WO2009018389A1 - Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same - Google Patents

Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same Download PDF

Info

Publication number
WO2009018389A1
WO2009018389A1 PCT/US2008/071659 US2008071659W WO2009018389A1 WO 2009018389 A1 WO2009018389 A1 WO 2009018389A1 US 2008071659 W US2008071659 W US 2008071659W WO 2009018389 A1 WO2009018389 A1 WO 2009018389A1
Authority
WO
WIPO (PCT)
Prior art keywords
cannabidiol
ester
carbamate
carbonate
compound
Prior art date
Application number
PCT/US2008/071659
Other languages
French (fr)
Other versions
WO2009018389A4 (en
Inventor
Audra Lynn Stinchcomb
Miroslaw Jerzy Golinski
Jeffery Lynn Howard
Dana Carmel Hammell
Stan Lee Banks
Original Assignee
Alltranz 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
Application filed by Alltranz Inc. filed Critical Alltranz Inc.
Priority to MX2010001242A priority Critical patent/MX2010001242A/en
Priority to CN200880100836A priority patent/CN101815697A/en
Priority to JP2010520166A priority patent/JP2010535238A/en
Priority to EP08796904.4A priority patent/EP2176208B1/en
Priority to ES08796904.4T priority patent/ES2534900T3/en
Priority to DK08796904.4T priority patent/DK2176208T3/en
Priority to CA2694325A priority patent/CA2694325C/en
Publication of WO2009018389A1 publication Critical patent/WO2009018389A1/en
Publication of WO2009018389A4 publication Critical patent/WO2009018389A4/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/04—Antipruritics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/52—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C07C69/68—Lactic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • compositions for delivering pharmaceutically active agents both systemically and locally suitable for treating and preventing diseases and disorders, as well as improving cosmetic appearance.
  • cannabidiol cannabidiol
  • CBD cannabidiol
  • cannabidiol lacks the psychoactive effects seen in many of the other cannabinoids, including ⁇ 9 -tetrahydrocannabinol, which is currently available in an oral dosage, sold under the trade name Marinol ® .
  • cannabinoids can reduce a patient's nausea and vomiting, independent of any pain relief achieved.
  • cannabinoids are particularly useful in patients experiencing nausea and vomiting secondarily to un- or under-treated pain.
  • AUDs diagnostic criteria for alcohol use disorders
  • the consumption of excessive amounts of alcohol results in a complex array of pharmacological effects that directly impact the ability to treat the condition. These effects directly impact the brain and include progressive neurodegeneration, impaired executive function and dependence leading to withdrawal-induced negative effects.
  • cannabinoids including cannabidiol
  • neuroprotective, anxiolytic and anti-convulsant effects which may be effective in preventing additional brain damage in persons with AUDs, while simultaneously decreasing the frequency of relapses.
  • Dystonia is a neurological movement disorder, with many known causes, and characterized by involuntary, continual muscular contractions causing twisting and repetitive movements or abnormal postures. Cannabinoids have been shown to reduce the symptoms of muscular contractions characterizing this disorder.
  • the etiological pathology of many diseases relates to the inflammatory processes caused by an individual's immune system.
  • the inflammation may result from (1) an otherwise appropriate immunoresponse to an outside trauma, such as brain swelling secondary to a closed head injury; (2) an overactive immunoresponse such as with an allergic reaction or dermatitis; or (3) an inappropriate auto- immunoresponse such as what causes certain forms of multiple sclerosis, inflammatory bowel disorders and arthritis.
  • Cannabinoids have been shown to regulate various steps in the immune response and could show some therapeutic benefit in treatment of certain inflammatory diseases such as psoriatic arthritis.
  • Rheumatoid arthritis affects approximately 0.5-1% of the United States population, and autoimmune diseases in general affect more than 20 million Americans. The pain associated with rheumatoid arthritis can often be disabling. Cannabinoids have been found to be useful as adjunct treatment for rheumatoid arthritis and joint pain secondary to other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus.
  • cannabinoids, cannabidiol, and cannabidiol prodrugs present a variety of pharmacological benefits, including, but not limited to, anti- inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective anticancer and immunomodulatory effects.
  • cannabidiol undergoes substantial first-pass metabolism when absorbed from the human gut after oral administration. Further, the oral bioavailability of any product is further diminished when a patient suffers from nausea or emesis, as either they avoid taking their oral medication or the oral dosage form does not remain in the GI tract for a sufficient amount of time to achieve a therapeutic dose.
  • cannabidiol it would be desirable to deliver therapeutically effective amounts of cannabidiol to a mammal in need thereof for the treatment of one or more medical conditions, such as pain, nausea or appetite stimulation, by a route of administration that does not depend upon absorption from the gastrointestinal tract of the mammal and not subject to first-pass metabolism upon absorption from the gastrointestinal tract.
  • a route of administration that does not depend upon absorption from the gastrointestinal tract of the mammal and not subject to first-pass metabolism upon absorption from the gastrointestinal tract.
  • One non-oral route of administration for the systemic delivery of cannabidiol is transdermal.
  • cannabidiol is poorly absorbed through membranes such as the skin of a mammal, such as a human. Therefore, the success of transdermally administering therapeutically effective quantities of cannabidiol to a mammal in need of such treatment within a reasonable time frame and over a suitable surface area has been substantially limited.
  • the epidermis and dermis of many mammals contains enzymes which are capable of metabolizing active pharmaceutical agents which pass through the stratum corneum.
  • the metabolic process occurring in the skin of mammals, such as humans can be utilized to deliver pharmaceutically effective quantities of cannanbidiol to the systemic circulation of a mammal in need thereof.
  • prodrugs of cannabidiol that can be transdermally administered to a mammal, such as a human, so that the metabolic product resulting from metabolism in the skin is cannabidiol which is systemically available for the treatment of a medical condition such as pain, nausea or appetite stimulation.
  • compositions comprising cannabidiol prodrugs suitable for transdermal delivery to a mammal in need thereof and methods of using cannabidiol prodrugs.
  • compositions can be systemically administered by other means, including: oral, buccal, sublingual, injection, rectal, vaginal and intranasal.
  • the metabolic process occurring in mammals, such as humans, can also be utilized to deliver pharmaceutically effective quantities of cannabidiol to the systemic circulation of a mammal in need thereof.
  • prodrugs of cannabidiol that can be administered to a mammal, such as a human, so that the metabolic product resulting from metabolism in the skin is cannabidiol which is available for the treatment of a medical condition such as pain, nausea or appetite stimulation.
  • compositions comprising cannabidiol prodrugs suitable for delivery to a mammal in need thereof and methods of using cannabidiol prodrugs.
  • prodrug of cannabidiol capable of oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal delivery; compositions suitable for oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal, vaginal delivery comprising prodrugs of cannabidiol; and methods of using prodrugs of cannabidiol whereby the resulting metabolic product was cannabidiol which is systemically available to a mammal in a therapeutically effective amount.
  • cannabinoids including cannabidiol
  • cannabinoids have been found to have localized benefits from topical administration.
  • topically administered cannabinoids have been found to be useful to alleviate pain and other conditions originating near the surface of the skin, including but not limited to pain associated with post-herpetic neuralgia, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis and psoriatic arthritis.
  • topically administered cannabinoids have been found to be useful to alleviate pain and other conditions associated with deeper tissues, such as peripheral neuropathic pain, including but not limited to the peripheral neuropathic pain associated with diabetic neuropathy, ankylosing spondylitis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, posttraumatic osteoarthritis, synovitis, and juvenile rheumatoid arthritis.
  • peripheral neuropathic pain including but not limited to the peripheral neuropathic pain associated with diabetic neuropathy, ankylosing spondylitis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain,
  • cannabinoids When cannabinoids are administered topically to treat pain and other conditions associated with deeper tissues, including peripheral neuropathic pain, it maybe useful to co-administer cannabinoids systemically. Also, it has been found that the topical administration of cannabinoids, including cannabidiol, can inhibit the growth of hair.
  • cannabidiol or a prodrug thereof In order to achieve these local benefits, it is advantageous for cannabidiol or a prodrug thereof to penetrate the stratum corneum but not be absorbed systemically. In such a case, the cannabidiol would concentrate in the skin and/or pilosebaceous unit, thus maximizing its local effect. Not only does the localized effect increase the potential therapeutic benefit, it lessens the frequency and severity of side-effects associated with cannabinoid administration because the amount of active compound circulating in the patient is minimized.
  • the cannabidiol can be incorporated into a prodrug with an active moiety that would improve the appearance and/or hydration of the skin.
  • compositions suitable for topical delivery comprising prodrugs of cannabidiol and methods of using prodrugs of cannabidiol whereby the resulting metabolic product was cannabidiol which is available at the site of administration in a mammal in a therapeutically effective amount but is not absorbed systemically.
  • prodrugs of cannabidiol are prodrugs of cannabidiol, methods of making prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using prodrugs of cannabidiol.
  • Compounds described herein include pharmaceutically acceptable prodrugs of cannabidiol.
  • One embodiment described herein includes pharmaceutically acceptable prodrugs of cannabidiol which are suitable for non-oral administration and are metabolized to cannabidiol.
  • a further embodiment described herein includes pharmaceutically acceptable prodrugs of cannabidiol which are suitable for transdermal administration and are metabolized to cannabidiol.
  • the pharmaceutically acceptable prodrugs of cannabidiol may be in any suitable form for administration to a mammal such as in the form of a free base, free acid, salt, hydrate, anhydrate, enantiomer, isomer, tautomer, polymorph, derivative, or the like, provided that the free base, salt, hydrate, enantiomer, isomer, tautomer, or any other pharmacologically suitable derivative is therapeutically active or undergoes conversion within or outside of the body to a therapeutically active form of cannabidiol.
  • compositions described herein comprise at least one pharmaceutically acceptable prodrug of cannabidiol and are suitable for transdermal, oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal administration.
  • the compositions described herein optionally include a vehicle or carrier for the administration of a prodrug of cannabidiol as well as optionally including pharmaceutically acceptable excipients such as solvents, thickening agents, penetration enhancers, wetting agents, lubricants, emollients, binders, taste enhancers, disintegrates, substances added to mask or counteract a disagreeable odor, fragrances or tastes, and substances added to improve appearance or texture of the composition.
  • prodrug refers to a compound that undergoes a chemical conversion, through a metabolic process or otherwise within the body of the mammal receiving the compound, into its active form that has medical effects.
  • illustrative cannabidiol prodrugs include those compounds of Formula (I):
  • R and R 2 can be the same or different and are each independently comprised of a hydrogen and/or a bio-labile linker (e.g. ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, carbonate, alkyl carbonate, carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, or other suitable bio-labile linking structure) and further comprising moieties which can be selected in order to control the rate and extent of absorption and metabolism, including transdermal absorption and metabolism.
  • a bio-labile linker e.g. ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, carbonate, al
  • Ri and R 2 cannot both be a hydrogen atom.
  • Several options for Ri and R 2 are disclosed herein. Also included herein is the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, polymorph, or derivative thereof of compounds of Formula I.
  • Additional embodiments contemplated by the present disclosure include, but are not limited to, those described in WO2007044215, WO2007035945, US2007066657, WO2007026215, WO2007020502, WO2007017264, WO2007009720, US2007004772, US2006287324, US2006287323, US2006287342, US2006287341, US2006089378, US2006079556, US2005143441, US7109216, US2004235854, US2005267161, US2005054659, US2007099990, US2006122229, US2006122230, US2004077650, US6974810, US2004248944, US6977266 and US2006052411 and United States Pat. App. Nos. 10/032,163.
  • “Pharmaceutically acceptable salts,” or “salts,” include the salt of a cannabidiol prodrug suitable for administration to a mammal and includes those prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, beta-hydroxybutyric, galactaric and galacturonic acids.
  • the following list
  • acid addition salts are prepared from the free base forms using conventional methodology involving reaction of the free base with a suitable acid.
  • suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • organic and inorganic acids are not meant to be exhaustive but merely illustrative as person of ordinary skill in the art would appreciate that other acids may be used to create pharmaceutically acceptable salts of cannabidiol and prodrugs of cannabidiol.
  • an acid addition salt is reconverted to the free base by treatment with a suitable base.
  • the basic salts are alkali metal salts, e.g., sodium salt.
  • Ri or R 2 is an ester. In a further embodiment both Ri and R 2 are esters which can be the same or different.
  • the preparation of CBD esters involves functionalizing the hydroxyl groups that are present within the molecular structure of cannabidiol.
  • the esters of either or both of Ri and/or R 2 are oxygenated.
  • either or both of Ri and/or R 2 are oxygenated esters which are oxaesters.
  • either or both of Rj and/or R 2 are oxaesters which are pegylated.
  • either or both of Rj and/or R 2 are pegylated oxaesters can independently have 1 ethylene glycol repeat unit, 2 ethylene glycol repeat units, 3 ethylene glycol repeat units, 4 ethylene glycol repeat units, 5 ethylene glycol repeat units, 6 ethylene glycol repeat units, 7 ethylene glycol repeat units, 8 ethylene glycol repeat units, 9 ethylene glycol repeat units, 10 ethylene glycol repeat units, 11 ethylene glycol repeat units, 12 ethylene glycol repeat units, 13 ethylene glycol repeat units, 14 ethylene glycol repeat units and 15 ethylene glycol repeat units.
  • either or both of Ri and/or R 2 are esters which are hydroxylated.
  • Ri and/or R 2 are esters which are alkyl ester
  • either or both of Ri and/or R 2 are alkyl esters independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons
  • either or both of Ri and/or R 2 are esters which are amino esters independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups
  • hi another embodiment, either or both of Ri and/or R 2 are amino esters which are alkylamino ester
  • either or both of Ri and/or R 2 are alkylamino esters independently having 1 amino
  • ester is a glycolic acid ester. In another embodiment the ester is a glycolic acid ester, a hyluronic ester or a lactic acid ester. Esters can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
  • Ri or R 2 is a carbamate. In a further embodiment both Ri and R 2 are carbamates which can be the same or different.
  • the preparation of CBD carbamates involves functionalizing the hydroxyl groups that are present within the molecular structure of cannabidiol.
  • the carbamates of either or both of Ri and/or R 2 are oxygenated.
  • either or both of Ri and/or R 2 are oxygenated carbamates which are oxacarbamates.
  • Ri and/or R 2 are oxacarbamates which are pegylated.
  • Ri and/or R 2 are pegylated oxacarbamates can independently have 1 ethylene glycol repeat unit, 2 ethylene glycol repeat units, 3 ethylene glycol repeat units, 4 ethylene glycol repeat units, 5 ethylene glycol repeat units, 6 ethylene glycol repeat units, 7 ethylene glycol repeat units, 8 ethylene glycol repeat units, 9 ethylene glycol repeat units, 10 ethylene glycol repeat units, 11 ethylene glycol repeat units, 12 ethylene glycol repeat units, 13 ethylene glycol repeat units, 14 ethylene glycol repeat units and 15 ethylene glycol repeat units.
  • either or both of Ri and/or R 2 are carbamates which are hydroxylated.
  • Ri and/or R 2 are carbamates which are alkyl carbamates.
  • R i and/or R 2 are alkyl carbamates independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons.
  • Ri and/or R 2 are carbamates which are amino carbamates independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups. In another embodiment, either or both of Ri and/or R 2 are amino carbamates which are alkylamino carbamates.
  • Ri and/or R 2 are alkylamino carbamates independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups and independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons.
  • the carbamate is a glycolic acid carbamate, a hyluronic carbamate or a lactic acid carbamate. Carbamates can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
  • R] or R 2 is a carbonate.
  • both Ri and R 2 are carbonates which can be the same or different.
  • the preparation of CBD carbonates involves functionalizing the hydroxyl groups that are present within the molecular structure of cannabidiol.
  • the carbonates of either or both of Ri and/or R 2 are oxygenated.
  • either or both of Ri and/or R 2 are oxygenated carbonates which are oxacarbonates.
  • either or both of Ri and/or R 2 are oxacarbonates which are pegylated.
  • Ri and/or R 2 are pegylated oxacarbonates can independently have 1 ethylene glycol repeat unit, 2 ethylene glycol repeat units, 3 ethylene glycol repeat units, 4 ethylene glycol repeat units, 5 ethylene glycol repeat units, 6 ethylene glycol repeat units, 7 ethylene glycol repeat units, 8 ethylene glycol repeat units, 9 ethylene glycol repeat units, 10 ethylene glycol repeat units, 11 ethylene glycol repeat units, 12 ethylene glycol repeat units, 13 ethylene glycol repeat units, 14 ethylene glycol repeat units and 15 ethylene glycol repeat units.
  • either or both of Ri and/or R 2 are carbonates which are hydroxylated.
  • Ri and/or R 2 are carbonates which are alkyl carbonates.
  • R J and/or R 2 are alkyl carbonates independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons.
  • Ri and/or R 2 are carbonates which are amino carbonates independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups. In another embodiment, either or both of Ri and/or R 2 are amino carbonates which are alkylamino carbonates.
  • Ri and/or R 2 are alkylamino carbonates independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups and independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons.
  • the carbonate is a glycolic acid carbonate, a hyluronic carbonate or a lactic acid carbonate. Carbonates can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
  • compositions comprising: (a) a cannabidiol prodrug selected from the group consisting of:
  • Ri and R 2 are independently selected from hydrogen, ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, glycolic acid ester, hyaluronic acid ester, lactic acid ester, carbonate, oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate, lactic acid carbonate, carbamate, oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carb
  • a method of administering a compound to a mammal comprising the steps of: (a) combining a compound selected from the group consisting of:
  • Ri and R 2 are independently selected from hydrogen, ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, glycolic acid ester, hyaluronic acid ester, lactic acid ester, carbonate, oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate, lactic acid carbonate, carbamate, oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carb
  • Additional embodiments include methods of transdermally delivering a cannabidiol to a mammal comprising the steps of:
  • Ri and R 2 are independently selected from hydrogen, ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, glycolic acid ester, hyaluronic acid ester, lactic acid ester, carbonate, oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate, lactic acid carbonate, carbamate, oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carb
  • a further embodiment described herein is a method of treating a medical condition in a mammal comprising the steps of administering a cannabidiol prodrug selected from the group consisting of:
  • Ri and R 2 are independently selected from hydrogen, ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, glycolic acid ester, hyaluronic acid ester, lactic acid ester, carbonate, oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate, lactic acid carbonate, carbamate, oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carb
  • the resulting prodrug is more hydrophilic than cannabidiol and therefore more water soluble.
  • the logio values of the water/octanol partition coefficient (log P) for cannabidiol and various prodrugs of cannabidiol are shown in Table 15.
  • a further embodiment is a prodrug of cannabidiol having a log P value less than that of cannabidiol.
  • a further embodiment is a prodrug of cannabidiol having a log P value greater than that of cannabidiol.
  • a further embodiment is a prodrug of cannabidiol having a log P value which is approximately equal to that of cannabidiol.
  • compositions described herein can, if desired, include one or more pharmaceutically acceptable excipients.
  • excipient herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or combined with a therapeutic agent (e.g., to create a pharmaceutical composition) to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition.
  • Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening agents, penetration enhancers, wetting agents, lubricants, emollients, substances added to mask or counteract a disagreeable odor, fragrances or taste, and substances added to improve appearance or texture of the composition. Any such excipients can be used in any dosage forms according to the present disclosure.
  • the foregoing classes of excipients are not meant to be exhaustive but merely illustrative as a person of ordinary skill in the art would recognize that additional types of excipients could be used to achieve the desired goals for delivery of the cannabidiol prodrug.
  • compositions of the disclosure containing excipients can be prepared by any technique known to a person of ordinary skill in the art of pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine or other related discipline that comprises admixing an excipient with a drug or therapeutic agent.
  • the cannabidiol prodrugs described herein can be combined with a penetration enhancing agent for transdermal or topical delivery.
  • penetration enhancing agents include C8-C22 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters of C6-C22 diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)
  • the cannabidiol prodrugs can be combined with a thickening or gelling agent.
  • thickening agents aka gelling agents
  • anionic polymers such as polyacrylic acid (CARBOPOL® by Noveon, Inc., Cleveland, Ohio), carboxypolymethylene, carboxymethylcellulose and the like, including derivatives of Carbopol® polymers, such as Carbopol® Ultrez 10, Carbopol® 940, Carbopol® 941, Carbopol® 954, Carbopol® 980, Carbopol® 981, Carbopol® ETD 2001, Carbopol® EZ-2 and Carbopol® EZ-3, and other polymers such as Pemulen® polymeric emulsifiers, and Noveon® polycarbophils.
  • thickening agents may generally be found in Remington's The Science and Practice of Pharmacy as well as the Handbook f Pharmaceutical Excipients, Arthur H. Kibbe ed. 2000.
  • Thickening agents or gelling agents are present in an amount sufficient to provide the desired rheological properties of the composition.
  • one or more pharmaceutically acceptable thickening agent or gelling agent are present in a total amount by weight of about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%, about 5.0%, about 5.25%, about 5.5%, about 5.75%, about 6.0%, about 6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%, about 7.5%, about 7.75%, about 8.0%, about 8.25%, about 8.5%, about 8.75%, about 9.0%, about 9.25%, about 9.5%, about 9.75%, about 10%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5% or about 15%.
  • a neutralizing agent is optionally present to assist in forming a gel.
  • Suitable neutralizing agents include sodium hydroxide (e.g., as an aqueous mixture), potassium hydroxide (e.g., as an aqueous mixture), ammonium hydroxide (e.g., as an aqueous mixture), triethanolamine, tromethamine (2-amino 2-hydroxymethyl-l, 3 propanediol), aminomethyl propanol (AMP), tetrahydroxypropyl ethylene diamine, diisopropanolamine, Ethomeen C-25 (Armac Industrial Division), Di-2 (ethylhexyl) amine (BASF-Wyandotte Corp., Intermediate Chemicals Division), triamylamine, Jeffamine D- 1000 (Jefferson Chemical Co.), b- Dimethylaminopropionitrite (American Cyanamid Co.), Armeen CD (Armac Industrial Division), Alamine 7D (Henkel Corporation), dodecylamine and morph
  • the formulation is a gel, an ointment, a cream or a patch and comprises a cannabidiol prodrug, optionally a penetration enhancing agent, a thickening agent, a lower alcohol, such as ethanol or isopropanol; and water.
  • the formulation is a gel, an ointment, a cream or a patch, further comprised of an aqueous solution of sodium hydroxide or triethanolamine or an aqueous solution of potassium hydroxide, or a combination thereof, in an amount sufficient, as is known in the art, to assist the gelling agent in forming a gel.
  • a solution of sodium hydroxide is used, such as, e.g., 0.1 N sodium hydroxide solution, 0.2 N sodium hydroxide solution, 0.5 N sodium hydroxide solution, 1.0 N sodium hydroxide solution, 1.5 N sodium hydroxide solution, 2.0 N sodium hydroxide solution, or any other suitable solution for providing an amount sufficient of the aqueous sodium hydroxide to form the desired gel.
  • the composition results from combining a gelling agent with a neutralizing agent such as about 1% to about 10% (wt/wt) 0.1 N sodium hydroxide.
  • a neutralizing agent such as about 1% to about 10% (wt/wt) 0.1 N sodium hydroxide.
  • other suitable neutralizing agents can be used as can other concentrations of aqueous sodium hydroxide so long as there is a sufficient amount of OH " ions to assist in the formation of a gel.
  • Additional embodiments include the following compositions:
  • compositions described herein optionally comprise one or more pharmaceutically acceptable wetting agents as excipients.
  • surfactants that can be used as wetting agents in compositions of the disclosure include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetosteary
  • Such wetting agents constitute in total about 0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of the total weight of the composition.
  • one or more pharmaceutically acceptable wetting agents are present in a total amount by weight of about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%, about 5.0%, about 5.25%, about 5.5%, about 5.75%, about 6.0%, about 6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%, about 7.5%, about 7.75%, about 8.0%, about 8.25%, about 8.5%, about 8.75%, about 9.0%, about 9.25%, about 9.5%, about 9.75% or about 10%.
  • compositions described herein optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients.
  • suitable lubricants include, either individually or in combination, glyceryl behapate (e.g., CompritolTM 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g., SterotexTM); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., CarbowaxTM 4000 and CarbowaxTM 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
  • glyceryl behapate e.g., CompritolTM 888
  • stearic acid and salts thereof including magnesium
  • Such lubricants if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25% to about 5%, of the total weight of the composition.
  • one or more pharmaceutically acceptable lubricants are present in a total amount by weight of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%,
  • compositions described herein optionally comprise an emollient.
  • emollients include mineral oil, mixtures of mineral oil and lanolin alcohols, cetyl alcohol, cetostearyl alcohol, petrolatum, petrolatum and lanolin alcohols, cetyl esters wax, cholesterol, glycerin, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, lecithin, allyl caproate, althea officinalis extract, arachidyl alcohol, argobase EUC, butylene glycol dicaprylate/dicaprate, acacia, allantoin, carrageenan, cetyl dimethicone, cyclomethicone, diethyl succinate, dihydroabietyl behenate, dioctyl adipate, ethyl laurate, ethyl palmitate, ethyl stearate, is
  • An emollient if present, is present in the compositions described herein in an amount of about 1% to about 30%, about 3% to about 25%, or about 5% to about 15%, by weight.
  • one or more emollients are present in a total amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, by weight.
  • compositions described herein comprise an antimicrobial preservative.
  • anti-microbial preservatives include acids, including but not limited to benzoic acid, phenolic acid, sorbic acids, alcohols, benzethonium chloride, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium propionate, or thimerosal.
  • the anti-microbial preservative if present, is present in an amount of about 0.1% to about 5%, about 0.2% to about 3%, or about 0.3% to about 2%, by weight, for example about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 1.2%, about 1.4%, about 1.6%, about 1.8%, about 2%, about 2.2%, about 2.4%, about 2.6%, about 2.8%, about 3.0%, about 3.2%, about 3.4%, about 3.6%, about 3.8%, about 4%, about 4.2%, about 4.4%, about 4.6%, about 4.8%, or about 5%.
  • compositions described herein optionally compromise one or more emulsifying agents.
  • emulsifying agent refers to an agent capable of lowering surface tension between a non-polar and polar phase and includes compounds defined elsewhere as “self emulsifying” agents.
  • Suitable emulsifying agents can come from any class of pharmaceutically acceptable emulsifying agents including carbohydrates, proteins, high molecular weight alcohols, wetting agents, waxes and finely divided solids.
  • the optional emulsifying agent if present, is present in a composition in a total amount of about 1% to about 15%, about 1% to about 12%, about 1% to about 10%, or about 1% to about 5% by weight of the composition.
  • one or more emulsifying agents are present in a total amount by weight of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%.
  • the water immiscible solvent comprises propylene glycol, and is present in a composition in an amount of about 1% to about 99%, by weight of the composition, for example about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99%.
  • Binding agents may be either dry or wet. Dry binding agents may include simple and complex carbohydrates (e.g., sucrose, glucose, fructose, maltose, lactose, maltodextrins, starch, modified starches, mannitol, sorbitol, maltitol, xylitol, and erthritol), cellulose, and cellulosic derivatives (e.g., microcrystalline cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose).
  • simple and complex carbohydrates e.g., sucrose, glucose, fructose, maltose, lactose, maltodextrins, starch, modified starches, mannitol, sorbitol, maltitol, xylitol, and erthritol
  • cellulose e.g., cellulosic derivatives (e.g., microcrystalline cellulose, carboxymethyl cellulose, and hydroxyethy
  • Wet binder agents may include, polyvinyl pyrrolidone, methycellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, xanthan gum, carrageenan gum, locust bean gum, alginates, and acacia.
  • a person of ordinary skill in the art of pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine or other related discipline that comprises admixing an excipient with a drug or therapeutic agent to a composition would be able to select the appropriate binding agent and the relative concentration of the binding agent.
  • compositions described herein may contain disintegrants, such as sodium starch glycolate, crosspovidone, crosscarmellose, microcrystalline cellulose and starch.
  • disintegrants such as sodium starch glycolate, crosspovidone, crosscarmellose, microcrystalline cellulose and starch.
  • compositions disclosed herein may contain lubricants, such as magnesium stearate, stearic acid and its pharmaceutically acceptable salts, talc, vegetable oils, and waxes.
  • lubricants such as magnesium stearate, stearic acid and its pharmaceutically acceptable salts, talc, vegetable oils, and waxes.
  • compositions described herein may also optionally comprise one or more taste enhancers, such as sweeteners, including aspartame, acesulfame potassium, sucralose and saccharin or taste masking agents, such as flavorings.
  • taste enhancers such as sweeteners, including aspartame, acesulfame potassium, sucralose and saccharin or taste masking agents, such as flavorings.
  • sweeteners including aspartame, acesulfame potassium, sucralose and saccharin
  • taste masking agents such as flavorings.
  • compositions disclosed herein comprise one or more cannabidiol prodrugs in a total amount of between about 0.1% and about 95% by weight of the composition, for example about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95%.
  • terapéuticaally effective amount refers to an amount of compound or agent that is sufficient to elicit the required or desired therapeutic and/or prophylactic response, as the particular treatment context may require.
  • a therapeutically and/or prophylactically effective amount of a drug for a subject is dependent inter alia on the body weight of the subject as well as other factors known to a person of ordinary skill in the art.
  • a "subject" herein to which a therapeutic agent or composition thereof can be administered includes mammals such as a human subject of either sex and of any age, and also includes any nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or a horse as well as laboratory animals such as guinea pigs.
