WO2023154264A1 - Compositions pour le traitement topique d'une radiodermite - Google Patents

Compositions pour le traitement topique d'une radiodermite Download PDF

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Publication number
WO2023154264A1
WO2023154264A1 PCT/US2023/012482 US2023012482W WO2023154264A1 WO 2023154264 A1 WO2023154264 A1 WO 2023154264A1 US 2023012482 W US2023012482 W US 2023012482W WO 2023154264 A1 WO2023154264 A1 WO 2023154264A1
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WIPO (PCT)
Prior art keywords
composition
acid
cannabinoid
olive oil
formulation
Prior art date
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PCT/US2023/012482
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English (en)
Inventor
Purnendu Kumar SHARMA
Alon MANTEL
Srikanth MANNE
Vijendra Nalamothu
Ramanathan Lalgudi
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Akos Biosciences, 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.)
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Publication date
Priority claimed from US17/982,909 external-priority patent/US20230255900A1/en
Application filed by Akos Biosciences, Inc. filed Critical Akos Biosciences, Inc.
Publication of WO2023154264A1 publication Critical patent/WO2023154264A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • compositions, treatments, and methods for treating a patient with radiation dermatitis This is done by administering, in therapeutically effective amounts, specific compositions comprising a cannabinoid and olive oil.
  • the olive oil contains at least 0.1 wt% of a cyclopropene fatty acid or cyclopropane fatty acid (CPFA).
  • Radiation treatment is used to treat malignancies, and is also used during interventional procedures such as coronary angiography, embolization procedures, and indwelling catheter placements.
  • interventional procedures such as coronary angiography, embolization procedures, and indwelling catheter placements.
  • radiation dermatitis which is also known as radiodermatitis, x-ray dermatitis, radiation skin damage, or a radiation burn.
  • Radiation dermatitis is a side effect of external beam ionizing radiation, commonly applied for example during treatments for cancer and other disorders. The radiation can deposit energy at the surface of the skin or several centimeters below the skin surface, depending on where the maximum dose is deposited.
  • Radiation dermatitis generally manifests within a few days to weeks after the start of radiotherapy. Symptoms can include changes ranging from faint erythema (reddening) during the first 2 weeks of treatment before progressing to desquamation (peeling skin) to skin necrosis (death of skin cells) and ulceration, depending on the seventy of the reaction. Other changes in the skin can include the disappearance of follicular structures (pores); an increase in collagen and damage to elastic fibers in the dermis; a fragile surface skin (epidermis); and telangiectasia (prominent blood vessels).
  • the olive oil also contains at least 0.1 wt% of a molecule containing an aliphatic chain with a cyclopropyl or cyclopropenyl group, such as a cyclopropene fatty acid or cyclopropane fatty acid (CPFA).
  • CPFA cyclopropene fatty acid or cyclopropane fatty acid
  • FIG. 1 is a graph showing percent weight change over time for six groups of animals.
  • FIG. 2 is a graph showing the redness scoring over time for each group.
  • FIG. 3 is a graph showing the redness scoring over time, with the three CBD- treated groups condensed together.
  • FIG. 4 is a graph showing the blinded clinical dermatitis scoring over time for each group.
  • FIG. 5 is a graph showing the blinded clinical dermatitis over time, with the three CBD-treated groups condensed together.
  • composition comprising
  • comprising is used herein as requiring the presence of the named ingredients I components I steps and allowing the presence of other ingredients I components I steps.
  • the term “comprising” should be construed to include the term “consisting of”, which allows the presence of only the named ingredients I components I steps.
  • the term “consisting essentially of” should be construed to require the presence of the named ingredients I components I steps, and also permit the presence of other ingredients I components I steps that do not materially affect the basic and novel characteristics of the composition.
  • the basic and novel characteristics of the composition are its ability to treat radiation dermatitis.
  • Numerical values should be understood to include numerical values which are the same when reduced to the same number of significant figures and numerical values which differ from the stated value by less than the experimental error of conventional measurement technique of the type described in the present application to determine the value.
  • All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 2 grams to 10 grams” is inclusive of the endpoints, 2 grams and 10 grams, and all the intermediate values).
  • the endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and/or values.
  • up to X is used in this disclosure to indicate an amount of an ingredient. This term should be construed to require the ingredient to be present in an amount greater than zero, or in other words to exclude the value zero.
  • room temperature means a temperature from 20°C to 25°C.
  • the phrase "therapeutically effective amount” means a sufficient amount of the named ingredient to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician or other care provider within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; medical history of the patient, age, body weight, general health, sex and diet of the patient, the time of administration, route of administration, the duration of the treatment, other drugs being taken by the patient, and the like. A single administration may be sufficient to produce a therapeutic effect, but it is contemplated that multiple administrations will be used over a substantial period of time to assure continued response.
  • compositions and methods for the treatment of dermatological conditions especially radiation dermatitis which may arise after exposure to radiation, whether intentional (e.g. during medical treatment) or unintentional.
