0 (80:20).
  • An appropriate flow rate of the mobile phase would be 1 .5 mL and 100 ⁇ _ of the sample would be injected onto the column.
  • a PermeGear flow-through (In-Line, Riegelsville, Pa.) diffusion cell system is appropriate for the skin permeation studies. Trans-epidermal water loss can be measured (Evaporimeter EPITM, ServoMed, Sweden) after securing the skin in the cells. Pieces of skin with readings below 10 g/m2/h would be used for the diffusion studies. The skin surface in the diffusion cells would be maintained at 32°C with a circulating water bath. An appropriate receiver solution would be HEPES-buffered Hanks' balanced salts with gentamicin (to inhibit microbial growth) containing 40% polyethylene glycol 400 (pH 7.4), and the flow rate was adjusted to 1 .1 mL/h.
  • CBD CBD
  • the donor vehicle propylene glycol: Hanks' buffer (80:20)
  • permeation enhancers at 6% v/v
  • sonicated for 10 min and then applied onto the skin.
  • Excess quantity of the drug would be used in the donor compartment throughout the diffusion experiment in order to maintain maximum and constant chemical potential of the drug in the donor vehicle.
  • Each cell would appropriately be charged with 0.25 mL of the respective drug solution.
  • Samples would appropriately be collected in 6 h increments for 48 h. All the samples would appropriately be stored at 4°C until HPLC analysis.
  • Drug disposition in the skin samples would be measured at the completion of the 48h experiment.
  • the skin tissue would be rinsed with nanopure water and blotted with a paper towel.
  • the skin would be tape stripped twice using book tape (Scotch®, 3M, St. Paul, Minn.).
  • the skin in contact with the drug would be excised, minced with a scalpel and placed in a pre-weighed vial.
  • Drug would be extracted from the skin by equilibrating with 10 mL of ACN in a shaking water bath overnight at room temperature. Samples would be analyzed by HPLC to determine CBD content in micromoles ( ⁇ ) of drug per gram of wet tissue weight.
  • Statistical analysis of the in vitro human skin permeation data could be performed using SigmaStat 2.03.
  • a one-way ANOVA with Tukey post- hoc analysis could be used to test the statistical differences among the different treatments.
  • CBD cannabidiol
  • OA and IPA were very good solvents and it was surprising that IPA was so much better than ethanol.
  • the CBD was dissolved at a moderate concentration in a highly volatile solvent with some nonvolatile solvents that would keep CBD in solution (non-crystalline), i.e., prevent crystallization at high concentrations (of the order of 40-50%).
  • Form II 14%CBD/4.5%OA/13.5%PG/ 4.5%HDS/63.5%IPA. This solution also did not form crystals in one hour or overnight.
  • Form III 8% CBD in IPA. No crystals after an hour but overnight there were needlelike crystals that looked clear, not yellowish, under the microscope. The film of just liquid CBD in the microscope slide and on skin was of high friction, and probably would not be so acceptable to patients.
  • a 10% solution in IPA applied to 1 cm 2 would give about a l Omicron thick layer (10mg), about the thickness of stratum corneum. Made up 15%CBD in IPA and 15%CBD in 50/50 IPA/HDS with no crystals immediately.
  • Form V OA was added to form IV to prevent overnight crystallization. It was 7.6%CBD/8%OA/8%PMS/76.4%HDS with a residual CBD of 32%. There were no crystals overnight. Added further CBD and PMS to make 10%CBD/7.7%OA/8.7%PMS/73.6HDS with a residual of 38%CBD and with similar feel and no crystals.
  • Form VI 14%CBD/6%OA/6%PG/ 10%HDS/64 %IPA with a residual of 54%CBD. This formulation had crystals after 48 hours. Added Klucel and only a few crystals after 48hours. It was less tacky than the other two gels with higher OA and PG.
  • Form VII 15%CBD/10%argan/10%HDS/65%IPA with residual of 60%CBD. A few crystals were observed after 2-3 hours. After adding Klucel, the gel had a better feel than the ones with PG and OA.
  • Form VIII 15%CBD/5%PMS/10%OA/70%HDS. Good feel and no crystals.
  • Form IX 10%CBD/7%argan/7%ISA/9%PMS/67%HDS. No crystals.
  • Form X A HDS formulation without OA: 15%CBD/13%ISA/7%PMS/66%HDS with a residual of 43%CBD. No crystals.
  • Form XI 15%CBD/12.5%HDA/6%PMS/66.5%HDS with a residual CBD of 45%. No crystals, just droplets in PMS.