  • treat is to be broadly understood as referring to any response to, or anticipation of, a medical condition in a mammal, particularly a human, and includes but is not limited to:
  • a therapeutically effective amount of a cannabidiol prodrug is administered to treat a medical condition selected from the group consisting of: nausea, emesis, pain, wasting syndrome, HIV-wasting, chemotherapy induced nausea and vomiting, alcohol use disorders, dystonia, multiple sclerosis, inflammatory bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, systemic lupus erythematosus, anti-inflammatory, anti-convulsant, antipsychotic, anti-oxidant, neuroprotective, anti-cancer, immunomodulatory effects, peripheral neuropathic pain, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative
  • a medical condition selected
  • a single dosage unit of any formulation comprises a therapeutically effective amount or a therapeutically and/or prophylactically effective amount of a cannabidiol prodrug.
  • compositions described herein are suitable for transdermal administration.
  • transdermally administrable compositions are adapted for administration in and/or around the abdomen, back, chest, legs, arms, scalp or other suitable skin surface and may include formulations in which the cannabidiol prodrug is administered in patches, ointments, creams, suspensions, lotions, pastes, gels, sprays, foams or oils.
  • compositions described herein which are transdermally administrable include formulations in which the cannabidiol prodrug is placed in a glycol or gel formulation.
  • compositions described herein are suitable for topical administration.
  • topical administrable compositions are adapted for administration in and/or around the abdomen, back, chest, legs, arms, scalp or other suitable skin surface and may include formulations in which the cannabidiol prodrug is administered in patches, ointments, creams, suspensions, lotions, pastes, gels, sprays, foams or oils.
  • compositions described herein are suitable for oral administration.
  • compositions described herein that are orally administrable include formulations in which the cannabidiol prodrug is administered in tablets, capsules, suspensions, syrups or liquids.
  • the composition maybe formulated as extended release or long acting tablet or capsule, hi a further embodiment, the oral dosage form may be enteric coated using compositions and techniques known to a person of ordinary skill in the art.
  • compositions described herein are suitable for buccal administration.
  • compositions described herein that are bucally administrable may include formulations in which the cannabidiol prodrug is administered in lozenges, sprays, gels, pastes, dissolvable tablets or dissolvable strips.
  • compositions described herein are suitable for sublingual administration.
  • compositions described herein that are sublingually administrable may include formulations in which the cannabidiol prodrug is administered in lozenges, sprays, gels, pastes, dissolvable tablets or dissolvable strips.
  • compositions described herein are suitable for injectable administration.
  • compositions described herein that are injectably administrable may include formulations in which the cannabidiol prodrug is administered as an intravenous, intrathecal, subcutaneous or depot injection.
  • compositions described herein are suitable for rectal administration.
  • compositions described herein that are rectally administrable may include formulations in which the cannabidiol prodrug is placed in suppositories, ointments, creams, suspensions, solutions, lotions, pastes, gels, sprays, foams or oils.
  • compositions described herein are suitable for vaginal administration.
  • compositions described herein that are vaginally administrable may include formulations in which the cannabidiol prodrug is placed in suppositories, ointments, creams, suspensions, solutions, lotions, pastes, gels, sprays, foams or oils.
  • compositions described herein are suitable for ocular administration
  • compositions described herein that are ocularly administrable may include formulations in which the cannabidiol prodrug is placed in ointments, suspensions, solutions, gels or sprays.
  • compositions described herein are suitable for nasal administration.
  • compositions described herein that are nasally administrable may include formulations in which the cannabidiol prodrug is placed in ointments, suspensions, solutions, lotions, pastes, gels, sprays or mists.
  • the objective was to synthesize cannabidiol and cannabidiol prodrugs and assess the permeation of cannabidiol and its prodrugs through human abdominal skin in vitro. Cannabidiol and five cannabidiol prodrugs were synthesized and tested. Flow through diffusion cells were used for the permeation studies. HEPES -buffered Hanks' balanced salts containing 40% (polyethylene glycol) PEG 400 with gentamicin was used for the receiver compartment. Donor solution was comprised of either 100% propylene glycol (PG) solution or a rubbed in gel formulation. The flux and lag time values of cannabidiol and cannabidiol prodrugs were obtained from the permeation profiles. Drug accumulation in the skin after a 24 or 36 h diffusion experiment was determined as ⁇ mol/g wet tissue weight.
  • PG propylene glycol
  • prodrugs also have improved physiochemical properties that would make them suitable candidates for improved delivery via other routes of administration, including oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal.
  • the skin samples used in the following experiments were obtained from abdominal reduction surgery and dermatomed to a thickness of approximately 200 ⁇ m.
  • the skin samples used herein were frozen at -20 0 C for less than six months.
  • acetonitrile HPLC grade
  • trifluoroacetic acid triethylamine
  • 4-(2-hydroxy ethyl)-piperzine ethane sulfonic acid HPES
  • gentamicin sulfate p-toluene sulfonic acid
  • 4-dimethylaminopyridine isopropyl myristate (IPM)
  • IPM isopropyl myristate
  • sodium hydroxide sodium bicarbonate
  • Methanol HPLC grade
  • acetonitrile HPLC grade
  • 3-O-ethoxy-propionic acid diethyl ether, N ⁇ N'-dicyclohexyl carbodiimide, N,N-dimethylgylcine, polyethylene glycol 400 (PEG 400), and sodium sulfate anhydrous were purchased through VWR (West Chester, PA).
  • Propylene glycol (PG), olivetol, chloromethyl chloroformate, ethyl isocyanate, absolute ethanol, and Hanks' balanced salts modified powder were purchased from Sigma- Aldrich (St. Louis, MO).
  • Petroleum ether, ethyl acetate, hexane, chloroform, and dichloromethane were obtained from the University of Kentucky Chemical Stores (Lexington, KY). (+)-(lS,4R)-p-Mentha-2,8- dien-1-ol was purchased from Norac, Inc.(Azusa, CA). Carbopol ® 980 was obtained from Noveon, Inc. (Cleveland, OH). Nanopure water was obtained from a Barnstead filtration system (Dubuque, IA).
  • ⁇ -alanine,N,N-dimethyl (0.600 mg, 0.00512 mol), N,N'-dicyclohexyl carbodiimide (DCC) (1.05 g, 0.00512 mol), 4-dimethylaminopyridine (DMAP) (85 mg) were dissolved in dichloromethane (DCM) and stirred under nitrogen for 2 h; later cannabidiol (806 mg, 0.00264 mol) in DCM was added. The resulting reaction mixture stirred overnight and the solid was filtered on celite. The crude product was purified on silica column producing 300 mg (26.48%) of final compound (ALLOOlOl).
  • Cannabidiol (280 mg, 0.000890 mol) was added to activate DCC (550 mg, 0.00267 mol), DMAP (429 mg, 0.00133 mol), and N,N-dimethylglycine (275 mg, 0.002678 mol) in DCM at room temperature. After overnight stirring under nitrogen, the solid in the reaction mixture was filtered though celite and the reaction mixture purified on silica column by using chloroform and methanol (97:3) as eluent gave 70 mg of final compound (10.07%).
  • 1 L of receiver fluid was prepared by measuring 1 L of nanopure water into a graduated cylinder. 90% of the water was added to an Erlenmeyer flask. Hanks' salts (1 bottle) were added to the water along with 5.96 g of HEPES and 0.35 g of sodium bicarbonate. The pH of the solution was adjusted with 1 N sodium hydroxide solution to pH 7.4. The remaining water was added and the receiver fluid was filtered through a 0.2 ⁇ filter (Millipore, Billerica, MA). 50 mg of gentamicin was added to the filtered receiver fluid and 400 mL of the receiver fluid was removed and replaced with 400 mL of PEG 400.
  • Drugs were made up in either 100% PG or a gel formulation.
  • PG solution approximately 50- 120 mg of the appropriate drug was weighed into a glass silanized culture tube.
  • the gel formulation resulted from the mixing of absolute ethanol, nanopure water, IPM, Carbopol ® 980, 0.1 N aqueous sodium hydroxide solution and the respective drug.
  • Diffusion cells were kept at 32°C with a circulating water bath. Human epidermal skin was arranged in the diffusion cell with stratum corneum (upper layer of skin) facing the donor compartment. Permeation area of the skin was 0.95 cm 2 . Data was collected from a human skin donor with three to four diffusion cells per treatment.
  • Receiver solution was HEPES -buffered Hanks' balanced salts with gentamicin containing 40% PEG 400 at a pH of 7.4 and flow rate was adjusted to 0.8 mlVh.
  • Each cell was charged with 0.050 mL of the respective drug formulation (donor solution) or with 0.035 mL of gel formulation which was rubbed into the skin for 15 sec with a Teflon coated rod. The formulation was applied to ensure complete coverage. Diffusion cells were covered with a cap for the duration of the study.
  • the skin tissue was removed from the diffusion cell, rinsed with nanopure water, and blotted dry with a paper towel.
  • the skin was tape stripped twice using book tape (ScotchTM, 3M, St. Paul, MN) to remove drug formulation adhering to the tissue surface.
  • the area of skin in contact with the drug was cut out, chopped up and placed in a pre- weighed scintillation vial.
  • Ten rnL of acetonitrile was added to the vial and drug was extracted from the skin by shaking at room temperature overnight. The following day a 0.1 niL aliquot was removed and diluted with an additional 0.9 mL of acetonitrile. The diluted sample was added to the silanized HPLC vial for analysis.
  • ALLOOlOl and ALLOO 102 permeated through the human skin as cannabidiol. No intact prodrug was found in the diffusion samples (receiver samples) for either ALLOOlOl or ALL00102. Both cannabidiol and intact prodrug were found in the skin disposition (tissue) samples. ALLOOlOl and ALLOO 102 did have higher total cannabidiol in the skin compared to cannabidiol. No flux enhancement was seen with ALLOOlOl or ALL00102 prodrugs.
  • ALLOO 103 and ALLOO 104 did not permeate (or were below LOD) through the skin with both the PG donor solution and gel formulation. Some intact prodrug was found in the skin samples but very little cannabidiol was detected for ALLOO 103 and ALLOO 104. The mean flux enhancement between the two ALLOO 1005 gel formulation experiments was 2.5. ALLOO 105 permeated primarily as intact prodrug. The cumulative amount of total cannabidiol equivalents (nmol) delivered from ALL00105 was 3.1-5.9 fold higher when compared to cannabidiol. The same results were not seen with the propylene glycol donor solution which did not show any enhancement.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • n is the number of skin samples tested.
  • the objective was to synthesize cannabidiol prodrugs and assess the permeation of cannabidiol and various prodrugs of cannabidiol through human abdominal skin in vitro. Cannabidiol and numerous cannabidiol prodrugs were synthesized and several were tested. Flow through diffusion cells were used for the permeation studies. HEPES -buffered Hanks' balanced salts containing 40% PEG 400 with gentamicin or 40% aqueous PEG 400 with gentamicin were used for the receiver compartment. Donor solution was comprised of 90:8:2 PG:H 2 ⁇ :IPM solution or gel formulation. The flux and lag time values of cannabidiol and cannabidiol prodrugs were obtained from the permeation profiles. Drug accumulation in the skin after a 24, 30 or 42 h diffusion experiment was determined as ⁇ mol/g wet tissue weight.
  • prodrugs also have improved physicochemical properties that would make them suitable candidates for improved delivery via other routes of administration, including oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal.
  • the skin samples used in the following experiments were obtained from abdominal reduction surgery and dermatomed to a thickness of approximately 200 ⁇ m.
  • the skin samples used herein were frozen at -20 0 C for less than six months.
  • Ethyl acetate, hexane, and dichloromethane (DCM) were obtained from the University of Kentucky Chemical Stores (Lexington, KY).
  • (+)- (lS,4R)-p-Mentha-2,8-dien-l-ol and olivetol were purchased from Norac, Inc.(Azusa, CA).
  • Carbopol ® 980 was obtained from Noveon, Inc. (Cleveland, OH).
  • Cannabidiol was purchased from Cayman Chemical Company (Ann Arbor, MI).
  • Nanopure water was obtained from a Barnstead NANOpure ® DiamondTM Ultrapure water filtration system (Dubuque, IA).
  • Argon and pre-purified nitrogen were purchased from Scott Gross Company (Lexington, KY).
  • the compound 3,6,9,12-tetraoxatridecanoic acid was synthesized according to the procedures found in Macromolecules, 39 (12), 3978 -3979, 2006.
  • ALLOOlOl CBD bis(3-(dimethylamino)propionate)
  • ALL00150 CBD 3-(dimethylamino)propionate
  • Cannabidiol 100 mg, 0.00032 mol
  • 3-dimethylaminopropionic acid hydrochloride 123 mg, 0.00080 mol
  • DMAP 117 mg, 0.00096 mol
  • the solution was stirred for 5 min at ambient temperature.
  • DCC 198 mg, 0.00096 mol
  • the mixture was allowed to stir for 5 h at ambient temperature.
  • Hexane was added and the precipitate removed by filtration.
  • the solution was reduced to a small volume under nitrogen. ALLOOlOl and ALLOO 150 were separated and isolated using a semi-preparatory Cg column with ACN:water (70:30).
  • ACN was removed from the eluent fraction for each fraction by rotary evaporation. The remaining aqueous layer was partitioned with DCM and the DCM dried over sodium sulfate. DCM was removed under a nitrogen stream and vacuum. The purified products appeared as transparent, viscous oil with light amber color.
  • ALLOOlOl was analyzed by LC/MS (Waters; Milford, MA) in electrospray positive mode. Masses were observed at 513.42 (M+l, 70%), 257.34 (100%) and 123.06 (15%).
  • ALL00105 CBD bis(N,N-dimethylglycinate)
  • ALL00148 CBD N,N-dimethylglycinate
  • Cannabidiol 200 mg, 0.00064 mol
  • N,N-dimethylglycine 196.8 mg, 0.00191 mol
  • DMAP 38.9 mg, 0.00032 mol
  • the solution was stirred for 5 min at ambient temperature.
  • DCC (459.3 mg, 0.00223 mol) was added to mixture.
  • the mixture was allowed to stir overnight at ambient temperature.
  • Hexane was added and precipitate removed by filtration.
  • the solution was reduced to a small volume under nitrogen. ALLOO 105 and ALLOO 148 were separated and isolated using a semi-preparatory Cg column with ACNrwater (75:25).
  • ACN was removed from the eluent fraction for each fraction by rotary evaporation. The remaining aqueous layer was partitioned with DCM and DCM dried over sodium sulfate. DCM was removed under a nitrogen stream and vacuum. The purified products appeared as transparent, viscous oil with light amber color.
  • ALLOO 105 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 485.31 (M+l).
  • ALLOO 148 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 417.15 (M+18, 30%), 315.23 (CBD+1, 100%).
  • ALL00131 CBD 3,6,9, 12-tetraoxatridecanoate
  • ALL00132 CBD di(3, 6,9, 12-tetraoxatridecanoate)
  • Cannabidiol 100 mg, 0.00033 mol
  • 3,6,9,12-Tetraoxatridecanoic acid (98.9 mg, 0.00045 mol) prepared according to Macromolecules, 39 (12), 3978 -3979, 2006, and DMAP (11.7 mg, 0.00010 mol) were combined in 1 mL dry dichloromethane. The solution was stirred for 5 min at ambient temperature. DCC (111.4 mg, 0.00046 mol) was added to the mixture. The mixture was allowed to stir for 2 h at ambient temperature. Hexane was added and precipitate removed by filtration. The solution was reduced to a small volume under nitrogen.
  • ALLOOl 31 and ALLOO 132 were separated and isolated using a semi-preparatory silica column with hexane:ethyl acetate gradient. Solvent from each collected fraction was removed under vacuum. The purified products appeared as transparent, viscous oil with light amber color.
  • ALL00135 CBD 4-aminobutyl carbamate
  • ALL00136 CBD bis(4-aminobutyl carbamate)
  • Cannabidiol 44 mg, 0.00014 mol
  • Fmoc-4-aminobutyl isocyanate (68.0 mg, 0.00020 mol)
  • TEA 20 mg, 0.00038 mol
  • the solution was allowed to stir overnight.
  • the reaction mix was filtered.
  • the protected compounds were separated and isolated using a semi-preparatory silica column with hexane: ethyl acetate gradient. The solvent from each collected fraction was taken to dryness under a nitrogen stream and reconstituted in THF.
  • Solutions of DBU diluted 100-fold in THF
  • octanethiol diluted 10-fold in THF
  • ALLOO 135 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 429.26 (M+l, 100%), 315.16 (CBD+1, 65%), and 153.13 (22%).
  • ALLOO136 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 543.32 (M+l, 30%), 315.16 (CBD+1, 70%), 292.76 (100%) and 272.24 (45%).
  • ALL00137 CBD (S)-2,3-dihydroxypropanoate
  • ALL00139 CBD bis((S)-2,3-dihydroxypropanoate)
  • Cannabidiol 100 mg, 0.00032 mol
  • (S)-2,2-dimethyl-l,3-dioxalane-4-carboxylate 151.4 mg, 0.00035 mol
  • DMAP 11.7 mg, 0.00010 mol
  • the solution was stirred for 5 min at ambient temperature.
  • DCC 92.3 mg, 0.00045 mol
  • the mixture was allowed to stir overnight at ambient temperature.
  • Hexane was added and precipitate removed by filtration.
  • the solution was reduced to a small volume under nitrogen.
  • Acetonides of ALLOO 137 and ALLOO 139 were separated and isolated using a semi-preparatory silica column with hexane: ethyl acetate gradient. The solvent from each collected fraction was removed under vacuum. The purified products appeared as transparent, viscous oil with light amber color. Acetonides of ALLOO 137 and ALLOO 139 were deprotected using 1-octanethiol/zinc triflate and purified using silica column chromatography (HPLC) with hexane:ethyl acetate (7:3).
  • ALLOO 137 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 420.25 (M+l 8, 100%), 403.18 (M+l, 65%), 315.23 (CBD+1, 15%).
  • ALLOO 139 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 508.23 (M+ 18, 100%), 491.15 (M+l, 18%), 315.16 (CBD+1, 5%).
  • ALL00140 CBD 2-[2-(2-methoxyethoxy)ethoxy]acetate
  • ALL00141 CBD bis(2-[2-(2-methoxyethoxy)ethoxy]acetate)
  • Cannabidiol 105 mg, O.OOO33 mol
  • 2-[2-(2-methoxyethoxy)ethoxy] acetic acid 83.3 mg, 0.00047 mol
  • DMAP 12.3 mg, 0.00011 mol
  • ALLOO 140 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 492.37 (M+18, 100%) and 475.37 (M+l, 35%).
  • ALL00141 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 652.51 (M+18, 100%) and 635.52 (M+l, 10%).
  • Cannabidiol 42 mg, 0.00013 mol
  • acetyl chloride (26.3 mg, 0.00033 mol)
  • TEA 35 mg, 0.00039 mol
  • ALLOO 142 was isolated using silica column chromatography and hexane:ethyl acetate (9:1). The purified product appeared as transparent, viscous oil with light amber color.
  • ALL00142 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 416.22 (M+18, 100%), 399.14 (M+l, 10%).
  • Cannabidiol 44 mg, 0.00013 mol
  • methyl chloroformate 31.7 mg, 0.00034 mol
  • TEA 18.4 mg, O.OOO35 mol
  • ALLOO 143 was isolated using silica column chromatography and hexane:ethyl acetate (9:1). The purified product appeared as transparent, viscous oil with light amber color.
  • Cannabidiol 150 mg, 0.00043 mol
  • formic acid 59.25 mg, 0.00129 mol
  • DMAP 36.6 mg, 0.00030 mol
  • the solution was stirred for 5 min at ambient temperature.
  • DCC 150 mg, 0.00142 mol
  • Hexane was added and precipitate removed by filtration.
  • the solution was reduced to a small volume under nitrogen.
  • ALLOO 145 and ALLOO 146 were separated and isolated using a semi-preparatory silica column with hexane:ethyl acetate (97:3). The solvent from each collected fraction was removed under vacuum.
  • the purified products appeared as transparent, viscous oil with light amber color.
  • Cannabidiol bis((t-butyldimethylsilyloxy)acetate) was dissolved in dichloromethane (0.2 mL), cooled to -15°C and treated with 0.2 mL of cold 2 M solution of triethylamine trihydrofluoride. The reaction mixture was left at 5°C for 65 h. The mixture was poured into an excess of aqueous saturated sodium bicarbonate/ethyl acetate cooled to 0 0 C with vigorous stirring. The aqueous layer was extracted twice with ethyl acetate, combined organic extracts were dried over anhydrous sodium sulfate and concentrated.
  • Cannabidiol (t-butyldimethylsilyloxy)acetate (80 mg) was dissolved in dry dichloromethane (0.25 mL), cooled to -15°C and treated with 0.25 mL of cold 2 M solution of triethylamine trihydrofluoride in dichloromethane. The reaction mixture was left at 5°C for 65 h. The mixture was poured to an excess of aqueous saturated sodium bicarbonate/ethyl acetate cooled to O 0 C with vigorous stirring. Aqueous layer was extracted twice with ethyl acetate, the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated.
  • Cannabidiol L-(t-butyldimethylsilyl)lactate (15.1 mg) was dissolved in dry dichloromethane (0.1 mL), cooled to -15°C and treated with 0.1 mL of cold 2M solution of triethylamine trihydrofluoride in dichloromethane. The reaction mixture was left at 5 0 C for 65 h. The mixture was poured to an excess of aqueous saturated sodium bicarbonate/ethyl acetate cooled to 0 0 C with vigorous stirring. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with hexane-ethyl acetate (gradient 10:1, 6:1, 4: 1) to afford 9.8 mg (82 %) of CBD L-lactate (ALL00151) as an oil.
  • One or both of the hydroxyl groups on the cannabidiol molecule can be functionalized with various substituents (e.g., hyaluronic acid, lactic acid and glycolic acid) and optionally combined with dermatologically acceptable vehicles to form a cosmetic composition for application to the skin of mammal, such as a human.
  • substituents e.g., hyaluronic acid, lactic acid and glycolic acid
  • dermatologically acceptable vehicles e.g., hyaluronic acid, lactic acid and glycolic acid
  • the scheme below represents a possible method for attachment of cannabidiol to hyaluronic acid using carbonate linkage and the TBDMS ether as a protective group. It may be anticipated that most of the primary hydroxyl group of the polymer would be involved in the formation of the linkage to the drug. Additional and/or different sets of protective group/deprotection methods could be used.
  • glycolic acid and lactic acid could be attached to either or cannabidiol hydroxyl groups through an ester linkage or with the carbonate linkage by use of the 2-hydroxy group of acids.
  • Cannabidiol could be also attached in a similar manner to a polymeric compound, such as hyaluronic acid. Using an additional spacer (e.g. 2-aminoethanol or glycine), the attachment in all cases could also be achieved through a carbamate linkage.
  • cannabidiol may be attached to carboxylic groups of + acid through the ester linkage or through a carbamate linkage through the use of an additional spacer (e.g. 2-aminoethanol).
  • an additional spacer may also be used when attaching cannabidiol to hydroxyl groups of hyaluronic acid.
  • One ( 1) L of receiver fluid was prepared by measuring 1 L of nanopure water into a graduated cylinder. 90% of the water was added to an Erlenmeyer flask. Hanks' salts (1 bottle) were added to the water along with 5.96 g of HEPES and 0.35 g of sodium bicarbonate. The pH of the solution was adjusted with 1 N sodium hydroxide solution to pH 7.4. The remaining water was added and the receiver fluid was filtered through a 0.2 ⁇ filter (Millipore, Billerica, MA). Fifty (50) mg of gentamicin was added to the filtered receiver fluid and 400 mL of the receiver fluid was removed and replaced with 400 mL of PEG 400.
  • the receiver fluid was prepared by measuring 600 mL of nanopure H 2 O into a graduated cylinder.
  • the H 2 O was filtered through a 0.2 ⁇ filter (Millipore, Billerica, MA). Fifty (50) mg of gentamicin was added to the filtered H 2 O and 400 mL of PEG 400 was added.
  • the prodrugs were made up in a solution of 45:4: 1 PG:H 2 O:IPM.
  • the appropriate amount of drug was weighed into a glass silanized culture tube and IPM was added, the 50 ⁇ L of PG to coat the drug, then an additional 247 ⁇ L PG was added and the donor solution was vortexed again. Finally 26 ⁇ L of water was added.
  • the gel formulation resulted from the mixing of absolute ethanol, nanopure water, IPM, Carbopol ® 980, 0.1 N sodium hydroxide solution and the respective drug.
  • the gel formulation was comprised of absolute ethanol, nanopure water, IPM, Carbopol® 980, 0.1 sodium hydroxide solution and respective drug.
  • the anhydrous gel was comprised of absolute ethanol, PEG monoethyl ether 550, Klucel® hydroxypropylcellulose, and respective drug.
  • Diffusion cells were kept at 32°C with a circulating water bath. Human epidermal skin was arranged in the diffusion cell with stratum corneum (upper layer of skin) facing the donor compartment. The permeation area of the skin was 0.95 cm 2 . The data was collected from a human skin donor with three diffusion cells per treatment.
  • the receiver solution was HEPES -buffered Hanks' balanced salts with gentamicin containing 40% PEG 400 at a pH of 7.4 or 40% aqueous PEG 400 and flow rate was adjusted to 0.8 mL/h.
  • Each cell was charged with 0.10 mL of the respective drug formulation (donor solution) or 50 ⁇ L of gel formulation which was rubbed into the skin for 15 sec with a Teflon coated rod. The formulation was applied to ensure complete coverage. The formulation was applied to ensure complete coverage. Diffusion cells were covered with a stopper or cap for the duration of the study.
  • the skin tissue was removed from the diffusion cell, rinsed with nanopure water, and blotted dry with a paper towel.
  • the skin was tape stripped twice using book tape (ScotchTM, 3M, St. Paul, MN) to remove drug formulation adhering to the tissue surface.
  • the area of skin in contact with the drug was cut out, chopped up and placed in a pre- weighed scintillation vial.
  • Ten (10) mL of acetonitrile was added to the vial and drug was extracted from the skin by shaking at room temperature overnight. The following day a 1 mL aliquot was removed transferred into a silanized HPLC vial for analysis.
  • the skin tissue was rinsed 3 times with nanopure water for 10 s each and wiped off with an alcohol pad.
  • the entire piece of skin was blotted dry and tape stripped twice using book tape 845 (Scotch , 3M, St. Paul, MN) to remove any drug formulation adhering to the surface.
  • the skin was rinsed an additional time with nanopure water and blotted dry again.
  • the area of skin in contact with the drug was removed, minced with a scalpel, and placed in a pre-weighed scintillation vial. Drug was extracted from the area of skin in contact with the drug by equilibrating with 10 mL of ACN while shaking in a water bath overnight.
  • the cumulative quantity of drug collected in the receiver compartment was plotted as a function of time.
  • the flux value for a given experiment was obtained from the slope of a steady-state portion of the cumulative amount of drug permeated vs. time plot.
  • Lag time was obtained from the x-intercept of the steady state portion of the cumulative amount of drug permeated vs. time plot.
  • total cannabidiol the combined results of the delivered prodrug and cannabidiol from the prodrug are listed as "total cannabidiol.” These values represent the data as total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug.
  • the cannabidiol prodrugs synthesized in Example 2 were all oily compounds.
  • ALLOOlOl permeated through the skin as mono-substituted prodrug (ALL00150) only. ALLOOlOl did not increase the flux compared to cannabidiol. ALLOOlOl was detected in the skin as trace small amounts of intact prodrug but mostly as mono- substituted prodrug, ALLOO 150, and cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time was decreased compared to cannabidiol.
  • ALL00148 mono-substituted prodrug
  • ALL00105 did not increase the flux compared to cannabidiol.
  • ALL00105 was detected in the skin as mono-substituted prodrug, ALL00148, and cannabidiol.
  • Total skin concentrations were higher compared to cannabidiol.
  • Lag time was not decreased compared to cannabidiol.
  • ALLOOl 31 permeated through the skin as intact prodrug and cannabidiol. ALL00131 did not increase the flux compared to cannabidiol. ALL00131 was detected in the skin only as prodrug. Total skin concentrations were not higher compared to cannabidiol. Lag time was similar to cannabidiol.
  • ALLOO 132 permeated through the skin as intact prodrug, mono- substituted prodrug (ALL00131), and cannabidiol. ALL00132 did not increase the flux compared to cannabidiol. ALLOO 132 was detected in the skin as prodrug and small amounts as mono-substituted prodrug, ALL00131. Total skin concentrations were not higher compared to cannabidiol. Lag time wasn't decreased compared to cannabidiol.
  • ALLOOl 37 did not permeate through the skin or was below detection in the receiver samples. ALLOO 137 was detected in the skin as prodrug and trace amounts of cannabidiol. Total skin concentrations were not higher compared to cannabidiol.
  • ALLOO 140 permeated through the skin as intact prodrug and cannabidiol.
  • ALL00140 did not increase the flux compared to cannabidiol.
  • ALL00140 was detected mostly as prodrug in the skin with small amounts of cannabidiol.
  • Total skin concentrations were not higher compared to cannabidiol.
  • Lag time was slightly decreased compared to cannabidiol.
  • ALLOO 142 did not permeate through the skin or was below detection in the receiver samples. ALLOO 142 was detected in the skin only as intact prodrug. Total skin concentrations were not higher compared to cannabidiol.
  • ALLOO 143 did not permeate through the skin or was below detection in the receiver samples. ALL00143 was detected in the skin as prodrug and trace amounts of cannabidiol. Total skin concentrations were not higher compared to cannabidiol.
  • ALLOO 145 permeated through the skin as approximately 50% mono-substituted prodrug (ALL00146) and approximately 50% cannabidiol. ALL00145 did not increase the flux compared to cannabidiol. ALLOO 145 was detected in the skin as prodrug, mono-substituted prodrug, ALLOO 146, and cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time wasn't decreased compared to cannabidiol.
  • ALLOO 146 permeated through the skin through the skin as intact prodrug and cannabidiol.
  • ALLOO 146 did slightly increase the flux compared to cannabidiol.
  • ALL00146 was detected in the skin as intact prodrug and cannabidiol.
  • Total skin concentrations were not higher compared to cannabidiol.
  • Lag time was similar to cannabidiol.
  • ALLOO 147 permeated through the skin as intact prodrug, mono- substituted prodrug (ALL00149), and cannabidiol. ALL00147 did not increase the flux compared to cannabidiol. ALLOO 147 was detected in the skin as prodrug, mono-substituted prodrug, ALL00149, and cannabidiol. Total skin concentrations were not higher compared to cannabidiol. Lag time was not decreased compared to cannabidiol.
  • ALLOO 148 permeated through the skin through the skin as intact prodrug only. ALL00148 did not increase the flux compared to cannabidiol. ALL00148 was detected in the skin as mostly intact prodrug and small amounts of cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time was similar to cannabidiol.
  • Decreased lag time may benefit patients by delivering the drug more quickly which is beneficial for pain management and nausea. Long lag times are more useful for topical and follicular therapies where drug absorption is attenuated. Cannabidiol prodrugs may increase permeation more if drug solution solvent systems were optimized or if they were formulated with enhancers. Many of these prodrugs may be useful in targeting topical/follicular applications instead of transdermal applications. By targeting topical administration, drug delivery could focus on a localized delivery compared to a systemic delivery. Also, follicular delivery may be targeted for administration with or without microparticle formulations.
  • ALLOO 146 permeated through the skin as cannabidiol only, no prodrug was detected in the receiver fluid. ALL00146 didn't increase the flux compared to cannabidiol. ALLOO 146 was detected in the skin as small amount of cannabidiol with the remaining being prodrug. Total skin concentrations were slightly higher compared to cannabidiol. Lag time was higher compared to cannabidiol. [00257] In gel formulation, ALLOO 150 did not permeate through the skin. ALLOO 150 was detected in the skin as primarily ALLOO 150 with a small amount of cannabidiol. Total skin concentrations were higher compared to cannabidiol.
  • ALLOO 150 did not permeate through the skin. ALLOO 150 was detected in the skin as ALLOO 150 and cannabidiol. Total skin concentrations were higher compared to cannabidiol.
  • Total skin concentrations were't higher compared to cannabidiol.
  • ALL00149 did increase the flux compared to cannabidiol by 1.4.
  • ALL00149 was detected in the skin as primarily ALL00149 with a trace amount of cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time of ALLOO 149 was lower compared to cannabidiol.
  • n the number of skin samples tested.
  • total CBD total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug Wherein "n” equals the number of skin samples tested.
  • the terms "about” and “approximately” when referring to a numerical value shall have their plain and ordinary meanings to a person of ordinary skill in the art to which the disclosed subject matter is most closely related or the art relevant to the range or element at issue.
  • the amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors which may be considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed subject matter, as well as other considerations known to those of skill in the art.
  • the use of differing amounts of significant digits for different numerical values is not meant to limit how the use of the words “about” or “approximately” will serve to broaden a particular numerical value or range.
  • any ranges, ratios and ranges of ratios that can be formed by, or derived from, any of the data disclosed herein represent further embodiments of the present disclosure and are included as part of the disclosure as though they were explicitly set forth. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary. Accordingly, a person of ordinary skill in the art most closely related to a particular range, ratio or range of ratios will appreciate that such values are unambiguously derivable from the data presented herein.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Psychiatry (AREA)
  • Biotechnology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Toxicology (AREA)
  • Communicable Diseases (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Described herein are cannabidiol prodrugs, methods of making cannabidiol prodrugs, formulations comprising cannabidiol prodrugs and methods of using cannabidiols. One embodiment described herein relates to the transdermal or topical administration of a cannabidiol prodrug for treating and preventing diseases and/or disorders.