  • the compositions may also be useful in the treatment of various other medical conditions, such as for pain management, or for inflammatory conditions.
  • the compositions are intended to be applied topically.
  • the compositions include specified amounts of (A) a cannabinoid; and (B) olive oil as a carrier or solubilizer for the cannabinoid.
  • compositions also include (C) an emulsifier; (D) diethylene glycol monoethyl ether; (E) polysorbate 80; (F) a gelling agent; (G) a fatty alcohol; and (H) water.
  • compositions of the present disclosure include (A) a cannabinoid, which is non-psychoactive.
  • a cannabinoid is a compound derived from the cannabis plant, also known as cannabis or hemp. Over 60 different cannabinoids are known to be naturally present in the cannabis plant. Cannabinoids can also be found in other plants such as, without limitation, rhododendron, licorice, liverwort, echinacea, clove, black pepper, broccoli, ginseng carrots, sunflowers, electric daisy, kava, tea plants, cacao, and black truffles. Cannabinoids can also be synthetically produced and are commercially available, for example from PureForm Global (Los Angeles, California).
  • cannabinoids which bind to the CBi receptor are also known, such as benzoylindoles, cyclohexylphenols, naphthoylindoles, and phenylacetylindoles.
  • Some non-limiting examples of cannabinoids include cannabigerolic acid, cannabigerol, cannabinols, and cannabidiols.
  • the cannabinoid can be any cannabinoid or derivative thereof.
  • the cannabinoid can be a cannabidiol, cannabigerol, cannabichromene, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabitriol, dehydrocannabifuran, cannabifuran, cannabichromanon, or cannabiripsol.
  • cannabidiols include cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), and cannabidiorcol (CBD-Ci).
  • CBDA cannabidiolic acid
  • CBD cannabidiol
  • CBD cannabidiol
  • CBD cannabidiol
  • CBDDM cannabidiol monomethylether
  • CBD-C4 cannabidiol-C4
  • CBDVA cannabidivarinic acid
  • CBDDV cannabidivarin
  • CBD-Ci cannabidiorcol
  • cannabigerols examples include cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethyleither (CBGM), cannabigerovarinic acid (CBGVA), and cannabigerovarin (CBGV).
  • Examples of cannabichromenes include cannabichromenic acid (CBC), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), and cannabichromevarin (CBCV).
  • Examples of tetrahydrocannabinols include D-9-tetrahydrocannabinolic acid A (THCA-A), D-9-tetrahydrocannabinolic acid B (THCA-B), D-9-tetrahydrocannabinol (THC), D-9-tetrahydrocannabinolic acid-C4 (THCA-C4), A-9-tetrahydrocannabinol-C4 (THC-C4), D-9-tetrahydrocannabivarinic acid (THCVA), D-9-tetrahydrocannabivarin (THCV), D-9-tetrahydrocannabiorcolic acid (THCA-Ci), D-9-tetrahydrocannabiorcol
  • cannabicyclols include cannabicyclolic acid (CBLA), cannabicyclol (CBL), and cannabicyclovarin (CBLV).
  • cannabielsoins examples include cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), and cannabielsoin (CBE).
  • cannabinols and cannabinodiols include cannabinolic acid (CBNA), cannabinol (CBN), cannabinol-C4 (CBN-Cr), cannabivarin (CBV), cannabinol- C2 (CBN-C2), cannabiorcol (CBN-Ci), cannabinodiol (CBND), and cannabinodivarin (CBVD).
  • cannabitriols examples include cannabitriol (CBT), 10-ethoxy-9-hydroxy-A- 6a-tetrahydrocannabinol, cannabitriolvarin (CBTV), and ethoxy-cannabitriolvarin (CBTYE).
  • Cannabifurans include dehydrocannabifuran (DCBF) and cannabifuran (CBF).
  • DCBF dehydrocannabifuran
  • CBF cannabifuran
  • cannabinoids include cannabichromanon (CBCN), 10-oxo- A-6a-tetrahydrocannabinol (OTHC), cannabiripsol (CBR), and trihydroxy -D-9- tetrahydrocannabinol (triOH-THC).
  • hydroxyl, methyl, and olefinic groups can be modified to enhance binding affinity to cannabinoid receptors CB1 or CB2.
  • the groups may be modified through acetylation, methylation, or neutralization to form salts. Examples of such derivatives are illustrated in structures (CM-1 ) through (CM-5):
  • CM-1 and CM-2 are acetylated, and (CM- 2) is also carboxylated.
  • the hydroxyl groups in derivative (CM-3) have been methylated.
  • the sodium and potassium salts of CBD are illustrated in derivatives (CM-4) and (CM-5).
  • Other salts, such as lithium or cesium, are also contemplated.
  • the cannabinoid is a cannabidiol or a cannabidiol derivative.