  • Form XII 15%CBD/12.5%ODDA/6%PMS/66.5%HDS with a residual CBD of 45%. No crystals, just droplets in PMS.
  • Form XIII 15%CBD/10%HDA/40%IPA/35%HDS with a residual CBD of 60%. No crystals. Reason for reducing IPA was to reduce potential for stinging, odour, and cooling. .
  • Form XIX 15%CBD/10%ODDA/40%IPA/35%HDS with a residual CBD of 60%. No crystals.
  • p Added Klucel to Form XIII and XIX. They were not as viscous, since the HDS level was high, but they felt very good on the skin and not so tacky.
  • Form XX 7.2%CBD/6.3%PMS/1 .4%MO/1 .8%IPA/83.3%HDS. No crystal of CBD and great feel with a residual CBD of 48%.
  • Form XXI 20%CBD/10%ODDA/70%IPA with a residual CBD of 67% and no crystals.
  • Form XXII 9.5 CBD/4.8%ODDA/57.1 %EtOH/28.6%HDS with no crystals and a residual CBD of 66%.
  • Form XXIII 10%CBD/12.5%PMS/4.5%IPA/72%HDS with good feel and no crystals with a residual CDB of 42%. Added about 4% petrolatum and had a hazy solution (from petrolatum) with no crystals.
  • CBD2 is an off-white powder of crystals that produced clear solutions in marked contrast to CBD1 solutions that were coloured by the end of the day. None of the CBD2 solutions were coloured at the end of day 1 and looked clear. The CBD2 material dissolved like the CBD1 therefore the CBD2 is CBD without the discoloration properties of CBD1 .
  • AE which was initially avoided due to an intense purple color using CBD 1 , was found to be the best replacement and even superior to HAD. It did have a slight purple color when CBD was dissolved in pure AE at the 10% level but not in the formulations using AE.
  • CBD dissolved at the 10% level in AE and barely 9.5% in IPM. Further exploration was not conducted due to the small amount of drug API available for non- GMP work. CBD is soluble greater than 10% but probably not in excess of 20%, as the time to dissolve additional CBD was taking considerably longer.
  • the acne formulations were alcohol (isopropyl alcohol [IPA]) based to allow for thickening with Klucel and silioxane (hexylmethyldisiloxane [HDS]) based for spray on formulations.
  • the psoriasis formulations were siloxane based and thickened with polymethylsiloxane 10 6 cSt (PMS). All the formulations would be suitable for human studies, and under microscope evaluation post evaporation all formulations did not crystalize CBD.
  • the residual solubilizer was 2-hexyldecyl alcohol (HDA) and residual concentrations were 60% to 67%.
  • A-1 5%CBD/2.5%HDA/50%IPA/41 %HDS/1 %KlucelMF
  • Psoriasis Formulations (similar to the acne spray but with more PMS)
  • Test Product Dose and Mode of Administration, Batch Number: Test Product: BTX 1308 5% (w/w) Solution.
  • Test Product BTX 1308 5% (w/w) Solution.
  • CBD cannabidiol
  • Each milliliter of the BTX 1308 5% (w/w) Solution contains 37.5 mg of CBD. Participants will apply 3 mL of the BTX 1308 5% (w/w) Solution twice daily resulting in a maximum of 225 mg of CBD applied daily.
  • Each subject should have the following symptoms of psoriasis:
  • Subjects must be willing to limit sun exposure overall. Subjects are prohibited from sunbathing or intentional tanning or intense sun exposure including the use of tanning booths/lights or other artificial UV light sources throughout the study.
  • plaque psoriasis e.g., atopic dermatitis, contact dermatitis, tinea corporis, cutaneous lymphoma, etc.
  • any topical anti-psoriatic e.g., salicylic acid, anthralin, tar, etc.
  • any topical corticosteroid medications e.g., topical retinoids (e.g., tazarotene, tretinoin), topical Vitamin D analogs (e.g., calcipotriene), topical immunosuppressants (e.g., tacrolimus, pimecrolimus) within 2 weeks prior to study entry.
  • topical anti-psoriatic e.g., salicylic acid, anthralin, tar, etc.
  • topical retinoids e.g., tazarotene, tretinoin
  • topical Vitamin D analogs e.g., calcipotriene
  • topical immunosuppressants e.g., tacrolimus, pimecrolimus
  • Safety will be the primary outcome measure.