Description

PRODRUGS OF CANNABIDIOL, COMPOSITIONS COMPRISING PRODRUGS OF CANNABIDIOL AND METHODS OF USING THE SAME
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 601952,146 filed on July 30, 2007 and is hereby incorporated by reference.
FIELD
[0002] Described herein are pharmaceutically active agents (e.g., prodrugs of cannabidiol) suitable for local and systemic delivery to a mammal, including systemic transdermal delivery and topical delivery; compositions for delivering pharmaceutically active agents both systemically and locally; and the use of such compositions in treating and preventing diseases and disorders, as well as improving cosmetic appearance.
BACKGROUND
[0003] The clinical usefulness of the cannabinoids, including cannabidiol ("CBD"), to provide analgesia and neuroprotection, reduce inflammation, help alleviate nausea and emesis, as well as treat epilepsy, anxiety disorders, and glaucoma, has been well-recognized. In addition, it is also well-known that cannabidiol lacks the psychoactive effects seen in many of the other cannabinoids, including Δ9-tetrahydrocannabinol, which is currently available in an oral dosage, sold under the trade name Marinol®.
[0004] Pain is the most frequently reported symptom and it is a common clinical problem which confronts the clinician. Millions of people in the USA suffer from severe pain that, according to numerous recent reports, is chronically under-treated or inappropriately managed. Similarly, millions of people also suffer from severe nausea and/or frequent emesis. Moreover, all too frequently, many patients suffering from chronic, under-treated or unretractable pain also suffer from lack of appetite, nausea and/or frequent emesis, such that a patient is unable to receive effective therapeutic doses of oral pain medications, thereby exacerbating their pain. Cannabinoids, including cannabidiol, are effective in alleviating pain. Moreover, cannabinoids, including cannabidiol, can reduce a patient's nausea and vomiting, independent of any pain relief achieved. Thus cannabinoids are particularly useful in patients experiencing nausea and vomiting secondarily to un- or under-treated pain. [0005] A notable percentage of the U.S. population satisfy the diagnostic criteria for alcohol use disorders ("AUDs"). The consumption of excessive amounts of alcohol results in a complex array of pharmacological effects that directly impact the ability to treat the condition. These effects directly impact the brain and include progressive neurodegeneration, impaired executive function and dependence leading to withdrawal-induced negative effects. It is known that the cannabinoids, including cannabidiol, have neuroprotective, anxiolytic and anti-convulsant effects, which may be effective in preventing additional brain damage in persons with AUDs, while simultaneously decreasing the frequency of relapses.
[0006] Dystonia is a neurological movement disorder, with many known causes, and characterized by involuntary, continual muscular contractions causing twisting and repetitive movements or abnormal postures. Cannabinoids have been shown to reduce the symptoms of muscular contractions characterizing this disorder.
[0007] The etiological pathology of many diseases relates to the inflammatory processes caused by an individual's immune system. The inflammation may result from (1) an otherwise appropriate immunoresponse to an outside trauma, such as brain swelling secondary to a closed head injury; (2) an overactive immunoresponse such as with an allergic reaction or dermatitis; or (3) an inappropriate auto- immunoresponse such as what causes certain forms of multiple sclerosis, inflammatory bowel disorders and arthritis. Regardless of the underlying cause of the inflammation, it is therapeutically desirable under these circumstances to regulate the immune system and lessen the inflammatory response. Cannabinoids have been shown to regulate various steps in the immune response and could show some therapeutic benefit in treatment of certain inflammatory diseases such as psoriatic arthritis.
[0008] Rheumatoid arthritis affects approximately 0.5-1% of the United States population, and autoimmune diseases in general affect more than 20 million Americans. The pain associated with rheumatoid arthritis can often be disabling. Cannabinoids have been found to be useful as adjunct treatment for rheumatoid arthritis and joint pain secondary to other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus.
[0009] In addition to the above-discussed therapeutics benefits, cannabinoids, cannabidiol, and cannabidiol prodrugs present a variety of pharmacological benefits, including, but not limited to, anti- inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective anticancer and immunomodulatory effects.
[0010] Given these systemic therapeutic benefits, it would be advantageous to develop a composition in which cannabidiol is delivered to achieve a therapeutically effective concentration in a patient. Unfortunately, as with the other cannabinoids, cannabidiol undergoes substantial first-pass metabolism when absorbed from the human gut after oral administration. Further, the oral bioavailability of any product is further diminished when a patient suffers from nausea or emesis, as either they avoid taking their oral medication or the oral dosage form does not remain in the GI tract for a sufficient amount of time to achieve a therapeutic dose.
[0011] Therefore, in view of the foregoing, it would be desirable to deliver therapeutically effective amounts of cannabidiol to a mammal in need thereof for the treatment of one or more medical conditions, such as pain, nausea or appetite stimulation, by a route of administration that does not depend upon absorption from the gastrointestinal tract of the mammal and not subject to first-pass metabolism upon absorption from the gastrointestinal tract. One non-oral route of administration for the systemic delivery of cannabidiol is transdermal.
[0012] Unfortunately, due to its highly hydrophobic nature, cannabidiol is poorly absorbed through membranes such as the skin of a mammal, such as a human. Therefore, the success of transdermally administering therapeutically effective quantities of cannabidiol to a mammal in need of such treatment within a reasonable time frame and over a suitable surface area has been substantially limited.
[0013] However, the epidermis and dermis of many mammals, such as humans and guinea pigs, contains enzymes which are capable of metabolizing active pharmaceutical agents which pass through the stratum corneum. The metabolic process occurring in the skin of mammals, such as humans, can be utilized to deliver pharmaceutically effective quantities of cannanbidiol to the systemic circulation of a mammal in need thereof. Described herein are prodrugs of cannabidiol that can be transdermally administered to a mammal, such as a human, so that the metabolic product resulting from metabolism in the skin is cannabidiol which is systemically available for the treatment of a medical condition such as pain, nausea or appetite stimulation. Also described herein are compositions comprising cannabidiol prodrugs suitable for transdermal delivery to a mammal in need thereof and methods of using cannabidiol prodrugs. [0014] Therefore, a significant advancement in the art would occur with the development of a cannabidiol prodαig capable of transdermal delivery; compositions suitable for transdermal delivery comprising prodrugs of cannabidiol; and methods of using prodrugs of cannabidiol whereby the resulting metabolic product was cannabidiol which is locally or systemically available to a mammal in a therapeutically effective amount.
[0015] In addition, pharmaceutical compositions can be systemically administered by other means, including: oral, buccal, sublingual, injection, rectal, vaginal and intranasal. The metabolic process occurring in mammals, such as humans, can also be utilized to deliver pharmaceutically effective quantities of cannabidiol to the systemic circulation of a mammal in need thereof. Described herein are prodrugs of cannabidiol that can be administered to a mammal, such as a human, so that the metabolic product resulting from metabolism in the skin is cannabidiol which is available for the treatment of a medical condition such as pain, nausea or appetite stimulation. Also described herein are compositions comprising cannabidiol prodrugs suitable for delivery to a mammal in need thereof and methods of using cannabidiol prodrugs.
[0016] Therefore, a significant advancement in the art would occur if one could develop a prodrug of cannabidiol capable of oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal delivery; compositions suitable for oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal, vaginal delivery comprising prodrugs of cannabidiol; and methods of using prodrugs of cannabidiol whereby the resulting metabolic product was cannabidiol which is systemically available to a mammal in a therapeutically effective amount.
[0017] In addition to the benefits of systemically administered cannabidiol discussed above, cannabinoids, including cannabidiol, have been found to have localized benefits from topical administration. For example, topically administered cannabinoids have been found to be useful to alleviate pain and other conditions originating near the surface of the skin, including but not limited to pain associated with post-herpetic neuralgia, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis and psoriatic arthritis. In addition, topically administered cannabinoids have been found to be useful to alleviate pain and other conditions associated with deeper tissues, such as peripheral neuropathic pain, including but not limited to the peripheral neuropathic pain associated with diabetic neuropathy, ankylosing spondylitis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, posttraumatic osteoarthritis, synovitis, and juvenile rheumatoid arthritis. When cannabinoids are administered topically to treat pain and other conditions associated with deeper tissues, including peripheral neuropathic pain, it maybe useful to co-administer cannabinoids systemically. Also, it has been found that the topical administration of cannabinoids, including cannabidiol, can inhibit the growth of hair.
[0018] In order to achieve these local benefits, it is advantageous for cannabidiol or a prodrug thereof to penetrate the stratum corneum but not be absorbed systemically. In such a case, the cannabidiol would concentrate in the skin and/or pilosebaceous unit, thus maximizing its local effect. Not only does the localized effect increase the potential therapeutic benefit, it lessens the frequency and severity of side-effects associated with cannabinoid administration because the amount of active compound circulating in the patient is minimized. The cannabidiol can be incorporated into a prodrug with an active moiety that would improve the appearance and/or hydration of the skin.
[0019] Therefore, a significant advancement in the art would occur with the development of a cannabidiol prodrug capable of topical delivery, such that it penetrates the outer layer of the skin but is not absorbed into circulation; compositions suitable for topical delivery comprising prodrugs of cannabidiol and methods of using prodrugs of cannabidiol whereby the resulting metabolic product was cannabidiol which is available at the site of administration in a mammal in a therapeutically effective amount but is not absorbed systemically.
SUMMARY
[0020] Described herein are prodrugs of cannabidiol, methods of making prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using prodrugs of cannabidiol.
[0021] Other embodiments, objects, features and advantages will be set forth in the detailed description of the embodiments that follows, and in part will be apparent from the description, or may be learned by practice, of the claimed invention. These objects and advantages will be realized and attained by the processes and compositions particularly pointed out in the written description and claims hereof. The foregoing Summary has been made with the understanding that it is to be considered as a brief and general synopsis of some of the embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the appended claims are lawfully entitled.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 is a line graph illustrating the representative permeation profile of cannabidiol (n=3) and ALL00105 (n=4) in a gel formulation, wherein "n" is the number of skin samples tested.
[0023] Figure 2 is a line graph illustrating the representative permeation profile of cannabidiol (n=2) and ALL00105 (n=2) in a gel formulation, wherein "n" is the number of skin samples tested.
[0024] Figure 3 is a bar graph illustrating the skin disposition of cannabidiol (n=3) and ALLOOlOl (n=3) in propylene glycol, wherein "n" is the number of skin samples tested.
[0025] Figure 4 is a bar graph illustrating the skin disposition of cannabidiol (n=4) and ALL00102 (n=4) in propylene glycol, wherein "n" is the number of skin samples tested.
[0026] Figure 5 is a graph illustrating the permeation profile of CBD (n=3), ALL00131 (n=3), ALL00132 (n=2), and ALL00140 (n=3), wherein "n" is the number of skin samples tested.
[0027] Figure 6 is a graph illustrating the permeation profile of CBD (n=3), ALL00105 (n=l), ALL00145 (n=3) and ALL00147 (n=2) in 90:8:2 PG:H2O:IPM donor solution with 40% aqueous PEG 400 receiver fluid, wherein "n" is the number of skin samples tested.
[0028] Figure 7 is a graph illustrating the permeation profile of CBD (n=2), ALLOOlOl (n=2), ALL00146 (n=2) and ALL00148 (n=3) in gel formulation with 40% aqueous PEG 400 receiver fluid, wherein "n" is the number of skin samples tested.
[0029] Figure 8 is a bar graph illustrating the skin disposition of CBD (n=3), ALL00131 (n=3), ALL00132 (n=2), and ALL00140 (n=3) in 90:8:2 PG:H2O:IPM donor solution with 60/40 Hanks'/PEG 400 receiver fluid, wherein "n" is the number of skin samples tested. [0030] Figure 9 is a bar graph illustrating the skin disposition of CBD (n=3), ALLOO 137 (n=3), ALL00142 (n=3), and ALL00143 (n=3) in 90:8:2 PG:H20:IPM donor solution with 40% aqueous PEG 400 receiver fluid, wherein "n" is the number of skin samples tested.
[0031] Figure 10 is a bar graph illustrating the skin disposition of CBD (n=3), ALL00105 (n=3), ALL00145 (n=3), and ALL00147 (n=2) in 90:8:2 PG:H2O:IPM donor solution with 40% aqueous PEG 400 receiver fluid, wherein "n" is the number of skin samples tested.
[0032] Figure 11 is a bar graph illustrating the skin disposition of CBD (n=2), ALLOOlOl (n=2), ALL00146 (n=2), and ALL00148 (n=3) in gel formulation with 40% aqueous PEG 400 receiver fluid, wherein "n" is the number of skin samples tested.
[0033] Figure 12 is a graph illustrating the permeation profile of CBD (n=2), ALL00146 (n=2), and ALLOO 150 (n=3) in gel formulation with 40% aqueous PEG 400 receiver fluid, wherein "n" is the number of skin samples tested.
[0034] Figure 13 is a bar graph illustrating the skin disposition of CBD (n=2), ALLOO 146 (n=3), and ALL00150 (n=3) in gel formulation with 40% aqueous PEG 400 receiver fluid, wherein "n" is the number of skin samples tested.
[0035] Figure 14 is a bar graph illustrating the skin disposition of CBD (n=2) and ALLOO 150 (n=3) in an anhydrous gel formulation with 40% aqueous PEG 400 receiver fluid, wherein "n" is the number of skin samples tested.
DESCRIPTION
[0036] While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
[0037] Compounds described herein include pharmaceutically acceptable prodrugs of cannabidiol. One embodiment described herein includes pharmaceutically acceptable prodrugs of cannabidiol which are suitable for non-oral administration and are metabolized to cannabidiol. A further embodiment described herein includes pharmaceutically acceptable prodrugs of cannabidiol which are suitable for transdermal administration and are metabolized to cannabidiol. The pharmaceutically acceptable prodrugs of cannabidiol may be in any suitable form for administration to a mammal such as in the form of a free base, free acid, salt, hydrate, anhydrate, enantiomer, isomer, tautomer, polymorph, derivative, or the like, provided that the free base, salt, hydrate, enantiomer, isomer, tautomer, or any other pharmacologically suitable derivative is therapeutically active or undergoes conversion within or outside of the body to a therapeutically active form of cannabidiol.
[0038] Compositions described herein comprise at least one pharmaceutically acceptable prodrug of cannabidiol and are suitable for transdermal, oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal administration. The compositions described herein optionally include a vehicle or carrier for the administration of a prodrug of cannabidiol as well as optionally including pharmaceutically acceptable excipients such as solvents, thickening agents, penetration enhancers, wetting agents, lubricants, emollients, binders, taste enhancers, disintegrates, substances added to mask or counteract a disagreeable odor, fragrances or tastes, and substances added to improve appearance or texture of the composition.
[0039] The term prodrug as used herein refers to a compound that undergoes a chemical conversion, through a metabolic process or otherwise within the body of the mammal receiving the compound, into its active form that has medical effects.
[0040] In one embodiment, illustrative cannabidiol prodrugs include those compounds of Formula (I):
Figure imgf000009_0001
(D wherein R) and R2 can be the same or different and are each independently comprised of a hydrogen and/or a bio-labile linker (e.g. ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, carbonate, alkyl carbonate, carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, or other suitable bio-labile linking structure) and further comprising moieties which can be selected in order to control the rate and extent of absorption and metabolism, including transdermal absorption and metabolism. However, Ri and R2 cannot both be a hydrogen atom. Several options for Ri and R2 are disclosed herein. Also included herein is the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, polymorph, or derivative thereof of compounds of Formula I.
[0041] Additional embodiments contemplated by the present disclosure include, but are not limited to, those described in WO2007044215, WO2007035945, US2007066657, WO2007026215, WO2007020502, WO2007017264, WO2007009720, US2007004772, US2006287324, US2006287323, US2006287342, US2006287341, US2006089378, US2006079556, US2005143441, US7109216, US2004235854, US2005267161, US2005054659, US2007099990, US2006122229, US2006122230, US2004077650, US6974810, US2004248944, US6977266 and US2006052411 and United States Pat. App. Nos. 10/032,163.
[0042] "Pharmaceutically acceptable salts," or "salts," include the salt of a cannabidiol prodrug suitable for administration to a mammal and includes those prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, beta-hydroxybutyric, galactaric and galacturonic acids. The following list of pharmaceutically acceptable salts is not meant to be exhaustive but merely illustrative as person of ordinary skill in the art would appreciate that other pharmaceutically acceptable salts of cannabidiol and prodrugs of cannabidiol may be prepared.
[0043] In one embodiment, acid addition salts are prepared from the free base forms using conventional methodology involving reaction of the free base with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. The following list of organic and inorganic acids is not meant to be exhaustive but merely illustrative as person of ordinary skill in the art would appreciate that other acids may be used to create pharmaceutically acceptable salts of cannabidiol and prodrugs of cannabidiol. In other embodiments, an acid addition salt is reconverted to the free base by treatment with a suitable base. In still other embodiments, the basic salts are alkali metal salts, e.g., sodium salt.
[0044] In one embodiment, Ri or R2 is an ester. In a further embodiment both Ri and R2 are esters which can be the same or different. The preparation of CBD esters involves functionalizing the hydroxyl groups that are present within the molecular structure of cannabidiol. hi another embodiment, the esters of either or both of Ri and/or R2 are oxygenated. In another embodiment, either or both of Ri and/or R2 are oxygenated esters which are oxaesters. hi another embodiment, either or both of Rj and/or R2 are oxaesters which are pegylated. hi further embodiments, either or both of Rj and/or R2 are pegylated oxaesters can independently have 1 ethylene glycol repeat unit, 2 ethylene glycol repeat units, 3 ethylene glycol repeat units, 4 ethylene glycol repeat units, 5 ethylene glycol repeat units, 6 ethylene glycol repeat units, 7 ethylene glycol repeat units, 8 ethylene glycol repeat units, 9 ethylene glycol repeat units, 10 ethylene glycol repeat units, 11 ethylene glycol repeat units, 12 ethylene glycol repeat units, 13 ethylene glycol repeat units, 14 ethylene glycol repeat units and 15 ethylene glycol repeat units. In a further embodiment, either or both of Ri and/or R2 are esters which are hydroxylated. hi a further embodiment, either or both of Ri and/or R2 are esters which are alkyl ester, hi additional embodiments, either or both of Ri and/or R2 are alkyl esters independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons, hi other embodiments, either or both of Ri and/or R2 are esters which are amino esters independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups, hi another embodiment, either or both of Ri and/or R2 are amino esters which are alkylamino ester, hi a further embodiment, either or both of Ri and/or R2 are alkylamino esters independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups and independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons. In another embodiment the ester is a glycolic acid ester. In another embodiment the ester is a glycolic acid ester, a hyluronic ester or a lactic acid ester. Esters can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
[0045] In one embodiment, Ri or R2 is a carbamate. In a further embodiment both Ri and R2 are carbamates which can be the same or different. The preparation of CBD carbamates involves functionalizing the hydroxyl groups that are present within the molecular structure of cannabidiol. In another embodiment, the carbamates of either or both of Ri and/or R2 are oxygenated. In another embodiment, either or both of Ri and/or R2 are oxygenated carbamates which are oxacarbamates. In another embodiment, either or both of Ri and/or R2 are oxacarbamates which are pegylated. In further embodiments, either or both of Ri and/or R2 are pegylated oxacarbamates can independently have 1 ethylene glycol repeat unit, 2 ethylene glycol repeat units, 3 ethylene glycol repeat units, 4 ethylene glycol repeat units, 5 ethylene glycol repeat units, 6 ethylene glycol repeat units, 7 ethylene glycol repeat units, 8 ethylene glycol repeat units, 9 ethylene glycol repeat units, 10 ethylene glycol repeat units, 11 ethylene glycol repeat units, 12 ethylene glycol repeat units, 13 ethylene glycol repeat units, 14 ethylene glycol repeat units and 15 ethylene glycol repeat units. In a further embodiment, either or both of Ri and/or R2 are carbamates which are hydroxylated. In a further embodiment, either or both of Ri and/or R2 are carbamates which are alkyl carbamates. In additional embodiments, either or both of R i and/or R2 are alkyl carbamates independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons. In other embodiments, either or both of Ri and/or R2 are carbamates which are amino carbamates independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups. In another embodiment, either or both of Ri and/or R2 are amino carbamates which are alkylamino carbamates. In a further embodiment, either or both of Ri and/or R2 are alkylamino carbamates independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups and independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons. In another embodiment the carbamate is a glycolic acid carbamate, a hyluronic carbamate or a lactic acid carbamate. Carbamates can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
[0046] In one embodiment, R] or R2 is a carbonate. In a further embodiment both Ri and R2 are carbonates which can be the same or different. The preparation of CBD carbonates involves functionalizing the hydroxyl groups that are present within the molecular structure of cannabidiol. In another embodiment, the carbonates of either or both of Ri and/or R2 are oxygenated. In another embodiment, either or both of Ri and/or R2 are oxygenated carbonates which are oxacarbonates. In another embodiment, either or both of Ri and/or R2 are oxacarbonates which are pegylated. In further embodiments, either or both of Ri and/or R2 are pegylated oxacarbonates can independently have 1 ethylene glycol repeat unit, 2 ethylene glycol repeat units, 3 ethylene glycol repeat units, 4 ethylene glycol repeat units, 5 ethylene glycol repeat units, 6 ethylene glycol repeat units, 7 ethylene glycol repeat units, 8 ethylene glycol repeat units, 9 ethylene glycol repeat units, 10 ethylene glycol repeat units, 11 ethylene glycol repeat units, 12 ethylene glycol repeat units, 13 ethylene glycol repeat units, 14 ethylene glycol repeat units and 15 ethylene glycol repeat units. In a further embodiment, either or both of Ri and/or R2 are carbonates which are hydroxylated. In a further embodiment, either or both of Ri and/or R2 are carbonates which are alkyl carbonates. In additional embodiments, either or both of RJ and/or R2 are alkyl carbonates independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons. In other embodiments, either or both of Ri and/or R2 are carbonates which are amino carbonates independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups. In another embodiment, either or both of Ri and/or R2 are amino carbonates which are alkylamino carbonates. In a further embodiment, either or both of Ri and/or R2 are alkylamino carbonates independently having 1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groups and independently having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons. In another embodiment the carbonate is a glycolic acid carbonate, a hyluronic carbonate or a lactic acid carbonate. Carbonates can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
[0047] Further embodiments described herein are pharmaceutical compositions comprising: (a) a cannabidiol prodrug selected from the group consisting of:
Figure imgf000014_0001
wherein Ri and R2 are independently selected from hydrogen, ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, glycolic acid ester, hyaluronic acid ester, lactic acid ester, carbonate, oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate, lactic acid carbonate, carbamate, oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carbamate; and wherein R1 and R2 can not both be hydrogen; and
(b) a pharmaceutical excipient.
[0048] A method of administering a compound to a mammal comprising the steps of: (a) combining a compound selected from the group consisting of:
Figure imgf000015_0001
wherein Ri and R2 are independently selected from hydrogen, ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, glycolic acid ester, hyaluronic acid ester, lactic acid ester, carbonate, oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate, lactic acid carbonate, carbamate, oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carbamate; and wherein R| and R2 can not both be hydrogen; with a pharmaceutical excipient to form a pharmaceutical composition;
(b) creating a dosage form suitable for administration to a mammal from the pharmaceutical composition; and