  • cannabidiol and “CBD” are intended to refer to the compound 2-[(1 R,6R)-6-lsopropenyl-3-methylcyclohex-2-en-1 -yl]-5-pentylbenzene-1 ,3- diol, which is also designated as CAS# 13956-29-1.
  • CBD is a major non-psychoactive constituent of cannabis, in contrast to delta-9-tetrahydrocannabinol (THC) which is limited in therapeutic applications due to its psychoactive effects.
  • THC delta-9-tetrahydrocannabinol
  • CBD can be provided as “full-spectrum CBD,” “broad spectrum CBD,” or “CBD isolate.”
  • Full-spectrum CBD includes cannabinoids, terpenes, and flavonoids, as well as other less plentiful components (sterols, thiols, phenols, lipids or waxes, and fibrous materials).
  • Full-spectrum CBD from cannabis includes CBD and THC as well as more than 100 minor cannabinoids present in small amounts; more than 150 terpenes which affect the plant’s fragrance; and about 20 different flavonoids.
  • Full-spectrum CBD can contain up to 0.3% THC.
  • CBD includes the same ingredients as fullspectrum CBD, except THC has been specifically removed.
  • CBD isolate is only CBD. These materials can be provided in liquid form or powder form, and can be produced using conventional manufacturing processes.
  • CBD and THC are derived from cannabigerol (CBG), which itself is a cannabinoid and is one of the higher concentration constituents of fullspectrum CBD and broad-spectrum CBD.
  • CBD cannabigerol
  • Synthetic CBD is chemically produced in the laboratory, and as such is also free of THC and other plant compounds. Such laboratory manufacturing processes are conventional. Synthetic CBD and CBD isolate may be generally referred to separately or together as synthetic CBD.
  • cannabidiol derivatives may include cannabidiol acetate and cannabidiol-2’,6’-dimethyl ether.
  • Other examples of cannabidiol derivatives may include conjugate molecules formed from an active agent which is linked to a cannabinoid moiety through a specified linker, such as the steroid-cannabinoid conjugates described in PCT publications WO 2020/263888 A1 and WO 2021/076197 A1 .
  • the cannabinoid is present in the compositions I formulations of the present disclosure in a pharmaceutically effective amount.
  • the cannabinoid is present in concentrations of from about 3 wt% to about 25 wt%, i.e. about 30 milligram per milliliter (mg/mL) to about 250 mg/mL.
  • the cannabinoid is present in concentrations of from about 0.1 wt% to about 25 wt%, i.e. about 1 milligram per milliliter (mg/mL) to about 200 mg/mL.
  • the cannabinoid is present in concentrations of from about 0.1 wt% to about 20 wt%, or from about 0.1 wt% to about 15 wt%, or about 0.1 wt% to about 10 wt%, or about 0.1 wt% to about 5 wt%, or about 1 wt% to about 20 wt%, or about 1 wt% to about 15 wt%, or about 1 wt% to about 10 wt%, or about 1 wt% to about 5 wt%.
  • concentrations may be suitable for use in cosmeceuticals or nutraceuticals.
  • the cannabinoid is CBD, which is present in concentrations of about 30 mg/mL to about 250 mg/mL, or about 30 mg/mL, or about 60 mg/mL, or about 90 mg/mL, or about 120 mg/mL, or about 150 mg/mL, or about 180 mg/mL, or about 210 mg/mL, or about 250 mg/mL, or in ranges bounded by any two of these values.
  • the cannabinoid in the compositions I formulations of the present disclosure is preferably a cannabinoid derived from natural products having no or low THC content, such as that produced by PureForm Global, Inc., Los Angeles, CA.
  • (B) Olive oil is a liquid fat or oil extracted from olives, the fruit of the olive tree,
  • O/ea europaea The oil is separated from the other vegetable material in olives by various types of mechanical or chemical extraction processes, such as by pressing.
  • Olive oil contains mainly high amounts of oleic acid, along with lower amounts of other fatty acids such as linoleic acid and palmitic acid.
  • Olive oil is believed to contain the following fatty acids in the approximate listed ranges (based on total weight of the oil) in Table 1 :
  • One measure of olive oil is the weight percent of free oleic acid. In the United States, extra virgin olive oil has a free fatty acid content of 0.8 wt% or less, and virgin olive oil has a free fatty acid content of 2 wt% or less.
  • the grade of the olive oil used in the compositions I formulations of the present disclosure is not believed to be significant other than its suitability for topical use, such as CAS# 8001 -25-0.
  • the olive oil may be modified to comprise at least 0.1 wt% of at least one molecule containing an aliphatic chain with at least one cyclopropyl or cyclopropenyl group.
  • the oil comprises from at least 0.1 wt% to about 12 wt% of the at least one molecule, or at least 0.1 wt% to about 10 wt% of the at least one molecule, including from about 0.5 wt% to about 5 wt%, or from about 1 wt% to about 4 wt%, or a range made from any combination of two of these listed endpoints.