  • the safety outcome measures to be assessed are:
  • THC tetrahydrocannabinol
  • Psoriasis Area Severity Index obtained at the Baseline (Day 1 ), Day 28, Day 56, and Day 84 visits.
  • IGA Investigator's Global Assessment
  • Target lesion size assessment and lesion scaling score carried out at the Baseline (Day 1 ), Day 28, Day 56, and Day 84 visits.
  • Cutaneous tolerability (erythema, scaling, dryness, burning/stinging, and irritant/allergic contact dermatitis) will be collected at Baseline (Day 1 ), Day 28, Day 56, and Day 84 and graded using the following scale: 0, None; 1 , Slight; 2, Moderate; 3, Severe.
  • a PASI Scoring form is provided as Figure 7.
  • a target lesion with the following characteristics will be chosen for treatment: located on the extremities (i.e., arms or legs) ; has an area of ⁇ 25 cm 2 ; a minimum plaque erythema of at least moderate severity (PASI grade ⁇ 3); a minimum plaque scaling severity of at least moderate severity (PASI grade ⁇ 3); and a minimum plaque elevation of at least moderate severity (PASI grade ⁇ 3).
  • An IGA on the target lesion will be conducted.
  • the participant must have an ISGA score of mild (2) or moderate (3) (see Table 3).
  • the IGA assesses the overall status of the target lesion at the time of the assessment.
  • the IGA is to be conducted by the same investigator/sub-investigator at all visits. No comparisons are made to previous assessments.
  • Baseline assessments for safety (CBC, chemistry, and urinalysis) will be obtained on Day 1 .
  • a blood sample will be obtained for study drug blood levels within 15 minutes prior to study drug application. If the participant is eligible to participate, Screening and Baseline may occur at the same visit. If the Screening Visit and Baseline Visit are not concurrent, UDS, PASI, and IGA will be repeated at the Baseline Visit.
  • CBC White blood cell (WBC) count (with automated differential for absolute neutrophils, lymphocytes, monocytes, eosinophils, and basophils), red blood cell (RBC) count, haemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), and platelet count
  • WBC White blood cell
  • RBC red blood cell
  • Urinalysis Color, clarity, specific gravity, pH, protein, glucose, leukocyte and esterase. If results are abnormal, the sample will be further assessed using microscopic analysis for red blood cells, white blood cells, squamous epithelial cells, and culture.
  • Plasma samples will be analysed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The limit of detection is 0.2 ng/mL.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • Participants will be randomised 2:1 using the Interactive Voice Response System (IVRSyinteractive Web-based Response System (IWRS) to receive either active BTX 1308 5% (w/w) Solution or Vehicle Solution. Participants will receive their first dose of study drug applied by the site staff and will be observed in the clinic for one hour after application. Cutaneous tolerability assessments will be conducted at one hour after the first application. Participants will be given four weeks of study drug and instructed in the proper application to cover their target psoriasis lesion and surrounding skin. Participants will be provided with a diary to record their daily study drug application and daily recording of burning/stinging and pruritus.
  • IWRS Interactive Voice Response System
  • Participants will return to the clinic on the morning of Day 28 for cutaneous tolerability assessments and a UDS for presence of THC prior to the application of study drug. Participants will also be queried for AEs and changes in concomitant medications. Diaries and study drug will be returned and reviewed for compliance and daily assessment of burning/stinging and pruritus. The site will obtain signs of psoriasis. The participant will then apply their morning dose of study drug during the visit for the clinical site to confirm correct application techniques. Another four weeks of study drug will be dispensed.
  • Participants will return to the clinic on the morning of Day 56 for cutaneous tolerability assessments and a UDS for presence of THC. Participants will also be queried for AEs and changes in concomitant medications. Diaries and study drug will be returned and reviewed for compliance and daily assessment of burning/stinging and pruritus. The site will obtain signs of psoriasis. The participant will then apply their morning dose of study drug during the visit for the clinical site to confirm correct application techniques. Four weeks of study drug will be dispensed along with the diary for the next 28 days of the study. The final study drug application will be the p.m. application on Day 84.
  • Participants will return to the clinic on the morning of Day 85 for safety assessments; blood samples for CBC and chemistry, urine samples for urinalysis, cutaneous tolerability assessments, and UDS for the presence of THC. Participants will be queried for AEs and changes in concomitant medications. Diaries and study drug will be returned and reviewed for compliance and daily assessment of burning/stinging and pruritus. The site will obtain signs of psoriasis. The study investigator will conduct an IGA. A blood sample will be obtained for study drug blood levels.