(c) administering the dosage form to a mammal.
[0049] Additional embodiments include methods of transdermally delivering a cannabidiol to a mammal comprising the steps of:
(a) selecting a cannabidiol prodrug from the group consisting of:
Figure imgf000016_0001
wherein Ri and R2 are independently selected from hydrogen, ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, glycolic acid ester, hyaluronic acid ester, lactic acid ester, carbonate, oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate, lactic acid carbonate, carbamate, oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carbamate; and wherein Ri and R2 can not both be hydrogen.
(b) combining the selected cannabidiol prodrug with a pharmaceutically acceptable excipient to form a pharmaceutical composition; and
(c) contacting the pharmaceutical composition with the skin of a mammal.
[0050] A further embodiment described herein is a method of treating a medical condition in a mammal comprising the steps of administering a cannabidiol prodrug selected from the group consisting of:
Figure imgf000017_0001
wherein Ri and R2 are independently selected from hydrogen, ester, oxygenated ester, oxaester, pegylated ester, hydroxylated ester, alkyl ester, amino ester, alkylamino ester, dialkylamino ester, glycolic acid ester, hyaluronic acid ester, lactic acid ester, carbonate, oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate, lactic acid carbonate, carbamate, oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carbamate; wherein Ri and R2 can not both be hydrogen; and wherein the medical condition is selected from the group consisting of: nausea, emesis, pain, wasting syndrome, HIV-wasting, chemotherapy induced nausea and vomiting, alcohol use disorders, dystonia, multiple sclerosis, inflammatory bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, systemic lupus erythematosus, anti-inflammatory, anti-convulsant, antipsychotic, anti-oxidant, neuroprotective, anti-cancer, immunomodulatory effects, peripheral neuropathic pain, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, synovitis, juvenile rheumatoid arthritis and inhibition of hair growth.
[0051] In one embodiment, the resulting prodrug is more hydrophilic than cannabidiol and therefore more water soluble. The logio values of the water/octanol partition coefficient (log P) for cannabidiol and various prodrugs of cannabidiol are shown in Table 15. A further embodiment is a prodrug of cannabidiol having a log P value less than that of cannabidiol. A further embodiment is a prodrug of cannabidiol having a log P value greater than that of cannabidiol. A further embodiment is a prodrug of cannabidiol having a log P value which is approximately equal to that of cannabidiol.
[0052] Pharmaceutical Excipients
[0053] The pharmaceutical compositions described herein can, if desired, include one or more pharmaceutically acceptable excipients. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or combined with a therapeutic agent (e.g., to create a pharmaceutical composition) to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition. Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening agents, penetration enhancers, wetting agents, lubricants, emollients, substances added to mask or counteract a disagreeable odor, fragrances or taste, and substances added to improve appearance or texture of the composition. Any such excipients can be used in any dosage forms according to the present disclosure. The foregoing classes of excipients are not meant to be exhaustive but merely illustrative as a person of ordinary skill in the art would recognize that additional types of excipients could be used to achieve the desired goals for delivery of the cannabidiol prodrug.
[0054] Compositions of the disclosure containing excipients can be prepared by any technique known to a person of ordinary skill in the art of pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine or other related discipline that comprises admixing an excipient with a drug or therapeutic agent.
[0055] In one embodiment, the cannabidiol prodrugs described herein can be combined with a penetration enhancing agent for transdermal or topical delivery. Non-limiting examples of penetration enhancing agents include C8-C22 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters of C6-C22 diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethyl ethers; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetic ester; N-alkylpyrrolidone; and terpenes. Additional penetration enhancers suitable for use can also be found in United States Pat. App. No. 10/032,163.
[0056] In one embodiment, the cannabidiol prodrugs can be combined with a thickening or gelling agent. Non-limiting examples of thickening agents (aka gelling agents) which ma be used herein include anionic polymers such as polyacrylic acid (CARBOPOL® by Noveon, Inc., Cleveland, Ohio), carboxypolymethylene, carboxymethylcellulose and the like, including derivatives of Carbopol® polymers, such as Carbopol® Ultrez 10, Carbopol® 940, Carbopol® 941, Carbopol® 954, Carbopol® 980, Carbopol® 981, Carbopol® ETD 2001, Carbopol® EZ-2 and Carbopol® EZ-3, and other polymers such as Pemulen® polymeric emulsifiers, and Noveon® polycarbophils. Additional thickening agents, enhancers and adjuvants may generally be found in Remington's The Science and Practice of Pharmacy as well as the Handbook f Pharmaceutical Excipients, Arthur H. Kibbe ed. 2000. Thickening agents or gelling agents are present in an amount sufficient to provide the desired rheological properties of the composition. Illustratively, one or more pharmaceutically acceptable thickening agent or gelling agent are present in a total amount by weight of about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%, about 5.0%, about 5.25%, about 5.5%, about 5.75%, about 6.0%, about 6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%, about 7.5%, about 7.75%, about 8.0%, about 8.25%, about 8.5%, about 8.75%, about 9.0%, about 9.25%, about 9.5%, about 9.75%, about 10%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5% or about 15%.
[0057] In one embodiment a neutralizing agent is optionally present to assist in forming a gel. Suitable neutralizing agents include sodium hydroxide (e.g., as an aqueous mixture), potassium hydroxide (e.g., as an aqueous mixture), ammonium hydroxide (e.g., as an aqueous mixture), triethanolamine, tromethamine (2-amino 2-hydroxymethyl-l, 3 propanediol), aminomethyl propanol (AMP), tetrahydroxypropyl ethylene diamine, diisopropanolamine, Ethomeen C-25 (Armac Industrial Division), Di-2 (ethylhexyl) amine (BASF-Wyandotte Corp., Intermediate Chemicals Division), triamylamine, Jeffamine D- 1000 (Jefferson Chemical Co.), b- Dimethylaminopropionitrite (American Cyanamid Co.), Armeen CD (Armac Industrial Division), Alamine 7D (Henkel Corporation), dodecylamine and morpholine. The neutralizing agent is present in an amount sufficient to form a gel which is suitable for contact with the skin of a mammal.
[0058] In one embodiment, the formulation is a gel, an ointment, a cream or a patch and comprises a cannabidiol prodrug, optionally a penetration enhancing agent, a thickening agent, a lower alcohol, such as ethanol or isopropanol; and water. In another embodiment, the formulation is a gel, an ointment, a cream or a patch, further comprised of an aqueous solution of sodium hydroxide or triethanolamine or an aqueous solution of potassium hydroxide, or a combination thereof, in an amount sufficient, as is known in the art, to assist the gelling agent in forming a gel.
[0059] In one embodiment, a solution of sodium hydroxide is used, such as, e.g., 0.1 N sodium hydroxide solution, 0.2 N sodium hydroxide solution, 0.5 N sodium hydroxide solution, 1.0 N sodium hydroxide solution, 1.5 N sodium hydroxide solution, 2.0 N sodium hydroxide solution, or any other suitable solution for providing an amount sufficient of the aqueous sodium hydroxide to form the desired gel. In one embodiment, the composition results from combining a gelling agent with a neutralizing agent such as about 1% to about 10% (wt/wt) 0.1 N sodium hydroxide. Of course, other suitable neutralizing agents can be used as can other concentrations of aqueous sodium hydroxide so long as there is a sufficient amount of OH" ions to assist in the formation of a gel.
[0060] Additional embodiments include the following compositions:
[0061] Gel formulation used with patches (18 mg/niL CBD or cannabidiol prodrug)
75.2% propylene glycol, USP
18.8% sterile water for injection, USP
6.0% diethylene glycol monoethyl ether (Transcutol HP), EP/USP/NF 5.0% hydroxyethylcellulose (Natrosol®), NF based on weight of other three components
[0062] Gel formulation used for rubbing into skin
72.5-67.5% absolute ethanol, USP/NF 20.38-15.38% sterile water for injection, USP
4 .72% 0.1 N NaOH (NF) in sterile water for injection, USP
1-10% cannabidiol or cannabidiol prodrug
0, .9% Carbopol 980®, NF
0, .5% isopropyl myristate, USP/NF
[0063] Gel formulation
78.1% absolute ethanol, USP/NF
15.3% sterile water for injection, USP
1.5% triethanolamine, NF
3.5% cannabidiol or cannabidiol prodrug
1.0% Carbopol 980®, NF
0.6% isopropyl myristate, USP/NF
[0064] Gel formulation
91.75-82.75% absolute ethanol, USP/NF
5.0% propylene glycol, USP
1-10% cannabidiol or cannabidiol prodrug
1.25% polyoxyethylene (15) cocoalkylamines (Ethomeen® C/25)
0.5% Carbopol 980®, NF
0.5% isopropyl myristate, USP/NF
[0065] Compositions described herein optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Non-limiting examples of surfactants that can be used as wetting agents in compositions of the disclosure include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acid esters, for example propylene glycol laurate (e.g., Lauroglycol rM of Gattefosse), sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Such wetting agents, if present, constitute in total about 0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of the total weight of the composition. Illustratively, one or more pharmaceutically acceptable wetting agents are present in a total amount by weight of about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%, about 5.0%, about 5.25%, about 5.5%, about 5.75%, about 6.0%, about 6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%, about 7.5%, about 7.75%, about 8.0%, about 8.25%, about 8.5%, about 8.75%, about 9.0%, about 9.25%, about 9.5%, about 9.75% or about 10%.
[0066] Compositions described herein optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients. Suitable lubricants include, either individually or in combination, glyceryl behapate (e.g., Compritol™ 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25% to about 5%, of the total weight of the composition. Illustratively, one or more pharmaceutically acceptable lubricants are present in a total amount by weight of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6.0%, about 6.1%, about 6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%, about 7.0%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8.0%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9.0%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9% or about 10.0%.
[0067] In another embodiment, the compositions described herein optionally comprise an emollient. Illustrative emollients include mineral oil, mixtures of mineral oil and lanolin alcohols, cetyl alcohol, cetostearyl alcohol, petrolatum, petrolatum and lanolin alcohols, cetyl esters wax, cholesterol, glycerin, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, lecithin, allyl caproate, althea officinalis extract, arachidyl alcohol, argobase EUC, butylene glycol dicaprylate/dicaprate, acacia, allantoin, carrageenan, cetyl dimethicone, cyclomethicone, diethyl succinate, dihydroabietyl behenate, dioctyl adipate, ethyl laurate, ethyl palmitate, ethyl stearate, isoamyl laurate, octanoate, PEG-75 lanolin, sorbitan laurate, walnut oil, wheat germ oil, super refined almond, super refined sesame, super refined soyabean, octyl palmitate, caprylic/capric triglyceride and glyceryl cocoate. An emollient, if present, is present in the compositions described herein in an amount of about 1% to about 30%, about 3% to about 25%, or about 5% to about 15%, by weight. Illustratively, one or more emollients are present in a total amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, by weight.
[0068] In one embodiment, the compositions described herein comprise an antimicrobial preservative. Illustrative anti-microbial preservatives include acids, including but not limited to benzoic acid, phenolic acid, sorbic acids, alcohols, benzethonium chloride, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium propionate, or thimerosal. The anti-microbial preservative, if present, is present in an amount of about 0.1% to about 5%, about 0.2% to about 3%, or about 0.3% to about 2%, by weight, for example about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 1.2%, about 1.4%, about 1.6%, about 1.8%, about 2%, about 2.2%, about 2.4%, about 2.6%, about 2.8%, about 3.0%, about 3.2%, about 3.4%, about 3.6%, about 3.8%, about 4%, about 4.2%, about 4.4%, about 4.6%, about 4.8%, or about 5%.
[0069] Compositions described herein optionally compromise one or more emulsifying agents. The term "emulsifying agent" refers to an agent capable of lowering surface tension between a non-polar and polar phase and includes compounds defined elsewhere as "self emulsifying" agents. Suitable emulsifying agents can come from any class of pharmaceutically acceptable emulsifying agents including carbohydrates, proteins, high molecular weight alcohols, wetting agents, waxes and finely divided solids. The optional emulsifying agent, if present, is present in a composition in a total amount of about 1% to about 15%, about 1% to about 12%, about 1% to about 10%, or about 1% to about 5% by weight of the composition. Illustratively, one or more emulsifying agents are present in a total amount by weight of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%.
[0070] In another embodiment, the water immiscible solvent comprises propylene glycol, and is present in a composition in an amount of about 1% to about 99%, by weight of the composition, for example about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99%.
[0071] Compositions described herein may optionally comprise one or more binding agents. Binding agents may be either dry or wet. Dry binding agents may include simple and complex carbohydrates (e.g., sucrose, glucose, fructose, maltose, lactose, maltodextrins, starch, modified starches, mannitol, sorbitol, maltitol, xylitol, and erthritol), cellulose, and cellulosic derivatives (e.g., microcrystalline cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose). Wet binder agents may include, polyvinyl pyrrolidone, methycellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, xanthan gum, carrageenan gum, locust bean gum, alginates, and acacia. Depending on the desired result, a person of ordinary skill in the art of pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine or other related discipline that comprises admixing an excipient with a drug or therapeutic agent to a composition would be able to select the appropriate binding agent and the relative concentration of the binding agent.
[0072] In another embodiment, the compositions described herein may contain disintegrants, such as sodium starch glycolate, crosspovidone, crosscarmellose, microcrystalline cellulose and starch. Depending on the desired result, a person of ordinary skill in the art of pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine or other related discipline that comprises admixing an excipient with a drug or therapeutic agent to a composition would be able to select the appropriate disintegrant and the relative concentration of the disintegrant.
[0073] In a further embodiment, the compositions disclosed herein may contain lubricants, such as magnesium stearate, stearic acid and its pharmaceutically acceptable salts, talc, vegetable oils, and waxes. Depending on the desired result, a person of ordinary skill in the art of pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine or other related discipline that comprises admixing an excipient with a drug or therapeutic agent to a composition would be able to select the appropriate lubricant and the relative concentration of the lubricant.
[0074] Compositions described herein may also optionally comprise one or more taste enhancers, such as sweeteners, including aspartame, acesulfame potassium, sucralose and saccharin or taste masking agents, such as flavorings. Depending on the desired result, a person of ordinary skill in the art of pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine or other related discipline that comprises admixing an excipient with a drug or therapeutic agent to a composition would be able to select the appropriate taste enhancer or taste making agent and the relative concentration of the taste enhancer or taste masking agent.
[0075] Therapeutic Uses
[0076] In one embodiment, compositions disclosed herein comprise one or more cannabidiol prodrugs in a total amount of between about 0.1% and about 95% by weight of the composition, for example about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95%. [0077] The term "therapeutically effective amount" or "therapeutically and/or prophylactically effective amount" as used herein refers to an amount of compound or agent that is sufficient to elicit the required or desired therapeutic and/or prophylactic response, as the particular treatment context may require.
[0078] It will be understood that a therapeutically and/or prophylactically effective amount of a drug for a subject is dependent inter alia on the body weight of the subject as well as other factors known to a person of ordinary skill in the art. A "subject" herein to which a therapeutic agent or composition thereof can be administered includes mammals such as a human subject of either sex and of any age, and also includes any nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or a horse as well as laboratory animals such as guinea pigs.
[0079] The terms "treat", "treated", "treating" and "treatment" are to be broadly understood as referring to any response to, or anticipation of, a medical condition in a mammal, particularly a human, and includes but is not limited to:
(i) preventing the medical condition from occurring in a subject, which may or may not be predisposed to the condition, but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the medical condition;
(ii) inhibiting the medical condition, i.e., arresting, slowing or delaying the onset, development or progression of the medical condition; or
(iii) relieving the medical condition, i.e., causing regression of the medical condition.
[0080] In one embodiment, a therapeutically effective amount of a cannabidiol prodrug is administered to treat a medical condition selected from the group consisting of: nausea, emesis, pain, wasting syndrome, HIV-wasting, chemotherapy induced nausea and vomiting, alcohol use disorders, dystonia, multiple sclerosis, inflammatory bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, systemic lupus erythematosus, anti-inflammatory, anti-convulsant, antipsychotic, anti-oxidant, neuroprotective, anti-cancer, immunomodulatory effects, peripheral neuropathic pain, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, synovitis, juvenile rheumatoid arthritis and inhibition of hair growth.
[0081] Pharmaceutical Dosage Forms
[0082] In one embodiment, a single dosage unit of any formulation comprises a therapeutically effective amount or a therapeutically and/or prophylactically effective amount of a cannabidiol prodrug.
[0083] In one embodiment, compositions described herein are suitable for transdermal administration. In another embodiment, transdermally administrable compositions are adapted for administration in and/or around the abdomen, back, chest, legs, arms, scalp or other suitable skin surface and may include formulations in which the cannabidiol prodrug is administered in patches, ointments, creams, suspensions, lotions, pastes, gels, sprays, foams or oils.
[0084] In another embodiment, compositions described herein which are transdermally administrable include formulations in which the cannabidiol prodrug is placed in a glycol or gel formulation.
[0085] In one embodiment, compositions described herein are suitable for topical administration. In another embodiment, topical administrable compositions are adapted for administration in and/or around the abdomen, back, chest, legs, arms, scalp or other suitable skin surface and may include formulations in which the cannabidiol prodrug is administered in patches, ointments, creams, suspensions, lotions, pastes, gels, sprays, foams or oils.
[0086] In another embodiment, the compositions described herein are suitable for oral administration. In another embodiment, compositions described herein that are orally administrable include formulations in which the cannabidiol prodrug is administered in tablets, capsules, suspensions, syrups or liquids. In an additional embodiment, the composition maybe formulated as extended release or long acting tablet or capsule, hi a further embodiment, the oral dosage form may be enteric coated using compositions and techniques known to a person of ordinary skill in the art.
[0087] In one embodiment, compositions described herein are suitable for buccal administration. In another embodiment, compositions described herein that are bucally administrable may include formulations in which the cannabidiol prodrug is administered in lozenges, sprays, gels, pastes, dissolvable tablets or dissolvable strips.
[0088] In one embodiment, compositions described herein are suitable for sublingual administration. In another embodiment, compositions described herein that are sublingually administrable may include formulations in which the cannabidiol prodrug is administered in lozenges, sprays, gels, pastes, dissolvable tablets or dissolvable strips.
[0089] In one embodiment, compositions described herein are suitable for injectable administration. In another embodiment, compositions described herein that are injectably administrable may include formulations in which the cannabidiol prodrug is administered as an intravenous, intrathecal, subcutaneous or depot injection.
[0090] In one embodiment, compositions described herein are suitable for rectal administration. In another embodiment, compositions described herein that are rectally administrable may include formulations in which the cannabidiol prodrug is placed in suppositories, ointments, creams, suspensions, solutions, lotions, pastes, gels, sprays, foams or oils.
[0091] In one embodiment, compositions described herein are suitable for vaginal administration. In another embodiment, compositions described herein that are vaginally administrable may include formulations in which the cannabidiol prodrug is placed in suppositories, ointments, creams, suspensions, solutions, lotions, pastes, gels, sprays, foams or oils.
[0092] In one embodiment, compositions described herein are suitable for ocular administration, hi another embodiment, compositions described herein that are ocularly administrable may include formulations in which the cannabidiol prodrug is placed in ointments, suspensions, solutions, gels or sprays. [0093] In one embodiment, compositions described herein are suitable for nasal administration. In another embodiment, compositions described herein that are nasally administrable may include formulations in which the cannabidiol prodrug is placed in ointments, suspensions, solutions, lotions, pastes, gels, sprays or mists.
EXAMPLES [0094] EXAMPLE 1 [0095] SECTION I. SUMMARY
[0096] The objective was to synthesize cannabidiol and cannabidiol prodrugs and assess the permeation of cannabidiol and its prodrugs through human abdominal skin in vitro. Cannabidiol and five cannabidiol prodrugs were synthesized and tested. Flow through diffusion cells were used for the permeation studies. HEPES -buffered Hanks' balanced salts containing 40% (polyethylene glycol) PEG 400 with gentamicin was used for the receiver compartment. Donor solution was comprised of either 100% propylene glycol (PG) solution or a rubbed in gel formulation. The flux and lag time values of cannabidiol and cannabidiol prodrugs were obtained from the permeation profiles. Drug accumulation in the skin after a 24 or 36 h diffusion experiment was determined as μmol/g wet tissue weight.
[0097] These prodrugs also have improved physiochemical properties that would make them suitable candidates for improved delivery via other routes of administration, including oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal.
[0098] SECTION IL METHODOLOGY
[0099] 1.0 Purpose: Synthesize cannabidiol prodrugs and assess the human skin permeation of cannabidiol and cannabidiol prodrugs in vitro.
Figure imgf000030_0001
Formula: C3IH48N2O6 Formula: C33H52N2O6 Formula: C31H46O6 MW: 512 MW: 572 MW: 514 ALL00101 ALL00102 ALL00103
Figure imgf000030_0002
Formula: C27H40N2O4 Formula: C29H44N2O4 Formula: C21H30N2 MW: 456 MW: 484 MW: 314 ALL00104 ALLOO 105 cannabidiol
[00100] 2.0 Skin details
[00101] The skin samples used in the following experiments were obtained from abdominal reduction surgery and dermatomed to a thickness of approximately 200 μm. The skin samples used herein were frozen at -200C for less than six months.
[00102] 3.0 Chemicals
[00103] The chemicals used in the experiment included: acetonitrile (HPLC grade), trifluoroacetic acid, triethylamine, 4-(2-hydroxy ethyl)-piperzine ethane sulfonic acid (HEPES), gentamicin sulfate, p-toluene sulfonic acid, 4-dimethylaminopyridine, isopropyl myristate (IPM), sodium hydroxide, and sodium bicarbonate were purchased through Fisher Scientific (Fairlawn, NJ). Methanol (HPLC grade), acetonitrile (HPLC grade), 3-O-ethoxy-propionic acid, diethyl ether, N^N'-dicyclohexyl carbodiimide, N,N-dimethylgylcine, polyethylene glycol 400 (PEG 400), and sodium sulfate anhydrous were purchased through VWR (West Chester, PA). Propylene glycol (PG), olivetol, chloromethyl chloroformate, ethyl isocyanate, absolute ethanol, and Hanks' balanced salts modified powder were purchased from Sigma- Aldrich (St. Louis, MO). Petroleum ether, ethyl acetate, hexane, chloroform, and dichloromethane were obtained from the University of Kentucky Chemical Stores (Lexington, KY). (+)-(lS,4R)-p-Mentha-2,8- dien-1-ol was purchased from Norac, Inc.(Azusa, CA). Carbopol® 980 was obtained from Noveon, Inc. (Cleveland, OH). Nanopure water was obtained from a Barnstead filtration system (Dubuque, IA).
[00104] 4.0 Synthesis of cannabidiol and cannabidiol prodrugs [00105] 4.1 Synthesis of cannabidiol
[00106] Olivetol (920 mg, 0.00511 mol) and p-toluene sulfonic acid (PTSA) ( 110 mg, 0.000578 mol) were dissolved in benzene; the resulting reaction mixture azeotroped for 2.5 h. The reaction mixture was cooled to room temperature and under argon (+)-(lS,4R)-p-Mentha- 2,8-dien-l-ol (586 mg, 0.00385 mol) was added and stirred at room temperature for 30 min. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with saturated sodium bicarbonate solution. The organic layer separated and was dried on anhydrous sodium sulfate. The ether layer evaporated and purified on silica column by using petroleum ether and diethyl ether as eluent (98:2). Finally 300 mg of cannabidiol (300 mg) was collected (24%).
[00107] 1HNMR (CDCl3): 6.23-6.41 (m,2H), 5.99 (s,lH,D2O exchangeable), 5.66 (s,lH), 4.56 (s,lH), 4.49 (bs,lH,D2O exchangeable) 4.46 (s,lH), 3.96 (m,lH), 2.00-2.47 (m,5H),1.87 (m,5H), 1.46-1.83 (m,6H), 1.23-1.48 (m,3H), 0.96-1.00 (m,3H).
[00108] 4.2 Synthesis of ALLOOlOl