  • Each molecule may be present in an amount within these ranges, or the total amount of such molecules in the oil may be within these ranges.
  • aliphatic refers to a hydrocarbon chain which is linear or branched, and which contains at least eight carbon atoms.
  • the carbon atoms of the cyclopropyl or cyclopropenyl group(s) are counted towards the number of carbon atoms in the hydrocarbon chain.
  • the hydrogen atoms on the hydrocarbon chain may be substituted with heteroatom-containing groups such as hydroxyl (-OH) or others, so long as the overall chain remains nonpolar and the molecule is insoluble in water.
  • Such molecules containing an aliphatic chain with at least one cyclopropyl or cyclopropenyl group may be natural or synthetic.
  • Non-limiting examples of such molecules include sterculic acid, malvalic acid, and dihydrosterculic acid.
  • Such molecules could be artificially synthesized, for example, by reacting an epoxy-containing molecule with a carboxylic acid containing a cyclopropyl group. The carboxylic acid group would react with the epoxy group to obtain a product that contains a hydroxyl group and the cyclopropyl group.
  • the molecule contains one or two cyclopropyl or cyclopropenyl groups.
  • each aliphatic chain contains up to 24 carbon atoms.
  • the molecule containing an aliphatic chain with at least one cyclopropyl or cyclopropenyl group is a cyclopropene fatty acid or a cyclopropane fatty acid (CPFA).
  • the fatty acid includes a carboxylic acid at the end of an aliphatic chain.
  • the fatty acid can be present in the form of a free fatty acid, or as an ester such as a triglyceride, phosopholipid, or a cholesteryl ester.
  • the cyclopropene fatty acid(s) are generally mono-unsaturated fatty acids (MLIFA), and not poly-unsaturated fatty acids.
  • the cyclopropane fatty acid(s) are generally saturated fatty acids. It is contemplated that the presence of CPFAs may improve the properties of the oil as a carrier for the cannabinoid. Thus, the addition of one or more CPFAs to an oil may result in a “synthetic” olive oil with improved performance.
  • the olive oil comprises from at least 0.1 wt% to about 12 wt% of the at least one CFPA, or at least 0.1 wt% to about 10 wt% of the at least one CFPA, including from about 0.5 wt% to about 5 wt%, or from about 1 wt% to about 4 wt%, or a range made from any combination of two of these listed endpoints.
  • Each CPFA may be present in an amount within these ranges, or the total amount of CPFAs in the oil may be within these ranges.
  • the CPFA is sterculic acid and/or malvalic acid and/or dihydrosterculic acid.
  • Sterculic acid is 8-(2-octylcycloprop-1 -en-1 -yl)octanoic acid, and contains a 9,10-cyclopropenyl group.
  • Malvalic acid is 7-(2-octylcycloprop-1 -en-1 - yl)heptanoic acid, and contains an 8,9-cyclopropenyl group.
  • Dihydrosterculic acid is similar to sterculic acid, but contains a 9,10-cyclopropyl group instead.
  • sterculic acid is present in an amount of about 0.4 wt% to about 6 wt% of the olive oil, or from about 0.4 to about 2 wt% of the olive oil.
  • malvalic acid is present in an amount of about 1 wt% to about 10 wt% of the olive oil, or from about 1 wt% to about 5 wt% of the olive oil.
  • dihydrosterculic acid is present in an amount of from about 1.5 wt% to about 12 wt% of the olive oil, including from about 1 .5 wt% to about 5 wt% of the olive oil. Any combination of two of these acids, or all three of these acids, may also be present in the olive oil, in an amount as listed.
  • the olive oil may further comprise vaccenic acid and/or heptadecenoic acid.
  • Vaccenic acid is (11 E)-octadec-11 -enoic acid.
  • vaccenic acid is present in an amount of about 0.5 wt% to about 3 wt% of the olive oil.
  • heptadecenoic acid is present in an amount of about 0.1 wt% to about 2 wt% of the olive oil. Both of these acids may also be present in the olive oil, in an amount as listed.
  • any combination of the CPFAs, along with vaccenic acid, and/or heptadecenoic acid, could be added to the olive oil to obtain a “synthetic” olive oil that has improved performance.
  • the cannabinoid may be better absorbed through the skin.
  • the olive oil acts as a solubilizer for the cannabinoid, particularly CBD, and serves as a carrier or vehicle for the cannabinoid.
  • the olive oil is thus present in the compositions I formulations of the present disclosure in an amount sufficient to act as a carrier or vehicle for the cannabinoid.
  • the olive oil can be present in an amount from about 75 wt% to about 97 wt% of the composition I formulation.
  • the olive oil is present in an amount of up to 27.75 wt% of the composition, including about 20 wt% to about 27 wt%.
  • the composition may also include (C) an emulsifier, which stabilizes the mixture by assisting in the mixing of aqueous and organic ingredients.