  • non-target lesions may be treated with topical corticosteroids but not topical antibiotics.
  • topical corticosteroids but not topical antibiotics.
  • Participants should limit exposure of the treatment area to sunlight during the study. Participants must not shower or wash the study application area for 4 hours after application of study drug. Participants should avoid swimming and heavy exercise for 4 hours after application of study drug.
  • Cutaneous tolerability scores for each parameter will be summarised for each visit.
  • the change from Baseline in the mean scores will be summarised for each visit.
  • Drug Levels Blood levels of study drug will be summarised for Baseline and Day 84. The mean, standard deviation (SD), median and range will be presented.
  • Demographics Demographics/Baseline characteristics will be summarised by age, gender, race, ethnicity, height, weight, target lesion size, and PASI of psoriasis.
  • IGA The change from Baseline for IGA on the target lesion will be assessed on Day 84. The mean, SD, median, and range will be presented. The proportion of participants with an IGA target lesion score of clear (0) or almost clear (1 ) and a decrease of 2-grades or more will be presented.
  • Target Lesion Size The change from Baseline in the size of the target lesion will be determined.
  • the efficacy variables PASI, Scaling Score, target lesion size and IGA will be collected at Screening/Baseline and all subsequent study visits. Subjects achieving PASI 50, PASI 75, PASI 90, and PASI 100 will be summarized at Baseline and study Days 28, 56, and 84. The IGA will be dichotomized into "success” and “failure” at study Days 28, 56, and 84 with a participant considered a "success” at each individual visit if the IGA decreases by at least 2 grades from than the Baseline score. The change from Baseline in the target lesion size (cm 2 ) will be summarized by visit.
  • Intact human cadaver skin was purchased from the New York Firefighter's Skin Bank ("NYFFSB", NY, NY). The skin tissue was dermatomed by the tissue bank to a thickness of some 250 ⁇ and shipped frozen on dry ice. Upon receipt of the donor skin, the skin pieces were stored at -20°C until used. Prior to use, the skin pieces were removed from the freezer and allowed to thaw fully at ambient temperature.
  • NYFFSB New York Firefighter's Skin Bank
  • Diffusion Cells 24 diffusion cells with 3.3ml receptor volume and a 0.55cm 2 receptor fluid exposure surface area.
  • LC/MS liquid chromatography mass spectrometry
  • Mobile Phase A was prepared by first transferring 1 .0 ml of formic acid (Sigma Aldrich: 56302) into a 2L media bottle. 1 L of HPLC grade water (Millipore: WX0008-1 ) was then measured in a volumetric cylinder and the contents transferred into the 2L media bottle. Finally, 630.6mg of ammonium formate was then weighed and also transferred to the media bottle. The mixture in the media bottle was then shaken until the contents were fully dissolved. Mobile Phase A was stored for less than one week during the course of the analysis.
  • Mobile Phase B was prepared by transferring 1 .0 ml of Formic acid (Sigma Aldrich: 56302) into a 2L media bottle. 1 L of HPLC grade methanol (Millipore: AX-0145P) was then measured in a volumetric cylinder and the contents transferred into the 2L media bottle. Finally, 630.6mg of ammonium formate was then weighed and also transferred to the media bottle. The mixture in the media bottle was shaken until the contents were fully mixed. Mobile Phase B was stored for less than one week during the course of the analysis.
  • CBD “Stock Solution” was prepared by first weighing 4mg of CBD with an analytical balance in a glass vial. The vial was then tared on the balance and 4ml of dimethyl sulfoxide ("DMSO") was introduced in to the glass vial with a pipettor. The vial was reweighed. The vial was then removed from the analytical balance and capped. The capped vial was vortexed and sonicated using an ultrasonication bath until the CBD was fully dissolved.
  • DMSO dimethyl sulfoxide
  • Table 6 Calibration standards and the corresponding concentration of the CBD.
  • the CBD was first prepared in a Stock Solution. Separate calibration standards were then prepared for by serial five-fold dilutions with DMSO. Standards Cal3 - Cal8 were used for the calibration curves.
  • Table 7 Chromatographic parameters for CBD detection.