[00109] β -alanine,N,N-dimethyl (0.600 mg, 0.00512 mol), N,N'-dicyclohexyl carbodiimide (DCC) (1.05 g, 0.00512 mol), 4-dimethylaminopyridine (DMAP) (85 mg) were dissolved in dichloromethane (DCM) and stirred under nitrogen for 2 h; later cannabidiol (806 mg, 0.00264 mol) in DCM was added. The resulting reaction mixture stirred overnight and the solid was filtered on celite. The crude product was purified on silica column producing 300 mg (26.48%) of final compound (ALLOOlOl).
[00110] 4.3 Synthesis of ALLOO 102 [00111] Cannabidiol (216 mg, 0.0006878 mol) was dissolved in dichloroniethane and reaction mixture cooled to 00C on ice bath and chloromethyl chloroformate (177 mg, 0.001375 mol) was added drop wise up to 30 min and the reaction mixture stirred overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water, the combined organic layer dried, evaporated, and purified on silica column by using petroleum ether and diethyl ether (9:1) as eluent. The title compound was as an oil compound (130 mg, 37%). This oily compound (130 mg, 0.000260 mol) was treated with excess of diethylamine to give the target compound (31.5 mg, 21%).
[00112] 1HNMR (CDCl3): 6.90 (s,2H), 5.83-5.84 (dd, 4H), 5.19 (S,1H, cyclic ethylenic), 4.54-4.55 (d,lH), 4.44-4.44 (d, IH), 3.50-3.55 (m,lH) 2.57-2.62 (m,3H),1.90-2.12 (m,2H),1.34- 1.59, 1.62-1.64 (m,l IH), 1.30-1.33 (m,5H), 0.90-0.92 (m,3H) 13C-NMR (CDCl3): 13.89, 19.27, 22.30, 23.31, 28.48, 30.02, 30.22, 31.23, 35.05, 37.87, 45.63, 72.19, 72.23, 72.28, 111.05, 122.12, 122.15, 122.18, 134.28, 142.53, 147.13, 149.10, 151.34 1HNMR (CDCl3): 6.81 (s,2H), 5.42 (s,lH), 4.68 (dd,2H), 3.69 (m,lH), 3.24-3.47 (m,10H), 2.49-2.57 (m,3H), 2.01 (m,2H), 1.69-1.95 (m,12 H), 1.15-1.46 (m,17H), 0.93-0.95 (m,3H) 13C-NMR (CDCl3): 13.71, 14.35, 14.62, 20.53, 22.76, 23.65, 29.50, 30.82, 30.99, 31.98, 35.62, 38.80, 41.61, 42.20, 46.08, 110.90 125.63, 126.36, 131.61, 141.50, 148.04, 150.30, 153.92.
[00113] 4.4 Synthesis of ALL00103
[00114] 3-O-ethoxy-propionic acid (0.507 mg, 0.0042 mol), DCC (889 mg, 0.00429 mol), and DMAP (138 mg) were dissolved in DCM under nitrogen, stirring for 2 h. Cannabidiol (450 mg, 0.00143 mol) was added in DCM for 30 min and resulting reaction mixture stirred overnight. The solid was filtered through celite, filtrate purified by using (75:25) petroleum ether, and diethyl ether was used as eluent giving 210 mg (51.4%) an oily final compound.
[00115] 1HNMR (CDCl3): 6.78 (s,2H), 5.20 (s,lH), 4.45-4.53 (dd,2H), 3.77-3.80 (m,4H), 3.58 (m,lH), 3.50-3.57 (t,4H), 2.57-2.90 (m,4H), 2.51-2.56 (t,2H), 2.10 (m,lH), 2.00 (m,lH), 1.61-1.90 (m,2H), 1.57-1.65 (m,9H), 1.30-1.32 (m,4H), 1.21-1.29 (t,6H), 0.85-0.90 (m,3H) 13C- NMR (CDCl3): 14.25, 15.35,19.84, 22.68, 23.59, 28.97, 30.56, 30.70, 31.67, 35.39, 38.46, 45.82, 65.78, 66.68, 111.13, 124.69, 126.02, 141.94, 147.80, 149.58, 169.78.
[00116] 4.5 Synthesis of ALLOO 104 [00117] Cannabidiol (284 mg, 0.000904 mol) and triethylamine (0.482 mL, 0.00226 mol) were dissolved in DCM and stirred at room temperature for 1 h. Ethyl isocyanate (0.1419 mL, 0.00180 mol) was added drop wise for 10 min to give the reaction mixture which stirred overnight. The solvents were evaporated and the crude product purified on silica column by using (8:2) hexane:ethyl acetate as eluent. The final compound (260 mg, 63%) collected was a semi solid.
[00118] 1HNMR (CDCl3): 6.77 (s,2H), 5.30 (m,lH), 4.11 (bs,2H), 4.42 (s,lH), 4.85 (s,lH), 3.15 (m,4H), 2.46-2.64 (m,3H), 2.10 (m,2H), 1.88 (2H), 1.25-1.66 (m,10H), 1.30 (m,5H), 1.17- 1.22 (m,5H), 0.88 (m,3H) 13C-NMR (CDCl3): 14.36, 14.53, 15.53, 19.87, 22.80, 23.71, 25.02, 29.17, 30.75, 30.90, 31.87, 35.61, 36.44, 36.97, 38.26, 46.24, 111.14, 124.60, 127.12, 132.37, 141.76, 147.97, 149.87, 154.26.
[00119] 4.6 Synthesis of ALL00105
[00120] Cannabidiol (280 mg, 0.000890 mol) was added to activate DCC (550 mg, 0.00267 mol), DMAP (429 mg, 0.00133 mol), and N,N-dimethylglycine (275 mg, 0.002678 mol) in DCM at room temperature. After overnight stirring under nitrogen, the solid in the reaction mixture was filtered though celite and the reaction mixture purified on silica column by using chloroform and methanol (97:3) as eluent gave 70 mg of final compound (10.07%).
[00121] 1HNMR (CDCl3 ): 6.42 (s,2H), 5.12 (s,lH), 4.20-4.40 (dd,2H), 2.21 (s,4H), 2.34- 2.40 (m,lH), 2.20-2.34 (m,13H), 2.00-2.10 (m,3H), 1.29-1.42 (m,10H), 1.13-1.26 (m,4H), 0.91- 0.92 (m,3H) 13C-NMR (CDCl3): 14.36, 20.16, 22.80, 23.90, 29.12, 30.67, 30.85, 31.75, 35.53, 38.86, 45.57, 45.86, 60.16, 111.23, 124.69, 125.94, 132.71, 142.17, 147.86, 149.38, 168.73.
[00122] 5.0 In vitro skin permeation studies
[00123] 5.1 Preparation of receiver fluid
[00124] 1 L of receiver fluid was prepared by measuring 1 L of nanopure water into a graduated cylinder. 90% of the water was added to an Erlenmeyer flask. Hanks' salts (1 bottle) were added to the water along with 5.96 g of HEPES and 0.35 g of sodium bicarbonate. The pH of the solution was adjusted with 1 N sodium hydroxide solution to pH 7.4. The remaining water was added and the receiver fluid was filtered through a 0.2 μ filter (Millipore, Billerica, MA). 50 mg of gentamicin was added to the filtered receiver fluid and 400 mL of the receiver fluid was removed and replaced with 400 mL of PEG 400.
[00125] 5.2 Preparation of drug formulations
[00126] Two different formulations were used for charging the donor compartment. Drugs were made up in either 100% PG or a gel formulation. For the PG solution, approximately 50- 120 mg of the appropriate drug was weighed into a glass silanized culture tube. The gel formulation resulted from the mixing of absolute ethanol, nanopure water, IPM, Carbopol® 980, 0.1 N aqueous sodium hydroxide solution and the respective drug.
[00127] 5.3 Permeation experiments
[00128] Dermatomed skin harvested from abdominoplasty, stored at -200C, was used for the experiments. A PermeGear flow-through (In-Line, Riegelsville, PA) diffusion cell system was used for the skin permeation studies.
[00129] Diffusion cells were kept at 32°C with a circulating water bath. Human epidermal skin was arranged in the diffusion cell with stratum corneum (upper layer of skin) facing the donor compartment. Permeation area of the skin was 0.95 cm2. Data was collected from a human skin donor with three to four diffusion cells per treatment.
[00130] Receiver solution was HEPES -buffered Hanks' balanced salts with gentamicin containing 40% PEG 400 at a pH of 7.4 and flow rate was adjusted to 0.8 mlVh. Each cell was charged with 0.050 mL of the respective drug formulation (donor solution) or with 0.035 mL of gel formulation which was rubbed into the skin for 15 sec with a Teflon coated rod. The formulation was applied to ensure complete coverage. Diffusion cells were covered with a cap for the duration of the study.
[00131] Samples were collected into scintillation vials in 3 h increments for either 24 h or 36 h. All the samples were stored at 4°C until extracted. An aliquot (0.5 mL) of the diffusion sample was placed into a silanized HPLC vial and 0.5 mL of acetonitrile was added to the sample, capped and vortexed.
[00132] At the end of the experiment, the skin tissue was removed from the diffusion cell, rinsed with nanopure water, and blotted dry with a paper towel. The skin was tape stripped twice using book tape (Scotch™, 3M, St. Paul, MN) to remove drug formulation adhering to the tissue surface. The area of skin in contact with the drug was cut out, chopped up and placed in a pre- weighed scintillation vial. Ten rnL of acetonitrile was added to the vial and drug was extracted from the skin by shaking at room temperature overnight. The following day a 0.1 niL aliquot was removed and diluted with an additional 0.9 mL of acetonitrile. The diluted sample was added to the silanized HPLC vial for analysis.
[00133] At the end of the experiment, a 0.01 mL aliquot of the PG donor solution was removed and added to a scintillation vial containing 10 mL of acetonitrile. The vials were vortexed and then sonicated for 15 min. An aliquot of 1 mL was removed and transferred into a silanized HPLC vial for analysis.
[00134] 6.0 Analytical method
[00135]
Figure imgf000035_0001
[00136] 7.0 Data analysis
[00137] Cumulative quantity of drug collected in the receiver compartment was plotted as a function of time. The flux value for a given experiment was obtained from the slope of a steady state portion of the cumulative amount of drug permeated vs. time plot. Lag time was obtained from the x-intercept of the steady state portion of the cumulative amount of drug permeated vs. time plot. In Tables 11-14, the combined results of the delivered prodrug and cannabidiol from the prodrug are listed as "total cannabidiol." These values represent the data as total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug.
[00138] SECTION III. RESULTS
[00139] No melting points were reported for cannabidiol or the cannabidiol prodrugs due to all compounds being in oil form. ALLOOlOl and ALLOO 102 permeated through the human skin as cannabidiol. No intact prodrug was found in the diffusion samples (receiver samples) for either ALLOOlOl or ALL00102. Both cannabidiol and intact prodrug were found in the skin disposition (tissue) samples. ALLOOlOl and ALLOO 102 did have higher total cannabidiol in the skin compared to cannabidiol. No flux enhancement was seen with ALLOOlOl or ALL00102 prodrugs. ALLOO 103 and ALLOO 104 did not permeate (or were below LOD) through the skin with both the PG donor solution and gel formulation. Some intact prodrug was found in the skin samples but very little cannabidiol was detected for ALLOO 103 and ALLOO 104. The mean flux enhancement between the two ALLOO 1005 gel formulation experiments was 2.5. ALLOO 105 permeated primarily as intact prodrug. The cumulative amount of total cannabidiol equivalents (nmol) delivered from ALL00105 was 3.1-5.9 fold higher when compared to cannabidiol. The same results were not seen with the propylene glycol donor solution which did not show any enhancement. Besides the enhanced flux with ALL00105, the lag time (gel formulation studies) of total cannabidiol was decreased 7-8 h compared to the parent drug. Decreased lag time benefits patients by delivering the drug more quickly which is beneficial for pain management and nausea. The other cannabidiol prodrugs may be successful if drug solutions were formulated with enhancers or may be useful in targeting topical treatment administration instead of transdermal administration (for systemic blood levels of drug). [00140] Table 1. Cannabidiol and cannabidiol prodrugs
Figure imgf000037_0001
[00141] Table 2. Permeation data of cannabidiol (n=3) in propylene glycol
24 h skin cone, FlUX Lag time
24 h cumulative
Compound amt (nmol) (μmol/g) (nmol/cm2/h) (h) cannabidiol (CBD) 12.2 ± 1.8
190.8 ± 10.7 222.7 ± 74.0 10.4 ± 2.0
Wherein "n" is the number of skin samples tested.
[00142] Table 3. Permeation data of CBD-low (n=2), ALLOOlOl (n=2), ALL00102 (n=2), and CBD-high (n=3) in propylene glycol
Figure imgf000037_0002
Wherein "n" is the number of skin samples tested.
[00143] Table 4. Permeation data of CBD-low (n=2), ALL00102 (n=3), and CBD-high (n=2) in propylene glycol
Figure imgf000038_0001
Wherein "n" is the number of skin samples tested.
[00144] Table 5. Permeation data of CBD-low (n=4), ALL00102 (n=2), and CBD-high (n=2) in propylene glycol
Figure imgf000038_0002
Wherein "n" is the number of skin samples tested.
[00145] Table 6. Permeation data of CBD (n=4) in propylene glycol
24 h skin cone, FlUX Lag time
24 h cumulative
Compound amt (nmol) (μmol/g) (nmol/cm2/h) (h)
CBD 49.2 ± 15.2 15.1 ± 3.4
27.5 ± 32.5 4.3 ± 2.4
Wherein "n" is the number of skin samples tested. [00146] Table 7. Permeation data of CBD (n=3) in propylene glycol
36 h skin cone, FlUX Lag time
36 h cumulative
Compound amt (nmol) (μmol/g) (nmol/cm2/h) (h)
CBD 13.4 ± 9.3
44.1 ± 15.5 15.7 ± 5.4 1.0 ± 0.7
Wherein "n" is the number of skin samples tested.
[00147] Table 8. Permeation data of CBD (n=3) in gel formulation
36 h skin cone, Flux Lag time
36 h cumulative
Compound amt (nmol) (μmol/g) (nmol/cm2/h) (h)
CBD 1.4 ± 1.7
28.4 ± 8.8 52.0 ± 42.7 2.0 ± 2.3
Wherein "n" is the number of skin samples tested.
[00148] Table 9. Permeation data of CBD (n=3) and ALL00102 (n=3) in gel formulation
Figure imgf000039_0001
Wherein "n" is the number of skin samples tested.
[00149] Table 10. Permeation data of CBD (n=4) and ALL00102 (n=4) in propylene glycol
Figure imgf000039_0002
Wherein "n" is the number of skin samples tested.
[00150] Table 11. Permeation data of CBD (n=3) and ALL00105 (n=3) in gel formulation
Figure imgf000040_0001
* total CBD= total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug
Wherein "n" is the number of skin samples tested.
[00151] Table 12. Permeation data of CBD (n=2) and ALL00105 (n=2) in gel formulation
Figure imgf000040_0002
Wherein "n" is the number of skin samples tested. [00152] Table 13. Permeation data of CBD (n=l) and ALL00105 (n=2) in propylene glycol
Figure imgf000041_0001
Wherein "n" is the number of skin samples tested.
[00153] Table 14. Permeation data of CBD (n=3) and ALL00103 (n=4) in propylene glycol
Figure imgf000041_0002
Wherein "n" is the number of skin samples tested. [00154] EXAMPLES 2, 2A AND 2B
[00155] Except as where indicated below, the methodology used in Examples 2A and 2B was the same as the methodology used in Example 2.
[00156] SECTION I. SUMMARY
[00157] The objective was to synthesize cannabidiol prodrugs and assess the permeation of cannabidiol and various prodrugs of cannabidiol through human abdominal skin in vitro. Cannabidiol and numerous cannabidiol prodrugs were synthesized and several were tested. Flow through diffusion cells were used for the permeation studies. HEPES -buffered Hanks' balanced salts containing 40% PEG 400 with gentamicin or 40% aqueous PEG 400 with gentamicin were used for the receiver compartment. Donor solution was comprised of 90:8:2 PG:H2θ:IPM solution or gel formulation. The flux and lag time values of cannabidiol and cannabidiol prodrugs were obtained from the permeation profiles. Drug accumulation in the skin after a 24, 30 or 42 h diffusion experiment was determined as μmol/g wet tissue weight.
[00158] These prodrugs also have improved physicochemical properties that would make them suitable candidates for improved delivery via other routes of administration, including oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal.
[00159] SECTION II. METHODOLOGY
[00160] 1.0 Purpose: The purpose of the example was to synthesize cannabidiol prodrugs and assess the human skin permeation of cannabidiol and cannabidiol prodrugs in vitro.
Figure imgf000042_0001
Formula: C3OH46O7 Formula: C^H62Oi2 MW: 518.68 MW: 722.90 ALL00131 ALLOOl 32
Figure imgf000042_0002
Formula: C26H4QN2O3 Formula: C31 H5ON4O4 Formula: C24H34O5 MW: 428.61 MW: 542.75 MW: 402.52 ALLOO135 ALLOO 136 ALLOO 137
Figure imgf000043_0001
Formula: C27H38Og Formula: C28H42O6 MW: 490.59 MW: 474.63 ALLOO 139 ALLOO 140
Figure imgf000043_0002
Formula: C35H54OiO Formula: C25H34O4 MW: 634.80 MW: 398.54 ALL00141 ALL00142
Figure imgf000043_0003
Formula: C25H34O6 Formula: C23H3o04 Formula: C22H3o03 MW: 430.53 MW: 370.48 MW: 342.47 ALL00143 ALL00145 ALLOO 146
Figure imgf000043_0004
Formula: C25H34O6 Formula: C25H37NO3 Formula: C23H32O4 MW: 430.53 MW: 399.57 MW: 372.50 ALL00147 ALL00148 ALL00149
Figure imgf000044_0001
Formula: C26H39NO3 Formula: C3]H4SN2O6 Formula: C26H44N2O4 MW: 413.59 MW: 512.72 MW: 484.67 ALLOO 150 ALLOOlOl ALLOO 105
Figure imgf000044_0002
Formula: C24H34O4 MW: 386.52 ALL00151
[00161] 2.0 Skin details
[00162] The skin samples used in the following experiments were obtained from abdominal reduction surgery and dermatomed to a thickness of approximately 200 μm. The skin samples used herein were frozen at -200C for less than six months.
[00163] 3.0 Chemicals
[00164] Chemicals used in the experiment included: trifluoroacetic acid, triethylamine (TEA), 4-(2-hydroxy ethyl)-piperzine ethane sulfonic acid (HEPES), gentamicin sulfate, isopropyl myristate (IPM), sodium hydroxide, octanethiol, 4-dimethylaminopyridine (DMAP), methyl chloroformate, and sodium bicarbonate (NaHCO3) were purchased through Fisher Scientific (Fairlawn, NJ). Methanol (HPLC grade), acetonitrile (HPLC grade), N5N1- dicyclohexyl carbodiimide (DCC), N,N-dimethylgylcine, polyethylene glycol 400 (PEG 400), formic acid, acetyl chloride, 3-dimethylaminopropionic acid hydrochloride, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and sodium sulfate (NaSO4) anhydrous were purchased through VWR (West Chester, PA). Propylene glycol (PG), olivetol, absolute ethanol, triethylamine trihydrofluoride, 2-[2-92-methoxyethoxy)ethoxy] acetic acid, methyl (R)-(+)-2,2- dimethyl-l,3-dioxolane-4-carboxylate, tetrahydrofuran (THF), triphosgene, L-(t- butyldimethylsilyloxy)lactic acid and Hanks' balanced salts modified powder were purchased from Sigma- Aldrich (St. Louis, MO). mono-Fmoc-l,4-butanediamine hydrochloride was purchased from Novabiochem (San Diego, CA). Ethyl acetate, hexane, and dichloromethane (DCM) were obtained from the University of Kentucky Chemical Stores (Lexington, KY). (+)- (lS,4R)-p-Mentha-2,8-dien-l-ol and olivetol were purchased from Norac, Inc.(Azusa, CA). Carbopol® 980 was obtained from Noveon, Inc. (Cleveland, OH). Cannabidiol was purchased from Cayman Chemical Company (Ann Arbor, MI). Nanopure water was obtained from a Barnstead NANOpure® Diamond™ Ultrapure water filtration system (Dubuque, IA). Argon and pre-purified nitrogen were purchased from Scott Gross Company (Lexington, KY). The compound 3,6,9,12-tetraoxatridecanoic acid was synthesized according to the procedures found in Macromolecules, 39 (12), 3978 -3979, 2006.
[00165] 4.0 Synthesis of cannabidiol prodrugs
[00166] 4.1 Synthesis of ALLOOlOl (CBD bis(3-(dimethylamino)propionate)) and ALL00150 (CBD 3-(dimethylamino)propionate)
[00167] Cannabidiol (100 mg, 0.00032 mol), 3-dimethylaminopropionic acid hydrochloride (123 mg, 0.00080 mol), and DMAP (117 mg, 0.00096 mol) were combined in 1 mL dry dichloromethane. The solution was stirred for 5 min at ambient temperature. DCC (198 mg, 0.00096 mol) was added to the mixture. The mixture was allowed to stir for 5 h at ambient temperature. Hexane was added and the precipitate removed by filtration. The solution was reduced to a small volume under nitrogen. ALLOOlOl and ALLOO 150 were separated and isolated using a semi-preparatory Cg column with ACN:water (70:30). ACN was removed from the eluent fraction for each fraction by rotary evaporation. The remaining aqueous layer was partitioned with DCM and the DCM dried over sodium sulfate. DCM was removed under a nitrogen stream and vacuum. The purified products appeared as transparent, viscous oil with light amber color.
[00168] ALLOOlOl was analyzed by LC/MS (Waters; Milford, MA) in electrospray positive mode. Masses were observed at 513.42 (M+l, 70%), 257.34 (100%) and 123.06 (15%). [00169] For ALL00150, the 1H NMR (400 MHz, CDCl3) was as follows: δ= 6.55(1H, br s, ArH); 6.4O(1H, d, J=1.8, ArH); 5.98(1H, br s, OH); 5.53(1H, br s, H-2); 4.59-4.62(1H, m); 4.45(1H, br s); 3.45-3.59(1H, m, H-3); 2.60-2.83(4H, m); 2.41-2.55(3H, m); 2.30(6H, s, NMe2); 2.16-2.27(1H, m); 2.03-2.12(1H, m); 1.70-1.84(2H, m); 1.77(3H, br s, 7-Me); 1.52-1.62(2H, m); 1.61(3H, s, 10-Me); 1.24-1.38(4H, m); 0.88(3H, t, J=7.0, CH2CH3)
[00170] 4.2 Synthesis of ALL00105 (CBD bis(N,N-dimethylglycinate)) and ALL00148 (CBD N,N-dimethylglycinate)
[00171] Cannabidiol (200 mg, 0.00064 mol), N,N-dimethylglycine (196.8 mg, 0.00191 mol), and DMAP (38.9 mg, 0.00032 mol) were combined in 1 mL dry dichloromethane. The solution was stirred for 5 min at ambient temperature. DCC (459.3 mg, 0.00223 mol) was added to mixture. The mixture was allowed to stir overnight at ambient temperature. Hexane was added and precipitate removed by filtration. The solution was reduced to a small volume under nitrogen. ALLOO 105 and ALLOO 148 were separated and isolated using a semi-preparatory Cg column with ACNrwater (75:25). ACN was removed from the eluent fraction for each fraction by rotary evaporation. The remaining aqueous layer was partitioned with DCM and DCM dried over sodium sulfate. DCM was removed under a nitrogen stream and vacuum. The purified products appeared as transparent, viscous oil with light amber color.
[00172] ALLOO 105 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 485.31 (M+l).
[00173] ALLOO 148 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 417.15 (M+18, 30%), 315.23 (CBD+1, 100%).
[00174] 4.3 Synthesis of ALL00131 (CBD 3,6,9, 12-tetraoxatridecanoate) and ALL00132 (CBD di(3, 6,9, 12-tetraoxatridecanoate))
[00175] Cannabidiol (100 mg, 0.00033 mol), 3,6,9,12-Tetraoxatridecanoic acid (98.9 mg, 0.00045 mol) prepared according to Macromolecules, 39 (12), 3978 -3979, 2006, and DMAP (11.7 mg, 0.00010 mol) were combined in 1 mL dry dichloromethane. The solution was stirred for 5 min at ambient temperature. DCC (111.4 mg, 0.00046 mol) was added to the mixture. The mixture was allowed to stir for 2 h at ambient temperature. Hexane was added and precipitate removed by filtration. The solution was reduced to a small volume under nitrogen. ALLOOl 31 and ALLOO 132 were separated and isolated using a semi-preparatory silica column with hexane:ethyl acetate gradient. Solvent from each collected fraction was removed under vacuum. The purified products appeared as transparent, viscous oil with light amber color.
[00176] For ALL00131, the 1H NMR (400 MHz, CDCl3) was as follows: δ= 6.56QH, br s, ArH); 6.43(1H, d, J=1.8, ArH); 6.01(1H, br s, OH); 5.53(1H, br s, H-2); 4.58-4.62(1H, m); 4.43QH, br s); 4.35(2H, br s, OCH2CO2); 3.76-3.86(2H, m, PEG); 3.63-3.76(8H, m, PEG); 3.54-3.57(2H, m, PEG); 3.47QH, br s, H-3); 3.38(s, 3H, CH2OCH3); 2.47-2.53(2H, m, benzylic CH2); 2.4O-2.47(1H, m); 2.14-2.25(1H, m); 2.02-2.14(1H, m); 1.65-1.86(2H, m); 1.77(3H, br s, 7-Me); 1.52-1.64(2H, m); 1.58(3H, s, 10-Me); 1.23-1.37(4H, m); 0.88(3H, t, J=7.0, CH2CH3).
[00177] For ALL00132, the 1H NMR (400 MHz, CDCl3) was as follows: δ= 6.75(2H, s, ArH); 5.18(1H, br s, H-2); 4.52-4.55(1H, m); 4.42-4.45(1H, m); 4.37,4.34 and 4.22(4H, br singlets, OCH2CO2); 3.76-3.86(4H, m, PEG); 3.63-3.76(16H, m, PEG); 3.53-3.57(4H, m, PEG); 3.43-3.51(1H, m, H-3); 3.38(s, 6H, CH2OCH3); 2.51-2.62(3H, m); 2.07-2.20(1H, m); 1.97- 2.06(1H, m); 1.67-1.82(2H, m); 1.66(3H, br s, 7-Me); 1.52-1.63(2H, m); 1.54(3H, s, 10-Me); 1.23-1.38(4H, m); 0.88(3H, t, J=7.0, CH2CH3)
[00178] 4.4 Synthesis of ALL00135 (CBD 4-aminobutyl carbamate) and ALL00136 (CBD bis(4-aminobutyl carbamate))
[00179] To a stirred solution of mono-Fmoc-l,4-butanediamine hydrochloride (461 mg, 1.33 mmol) in saturated NaHCO3 aqueous solution (33.3 mL) and dichloromethane (22.2 mL) was added to triphosgene (592 mg, 2.0 mmol) in dichloromethane (5 mL) at ambient temperature. After stirring for 1 h, the product was extracted with dichloromethane (40 mL), and dichloromethane layer was dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in ethyl acetate and product was precipitated with addition of hexane. Fmoc-4- aminobutyl isocyanate was collected by filtration as a white solid (305 mg, 68%).
[00180] Cannabidiol (44 mg, 0.00014 mol), Fmoc-4-aminobutyl isocyanate (68.0 mg, 0.00020 mol), and TEA (20 mg, 0.00038 mol) were combined in 2 mL dry dichloromethane under argon. The solution was allowed to stir overnight. The reaction mix was filtered. The protected compounds were separated and isolated using a semi-preparatory silica column with hexane: ethyl acetate gradient. The solvent from each collected fraction was taken to dryness under a nitrogen stream and reconstituted in THF. [00181] Solutions of DBU (diluted 100-fold in THF) and octanethiol (diluted 10-fold in THF) were prepared. DBU solution (0.2 mL) and ocatanethiol solution (0.1 mL) were added to each solution containing a protected compound and stirred for 0.5-1 h. ALLOO 135 and ALL00136 were isolated using silica column chromatography and eluted with DCM:methanol (80:20). The purified products appeared as transparent, viscous oil with light amber color.
[00182] ALLOO 135 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 429.26 (M+l, 100%), 315.16 (CBD+1, 65%), and 153.13 (22%).
[00183] ALLOO136 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 543.32 (M+l, 30%), 315.16 (CBD+1, 70%), 292.76 (100%) and 272.24 (45%).
[00184] 4.5 Synthesis of ALL00137 (CBD (S)-2,3-dihydroxypropanoate) and ALL00139 (CBD bis((S)-2,3-dihydroxypropanoate))
[00185] Cannabidiol (100 mg, 0.00032 mol), (S)-2,2-dimethyl-l,3-dioxalane-4-carboxylate (151.4 mg, 0.00035 mol), and DMAP (11.7 mg, 0.00010 mol) were combined in 1 mL dry dichloromethane. The solution was stirred for 5 min at ambient temperature. DCC (92.3 mg, 0.00045 mol) was added to the mixture. The mixture was allowed to stir overnight at ambient temperature. Hexane was added and precipitate removed by filtration. The solution was reduced to a small volume under nitrogen. Acetonides of ALLOO 137 and ALLOO 139 were separated and isolated using a semi-preparatory silica column with hexane: ethyl acetate gradient. The solvent from each collected fraction was removed under vacuum. The purified products appeared as transparent, viscous oil with light amber color. Acetonides of ALLOO 137 and ALLOO 139 were deprotected using 1-octanethiol/zinc triflate and purified using silica column chromatography (HPLC) with hexane:ethyl acetate (7:3).
[00186] ALLOO 137 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 420.25 (M+l 8, 100%), 403.18 (M+l, 65%), 315.23 (CBD+1, 15%).
[00187] ALLOO 139 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 508.23 (M+ 18, 100%), 491.15 (M+l, 18%), 315.16 (CBD+1, 5%).
[00188] 4.6 Synthesis of ALL00140 (CBD 2-[2-(2-methoxyethoxy)ethoxy]acetate) and ALL00141 (CBD bis(2-[2-(2-methoxyethoxy)ethoxy]acetate)) [00189] Cannabidiol (105 mg, O.OOO33 mol), 2-[2-(2-methoxyethoxy)ethoxy] acetic acid (83.3 mg, 0.00047 mol), and DMAP (12.3 mg, 0.00011 mol) were combined in 1 niL dry dichloromethane. The solution was stirred for 5 min at ambient temperature. DCC (117 mg, 0.00056 mol) was added to the mixture. The mixture was allowed to stir for 5 h at ambient temperature. Hexane was added and precipitate removed by filtration. The solution was reduced to a small volume under nitrogen. ALL00140 and ALL00141 were separated and isolated using a semi-preparatory silica column with hexane: ethyl acetate gradient. The solvent from each collected fraction was removed under vacuum. The purified products appeared as transparent, viscous oil with light amber color.
[00190] ALLOO 140 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 492.37 (M+18, 100%) and 475.37 (M+l, 35%).
[00191] ALL00141 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 652.51 (M+18, 100%) and 635.52 (M+l, 10%).
[00192] 4.7 Synthesis of ALLOO 142 (CBD diacetate)
[00193] Cannabidiol (42 mg, 0.00013 mol), acetyl chloride (26.3 mg, 0.00033 mol), and TEA (35 mg, 0.00039 mol) were combined in 0.5 mL dry dichloromethane. The solution was allowed to stir overnight. Hexane was added and reaction mix filtered. ALLOO 142 was isolated using silica column chromatography and hexane:ethyl acetate (9:1). The purified product appeared as transparent, viscous oil with light amber color.
[00194] ALL00142 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 416.22 (M+18, 100%), 399.14 (M+l, 10%).
[00195] 4.8 Synthesis of ALL00143 (CBD bis(methyl carbonate))
[00196] Cannabidiol (44 mg, 0.00013 mol), methyl chloroformate (31.7 mg, 0.00034 mol), and TEA (18.4 mg, O.OOO35 mol) were combined in 2 mL dry dichloromethane. The solution was allowed to stir overnight. Hexane was added and the reaction mix filtered. ALLOO 143 was isolated using silica column chromatography and hexane:ethyl acetate (9:1). The purified product appeared as transparent, viscous oil with light amber color.