  • the emulsifier may be a surfactant, which itself may be anionic, nonionic, amphoteric, cationic, and zwitterionic surfactants, or a combination thereof.
  • Anionic surfactants are well-known to those skilled in the art. Examples include anionic sulfonate or sulfonic acid surfactants, alkylbenzene sulfonates, primary and secondary alkylsulfates, alkyl ether sulfates, and fatty acid ester sulfonates. These surfactants typically have from 9 to 22 carbon atoms. The sulfates can be linear or branched. Other suitable anionic surfactants can include fatty methyl ester sulfonates, alkyl ethyoxy sulfates (AES), and/or alkyl polyalkoxylated carboxylates (AEC). Mixutres are also contemplated. Salt forms of anionic surfactants are also contemplated.
  • nonionic surfactants include alkoxylated nonionic surfactants typically having from 6 to 22 carbon atoms. Such surfactants can be linear, branched, cyclic, or aromatic. Sometimes, the nonionic surfactant is derived from a primary or secondary alcohol. The nonionic surfactants can be "capped," wherein one or more -OH groups are replaced by -OR wherein R is typically C1-C3 alkyl.
  • Cationic surfactants can also be used. Examples include cationic esters and quaternary ammonium salts of the general formula RI R2RSR4N + X’, wherein the R groups are long or short hydrocarbyl chains, typically alkyl, hydroxyalkyl or ethoxylated alkyl groups, and X is a solubilizing group. Other examples of cationic surfactants include alkyltrimethylammonium salts or their hydroxyalkyl substituted analogs. The cationic surfactants can be either water-soluble or water-insoluble.
  • amphoteric surfactants include derivatives of aliphatic secondary and tertiary amines such as cocoamphoacetate, cocoamphodiacetate, lauroamphoacetate, lauroamphodiacetate, and mixtures thereof.
  • Examples of zwitterionic surfactants include derivatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, for example betaines. Amine oxide surfactants may also be used.
  • the emulsifier is sorbitan oleate, a nonionic surfactant with CAS# 1338-43-8.
  • Sorbitan oleate is commercially available as SPAN® 80 from Croda International PLC.
  • the emulsifier is present in the compositions I formulations of the present disclosure in an amount of up to 8 wt% of the composition. In more particular embodiments, the emulsifier is about 1 wt % to about 4 wt% of the composition, or about 2 wt% of the composition.
  • the composition may also contain (D) diethylene glycol monoethyl ether, which is CAS# 111-90-0, and is also known as TRANSCUTOL®, DGME, or DEGEE.
  • This ingredient is a solvent and solubilizer, and is associated with skin penetration enhancement that aids in topical application of the composition. In other words, this ingredient aids the composition in crossing the skin barrier.
  • the diethylene glycol monoethyl ether is present in the compositions I formulations of the present disclosure in an amount of up to about 15 wt% of the composition, including about 10 wt% to about 15 wt%, or about 13 wt%.
  • Polysorbate 80 is present in the compositions I formulations of the present disclosure in an amount of up to about 15 wt% of the composition, including about 10 wt% to about 15 wt%, or about 13 wt%.
  • the composition may also contain (E) polysorbate 80, which is CAS# 9005-65- 6. This ingredient is also known as TWEEN® 80 or polyoxyethylene (20) sorbitan monooleate. Polysorbate 80 is a nonionic surfactant, and acts as a stabilizer and emulsifier.
  • the polysorbate 80 is present in the compositions I formulations of the present disclosure in an amount of up to about 4 wt%, including about 1 wt% to about 4 wt%, or about 2 wt%.
  • the composition may also contain (F) a gelling agent or gellant, which aids in the formation of a gel or cream.
  • the gelling agent is a formulation containing about 20 wt% to about 40 wt% isohexadecane, with the balance being an acrylamide I acryloyldimethyltaurate copolymer, and polysorbate 80.
  • This formulation is commercially available as Sepineo® P600 from Seppic SA.
  • This formulation also acts as a thickening agent, an emulsifier, and/or a stabilizer. It is stable over a pH of 3 to 11 , and is nonthixotropic.
  • the gelling agent is present in the compositions I formulations of the present disclosure in an amount of up to about 5 wt%, including about 3 wt% to about 5 wt%, and about 4 wt%.
  • the composition may also contain (G) at least one fatty alcohol, which can act as an emollient, emulsifier, and/or thickening agent.
  • the fatty alcohol usually contains from 12 to 26 carbon atoms and is typically a primary alcohol.
  • Non-limiting examples of fatty alcohols include lauryl alcohol (C12), cetyl alcohol (C16), stearyl alcohol (C18), and oleyl alcohol (C18).
  • the fatty alcohol is cetostearyl alcohol, CAS# 67762-27-0, which is a mixture of predominantly cetyl alcohol and stearyl alcohol.
  • the fatty alcohol(s) is present in the compositions I formulations of the present disclosure in an amount of up to about 8 wt%, including from about 3 wt% to about 5 wt%, and about 4 wt%.