  • Chemstation software The AUCs of the CBD peaks were recorded and converted to ng/ml values using a calibration curve developed from the calibration standards' AUC values and known concentration values. These ⁇ g/ml values were imported into the study results Excel workbook. These concentrations were then multiplied by the receptor volume (3.3ml_) and divided by the surface area of the skin exposed to the receptor fluid (0.55cm 2 ) for an end cumulative amount in ⁇ g/cm 2 . For receptor fluid time points greater than 4hrs, this ⁇ g/cm 2 value was corrected for the sample aliquot volumes which were removed to compensate for the dilution caused by replacing the sample volume with fresh buffer solution.
  • the dilution factor (300 ⁇ aliquot/3.3ml receptor volume or 1/1 1 ) is multiplied by the ⁇ g/cm value calculated for the 4hr time point, the result of which is then added to the ⁇ g/cm concentration which is calculated using the 10hr AUC value. Equation 1 outlines the correction value for the dilution effect.
  • Equation #1A (Dilution correction):
  • the receptor fluid (the "Receptor Fluid”) consisted of phosphate buffered saline (“PBS”), sourced from Quality Biologicals with 0.01wt% NaN 3 (added as a preservative), 4 wt% hydroxypropyl-D-cyclodextrin (added to increase solubility of the Actives) and 1 wt% Brij O20.
  • PBS phosphate buffered saline
  • the PBS was supplied as 10X concentration and was diluted to 1 X concentration prior to the study by volumetrically adding distilled water at a 9:1 water to concentrated PBS ratio.
  • the solubility of CBD in the Receptor Fluid was previously measured to be ⁇ >50 g/ml and was determined to be sufficient to maintain sink conditions throughout the study.
  • Receptor Fluid After mixing the Receptor Fluid, degassing of the Receptor Fluid was accomplished according to Tioga's Standard Operating Procedure (“SOP") SOP Lab.007.1 'Degassing of receptor fluid for diffusion studies'. Receptor Fluid was filtered through a ZapCap CR 0.2 ⁇ membrane under vacuum; the Receptor Fluid, so filtered, was stirred for an additional 20 minutes under vacuum.
  • SOP Standard Operating Procedure
  • the cadaver skin piece was removed from the freezer and allowed to defrost in a Bio- safety hood for 30 minutes. Prior to opening the package, a visual inspection was used to confirm that the skin piece had been thoroughly defrosted. • The cadaver skin piece was removed from the package and placed in a distilled water bath for 30 seconds to wash off any cryoprotectants from the skin. The skin was then removed from the water bath and placed in a Bio-safety hood. The exterior surface of the skin was patted dry with a KimWipe, sprayed with fresh PBS, and then patted dry again.
  • the receptor wells were filled with degassed Receptor Fluid using a pipette.
  • the skin piece was cut into approximately 2 cm x 2 cm squares using skin scissors. The square sizes were adjusted as necessary according to the shape and dimensions of the skin piece, but were selected to be approximately uniform in size among all FDCs.
  • Receptor Fluid was added as necessary. Air bubbles in the receptor well, if any, were removed by tilting the FDC assembly such that the air escapes along the sample port. Receptor wells were filled with approximately 3.3 ml of Receptor Fluid.
  • the remaining FDCs were ranked according to the magnitudes of the measured tritiated water flux values. Test articles were then assigned to the batch of FDCs such that the replicates for each test article are each applied to a skin piece with nearly equivalent average tritiated water flux values. The ranking of skin pieces was carried out separately for each substrate.
  • Table 8 CBD dose per cell for the applied test articles.
  • the dose assumes a specific gravity of 0.75 for the formulations, and also assumes 100% of the applied 5 ⁇ of the formulation remains on the skin after spreading the formulation across the skin surface using a glass rod.
  • Samples were stored in a refrigerator at 4-8°C prior to LC/MS analysis. Samples were analyzed within 5 days of collection.
  • the skin was placed on a hot plate set at 60°C for one minute to help facilitate the separation of the skin.
  • the epidermal and dermal compartments were then separately placed into glass vials, into which 3ml of DMSO was added to extract the CBD from the tissue.
  • the skin pieces were then incubated at 40°C for 24hours with gentle agitation. After the 24hour incubation period, samples were collected from the extraction solvent and analyzed via LC/MS detection.
  • Table 9 Total accumulated dose (in g/cm 2 ) of CBD delivered over time.
  • the percent delivery assumes a specific gravity of 0.75 and that 100% of the 5 ⁇ _ applied dose remains on the skin after spreading the formulation with the glass rod. Percent delivery takes into account the varying concentrations of CBD present in each formulation.
  • Table 11 Flux of CBD over time (in g/cm2/hr).