[00197] For ALL00143, the 1H NMR (400 MHz, CDCl3) was as follows: δ= 6.82(2H, s, ArH); 5.17-5.21(1H, m, H-2); 4.51-4.55(1H, m); 4.42-4.46(1H, m); 3.86(6H, s, OCO2CH3); 3.60-3.68(1H, m, H-3); 2.65-2.73(1H, m); 2.53-2.59(2H, m, benzylic CH2); 2.16-2.28(1H, m); 1.93-2.O1(1H, m); 1.66-1.81(2H, m); 1.65(3H, br s, 7-Me); 1.54-1.63(2H, m); 1.58-1.60(3H, m, 10-Me); 1.24-1.37(4H, m); 0.88(3H, t, J=7.0, CH2CH3).
[00198] 4.9 Synthesis of ALL00145 (CBD diformate) and ALLOO 146 (CBD formate)
[00199] Cannabidiol (150 mg, 0.00043 mol), formic acid (59.25 mg, 0.00129 mol), and DMAP (36.6 mg, 0.00030 mol) were combined in 1 mL dry dichloromethane. The solution was stirred for 5 min at ambient temperature. DCC (150 mg, 0.00142 mol) was added to the mixture. The mixture was allowed to stir for 4 h at ambient temperature. Hexane was added and precipitate removed by filtration. The solution was reduced to a small volume under nitrogen. ALLOO 145 and ALLOO 146 were separated and isolated using a semi-preparatory silica column with hexane:ethyl acetate (97:3). The solvent from each collected fraction was removed under vacuum. The purified products appeared as transparent, viscous oil with light amber color.
[00200] For ALL00145, the 1H NMR (400 MHz, CDCl3) was as follows: δ= 8.16(2H, br s, CHO); 6.78(2H, s, ArH); 5.09-5.13(1H, m, H-2); 4.52-4.56 (IH, m); 4.41-4.45(1H, m); 3.60- 3.69(1H, m, H-3); 2.64-2.72(1H, m); 2.54-2.62(2H, m, benzylic CH2); 2.08-2.20(1H, m); 1.96- 2.05(1H, m); 1.75-1.82(1H, m); 1.66-1.75(1H, m); 1.654(3H, br s, 7-Me); 1.65-1.54(2H, m); 1.58-1.60(3H, m, 10-Me); 1.24-1.39(4H, m); 0.89(3H, t, J=7.0, CH2CH3).
[00201] For ALL00146, the 1H NMR (400 MHz, CDCl3) was as follows: δ= 8.18(1H, s, CHO); 6.78(1H, br s, ArH); 6.37(1H, d, J=1.5, ArH); 6.1O(1H, br s, OH); 5.53(1H, br s, H-2); 4.55-4.58(1H, m); 4.36(1H, br s); 3.62-3.72(1H, m, H-3); 2.48-2.54(2H, m, benzylic CH2); 2.41- 2.46(1H, m); 2.17-2.30(1H, m); 2.05-2.15(1H, m); 1.68-1.86(2H, m); 1.79(3H, br s, 7-Me); 1.53-1.63(2H, m); 1.60(3H, br s, 10-Me); 1.24-1.38(4H, m); 0.88(3H, t, J=7.0, CH2CH3).
[00202] 4.10 Synthesis ALL00147 (CBD diglycolate)
[00203] To a stirred solution of cannabidiol (31.4 mg, 0.1 mmol) and (t- butyldimethylsilyloxy)acetic acid (57.5 mg, 0.26 mmol) in dichloromethane (0.4 mL), 4- dimethylaminopyridine (10.3 mg, 0.05 mmol) was added followed by N,N'- dicyclohexylcarbodiimide (61.9 mg, 0.3 mmol). The mixture was stirred at ambient temperature for 4 h. The mixture was diluted with hexane (0.4 mL), filtered, concentrated under a reduced pressure, and chromatographed on silica gel with hexane-ethyl acetate (gradient 40:1, 20:1, 10:1) to afford CBD bis((t-butyldimethylsilyloxy)acetate) (44.4 mg, 67.4%) as an oil.
[00204] Cannabidiol bis((t-butyldimethylsilyloxy)acetate) was dissolved in dichloromethane (0.2 mL), cooled to -15°C and treated with 0.2 mL of cold 2 M solution of triethylamine trihydrofluoride. The reaction mixture was left at 5°C for 65 h. The mixture was poured into an excess of aqueous saturated sodium bicarbonate/ethyl acetate cooled to 00C with vigorous stirring. The aqueous layer was extracted twice with ethyl acetate, combined organic extracts were dried over anhydrous sodium sulfate and concentrated. Residue was chromatographed on silica gel with hexane-ethyl acetate (gradient 3:1, 2:1, 1:1) to afford 18.9 mg (65%) of cannabidiol diglycolate (ALLOO 147) as an oil.
[00205] For ALL00147, the 1H NMR (400 MHz, CDCl3) was as follows: δ= 6.79(2H, s, ArH); 5.17(1H, br s, H-2); 4.52-4.57(1H, m); 4.41-4.47(1H, m); 4.39, 4.36 and 4.22(4H, br singlets, OCH2CO2); 3.42-3.50(1H, m, H-3); 2.48-2.62(3H, m); 2.36(2H, t, J=5.6, OH); 2.08- 2.2O(1H, m); 1.99-2.08(1H, m); 1.68-1.83(2H, m); 1.66(3H, br s, 7-Me); 1.57-1.65(2H, m); 1.52-1.54(3H, s, 10-Me); 1.26-1.38(4H, m); 0.89 (3H, t, J=7.0, CH2CH3).
[00206] 4.11 Synthesis ALL00149 (CBD glycolate)
[00207] To a stirred solution of cannabidiol (125.8 mg, 0.4 mmol) and (t- butyldimethylsilyloxy)acetic acid (112.9 mg, 0.51 mmol) in dry dichloromethane (1 mL) was added of 4-dimethylaminopyridine (6.2 mg, 0.03 mmol) followed by N,N'- dicyclohexylcarbodiimide (123.8 mg, 0.6 mmol). The mixture was stirred at ambient temperature for 1 h. Additional amounts of the acid (26.6 mg) and N,N'- dicyclohexylcarbodiimide (31 mg) were added and stirring was continued for 1 h. Mixture was diluted with hexane (2 mL), filtered, and concentrated. The crude product was purified by preparative reverse phase HPLC (C8 column) with acetonitrile-water to afford cannabidiol (t- butyldimethylsilyloxy)acetate as an oil.
[00208] Cannabidiol (t-butyldimethylsilyloxy)acetate (80 mg) was dissolved in dry dichloromethane (0.25 mL), cooled to -15°C and treated with 0.25 mL of cold 2 M solution of triethylamine trihydrofluoride in dichloromethane. The reaction mixture was left at 5°C for 65 h. The mixture was poured to an excess of aqueous saturated sodium bicarbonate/ethyl acetate cooled to O0C with vigorous stirring. Aqueous layer was extracted twice with ethyl acetate, the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with hexane-ethyl acetate (gradient 10:1, 4:1, 3: 1) to afford 58 mg (95%) of cannabidiol glycolate (ALL00149) as an oil.
[00209] For ALLOO 149, the 1H NMR (400 MHz, CDCl3) was as follows: δ= 6.59(1H, br s, ArH); 6.43(1H, d, J=1.8, ArH); 6.03(1H, br s, OH); 5.53(1H, br s, H-2); 4.59-4.62(1H, m); 4.44QH, br s); 4.30-4.40(2H, m, OCH2CO2); 3.46(1 H, br s, H-3); 2.48-2.54(2H, m, benzylic CH2); 2.4O-2.47(1H, m); 2.39(2H, t, J=5.6, OH); 2.15-2.29(1H, m); 2.04-2.14(1H, m); 1.67- 1.86(2H, m); 1.78(3H, br s, 7-Me); 1.53-1.63(2H, m); 1.57(3H, br s, 10-Me); 1.23-1.37(4H, m); 0.88(3H, t, J=7.0, CH2CH3).
[00210] 4.12 Synthesis ALLOOl 51 (CBD L-lactate)
[00211] To a stirred solution of cannabidiol (220.1 mg, 0.7 mmol) and L-(t- butyldimethylsilyl)lactic acid (299.4 mg, 1.26 mmol) in dry dichloromethane (2 mL) was added 4-dimethylaminopyridine (14.4 mg, 0.07 mmol) followed by N,N'-dicyclohexylcarbodiimide (310.5 mg, 1.505 mmol). The mixture was stirred at ambient temperature for 1 h. Additional amounts of the acid (45 mg) and N,N'-dicyclohexylcarbodiimide (60 mg) were added and stirring was continued for 1.5 h. The mixture was diluted with hexane (3 mL), filtered, and concentrated. The crude product was purified by preparative reverse phase HPLC (C8 column) with acetonitrile-water to afford cannabidiol L-(t-butyldimethylsilyl)lactate as an oil and cannabidiol bis(L-(t-butyldimethylsilyl))lactate (an intermediate for cannabidiol di(L-lactate)).
[00212] Cannabidiol L-(t-butyldimethylsilyl)lactate (15.1 mg) was dissolved in dry dichloromethane (0.1 mL), cooled to -15°C and treated with 0.1 mL of cold 2M solution of triethylamine trihydrofluoride in dichloromethane. The reaction mixture was left at 50C for 65 h. The mixture was poured to an excess of aqueous saturated sodium bicarbonate/ethyl acetate cooled to 00C with vigorous stirring. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with hexane-ethyl acetate (gradient 10:1, 6:1, 4: 1) to afford 9.8 mg (82 %) of CBD L-lactate (ALL00151) as an oil.
[00213] For ALL00151, the 1H NMR (400 MHz, CDCl3) was as follows: δ=6.59(lH, br s, ArH); 6.37(1H, d, J=1.8, ArH); 6.02(1H, br s, OH); 5.52(1H, br s, H-2); 4.6O-4.63(1H, m); 4.44- 4.52(1H, m, OCHCO2); 4.44(1H, br s); 3.41(1H, br s, H-3); 2.77(1H, d, J=5.4, OH); 2.47- 2.53(2H, m, benzylic CH2); 2.4O-2.48(1H, m); 2.15-2.29(1H, m); 2.03-2.14(1H, m); 1.67- 1.86(2H, m); 1.78(3H, br s, 7-Me); 1.53-1.64(5H, m, aliphatic H and OCH(CH3)CO2); 1.59(3H, br s, 10-Me); 1.23-1.38(4H, m); 0.88(3H, t, J=7.0, CH2CH3).
[00214] 4.13 Proposed CBD-Hyaluronic acid
[00215] One or both of the hydroxyl groups on the cannabidiol molecule can be functionalized with various substituents (e.g., hyaluronic acid, lactic acid and glycolic acid) and optionally combined with dermatologically acceptable vehicles to form a cosmetic composition for application to the skin of mammal, such as a human. The scheme below represents a possible method for attachment of cannabidiol to hyaluronic acid using carbonate linkage and the TBDMS ether as a protective group. It may be anticipated that most of the primary hydroxyl group of the polymer would be involved in the formation of the linkage to the drug. Additional and/or different sets of protective group/deprotection methods could be used.
Figure imgf000054_0001
[00216] Also, glycolic acid and lactic acid could be attached to either or cannabidiol hydroxyl groups through an ester linkage or with the carbonate linkage by use of the 2-hydroxy group of acids. Cannabidiol could be also attached in a similar manner to a polymeric compound, such as hyaluronic acid. Using an additional spacer (e.g. 2-aminoethanol or glycine), the attachment in all cases could also be achieved through a carbamate linkage.
[00217] One of skill in the art would also recognize that, for example, cannabidiol may be attached to carboxylic groups of + acid through the ester linkage or through a carbamate linkage through the use of an additional spacer (e.g. 2-aminoethanol). In a further embodiment, an additional spacer may also be used when attaching cannabidiol to hydroxyl groups of hyaluronic acid. [00218] 5.0 Plasma stability studies
[00219] An approximated 1 mg/mL stock solution of each prodrug was prepared in 100 μL of ethanol and 900 μL of acetonitrile. Ten (10) μ L of stock was spiked into 1 niL of plasma and vortexed. The samples were kept sealed in an amber vial and samples were obtained to analyze for bioconversion to parent drug.
[00220] 6.0 In vitro skin permeation studies
[00221] 6.1 Preparation of receiver fluid 1
[00222] One ( 1) L of receiver fluid was prepared by measuring 1 L of nanopure water into a graduated cylinder. 90% of the water was added to an Erlenmeyer flask. Hanks' salts (1 bottle) were added to the water along with 5.96 g of HEPES and 0.35 g of sodium bicarbonate. The pH of the solution was adjusted with 1 N sodium hydroxide solution to pH 7.4. The remaining water was added and the receiver fluid was filtered through a 0.2 μ filter (Millipore, Billerica, MA). Fifty (50) mg of gentamicin was added to the filtered receiver fluid and 400 mL of the receiver fluid was removed and replaced with 400 mL of PEG 400.
[00223] 6.2 Preparation of receiver fluid 2
[00224] The receiver fluid was prepared by measuring 600 mL of nanopure H2O into a graduated cylinder. The H2O was filtered through a 0.2 μ filter (Millipore, Billerica, MA). Fifty (50) mg of gentamicin was added to the filtered H2O and 400 mL of PEG 400 was added.
[00225] 6.3.1 Preparation of drug formulation (Example 2)
[00226] The prodrugs were made up in a solution of 45:4: 1 PG:H2O:IPM. For this solution, the appropriate amount of drug was weighed into a glass silanized culture tube and IPM was added, the 50 μL of PG to coat the drug, then an additional 247 μL PG was added and the donor solution was vortexed again. Finally 26 μ L of water was added. The gel formulation resulted from the mixing of absolute ethanol, nanopure water, IPM, Carbopol® 980, 0.1 N sodium hydroxide solution and the respective drug.
[00227] 6.3.2 Preparation of drug formulation (Example 2A)
[00228] The gel formulation was comprised of absolute ethanol, nanopure water, IPM, Carbopol® 980, 0.1 sodium hydroxide solution and respective drug. The anhydrous gel was comprised of absolute ethanol, PEG monoethyl ether 550, Klucel® hydroxypropylcellulose, and respective drug.
[00229] 6.4 Permeation experiments
[00230] Dermatomed skin harvested from abdominoplasty, stored at -200C, was used for the experiments. A PermeGear flow-through (In-Line, Hellertown, PA) diffusion cell system was used for the skin permeation studies.
[00231] Diffusion cells were kept at 32°C with a circulating water bath. Human epidermal skin was arranged in the diffusion cell with stratum corneum (upper layer of skin) facing the donor compartment. The permeation area of the skin was 0.95 cm2. The data was collected from a human skin donor with three diffusion cells per treatment.
[00232] The receiver solution was HEPES -buffered Hanks' balanced salts with gentamicin containing 40% PEG 400 at a pH of 7.4 or 40% aqueous PEG 400 and flow rate was adjusted to 0.8 mL/h. Each cell was charged with 0.10 mL of the respective drug formulation (donor solution) or 50 μ L of gel formulation which was rubbed into the skin for 15 sec with a Teflon coated rod. The formulation was applied to ensure complete coverage. The formulation was applied to ensure complete coverage. Diffusion cells were covered with a stopper or cap for the duration of the study.
[00233] Samples were collected into scintillation vials in 3 h increments for either 24, 30, or 42 h. All the samples were stored at 4°C until extracted. An aliquot (0.5 mL) of the diffusion sample was placed into a silanized HPLC vial and 0.5 mL of acetonitrile was added to the sample, capped and vortexed.
[00234] At the end of the experiment, the skin tissue was removed from the diffusion cell, rinsed with nanopure water, and blotted dry with a paper towel. The skin was tape stripped twice using book tape (Scotch™, 3M, St. Paul, MN) to remove drug formulation adhering to the tissue surface. The area of skin in contact with the drug was cut out, chopped up and placed in a pre- weighed scintillation vial. Ten (10) mL of acetonitrile was added to the vial and drug was extracted from the skin by shaking at room temperature overnight. The following day a 1 mL aliquot was removed transferred into a silanized HPLC vial for analysis. At the end of the experiments dosed with a gel, the skin tissue was rinsed 3 times with nanopure water for 10 s each and wiped off with an alcohol pad. The entire piece of skin was blotted dry and tape stripped twice using book tape 845 (Scotch , 3M, St. Paul, MN) to remove any drug formulation adhering to the surface. The skin was rinsed an additional time with nanopure water and blotted dry again. The area of skin in contact with the drug was removed, minced with a scalpel, and placed in a pre-weighed scintillation vial. Drug was extracted from the area of skin in contact with the drug by equilibrating with 10 mL of ACN while shaking in a water bath overnight.
[00235] At the end of the experiment, a 0.01 mL aliquot of the donor solution was removed and added to a scintillation vial containing 10 mL of acetonitrile. The vials were vortexed and an aliquot of 1 mL was removed and transferred into a silanized HPLC vial for analysis. At the end of the experiments dosed with a gel, the donor compartment was rinsed 5 times with a known amount of nanopure water or ACN and then an aliquot of the nanopure water or ACN were diluted with ACN. The vials were vortexed and an aliquot of 1 mL was removed and transferred into a silanized HPLC vial for analysis.
[00236] 7.0.1 Analytical method (Example 2)
Figure imgf000058_0001
[00237] 7.0.2 Analytical method (Example 2A)
Figure imgf000058_0002
[00238] 7.0.3 Analytical method (Example 2B)
Figure imgf000059_0001
[00239] 8.0 Data analysis
[00240] The cumulative quantity of drug collected in the receiver compartment was plotted as a function of time. The flux value for a given experiment was obtained from the slope of a steady-state portion of the cumulative amount of drug permeated vs. time plot. Lag time was obtained from the x-intercept of the steady state portion of the cumulative amount of drug permeated vs. time plot. In Tables 16-19 and 21-23, the combined results of the delivered prodrug and cannabidiol from the prodrug are listed as "total cannabidiol." These values represent the data as total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug.
[00241] SECTION III. RESULTS
[00242] The cannabidiol prodrugs synthesized in Example 2 were all oily compounds.
[00243] In gel formulation, ALLOOlOl permeated through the skin as mono-substituted prodrug (ALL00150) only. ALLOOlOl did not increase the flux compared to cannabidiol. ALLOOlOl was detected in the skin as trace small amounts of intact prodrug but mostly as mono- substituted prodrug, ALLOO 150, and cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time was decreased compared to cannabidiol.
[00244] Li donor solution, ALLOO 105 permeated through the skin as mono-substituted prodrug (ALL00148) and cannabidiol. ALL00105 did not increase the flux compared to cannabidiol. ALL00105 was detected in the skin as mono-substituted prodrug, ALL00148, and cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time was not decreased compared to cannabidiol.
[00245] In donor solution, ALLOOl 31 permeated through the skin as intact prodrug and cannabidiol. ALL00131 did not increase the flux compared to cannabidiol. ALL00131 was detected in the skin only as prodrug. Total skin concentrations were not higher compared to cannabidiol. Lag time was similar to cannabidiol.
[00246] In donor solution, ALLOO 132 permeated through the skin as intact prodrug, mono- substituted prodrug (ALL00131), and cannabidiol. ALL00132 did not increase the flux compared to cannabidiol. ALLOO 132 was detected in the skin as prodrug and small amounts as mono-substituted prodrug, ALL00131. Total skin concentrations were not higher compared to cannabidiol. Lag time wasn't decreased compared to cannabidiol.
[00247] In donor solution, ALLOOl 37 did not permeate through the skin or was below detection in the receiver samples. ALLOO 137 was detected in the skin as prodrug and trace amounts of cannabidiol. Total skin concentrations were not higher compared to cannabidiol.
[00248] In donor solution, ALLOO 140 permeated through the skin as intact prodrug and cannabidiol. ALL00140 did not increase the flux compared to cannabidiol. ALL00140 was detected mostly as prodrug in the skin with small amounts of cannabidiol. Total skin concentrations were not higher compared to cannabidiol. Lag time was slightly decreased compared to cannabidiol.
[00249] In donor solution, ALLOO 142 did not permeate through the skin or was below detection in the receiver samples. ALLOO 142 was detected in the skin only as intact prodrug. Total skin concentrations were not higher compared to cannabidiol.
[00250] In donor solution, ALLOO 143 did not permeate through the skin or was below detection in the receiver samples. ALL00143 was detected in the skin as prodrug and trace amounts of cannabidiol. Total skin concentrations were not higher compared to cannabidiol.
[00251] In donor solution, ALLOO 145 permeated through the skin as approximately 50% mono-substituted prodrug (ALL00146) and approximately 50% cannabidiol. ALL00145 did not increase the flux compared to cannabidiol. ALLOO 145 was detected in the skin as prodrug, mono-substituted prodrug, ALLOO 146, and cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time wasn't decreased compared to cannabidiol.
[00252] In gel formulation, ALLOO 146 permeated through the skin through the skin as intact prodrug and cannabidiol. ALLOO 146 did slightly increase the flux compared to cannabidiol. ALL00146 was detected in the skin as intact prodrug and cannabidiol. Total skin concentrations were not higher compared to cannabidiol. Lag time was similar to cannabidiol.
[00253] In donor solution, ALLOO 147 permeated through the skin as intact prodrug, mono- substituted prodrug (ALL00149), and cannabidiol. ALL00147 did not increase the flux compared to cannabidiol. ALLOO 147 was detected in the skin as prodrug, mono-substituted prodrug, ALL00149, and cannabidiol. Total skin concentrations were not higher compared to cannabidiol. Lag time was not decreased compared to cannabidiol.
[00254] In gel formulation, ALLOO 148 permeated through the skin through the skin as intact prodrug only. ALL00148 did not increase the flux compared to cannabidiol. ALL00148 was detected in the skin as mostly intact prodrug and small amounts of cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time was similar to cannabidiol.
[00255] Decreased lag time may benefit patients by delivering the drug more quickly which is beneficial for pain management and nausea. Long lag times are more useful for topical and follicular therapies where drug absorption is attenuated. Cannabidiol prodrugs may increase permeation more if drug solution solvent systems were optimized or if they were formulated with enhancers. Many of these prodrugs may be useful in targeting topical/follicular applications instead of transdermal applications. By targeting topical administration, drug delivery could focus on a localized delivery compared to a systemic delivery. Also, follicular delivery may be targeted for administration with or without microparticle formulations.
[00256] In gel formulation, ALLOO 146 permeated through the skin as cannabidiol only, no prodrug was detected in the receiver fluid. ALL00146 didn't increase the flux compared to cannabidiol. ALLOO 146 was detected in the skin as small amount of cannabidiol with the remaining being prodrug. Total skin concentrations were slightly higher compared to cannabidiol. Lag time was higher compared to cannabidiol. [00257] In gel formulation, ALLOO 150 did not permeate through the skin. ALLOO 150 was detected in the skin as primarily ALLOO 150 with a small amount of cannabidiol. Total skin concentrations were higher compared to cannabidiol.
[00258] In an anhydrous gel formulation, ALLOO 150 did not permeate through the skin. ALLOO 150 was detected in the skin as ALLOO 150 and cannabidiol. Total skin concentrations were higher compared to cannabidiol.
[00259] Overall, concentrations of cannabidiol and ALLOO 150 in the skin treated with the anhydrous gel formulation were much lower compared to the ethanol based gel formulation.
[00260] In gel formulation for cannabidiol, ALLOO 147, and ALLOO 149 only one cell of each drug had detectable levels in the receiver fluid of the respective drug. However all three cells of each drug had detectable skin concentrations. Therefore the diffusion data reported here reflects the data collected.
[00261] ALL00147 permeated through the skin as cannabidiol (47.2%) and mono-prodrug, ALL00149 (45.6%) with a trace amount of ALL00147 (7.2%). ALL00147 did increase the flux compared to cannabidiol by 2 fold. ALLOO 147 was detected in the skin primarily as mono- prodrug, ALL00149 with a trace amount of ALL00147. Total skin concentrations weren't higher compared to cannabidiol.
[00262] ALLOO 149 permeated through the skin as primarily ALLOO 149 with a trace amount of cannabidiol. ALL00149 did increase the flux compared to cannabidiol by 1.4. ALL00149 was detected in the skin as primarily ALL00149 with a trace amount of cannabidiol. Total skin concentrations were higher compared to cannabidiol. Lag time of ALLOO 149 was lower compared to cannabidiol.
[00263] SECTION IV. TABLES
[00264] Table 15. Cannabidiol and cannabidiol prodrugs
Figure imgf000063_0001
*LogP calculated by ChemSketch 10.02 (Advanced Chemistry Development, Inc; Canada)
[00265] Table 16. Permeation data of CBD (n=3), ALL00131 (n=3), ALL00132 (n=2), and ALL00140 (n=3) in 90:8:2 PG:H2O:IPM donor solution with 60/40 Hanks'/PEG 400 receiver fluid
Figure imgf000064_0001
* total CBD= total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug
Wherein "n" equals the number of skin samples tested.
[00266] Table 17. Permeation data of CBD (n=3), ALL00137 (n=3), ALL00142 (n=3), and ALL00143 (n=3) in 90:8:2 PG:H2O:IPM donor solution with 40% aqueous PEG 400 receiver fluid
Figure imgf000065_0001
* total CBD= total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug Wherein "n" equals the number of skin samples tested.
[00267] Table 18. Permeation data of CBD (n=3), ALL00105 (n=l) ALL00145 (n=3), and ALL00147 (n=2) in 90:8:2 PG:H2O:IPM donor solution with 40% aqueous PEG 400 receiver fluid
Figure imgf000066_0001
* total CBD= total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug Wherein "n" equals the number of skin samples tested.
[00268] Table 19. Permeation data of CBD (n=2), ALLOOlOl (n=2) ALL00146 (n=2), and ALL00148 (n=3) in gel formulation with 40% aqueous PEG 400 receiver fluid
Figure imgf000067_0001
* total CBD= total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug Wherein "n" equals the number of skin samples tested.
[00269] Table 20. Plasma stability of cannabidiol prodrugs
Figure imgf000068_0001
[00270] Table 21. Permeation data of CBD (n=2), ALL00146 (n=2), and ALL00150 (n=3) in gel formulation with 40% aqueous PEG 400 receiver fluid.
Figure imgf000069_0001
total CBD= total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug Wherein "n" equals the number of skin samples tested.
[00271] Table 22. Permeation data of CBD (n=2) and ALL00150 (n=3) in an anhydrous gel formulation with 40% aqueous PEG 400 receiver fluid.
Figure imgf000069_0002
* total CBD= total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug Wherein "n" equals the number of skin samples tested. [00272] Table 23. Permeation data of CBD (n=l), ALL00146 (n=l), and ALL00150 (n=l) in gel formulation with 40% aqueous PEG 400 receiver fluid.
Figure imgf000070_0001
* total CBD= total cannabidiol equivalents delivered in the form of cannabidiol and/or prodrug [00273] Table 24. Plasma stability of cannabidiol prodrugs
Figure imgf000070_0002
[00274] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
[00275] The use of the terms "a," "an" and "the" and similar references in the context of this disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., such as, preferred, preferably) provided herein, is intended merely to further illustrate the content of the disclosure and does not pose a limitation on the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.
[00276] Alternative embodiments of the claimed disclosure are described herein, including the best mode known to the inventors for practicing the claimed invention. Of these, variations of the disclosed embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing disclosure. The inventors expect skilled artisans to employ such variations as appropriate (e.g., altering or combining features or embodiments), and the inventors intend for the invention to be practiced otherwise than as specifically described herein.
[00277] Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
[00278] The use of individual numerical values are stated as approximations as though the values were preceded by the word "about" or "approximately." Similarly, the numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word "about" or "approximately." In this manner, variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. As used herein, the terms "about" and "approximately" when referring to a numerical value shall have their plain and ordinary meanings to a person of ordinary skill in the art to which the disclosed subject matter is most closely related or the art relevant to the range or element at issue. The amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors which may be considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed subject matter, as well as other considerations known to those of skill in the art. As used herein, the use of differing amounts of significant digits for different numerical values is not meant to limit how the use of the words "about" or "approximately" will serve to broaden a particular numerical value or range. Thus, as a general matter, "about" or "approximately" broaden the numerical value. Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values plus the broadening of the range afforded by the use of the term "about" or "approximately." Thus, recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.
[00279] It is to be understood that any ranges, ratios and ranges of ratios that can be formed by, or derived from, any of the data disclosed herein represent further embodiments of the present disclosure and are included as part of the disclosure as though they were explicitly set forth. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary. Accordingly, a person of ordinary skill in the art most closely related to a particular range, ratio or range of ratios will appreciate that such values are unambiguously derivable from the data presented herein.