  • compositions I formulations of the present disclosure is (H) water.
  • water is present in an amount of about 33 wt% to about 50 wt%, including from about 36 wt% to about 45 wt%.
  • compositions I formulations of the present disclosure may include other ingredients besides the ingredients listed above.
  • Such ingredients may include an antioxidant, mineral oil, petrolatum, medium-chain triglycerides (MCT oil), sunflower oil and other components that provide structure or serve as stabilizers, thinners, thickeners, fragrances, moisturizers, emollients and/or ingredients that provide additional antiirritation or anti-inflammatory properties to the formulation.
  • MCT oil medium-chain triglycerides
  • sunflower oil and other components that provide structure or serve as stabilizers, thinners, thickeners, fragrances, moisturizers, emollients and/or ingredients that provide additional antiirritation or anti-inflammatory properties to the formulation.
  • the composition also includes (I) an antioxidant.
  • the antioxidant is butylated hydroxytoluene (BHT), which is CAS# 128-37-0.
  • BHT butylated hydroxytoluene
  • the antioxidant I BHT may be present in the amount of about 0.01 wt%.
  • the mineral oil is desirably an NF grade light mineral oil, which will not clog the pores of the skin.
  • United States Pharmacopeia (USP) standards should be met.
  • Petrolatum aka “petroleum jelly,” is useful in topical ointments as a carrier or base, as opposed to water-based cremes or gels.
  • Petrolatum is known to temporarily protect minor cuts, scrapes and burns, and for being effective in keeping skin moist during post-surgery healing.
  • Petrolatum comes in many grades.
  • pharmacy grade petrolatum will be used, such as white petrolatum USP meeting requirements for USP and FDA requirements of 21 CFR 172.880, which are commercially available.
  • Examples of additional emollients and oils that can be included in the topical formulation are medium-chain triglycerides (MCT oil), sunflower oil, long-chain triglycerides (LCT oil), long-chain fatty acids (e.g., myristic acid, palmitic acid, stearic acid, arachidic acid, linoleic acid), glycerine/glycerol, glycerol monolinoleate, coconut oil, corn oil, canola oil, avocado oil, vegetable oil, flaxseed oil, palm oil, palm kernel oil, peanut oil, rice bran oil, safflower oil, jojoba oil, argan oil, grapeseed oil, castor oil, wheat germ oil, peppermint oil, and sesame oil.
  • MCT oil medium-chain triglycerides
  • sunflower oil sunflower oil
  • long-chain fatty acids e.g., myristic acid, palmitic acid,
  • fragrances may also be variously and preferably included in the formulations disclosed herein, with fragrances typically at concentrations less than about 1 wt%.
  • compositions I formulation of the present disclosure comprise a pharmaceutically effective amount of a cannabinoid; and olive oil in an amount sufficient to act as a vehicle for the cannabinoid.
  • the amount of the cannabinoid may be from about 3 wt% to about 25 wt% of the composition.
  • the amount of the olive oil may be from about 75 wt% to about 97 wt% of the composition.
  • compositions I formulation of the present disclosure contain: about 3 wt% to about 25 wt% of a cannabinoid; up to 27.75 wt% of olive oil; up to 8 wt% of an emulsifier; up to 15 wt% of diethylene glycol monoethyl ether; up to 4 wt% of polysorbate 80; up to 5 wt% of a gelling agent; up to 8 wt% of a fatty alcohol; and balance water.
  • compositions I formulation of the present disclosure contain: about 3 wt% to about 25 wt% of the cannabinoid; about 20 wt% to about 27 wt% of the olive oil; about 1 wt% to about 4 wt% of the emulsifier; about 10 wt% to about 15 wt% of the diethylene glycol monoethyl ether; about 1 wt% to about 4 wt% of the polysorbate 80; about 3 wt% to about 5 wt% of the gelling agent; about 3 wt% to about 5 wt% of the fatty alcohol; and balance water.
  • compositions that consist essentially of: from about 3 wt% to about 25 wt% of a cannabinoid; about 27 wt% of olive oil; about 2 wt% of an emulsifier; about 13 wt% of diethylene glycol monoethyl ether; about 2 wt% of polysorbate 80; about 4 wt% of a formulation containing about 20 wt% to about 40 wt% isohexadecane, an acrylamide I acryloyldimethyltaurate copolymer, and polysorbate 80; about 4 wt% of a fatty alcohol; about 0.01 wt% of an antioxidant; and balance water.
  • compositions I formulations of the present disclosure can be made using methods known in the art.
  • the composition can be made by first mixing the cannabinoid with the olive oil and the diethylene glycol monoethyl ether to dissolve the cannabinoid, usually done at room temperature.
  • the emulsifier and fatty alcohol are then added and mixed at an elevated temperature such as about 55°C to about 60°C. This oil-phase mixture is then set aside.