  • the accumulated dose of CBD in the epidermis and dermis was also calculated as ⁇ g of CBD delivered per gram of tissue. This calculation assumes a weight of 10mg for the epidermal tissue and 40mg for the dermal tissues (these values are based on average values observed in previous experiments). These values are shown in Figure 6.
  • Table 12 Total accumulated dose in the skin (in g/gram tissue) of CBD delivered at 48hrs.
  • a two tailed Ttest with unequal variance was used to evaluate the CBD data sets over time.
  • the Ttest compared the transdermal data sets at 24 hours and 48 hours and the epidermal and dermal values.
  • Table 13 A two-tailed Ttest with unequal variance was done comparing the CBD data sets at 24 and 48hrs, plus the epidermal and dermal concentration (results shown are p- values).
  • A: 2.5wt% cannabidiol and B: 5.0wt% cannabidiol were statistically different at 24 and 48 hrs and in the epidermis with greater than 95% confidence (p-values are 0.040, 0.021 , and 0.013 respectively).
  • the dermal values for A: 2.5wt% cannabidiol and B: 5.0wt% cannabidiol were not statistically different with a p-value of 0.492.
  • C 2.5wt% cannabidiol and D: 5.0wt% cannabidiol were statistically different at 24 and 48 hrs and in the epidermis with greater than 90% confidence (p-values are 0.022, 0.080, and 0.035 respectively).
  • cannabinoids such as cannabidiol
  • cannabidiol in accordance with the present invention can deliver increased amounts of cannabidiol into the epidermis and dermis and be used to treat and/or improve the healing of psoriasis.
  • treatment in accordance with the present invention will result in a shortened healing time.

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Abstract

L'invention concerne une composition pharmaceutique comprenant un cannabinoïde et un siloxane, le cannabinoïde étant dissous dans la composition.
PCT/AU2018/050047 2017-02-15 2018-01-24 Formulations de cannabinoïdes pour le traitement du psoriasis WO2018148787A1 (fr)

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JP2019544844A JP2020508991A (ja) 2017-02-15 2018-01-24 乾癬の処置のためのカンナビノイドの製剤
EP18754611.4A EP3582769A4 (fr) 2017-02-15 2018-01-24 Formulations de cannabinoïdes pour le traitement du psoriasis
AU2018221882A AU2018221882A1 (en) 2017-02-15 2018-01-24 Formulations of cannabinoids for the treatment of psoriasis
BR112019017011A BR112019017011A2 (pt) 2017-02-15 2018-01-24 formulações de canabinoides para o tratamento de psoríase
US16/486,297 US20220313621A1 (en) 2017-02-15 2018-01-24 Formulations of cannabinoids for the treatment of psoriasis
CN201880023266.4A CN110520123A (zh) 2017-02-15 2018-01-24 用于治疗银屑病的大麻素制剂
CA3053505A CA3053505A1 (fr) 2017-02-15 2018-01-24 Formulations de cannabinoides pour le traitement du psoriasis
IL26873319A IL268733A (en) 2017-02-15 2019-08-15 Formulations of cannabinoids for the treatment of psoriasis

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WO2019144189A1 (fr) * 2018-01-24 2019-08-01 Botanix Pharmaceuticals Ltd Régime de dosage de cannabinoïde pour l'acné
WO2019144191A1 (fr) * 2018-01-24 2019-08-01 Botanix Pharmaceuticals Ltd Régime de dosage de cannabinoïde pour le psoriasis
WO2019144190A1 (fr) * 2018-01-24 2019-08-01 Botanix Pharmaceuticals Ltd Régime de dosage de cannabinoïde pour dermatite et affections cutanées inflammatoires
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WO2021080648A1 (fr) * 2019-10-25 2021-04-29 Gelest Technologies, Inc. Dérivés de cannabidiol à base de silicium et leurs compositions
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US10933008B1 (en) 2015-10-25 2021-03-02 Gelest Technologies, Inc. Silicon-based cannabidiol derivatives and compositions thereof
WO2019144189A1 (fr) * 2018-01-24 2019-08-01 Botanix Pharmaceuticals Ltd Régime de dosage de cannabinoïde pour l'acné
WO2019144191A1 (fr) * 2018-01-24 2019-08-01 Botanix Pharmaceuticals Ltd Régime de dosage de cannabinoïde pour le psoriasis
WO2019144190A1 (fr) * 2018-01-24 2019-08-01 Botanix Pharmaceuticals Ltd Régime de dosage de cannabinoïde pour dermatite et affections cutanées inflammatoires
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