Claims

CLAIMSWe claim:
1. A compound having the formula:
Figure imgf000073_0001
wherein Ri and R2 are independently selected from hydrogen, ester, carbonate, and carbamate; and wherein Ri and R2 can not both be hydrogen.
2. The compound of claim 1 wherein the ester is an oxygenated ester.
3. The compound of claim 2 wherein the oxygenated ester is selected from the group consisting of: an oxaester, a pegylated ester and a hydroxylated ester.
4. The compound of claim 1 wherein the ester is selected from the group consisting of: an alkyl ester, an amino ester, an alkylamino ester, dialkylamino ester, formic acid ester, glycolic acid ester, lactic acid ester and hyaluronic acid ester.
5. The compound of claim 1 wherein the carbamate is selected from the group consisting of: oxygenated carbamate, oxacarbamate, pegylated carbamate, hydroxylated carbamate, alkyl carbamate, amino carbamate, alkylamino carbamate, dialkylamino carbamate, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carbamate.
6. The compound of claim 1 wherein the carbonate is selected from the group consisting of: oxygenated carbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate, alkyl carbonate, amino carbonate, alkylamino carbonate, dialkylamino carbonate, glycolic acid carbonate, hyaluronic acid carbonate and lactic acid carbonate.
7. The compound of claim 1 selected from the group consisting of:
Figure imgf000074_0001
73
Figure imgf000075_0001
8. A pharmaceutical composition comprising:
(a) a compound as described in claim 1 ; and
(b) a pharmaceutically acceptable excipient.
9. A pharmaceutical composition comprising:
(a) a compound as described in claim 7; and
(b) a pharmaceutically acceptable excipient.
10. The use of a compound as described in claim 1 for the preparation of a medicament for the treatment of a medical condition in a mammal, wherein the medical condition is selected from the group consisting of: nausea, vomiting, emesis, pain, wasting syndrome, HIV-wasting, chemotherapy induced nausea and vomiting, alcohol use disorders, dystonia, multiple sclerosis, inflammatory bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, systemic lupus erythematosus, anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective, anti-cancer, immunomodulatory effects, peripheral neuropathic pain, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, bums, actinic keratosis, oral cavity sores and ulcers, post- episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic- postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, synovitis, juvenile rheumatoid arthritis and inhibition of hair growth.
11. The use of a compound as described in claim 7 for the preparation of a medicament for the treatment of a medical condition in a mammal, wherein the medical condition is selected from the group consisting of: nausea, vomiting, emesis, pain, wasting syndrome, HIV-wasting, chemotherapy induced nausea and vomiting, alcohol use disorders, dystonia, multiple sclerosis, inflammatory bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, systemic lupus erythematosus, anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective, anti-cancer, immunomodulatory effects, peripheral neuropathic pain, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post- episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic- postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, synovitis, juvenile rheumatoid arthritis and inhibition of hair growth.
12. The use of a compound as described in claim 10 wherein the cannabidiol prodrug is administered transdermally.
13. The use of a compound as described in claim 10 wherein the cannabidiol prodrug is administered topically.
14. A method of administering a compound to a mammal comprising the steps of:
(a) combining a compound of claim 1 with a pharmaceutical excipient to form a pharmaceutical composition;
(b) creating a dosage form suitable for administration to a mammal from the pharmaceutical composition; and
(c) administering the dosage form to a mammal.
15. A method of administering a compound to a mammal comprising the steps of:
(a) combining a compound of claim 7 with a pharmaceutical excipient to form a pharmaceutical composition;
(b) creating a dosage form suitable for administration to a mammal from the pharmaceutical composition; and
(c) administering the dosage form to a mammal.
16. The method of claim 15 wherein the compound is administered by a route selected from the group consisting of: transdermal, topical, oral, buccal, sublingual, intra venous, intra muscular, vaginal, rectal, ocular, nasal and follicular.
17. A cosmetic composition for application to the skin of a person comprising:
(a) a cannabidiol prodrug; and
(b) a dermatologically acceptable vehicle.
18. The composition of claim 17 wherein the cannabidiol prodrug is selected from the group consisting of:
Figure imgf000078_0001
wherein Ri and R2 are independently selected from the group consisting of: hydrogen, glycolic acid ester, lactic acid ester, hyaluronic acid ester, formic acid ester, glycolic acid carbamate, hyaluronic acid carbamate and lactic acid carbamate, glycolic acid carbonate, hyaluronic acid carbonate and lactic acid carbonate; and wherein Ri and R2 cannot both be hydrogen.
19. A cannabidiol prodrug having a log P value less than cannabidiol.
PCT/US2008/071659 2007-07-30 2008-07-30 Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same WO2009018389A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
MX2010001242A MX2010001242A (en) 2007-07-30 2008-07-30 Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same.
CN200880100836A CN101815697A (en) 2007-07-30 2008-07-30 Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
JP2010520166A JP2010535238A (en) 2007-07-30 2008-07-30 Cannabidiol prodrugs, compositions containing cannabidiol prodrugs and methods of use thereof
EP08796904.4A EP2176208B1 (en) 2007-07-30 2008-07-30 Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
ES08796904.4T ES2534900T3 (en) 2007-07-30 2008-07-30 Cannabidiol prodrugs, compositions comprising cannabidiol prodrugs and methods of use thereof
DK08796904.4T DK2176208T3 (en) 2007-07-30 2008-07-30 Prodrugs of cannabidiol, compositions containing prodrugs of cannabidiol and methods of use thereof
CA2694325A CA2694325C (en) 2007-07-30 2008-07-30 Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95274607P 2007-07-30 2007-07-30
US60/952,746 2007-07-30

Publications (2)

Publication Number Publication Date
WO2009018389A1 true WO2009018389A1 (en) 2009-02-05
WO2009018389A4 WO2009018389A4 (en) 2009-04-23

Family

ID=40011326

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/071659 WO2009018389A1 (en) 2007-07-30 2008-07-30 Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same

Country Status (10)

Country Link
US (1) US8293786B2 (en)
EP (1) EP2176208B1 (en)
JP (1) JP2010535238A (en)
CN (1) CN101815697A (en)
CA (1) CA2694325C (en)
DK (1) DK2176208T3 (en)
ES (1) ES2534900T3 (en)
MX (1) MX2010001242A (en)
PT (1) PT2176208E (en)
WO (1) WO2009018389A1 (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099670A2 (en) * 2008-02-08 2009-08-13 Nektar Therapeutics Al, Corporation Oligomer-cannabinoid conjugates
WO2010127033A1 (en) * 2009-04-28 2010-11-04 Alltranz Inc. Formulations of cannabidiol and methods of using the same
WO2011026144A1 (en) * 2009-08-31 2011-03-03 Alltranz Inc. Use of cannabidiol prodrugs in topical and transdermal administration with microneedles
WO2012030603A1 (en) * 2010-09-03 2012-03-08 Eastman Chemical Company Carbonate derivatives as skin care
US8293786B2 (en) 2007-07-30 2012-10-23 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
US8329938B2 (en) 2011-02-21 2012-12-11 Eastman Chemical Company Hydroxyalkanoic acid and hydroxyalkanoice acid oligomer esters of retinol
US8383842B2 (en) 2004-11-22 2013-02-26 Purdue Pharma L.P. Methods for purifying trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol
US8435556B2 (en) 2000-12-22 2013-05-07 Alltranz, Llc Transdermal delivery of cannabidiol
WO2014108899A1 (en) * 2013-01-08 2014-07-17 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Fluorinated cbd compounds, compositions and uses thereof
US8846723B2 (en) 2010-07-29 2014-09-30 Eastman Chemical Company Esters of O-substituted hydroxy carboxylic acids and preparations thereof
WO2015162610A1 (en) * 2014-04-21 2015-10-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Cyclohexenyl compounds, compositions comprising them and uses thereof
US20170362195A1 (en) * 2016-06-16 2017-12-21 Full Spectrum Laboratories Ltd Methods for the manufacture of cannabinoid prodrugs, pharmaceutical formulations and their use
KR20180120683A (en) * 2016-01-29 2018-11-06 더 유니버시티 오브 미시시피 The biologically active cannavidiol analog
WO2019030158A1 (en) 2017-08-07 2019-02-14 Enantia, S.L. A cocrystal of 2-[(1r,6r)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
WO2019059344A1 (en) 2017-09-22 2019-03-28 大日本住友製薬株式会社 Chemically activated water-soluble prodrug
EP3463304A4 (en) * 2016-05-24 2020-01-08 Bol Pharma Ltd. Compositions comprising cannabidiol and hyaluronic acid for treating inflammatory joint diseases
WO2020089424A1 (en) 2018-10-31 2020-05-07 Enantia, S.L. Solid compositions of cocrystals of cannabinoids
US10933008B1 (en) 2015-10-25 2021-03-02 Gelest Technologies, Inc. Silicon-based cannabidiol derivatives and compositions thereof
WO2021080648A1 (en) * 2019-10-25 2021-04-29 Gelest Technologies, Inc. Silicon-based cannabidiol derivatives and compositions thereof
EP3861996A1 (en) * 2020-02-04 2021-08-11 I+Med S. Coop. Controlled release system of phytocannabinoids formulations soluble in aqueous media, methods and uses thereof
WO2021173130A1 (en) 2020-02-26 2021-09-02 Vitality Biopharma, Inc. Novel cannabinoid glycosides and uses thereof
WO2021243467A1 (en) * 2020-06-05 2021-12-09 London Pharmaceuticals And Research Corporation Cannabinoid-hyaluronic acid bioconjugates
US11207291B2 (en) 2017-05-09 2021-12-28 Graphium Biosciences, Inc. Antimicrobial compositions comprising cannabinoids and methods of using the same
US11207414B2 (en) 2015-09-22 2021-12-28 Graphium Biosciences, Inc. Cannabinoid glycoside prodrugs and methods of synthesis
CN116685595A (en) * 2020-12-10 2023-09-01 盖列斯特有限公司 Silicon-based tetrahydrocannabinol derivatives and compositions thereof
EP4034100A4 (en) * 2019-09-26 2023-10-11 Firstlight Pharmaceuticals LLC Cannabinoid prodrug compounds
WO2024009324A1 (en) * 2022-07-08 2024-01-11 Council Of Scientific & Industrial Research Prodrugs of cannbidiol [cbd]-type phytocannabinoids and a process for preparation thereof
WO2024028516A1 (en) 2022-08-05 2024-02-08 Salud & Semillas, S.L. CANNABINOID SYNTHESIS STARTING OUT FROM OLIVETOL AND TERPENE IN DICHLOROMETHANE WITH FeCl3 * 6H2O AS CATALYST
EP4306524A3 (en) * 2017-08-29 2024-09-11 PureTech LYT, Inc. Lymphatic system-directing lipid prodrugs

Families Citing this family (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8343942B2 (en) * 2008-04-04 2013-01-01 University Of Utah Research Foundation Methods for treating interstitial cystitis
CN102712704B (en) * 2009-12-02 2015-01-07 陶氏环球技术有限责任公司 Three and four atom bridged dicarbonate compounds as internal donors in catalysts for polypropylene manufacture
WO2011123863A1 (en) 2010-04-02 2011-10-06 Alltranz Inc. Transdermally deliverable opioid prodrugs, abuse-resistant compositions and methods of using opioid prodrugs
CA2795158C (en) 2010-04-02 2019-10-22 Alltranz Inc. Abuse-deterrent transdermal formulations of opiate agonists and agonist-antagonists
US9566341B1 (en) 2011-04-27 2017-02-14 University Of Kentucky Research Foundation Compounds including Cox inhibitor moiety and enhanced delivery of active drugs using same
GB2514054A (en) 2011-09-29 2014-11-12 Gw Pharma Ltd A pharmaceutical composition comprising the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD)
WO2015074137A1 (en) 2013-11-20 2015-05-28 Mary Lynch Compositions and methods for treatment of ocular inflammation and pain
US9597279B2 (en) 2014-02-28 2017-03-21 HDDC Holdings, LLC Anti-aging dermal composition comprising herbal extracts
US20150324942A1 (en) * 2014-05-09 2015-11-12 Aari Ruben Selective enhancement of cannabis
GB2530001B (en) 2014-06-17 2019-01-16 Gw Pharma Ltd Use of cannabidiol in the reduction of convulsive seizure frequency in treatment-resistant epilepsy
GB2531282A (en) 2014-10-14 2016-04-20 Gw Pharma Ltd Use of cannabinoids in the treatment of epilepsy
GB2531281A (en) 2014-10-14 2016-04-20 Gw Pharma Ltd Use of cannabidiol in the treatment of intractable epilepsy
GB2531278A (en) 2014-10-14 2016-04-20 Gw Pharma Ltd Use of cannabidiol in the treatment of intractable epilepsy
CN104277917B (en) * 2014-10-24 2018-02-09 汉康(云南)生物科技有限公司 A kind of industrial hemp method of extraction of essential oil and its extraction equipment rich in cannabidiol
CN105037180B (en) * 2015-04-19 2017-10-10 安徽省逸欣铭医药科技有限公司 Central analgesia noval chemical compound, the Preparation method and use of a kind of double action
US9962340B2 (en) 2015-06-09 2018-05-08 Life Tech Global, Llc Device and method for the transdermal delivery of cannabidiol
GB2539472A (en) 2015-06-17 2016-12-21 Gw Res Ltd Use of cannabinoids in the treatment of epilepsy
GB2541191A (en) 2015-08-10 2017-02-15 Gw Pharma Ltd Use of cannabinoids in the treatment of epilepsy
GB2548873B (en) 2016-03-31 2020-12-02 Gw Res Ltd Use of Cannabidiol in the Treatment of SturgeWeber Syndrome
CA3021139A1 (en) * 2016-04-15 2017-10-19 Teewinot Technologies Limited Biosynthesis of cannabinoid prodrugs
US10499584B2 (en) 2016-05-27 2019-12-10 New West Genetics Industrial hemp Cannabis cultivars and seeds with stable cannabinoid profiles
GB2551986A (en) 2016-07-01 2018-01-10 Gw Res Ltd Parenteral formulations
GB2551987A (en) 2016-07-01 2018-01-10 Gw Res Ltd Oral cannabinoid formulations
GB2553139A (en) 2016-08-25 2018-02-28 Gw Res Ltd Use of cannabinoids in the treatment of multiple myeloma
WO2018064654A1 (en) 2016-10-01 2018-04-05 James Smeeding Pharmaceutical compositions comprising a statin and a cannabinoid and uses thereof
GB2557921A (en) 2016-12-16 2018-07-04 Gw Res Ltd Use of cannabinoids in the treatment of angelman syndrome
GB2559774B (en) 2017-02-17 2021-09-29 Gw Res Ltd Oral cannabinoid formulations
CN107137604A (en) * 2017-03-22 2017-09-08 哈尔滨惠美佳生物科技有限公司 A kind of cannabidiol liquid preparation with angst resistance effect and preparation method thereof
CN109498606A (en) * 2017-09-15 2019-03-22 汉义生物科技（北京）有限公司 A kind of composition containing cannabidiol and/or cannabidivarin and its application in treatment dysmenorrhea
HRP20220277T1 (en) 2017-09-28 2022-05-13 Zynerba Pharmaceuticals, Inc. Treatment of fragile x syndrome and autism with cannabidiol
WO2019082171A1 (en) * 2017-10-27 2019-05-02 Alvit Pharma Oral cannabinoid compositions with improved bioavailability
GB2569961B (en) 2018-01-03 2021-12-22 Gw Res Ltd Pharmaceutical
CA3090545A1 (en) 2018-02-28 2019-09-06 University Of Southern California Compositions and methods for modulating inflammatory and degenerative disorder
GB201806953D0 (en) 2018-04-27 2018-06-13 Gw Res Ltd Cannabidiol Preparations
US20190328884A1 (en) * 2018-04-30 2019-10-31 Chemic Laboratories, Inc. Compositions and methods of their use
GB201807942D0 (en) 2018-05-16 2018-06-27 Klaria Pharma Holding Ab Pharmaceutical formulation
CN110575448A (en) * 2018-06-08 2019-12-17 云南汉素生物科技有限公司 Cannabidiol composition and application thereof
AU2019324127A1 (en) 2018-08-20 2021-04-08 Bessor Pharma, Llc Applications of known and novel cannabinoids
US11185526B2 (en) 2018-09-04 2021-11-30 Babak Ghalili Cannabinoid, menthol and caffeine dissolvable film compositions, devices and methods
US11376227B2 (en) 2018-09-04 2022-07-05 Babak Ghalili Cannabinoid and menthol gum and lozenge compositions and methods
US11147775B2 (en) 2018-09-04 2021-10-19 Babak Ghalili Cannabinoid and menthol gel compositions, patches and methods
US10813889B2 (en) 2018-09-04 2020-10-27 Babak Ghalili Cannabinoid and menthol compositions and methods
US20200069604A1 (en) * 2018-09-04 2020-03-05 Babak Ghalili Cannabinoid and anesthetic compositions and methods
US11235013B2 (en) 2018-09-04 2022-02-01 Babak Ghalili Cannabinoid, menthol and caffeine dissolvable film compositions, devices and methods
US10987321B2 (en) * 2018-09-04 2021-04-27 Babak Ghalili Cannabinoid and anesthetic compositions and methods
EP3923915A4 (en) * 2019-02-11 2023-03-22 John Robert Chancey Methods of making and using phytocannabinoids complexed with a protein, peptide, amino acid, polysaccharide, disaccharide, ormonosaccharide
CN111943813B (en) * 2019-05-17 2023-04-14 上海特化医药科技有限公司 Preparation method of cannabidiol compound
JP2022539523A (en) * 2019-06-24 2022-09-12 ダイヴァース バイオテック， インコーポレイテッド cannabinoid conjugate molecule
US12016829B2 (en) 2019-10-11 2024-06-25 Pike Therapeutics Inc. Pharmaceutical composition and method for treating seizure disorders
AU2020366147B2 (en) 2019-10-14 2024-09-05 Pike Therapeutics Inc. Transdermal delivery of cannabidiol
US12121617B2 (en) 2019-10-14 2024-10-22 Pike Therapeutics Inc. Transdermal delivery of cannabidiol
CA3162182A1 (en) * 2019-11-24 2021-05-27 Kashiv Biosciences, Llc Prodrugs of fulvestrant
CA3074150A1 (en) * 2020-02-18 2021-08-18 Ovation Science, Inc. Composition and method for transdermal delivery of cannabidiol (cbd) and delta9-tetrahydrocannabinol (thc)
GB202002754D0 (en) 2020-02-27 2020-04-15 Gw Res Ltd Methods of treating tuberous sclerosis complex with cannabidiol and everolimus
WO2021177937A1 (en) * 2020-03-02 2021-09-10 Babak Ghalili Cannabinoid and menthol compositions and methods
WO2021177936A1 (en) * 2020-03-02 2021-09-10 Babak Ghalili Cannabinoid and anesthetic compositions and methods
CN111423312B (en) * 2020-03-31 2021-05-07 云南西草资源开发有限公司 Method for extracting cannabidiol by utilizing purple sulfur bacteria fermentation and application thereof
WO2021211915A1 (en) * 2020-04-17 2021-10-21 University Of Connecticut Polycannabinoids, compounds, compositions and methods of use
CN111557900B (en) * 2020-05-22 2023-05-12 广州大洲生物医药科技有限公司 Cannabidiol cream, preparation method and application thereof
US11160757B1 (en) 2020-10-12 2021-11-02 GW Research Limited pH dependent release coated microparticle cannabinoid formulations
CN112279786B (en) * 2020-11-23 2023-05-09 汤文建 Cannabidiol carbamate compound, pharmaceutical preparation, preparation method and application
CN116234812A (en) * 2020-11-25 2023-06-06 成都百裕制药股份有限公司 Preparation method of cannabinoid compounds
US20220241163A1 (en) * 2021-02-04 2022-08-04 Ariel Scientific Innovations Ltd. Preparation of hyaluronic acid cbd conjugates
WO2022213931A1 (en) * 2021-04-06 2022-10-13 山东绿叶制药有限公司 Prodrug of cannabidiol, and pharmaceutical composition and use thereof
TW202304857A (en) * 2021-04-07 2023-02-01 加拿大商美蒂普爾製藥公司 Endocannabinoid system-targeting prodrugs and therapeutic uses thereof
WO2023009817A2 (en) * 2021-07-29 2023-02-02 Emory University Phosphate prodrugs of cannabinoids
CN113735709B (en) * 2021-09-17 2022-03-18 中国农业科学院农产品加工研究所 Cannabidiol-2-butyrate and application thereof
CN113666824B (en) * 2021-09-17 2022-03-22 中国农业科学院农产品加工研究所 Cannabidiol-2-propionate and application thereof
CN116253671A (en) * 2021-12-10 2023-06-13 德义制药有限公司 Cannabidiol derivative and preparation method and application thereof
US11660348B1 (en) 2022-02-01 2023-05-30 Akos Biosciences, Inc. Cannabinoid conjugate molecules
US11883499B2 (en) 2022-02-01 2024-01-30 Akos Biosciences, Inc. Cannabinoid conjugate molecules
CN114315680B (en) * 2022-03-07 2022-07-19 中国农业科学院农产品加工研究所 Cannabidiol-2-pyrrolidine acid ester and application thereof
CN114292249B (en) * 2022-03-07 2022-07-19 中国农业科学院农产品加工研究所 Cannabidiol-2-piperazinoate and application thereof
WO2023235386A1 (en) * 2022-05-31 2023-12-07 Trait Biosciences, Inc. Water-soluble cannabinoid prodrugs compositions and methods of synthesizing the same
CN116178246A (en) * 2023-02-21 2023-05-30 复旦大学 Cannabidiol amide water-soluble prodrug and preparation method thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999053917A1 (en) * 1998-04-21 1999-10-28 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Cannabinoids as antioxidants and neuroprotectants
US20020111377A1 (en) * 2000-12-22 2002-08-15 Albany College Of Pharmacy Transdermal delivery of cannabinoids
WO2004039317A2 (en) * 2002-10-25 2004-05-13 Euro-Celtique S.A. Analogs and prodrugs of buprenorphine
WO2004082620A2 (en) * 2003-03-13 2004-09-30 Controlled Chemicals, Inc. Oxycodone conjugates with lower the abuse potential and extended duration of action
WO2006133941A2 (en) * 2005-06-16 2006-12-21 Euro-Celtique S.A. Cannabinoid active pharmaceutical ingredient for improved dosage forms
WO2008107879A1 (en) * 2007-03-05 2008-09-12 Yissum Research Development Company Of The Hebrew University Of Jerusalem Novel cannabidiol derivatives and their use as anti-inflammatory agents