  • an aqueous-phase mixture is made separately by combining water and polysorbate 80, and optional antioxidant if present and mixing. This can also be done at an elevated temperature such as about 55°C to about 60°C.
  • the oil-phase mixture and the aqueous-phase mixture are then combined and homogenized to form an emulsion. While mixing, the temperature is reduced.
  • the SepineoTM P600 (F) is added around 40°C, and mixing is continued until the temperature is reduced to room temperature.
  • compositions I formulations of the present disclosure are intended to be applied topically to the skin of the user / patient. This results in the active ingredient being delivered to local tissue.
  • the formulations may also operate transdermally, delivering the active ingredient across the skin and into systemic circulation.
  • the topical formulation may be in the form of a cream, gel, hydrogel, liquid, lotion, or ointment.
  • the topical formulation may be applied manually, sprayed, or by syringe, applicator, or other dispensing means.
  • the topical formulation could alternatively be provided in the form of a matrix-type delivery system, where the formulation is absorbed or suspended in a matrix that is then adhered to a backing membrane (commonly referred to as a bandage or a patch).
  • topical formulations of the present disclosure desirably have the advantages of efficacy, safety, tolerability, speed of healing, and lowered sensation of pain for the user I patient.
  • a single formulation may be used to treat or ameliorate radiation dermatitis. This is done by applying the topical formulation to the skin of the user I subject I patient. In some embodiments, the topical formulation is applied after the radiation exposure.
  • the duration of the treatment may be between 24 hours and 14 days. In another example, the duration of the treatment may be between 24 hours and 30 days. In another example, the duration of the treatment is between 1 month to 12 months. With respect to time, the application may be on a regular or irregular schedule, as desired.
  • the topical formulation is used as needed to ameliorate pain or assist in healing.
  • two different formulations are used together to treat or ameliorate radiation dermatitis.
  • a first formulation comprising a cannabinoid is administered to the patient for a first time period.
  • a second formulation comprising the cannabinoid is administered to the patient for a second time period.
  • the second formulation contains a higher dosage of the cannabinoid than the first formulation.
  • the formulations are made for topical application I administration.
  • the two formulations may be designed to have different permeation rates through the skin, too.
  • the first formulation contains about 3 wt% of the cannabinoid
  • the second formulation contains about 12 wt% of the cannabinoid.
  • the first formulation contains about 3 wt% to about 12 wt% of the cannabinoid
  • the second formulation contains about 12 wt% to about 25 wt% of the cannabinoid (but higher than the first formulation).
  • the second formulation contains at least 6 wt% (by absolute amt) more of the cannabinoid than the first formulation. For example, if the first formulation contains 3 wt%, the second formulation contains 9 wt% or more.
  • the second formulation contains at least 100% more (relative amt) of the cannabinoid than the first formulation, and up to 400% more. For example, if the first formulation contains 3 wt%, the second formulation contains 6 wt% or more.
  • the duration of the first time period and the second time period can vary, and do not need to be the same.
  • the first time period is from about 7 days to about 14 days.
  • the second time period is from about 7 days to about 14 days. In still other embodiments, the second time period is at least 7 days longer than the first time period.
  • the present disclosure in a further aspect includes providing a kit comprising the topical composition of the present disclosure; and in a further example providing a kit comprising the topical composition of the present disclosure and any or all of an applicator, such as a pad, utensil, spatula, sprayer or droplet dispenser; and / or a bandage, such as a dermal patch, wrap or other form of bandage and instructions for use thereof.
  • an applicator such as a pad, utensil, spatula, sprayer or droplet dispenser
  • a bandage such as a dermal patch, wrap or other form of bandage and instructions for use thereof.
  • a 3D in vitro skin model containing epidermal keratinocytes and dermal fibroblasts was used. Some tissues were irradiated with 200 mJ UVB I cm 2 . Test materials were applied topically for 24 hours (after UVB exposure) and an MTT assay was used to check the viability of cells. The following treatment groups were used:
  • CBD in olive oil in concentrations of 30, 60, 120, and 250 mg/mL;
  • Group A was compared to Group F, to show the effect of olive oil by itself on gene expression. Seven genes were found to have a linear fold change (FC) of 2 or greater. Those genes were ADRB2, ATP7A, FA2H, MT1 F, NOCT, PTGS2, and SERPINH1. FA2H, SERPINH1 , and PTGS2 are genes that promote epidermal barrier formation and pain and inflammation. ADRB2, ATP7A, and MT1 F are associated with pigmentation of skin. The expression of the NOCT gene was turned on, which plays a role in circadian rhythm regulation.
  • Groups G-K were compared to determine the effect of CBD dissolved in olive oil in UV exposed tissues.
  • Group K was used as the baseline.
  • the regulated genes were associated with cell renewal, tissue remodeling, anti-apoptotic pathway, and extracellular matrix integrity.
  • the regulated genes were associated with antioxidant/stress response.
  • Groups A-E were compared to determine the effect of CBD dissolved in olive oil on healthy tissues.
  • Group A was used as the baseline.
  • FC of 2 or greater was seen in only four genes, including IL20RA, IL24, MT1 G, and SPINK7.
  • the control group (Group 1 ) was not irradiated.
  • the animals in Groups 2-6 were anesthetized via a single intraperitoneal injection of xylazine and ketamine prior to being administered a single dose of 30 Grays (Gy) of radiation directed at a 2 cm x 4 cm patch of shaved dorsal skin on Day 0.
  • Radiation was generated by a 160 kVp (15-ma) X-ray source at a focal distance of 10 cm, hardened with a 0.35 mm Cu filtration system at a rate of approximately 3.2 Gy/m inute.
  • the animals were housed by group, 12 per cage. Four animals were euthanized on each of Days 0, 1 , and 14, and all remaining animals were euthanized on Day 28. Two of the 24 animals were euthanized due to excess weight loss, inability to eat, or moribundity. [0119] The animals in Groups 1 and 2 did not receive treatment. Dosing for animals in Groups 3-6 began on Day 0 immediately after radiation. Treatments were administered topically (0.1 mL per animal) daily from Days 0-28.
  • FIG. 1 is a graph showing percent weight change over time for the six groups. Generally, the 30 mg/mL and 120 mg/mL CBD-treated groups most closely followed the curve of the naive group. The differences between the three CBD-treated groups and the other three groups was not found to be statistically significant.
  • FIG. 2 is a graph showing the redness scoring over time for each group.
  • FIG. 3 is a graph showing the redness scoring over time, with the three CBD-treated groups condensed together. In both graphs, the naive group (Group 1 ) had redness score of zero (as expected).
  • FIG. 4 is a graph showing the blinded clinical dermatitis scoring over time for each group.
  • FIG. 5 is a graph showing the blinded clinical dermatitis over time, with the three CBD-treated groups condensed together. Again, in both graphs, the naive group (Group 1 ) had a dermatitis score of zero (as expected).
  • the irradiated animals (Group 2) had a significantly higher percentage of days with moderate dermatitis compared to the Olive oil only group (Group 3).
  • All CBD-treated groups (Groups 4, 5, 6) had a significantly lower percentage of days with moderate dermatitis compared to the irradiated group (Group 2).
  • the 30/mg/mL CBD group (Group 4) had a significantly lower percentage of days with moderate dermatitis compared to the Olive oil only group (Group 3).
  • SIMALINE L80 is a mixture of sorbitan oleate and PEG-30 dipolyhydroxystearate, CAS #s 1338-43-8 and 70142-34-6.
  • HPC is hydroxypropyl cellulose.
  • Poloxomer 407 is a triblock copolymer of with a central block of polypropylene glycol flanked by two blocks of polyethylene glycol, and is CAS# 691397-13-4.

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Abstract

La présente divulgation concerne des compositions topiques et des méthodes pour le traitement d'une radiodermite. Les compositions comprennent des formulations spécifiques d'un cannabinoïde et d'huile d'olive, conjointement avec d'autres ingrédients spécifiés.
PCT/US2023/012482 2022-02-11 2023-02-07 Compositions pour le traitement topique d'une radiodermite WO2023154264A1 (fr)

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US63/321,281 2022-03-18
US202263390933P 2022-07-20 2022-07-20
US63/390,933 2022-07-20
US17/982,909 US20230255900A1 (en) 2022-02-11 2022-11-08 Compositions for topical treatment of radiation dermatitis
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WO2017027553A1 (fr) * 2015-08-11 2017-02-16 KannaInnovations LLC Compositions topiques comprenant des hydroxyacides et des cannabinoïdes pour les soins de la peau
WO2019144190A1 (fr) * 2018-01-24 2019-08-01 Botanix Pharmaceuticals Ltd Régime de dosage de cannabinoïde pour dermatite et affections cutanées inflammatoires
WO2019234743A1 (fr) * 2018-06-06 2019-12-12 Icdpharma Ltd. Compositions synergiques anti-inflammatoires comprenant des cannabinoïdes et de la réglisse
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WO2020263888A1 (fr) 2019-06-24 2020-12-30 Diverse Biotech, Inc. Molécules conjuguées de cannabinoïdes
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WO2017027553A1 (fr) * 2015-08-11 2017-02-16 KannaInnovations LLC Compositions topiques comprenant des hydroxyacides et des cannabinoïdes pour les soins de la peau
WO2019144190A1 (fr) * 2018-01-24 2019-08-01 Botanix Pharmaceuticals Ltd Régime de dosage de cannabinoïde pour dermatite et affections cutanées inflammatoires
WO2019234743A1 (fr) * 2018-06-06 2019-12-12 Icdpharma Ltd. Compositions synergiques anti-inflammatoires comprenant des cannabinoïdes et de la réglisse
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