Family Cites Families (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3968125A (en) * 1973-11-05 1976-07-06 Eli Lilly And Company Dihydroxyhexahydrodibenzo[b,d]pyrans
US4260764A (en) * 1976-12-22 1981-04-07 Pfizer Inc. 9-Hydroxyoctahydrobenzo [C] quinolines and intermediates therefor
US4235913A (en) * 1977-06-07 1980-11-25 Pfizer Inc. 9-Hydroxyhexahydrodibeno[b,d]pyrans, 1-substituted-9-hydroxyhexahydrodibenzo]b,d]pyrans
US4133819A (en) * 1977-06-17 1979-01-09 Pfizer Inc. Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents
US4263438A (en) * 1977-09-13 1981-04-21 Pfizer Inc. 3-[2,4-(Disubstituted)-phenyl]azacycloalkanones as analgesics
US4283569A (en) * 1977-09-13 1981-08-11 Pfizer Inc. Hydroxyalkyl and oxoalkyl substituted phenols as analgesics and sedatives
US4270005A (en) * 1977-11-14 1981-05-26 Pfizer Inc. 1,9-Dihydroxyoctahydrophenanthrenes and intermediates therefor
US4243674A (en) * 1978-06-12 1981-01-06 Pfizer Inc. 9-Hydroxydibenzo[b,d]pyrans and intermediates therefore
US4206225A (en) * 1978-09-22 1980-06-03 Pfizer Inc. 2,10-Disubstituted dibenzo[b,d]pyrans and benzo[c]quinolines
US4371720A (en) * 1980-09-19 1983-02-01 Pfizer Inc. 2-Hydroxy-4-(substituted) phenyl cycloalkanes and derivatives
US4663474A (en) * 1983-02-22 1987-05-05 Pfizer Inc. Synthetic intermediates for a chiral 3-(substituted-phenyl)-4-(3-hydroxypropyl) cyclohexanol
IL80411A (en) * 1986-10-24 1991-08-16 Raphael Mechoulam Preparation of dibenzopyranol derivatives and pharmaceutical compositions containing them
GB8804164D0 (en) * 1988-02-23 1988-03-23 Tucker J M Bandage for administering physiologically active compound
US5223262A (en) * 1989-02-23 1993-06-29 University Of Utah Transdermal delivery system utilizing one way membranes
US5521215A (en) * 1989-11-07 1996-05-28 Ramot University Authority For Applied Research And Industrial Development Ltd. NMDA-blocking pharmaceuticals
US5166145A (en) * 1990-09-10 1992-11-24 Alza Corporation Antiemetic therapy
IL101927A0 (en) 1992-05-19 1992-12-30 Yissum Res Dev Co Probe for cannabinoid receptors
FR2692575B1 (en) * 1992-06-23 1995-06-30 Sanofi Elf NOVEL PYRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
IL103932A (en) 1992-11-30 1997-02-18 Yissum Res & Dev Fatty acid and pharmaceutical compositions containing them
US5389375A (en) * 1993-05-21 1995-02-14 University Of Mississippi Stable suppository formulations effecting bioavailability of Δ9 -thc
IT1271267B (en) 1994-12-14 1997-05-27 Valle Francesco Della MONO AND BICARBOXYLIC ACID AMIDES WITH AMINO ALCOHOLS, SELECTIVELY ACTIVE ON THE PERIPHERAL RECEPTOR OF CANNABINOIDS
US5716928A (en) * 1995-06-07 1998-02-10 Avmax, Inc. Use of essential oils to increase bioavailability of oral pharmaceutical compounds
FR2741621B1 (en) * 1995-11-23 1998-02-13 Sanofi Sa NOVEL PYRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
FR2742148B1 (en) * 1995-12-08 1999-10-22 Sanofi Sa NOVEL PYRAZOLE-3-CARBOXAMIDE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US6017919A (en) * 1996-02-06 2000-01-25 Japan Tobacco Inc. Compounds and pharmaceutical use thereof
EP0971588B1 (en) 1997-01-21 2004-03-17 Smithkline Beecham Corporation Novel cannabinoid receptor modulators
FR2758723B1 (en) * 1997-01-28 1999-04-23 Sanofi Sa USE OF CENTRAL CANNABINOID RECEPTOR ANTAGONISTS FOR THE PREPARATION OF DRUGS
DE19706903A1 (en) * 1997-02-21 1998-08-27 Bayer Ag Use of known agonists of the central cannabinoid receptor CB 1
US6113940A (en) * 1997-03-03 2000-09-05 Brooke; Lawrence L. Cannabinoid patch and method for cannabis transdermal delivery
US6328992B1 (en) * 1997-03-03 2001-12-11 Lawrence L. Brooke Cannabinoid patch and method for cannabis transdermal delivery
WO1998041519A1 (en) 1997-03-18 1998-09-24 Smithkline Beecham Corporation Novel cannabinoid receptor agonists
US6132762A (en) * 1997-05-05 2000-10-17 Cristobal; Walter Transcutaneous application of marijuana
US5804592A (en) * 1997-05-30 1998-09-08 Unimed Pharmaceuticals, Inc. Method for improving disturbed behavior and elevating mood in humans
JPH1180124A (en) 1997-07-11 1999-03-26 Japan Tobacco Inc Quinoline compound and its medicine use
US6162829A (en) * 1997-10-17 2000-12-19 Atlantic Pharmaceuticals, Inc. (3R,4R)-Δ8 -tetrahydrocannabinol-11-oic acids useful as antiinflammatory agents and analgesics
WO1999024471A1 (en) 1997-11-10 1999-05-20 The Research Foundation Of State University Of New York Opiate, cannabinoid, and estrogen receptors
US5847128A (en) * 1998-05-29 1998-12-08 Virginia Commonwealth University Water soluble derivatives of cannabinoids
IT1302264B1 (en) 1998-09-24 2000-09-05 Innovet Italia Srl DERIVATIVES WITH N-ACYL VANILLYAMIDE STRUCTURE ABLE TO ACTIVATE PERIPHERAL IRECEPTORS OF CANNABINOIDS
WO2000032200A1 (en) 1998-11-24 2000-06-08 Alexandros Makriyannis Cannabimimetic lipid amides as useful medications
JP2000256323A (en) * 1999-01-08 2000-09-19 Japan Tobacco Inc 2-oxoquinoline compound and its medicinal use
WO2000045813A1 (en) * 1999-02-04 2000-08-10 New Millennium Pharmaceutical Research, Inc. Method for enhancement of delivery of thc by the administration of its prodrugs via the nasal route
US6566560B2 (en) * 1999-03-22 2003-05-20 Immugen Pharmaceuticals, Inc. Resorcinolic compounds
CN1561990A (en) * 1999-03-22 2005-01-12 免疫力药品有限公司 Treatment of immune diseases
IL136839A (en) * 2000-06-16 2006-12-10 Yissum Res Dev Co Pharmaceutical compositions comprising cannabidiol derivatives, and processes for the preparation of same
US8449908B2 (en) * 2000-12-22 2013-05-28 Alltranz, Llc Transdermal delivery of cannabidiol
US6503532B1 (en) * 2001-04-13 2003-01-07 Murty Pharmaceuticals, Inc. Pharmaceutical composition containing tetrahydrocannabinol and a transdermal/transcutaneous delivery method thereof
WO2006043260A2 (en) * 2004-10-22 2006-04-27 Pharmos Corporation Orally effective cannabinoid analogs
CN101228146A (en) * 2005-05-31 2008-07-23 法玛氏公司 Benzofuran derivatives with therapeutic activities
GB2439393B (en) 2006-06-23 2011-05-11 Gw Pharma Ltd Cannabinoids for use in the treatment of neuropathic pain
JP2010535238A (en) 2007-07-30 2010-11-18 オールトランツ インコーポレイティド Cannabidiol prodrugs, compositions containing cannabidiol prodrugs and methods of use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999053917A1 (en) * 1998-04-21 1999-10-28 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Cannabinoids as antioxidants and neuroprotectants
US20020111377A1 (en) * 2000-12-22 2002-08-15 Albany College Of Pharmacy Transdermal delivery of cannabinoids
WO2004039317A2 (en) * 2002-10-25 2004-05-13 Euro-Celtique S.A. Analogs and prodrugs of buprenorphine
WO2004082620A2 (en) * 2003-03-13 2004-09-30 Controlled Chemicals, Inc. Oxycodone conjugates with lower the abuse potential and extended duration of action
WO2006133941A2 (en) * 2005-06-16 2006-12-21 Euro-Celtique S.A. Cannabinoid active pharmaceutical ingredient for improved dosage forms
WO2008107879A1 (en) * 2007-03-05 2008-09-12 Yissum Research Development Company Of The Hebrew University Of Jerusalem Novel cannabidiol derivatives and their use as anti-inflammatory agents

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
ABU-LAFI ET AL.: "Role of hydroxyl groups in chiral recognition of cannabinoids by carbamated amylose", JOURNAL OF CHROMATOGRAPHY, vol. 679, 1994, pages 47 - 58, XP002505687 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HANDRICK, G. RICHARD ET AL: "Hashish. 20. Synthesis of (.+-.)-.DELTA.1- and .DELTA.6-3,4-cis-cannabidiols and their isomerization by acid catalysis", XP002505689, retrieved from STN Database accession no. 87:68497 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HATTORI, HIDEKI ET AL: "Gas chromatography/negative ion chemical ionization mass spectrometry of cannabinoids in human samples", XP002505694, retrieved from STN Database accession no. 100:97716 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KNAUS, E. E. ET AL: "The separation, identification, and quantitation of cannabinoids and their t-butyldimethylsilyl, trimethylsilylacetate, and diethylphosphate derivatives using high-pressure liquid chromatography, gas-liquid chromatography, and mass spectrometry", XP002505690, retrieved from STN Database accession no. 86:38182 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MADINAVEITIA, A. ET AL: "Cannabis indica. XI. An examination of the alkali-soluble portion of American-hemp resin", XP002505693, retrieved from STN Database accession no. 37:3626 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MECHOULAM, R. ET AL: "Hashish. IV. Isolation and structure of annabinolic, cannabidiolic, and cannabigerolic acids", XP002505691, retrieved from STN Database accession no. 63:16677 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PETRZILKA, T. ET AL: "Synthesis of hashish components. IV", XP002505692, retrieved from STN Database accession no. 71:21989 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; WEINER, BEN Z. ET AL: "Monomers and polymers of .DELTA.1(6)-tetrahydrocannabinol and cannabidiol", XP002505688, retrieved from STN Database accession no. 84:59754 *
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY , 10(1), 79-83 CODEN: EJMCA5; ISSN: 0223-5234, 1975 *
HELVETICA CHIMICA ACTA , 52(4), 1102-34 CODEN: HCACAV; ISSN: 0018-019X, 1969 *
IYO MASU KENKYUKAI KOENSHU , 8, 159-60 CODEN: KIMKDN; ISSN: 0910-870X, 1983 *
JOURNAL OF CHROMATOGRAPHIC SCIENCE , 14(11), 525-30 CODEN: JCHSBZ; ISSN: 0021-9665, 1976 *
JOURNAL OF ORGANIC CHEMISTRY , 42(15), 2563-8 CODEN: JOCEAH; ISSN: 0022-3263, 1977 *
JOURNAL OF THE CHEMICAL SOCIETY 628-30 CODEN: JCSOA9; ISSN: 0368-1769, 1942 *
PILLAI OMATHANU ET AL: "Physicochemical Evaluation, in Vitro Human Skin Diffusion, and Concurrent Biotransformation of 3-0-Alkyl Carbonate Prodrugs of Naltrexone", PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 21, no. 7, 1 January 2004 (2004-01-01), pages 1146 - 1152, XP002469233, ISSN: 0724-8741 *
STINCHCOMB A L ET AL: "PERMEATION OF BUPRENORPHINE AND ITS 3-ALKYL-ESTER PRODRUGS THROUGH HUMAN SKIN", PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 13, no. 10, 1 October 1996 (1996-10-01), pages 1519 - 1523, XP008016388, ISSN: 0724-8741 *
TETRAHEDRON , 21(5), 1223-9 CODEN: TETRAB; ISSN: 0040-4020, 1965 *

Cited By (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8435556B2 (en) 2000-12-22 2013-05-07 Alltranz, Llc Transdermal delivery of cannabidiol
US8449908B2 (en) 2000-12-22 2013-05-28 Alltranz, Llc Transdermal delivery of cannabidiol
US8937097B2 (en) 2004-11-22 2015-01-20 Purdue Pharma L.P. Methods for purifying trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol
US8383842B2 (en) 2004-11-22 2013-02-26 Purdue Pharma L.P. Methods for purifying trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol
US9675581B2 (en) 2004-11-22 2017-06-13 Svc Pharma Lp Methods for purifying trans-(−)-Δ9-tetrahydrocannabinol and trans- (+)-Δ9-tetrahydrocannabinol
US9744151B2 (en) 2004-11-22 2017-08-29 Svc Pharma Lp Methods for purifying trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol
US9278083B2 (en) 2004-11-22 2016-03-08 Svc Pharma Lp Methods for purifying trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol
US8293786B2 (en) 2007-07-30 2012-10-23 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
WO2009099670A2 (en) * 2008-02-08 2009-08-13 Nektar Therapeutics Al, Corporation Oligomer-cannabinoid conjugates
WO2009099670A3 (en) * 2008-02-08 2010-01-28 Nektar Therapeutics Oligomer-cannabinoid conjugates
US8829043B2 (en) 2008-02-08 2014-09-09 Nektar Therapeutics Oligome-cannabinoid conjugates
US9155797B2 (en) 2008-02-08 2015-10-13 Nektar Therapeutics Oligomer-cannabinoid conjugates
WO2010127033A1 (en) * 2009-04-28 2010-11-04 Alltranz Inc. Formulations of cannabidiol and methods of using the same
JP2012525416A (en) * 2009-04-28 2012-10-22 オールトランツ インコーポレイティド Cannabidiol formulation and method of use
WO2011026144A1 (en) * 2009-08-31 2011-03-03 Alltranz Inc. Use of cannabidiol prodrugs in topical and transdermal administration with microneedles
US8846723B2 (en) 2010-07-29 2014-09-30 Eastman Chemical Company Esters of O-substituted hydroxy carboxylic acids and preparations thereof
US9532938B2 (en) 2010-07-29 2017-01-03 Eastman Chemical Company Esters of O-substituted hydroxy carboxylic acids and preparations thereof
US8613940B2 (en) 2010-09-03 2013-12-24 Eastman Chemical Company Carbonate derivatives as skin care
WO2012030603A1 (en) * 2010-09-03 2012-03-08 Eastman Chemical Company Carbonate derivatives as skin care
US8329938B2 (en) 2011-02-21 2012-12-11 Eastman Chemical Company Hydroxyalkanoic acid and hydroxyalkanoice acid oligomer esters of retinol
US10441553B2 (en) 2013-01-08 2019-10-15 Universidade de Sao Paulo—USP Fluorinated CBD compounds, compositions and uses thereof
AU2018200570B2 (en) * 2013-01-08 2019-09-26 Universidade De Sao Paulo - Usp Fluorinated cbd compounds, compositions and uses thereof
US9782360B2 (en) 2013-01-08 2017-10-10 Universidade de Sao Paulo—USP Fluorinated CBD compounds, compositions and uses thereof
AU2014206036B2 (en) * 2013-01-08 2017-11-02 Universidade De Sao Paulo - Usp Fluorinated CBD compounds, compositions and uses thereof
US9447019B2 (en) 2013-01-08 2016-09-20 Universidade De Sao Paulo-Usp Fluorinated CBD compounds, compositions and uses thereof
WO2014108899A1 (en) * 2013-01-08 2014-07-17 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Fluorinated cbd compounds, compositions and uses thereof
WO2015162610A1 (en) * 2014-04-21 2015-10-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Cyclohexenyl compounds, compositions comprising them and uses thereof
US11149014B2 (en) 2014-04-21 2021-10-19 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Method for treating pain or associated condition or symptom
US10239848B2 (en) 2014-04-21 2019-03-26 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Cyclohexenyl compounds, compositions comprising them and uses thereof
US11207414B2 (en) 2015-09-22 2021-12-28 Graphium Biosciences, Inc. Cannabinoid glycoside prodrugs and methods of synthesis
US10933008B1 (en) 2015-10-25 2021-03-02 Gelest Technologies, Inc. Silicon-based cannabidiol derivatives and compositions thereof
KR20180120683A (en) * 2016-01-29 2018-11-06 더 유니버시티 오브 미시시피 The biologically active cannavidiol analog
US11337951B2 (en) 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
EP3407973A4 (en) * 2016-01-29 2019-09-11 The University Of Mississippi Biologically active cannabidiol analogs
US11596617B2 (en) 2016-01-29 2023-03-07 University Of Mississippi Biologically active cannabidiol analogs
AU2017212651B2 (en) * 2016-01-29 2020-01-23 University Of Mississippi Biologically active cannabidiol analogs
US11337952B2 (en) 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
US10709681B2 (en) 2016-01-29 2020-07-14 University Of Mississippi Biologically active cannabidiol analogs
KR102202133B1 (en) * 2016-01-29 2021-01-14 더 유니버시티 오브 미시시피 Biologically active cannabidiol analogues
US11337950B2 (en) 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
US11344525B2 (en) 2016-01-29 2022-05-31 University Of Mississippi Biologically active cannabidiol analogs
EP3463304A4 (en) * 2016-05-24 2020-01-08 Bol Pharma Ltd. Compositions comprising cannabidiol and hyaluronic acid for treating inflammatory joint diseases
WO2017216362A1 (en) * 2016-06-16 2017-12-21 Full Spectrum Laboratories Ltd Methods for the manufacture of cannabinoid prodrugs, pharmaceutical formulations and their use
US20170362195A1 (en) * 2016-06-16 2017-12-21 Full Spectrum Laboratories Ltd Methods for the manufacture of cannabinoid prodrugs, pharmaceutical formulations and their use
US11207291B2 (en) 2017-05-09 2021-12-28 Graphium Biosciences, Inc. Antimicrobial compositions comprising cannabinoids and methods of using the same
US12036202B2 (en) 2017-05-09 2024-07-16 Graphium Biosciences, Inc. Antimicrobial compositions comprising cannabinoids and methods of using the same
WO2019030158A1 (en) 2017-08-07 2019-02-14 Enantia, S.L. A cocrystal of 2-[(1r,6r)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
US11168047B2 (en) 2017-08-07 2021-11-09 Enantia, S.L. Cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-l,3-diol
EP4306524A3 (en) * 2017-08-29 2024-09-11 PureTech LYT, Inc. Lymphatic system-directing lipid prodrugs
WO2019059344A1 (en) 2017-09-22 2019-03-28 大日本住友製薬株式会社 Chemically activated water-soluble prodrug
US11993563B2 (en) 2018-10-31 2024-05-28 Enantia S.L. Solid compositions of cocrystals of cannabinoids
WO2020089424A1 (en) 2018-10-31 2020-05-07 Enantia, S.L. Solid compositions of cocrystals of cannabinoids
US11980602B2 (en) 2019-09-26 2024-05-14 Firstlight Pharmaceuticals Llc Cannabinoid prodrug compounds
EP4034100A4 (en) * 2019-09-26 2023-10-11 Firstlight Pharmaceuticals LLC Cannabinoid prodrug compounds
JP7475731B2 (en) 2019-09-26 2024-04-30 ファーストライト ファーマシューティカルズ，エルエルシー Cannabinoid Prodrug Compounds
WO2021080648A1 (en) * 2019-10-25 2021-04-29 Gelest Technologies, Inc. Silicon-based cannabidiol derivatives and compositions thereof
WO2021156291A1 (en) * 2020-02-04 2021-08-12 I+Med S. Coop. Controlled release system of phytocannabinoids formulations soluble in aqueous media, methods and uses thereof
EP3861996A1 (en) * 2020-02-04 2021-08-11 I+Med S. Coop. Controlled release system of phytocannabinoids formulations soluble in aqueous media, methods and uses thereof
WO2021173130A1 (en) 2020-02-26 2021-09-02 Vitality Biopharma, Inc. Novel cannabinoid glycosides and uses thereof
EP4161580A4 (en) * 2020-06-05 2024-05-15 London Pharmaceuticals and Research Corporation Cannabinoid-hyaluronic acid bioconjugates
EP4161580A1 (en) * 2020-06-05 2023-04-12 London Pharmaceuticals and Research Corporation Cannabinoid-hyaluronic acid bioconjugates
WO2021243467A1 (en) * 2020-06-05 2021-12-09 London Pharmaceuticals And Research Corporation Cannabinoid-hyaluronic acid bioconjugates
CN116685595A (en) * 2020-12-10 2023-09-01 盖列斯特有限公司 Silicon-based tetrahydrocannabinol derivatives and compositions thereof
WO2024009324A1 (en) * 2022-07-08 2024-01-11 Council Of Scientific & Industrial Research Prodrugs of cannbidiol [cbd]-type phytocannabinoids and a process for preparation thereof
WO2024028516A1 (en) 2022-08-05 2024-02-08 Salud & Semillas, S.L. CANNABINOID SYNTHESIS STARTING OUT FROM OLIVETOL AND TERPENE IN DICHLOROMETHANE WITH FeCl3 * 6H2O AS CATALYST

Also Published As

Publication number Publication date
US8293786B2 (en) 2012-10-23
CA2694325A1 (en) 2009-02-05
EP2176208A1 (en) 2010-04-21
DK2176208T3 (en) 2015-04-27
PT2176208E (en) 2015-05-11
CA2694325C (en) 2015-09-22
US20090036523A1 (en) 2009-02-05
WO2009018389A4 (en) 2009-04-23
EP2176208B1 (en) 2015-01-21
ES2534900T3 (en) 2015-04-30
CN101815697A (en) 2010-08-25
MX2010001242A (en) 2010-07-02
JP2010535238A (en) 2010-11-18

Similar Documents

Publication Publication Date Title
EP2176208B1 (en) Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
US20240083866A1 (en) Prodrugs of tetrahydrocannabinol compositions comprising prodrugs of tetrahydrocannabinol and methods of using the same
CA2760460C (en) Transdermal formulations of cannabidiol comprising a penetration enhancer and methods of using the same

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200880100836.1

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08796904

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 351/DELNP/2010

Country of ref document: IN

Ref document number: 2008796904

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2694325

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 203511

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2010520166

Country of ref document: JP

Ref document number: MX/A/2010/001242

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE