JPWO2021074790A5 - - Google Patents

Description

Cannabis (marijuana) is classified as a Schedule I drug in the United States. Cannabis is a flowering plant that contains over 400 types of phytonutrients (micronutrients). More than 100 terpenoids, essential oils, antioxidants, and cannabinoids are extracted from plants. Among all the phytochemicals, only tetrahydrocannabinol (THC) showed significant psychoactive effects. Many research papers have been published regarding THC due to its psychoactive and therapeutic effects. In addition to THC, there are other drugs such as cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG), tetrahydrocambivarin (THCV), delta 9-tetrahydrocambinol (delta 9 THC), etc. Ingredients that exhibit therapeutic effects without psychoactive effects are being researched. Cannabis and its derivatives are associated with pain, type 2-related metabolic disorders, decreased intraocular pressure, Dravet syndrome, Lennox-Gastaut syndrome (LGS), epilepsy , nausea associated with AIDS, pain and wasting, arthritis and Used to treat rheumatism, migraines, muscle spasms associated with multiple sclerosis and paralysis, alcohol and drug withdrawal, stress and depression, asthma, fibromyalgia, inflammatory pain, pain and/or inflammation associated with chemotherapy. It has been shown to be able to act as an antibacterial agent . FDA-approved Marinol and Syndros contain delta-9-THC and are currently used to treat nausea, vomiting, and loss of appetite associated with chemotherapy. Furthermore, in April 2016, the FDA designated cannabidiol as an orphan drug for the treatment of tuberous sclerosis syndrome (TSC), Dravet syndrome, and Lennox-Gastaut syndrome. Cannabidiol is an orally effective treatment for pain and inflammation. (Non-patent document 4).

Cannabidiol IUPAC name: 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
_{Chemical formula} : _C21H30O2
Molecular weight: 314.46 Daltons The chemical structure is shown below as Formula I.

テトラヒドロカンナビノール（ＴＨＣ）
ＩＵＰＡＣ名：（－）－（６ａＲ，１０ａＲ）－６，６，９－Ｔｒｉｍｅｔｈｙｌ－３－ｐｅｎｔｙｌ－６ａ，７，８，１０ａ－ｔｅｔｒａｈｙｄｒｏ－６Ｈ－ｂｅｎｚｏ［ｃ］ｃｈｒｏｍｅｎ－１－ｏｌ
化学式：Ｃ_２１Ｈ_３０ Ｏ_２
分子量３１４．４７ダルトン
化学構造式を下記式ＩＩに示す。

Tetrahydrocannabinol (THC)
IUPAC name: (-)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
_{Chemical formula} : _C21H30O2
The chemical structural formula with a molecular weight of 314.47 Daltons is shown in Formula II below.

The compound may be in the form of a pharmaceutically acceptable salt, such as an acid addition salt or a basic salt, or a solvate thereof, including a hydrate thereof. Suitable acid addition salts are formed from acids that form non-toxic salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, phosphoric acid. Hydrogen salt , acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzene Examples include sulfonate, p-toluenesulfonate, and pamoate. Suitable basic salts are formed from bases that form non-toxic salts, examples include sodium, potassium, aluminum, calcium, magnesium, zinc, and diethanolamine salts.

Synthetic cannabinoids used herein include at least the following:
AM-087 is a cannabinoid agonist derivative of Δ8THC substituted in the side chain at position 3 and is a potent CB1 agonist analgesic; AM-251 is an inverse agonist of the CB1 cannabinoid receptor and is also structurally similar to the biaryl pyrazole cannabinoid receptor antagonist and μ-opioid receptor antagonist SR141716A (rimonabant); metanandamide (AM-356) is a stable chiral analog of anandamide and has a acts on cannabinoid receptors with a Ki of 17.9 nM and CB2 of 868 nM; AM-374-palmitylsulfonyl fluoride; AM-381-stearylsulfonyl fluoride; AM404 is also known as N-arachidonoylaminophenol. AM-, the active metabolite of paracetamol (acetaminophen), is thought to induce analgesic analgesic effects through its activity on the endocannabinoid, COX, and TRPV systems present in pain and thermoregulatory pathways; AM-411 is an analgesic that is a cannabinoid agonist; AM-411 is a potent and highly selective full CB1 agonist that exhibits effects similar to other cannabinoid agonists such as analgesia, sedation, and anxiolytic; AM661-1-(N-Methyl-2- JWH-018 (1-pentyl - 3-(1-naphthoyl) indole ) or AM-678 is an analgesic chemical in the naphthoylindole family. , acts as a full agonist at CB1 and CB2 cannabinoid receptors, with some selectivity for CB2; AM-679 acts as a moderately potent agonist at cannabinoid receptors; AM-694 (1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole) acts as a potent and selective agonist at the cannabinoid receptor CB1; AM-735-3-bornyl- Δ8-THC is a mixed CB1/CB2 agonist; AM-855 is an analgesic cannabinoid agonist for both CB1 and CB2 with moderate selectivity for CB1; AM881 is a chlorine-substituted anandamide agonist. For stereoisomers, Ki = 5.3 nM for CB1 and 95 nM for CB2; AM-883 is an allyl-substituted stereoisomer of anandamide with Ki = 9.9 nM for CB1 and 226 nM for CB2; AM-905 is an analgesic cannabinoid. AM-906 is a cannabinoid agonist and analgesic that is a potent and selective agonist of the CB1 cannabinoid receptor; AM-919 is a potent analgesic cannabinoid receptor agonist at CB1 and CB2 receptors; AM-926 is a potent analgesic cannabinoid receptor agonist at CB1 and CB2 receptors with moderate selectivity for CB1. AM-938 is an analgesic that is a cannabinoid receptor agonist and is a strong agonist at CB1 and CB2 receptors, but is moderately selective for CB2. AM-1116 is a dimethylated stereoisomer of anandamide; AM-1172 is an endocannabinoid analog designed as a potent and selective AEA uptake inhibitor and is resistant to FAAH hydrolysis. AM-1220 is a potent and moderately selective agonist for the cannabinoid receptor CB1; AM-1221 acts as a potent and selective agonist for the cannabinoid receptor CB2; AM- AM-1241 (1-(5-fluoropentyl)-3(naphthalene-1-oil)-6-nitroindole) acts as a potent and reasonably selective agonist for the cannabinoid receptor CB1; -(Methylpiperidin-2-ylmethyl)-3-(2-iodo-5 - nitrobenzoyl)indole) is a potent and selective agonist for the cannabinoid receptor CB2, and is particularly effective in reducing hyperalgesia and allodynia in mammals. AM-1248 has an analgesic effect on "atypical" pain such as arthritis, and has also shown efficacy in the treatment of amyotrophic lateral sclerosis in mammalian models; AM-1710 exhibits 54-fold selectivity for CB1 and is a CB2-selective cannalactone; AM-1714 has a rational agonist for the peripheral cannabinoid receptor CB2. AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole) acts as a full agonist of cannabinoid receptors, with analgesic and antiallodynic effects; Potently acting but non-selective; AM-2212 acts as a potent agonist at both CB1 and CB2; AM-2213 acts as a potent agonist at both CB1 and CB2; AM-2232 (1-(4-cyanobutyl)-3-(naphthalene-1-oil)indole) acts as a potent, non-selective agonist of the cannabinoid receptors CB1 and CB2; Acts as a potent full agonist of CB2 and has been found to completely displace THC in certain mammalian studies, with potency lower than JWH-018 and higher than WIN55,212-2; AM -2389 acts as a potent and reasonably selective agonist for the CB1 receptor; AM-3102 is an analog of oleoylethanolamide, an endogenous agonist of growth factor-activated receptor alpha (PPARα). AM-4030 is a strong agonist of CB1 and CB2, but is a moderately selective analgesic for CB1; AM-4054 is a weak cannabinoid agonist at CB1 and CB2; AM-4113 is a CB1-selective neutral antagonist; AM-6545 is a peripherally selective silent antagonist for CB1 JWH - 007 is an analgesic that acts as a cannabinoid agonist at the CB1 and CB2 receptors, and has some selectivity for CB2. Yes; JWH-015 acts as a subtype-selective cannabinoid agonist that binds to CB2 nearly 28 times more strongly than CB1, and has been shown to have immunomodulatory effects and may be useful in the treatment of pain and inflammation. JWH-018 is an analgesic that acts as a full agonist at the CB1 and CB2 cannabinoid receptors and has effects similar to THC; JWH-019- acts as a full agonist at the CB1 and CB2 receptors. , is an analgesic in the naphthoyl indole family that acts as a cannabinoid agonist at the CB1 and CB2 receptors; JWH-030 is a partial agonist at the CB1 receptor; JWH-047 is a potent agonist at the CB2 receptor. JWH-048 is a potent and selective agonist of CB2 receptors; JWH-051 is an analgesic with high affinity for CB1 receptors. is a stronger agonist for CB2 ; JWH-057 is a 1-deoxy analog of Δ8-THC and has very high affinity for CB2 receptors, but less affinity for CB1 receptors. JWH-073 is a sedative that acts as a cannabinoid agonist at both CB1 and CB2 receptors, which is somewhat selective for the CB1 subtype; JWH-098 is a potent and fairly selective CB2 agonist; JWH-116 is a CB1 ligand; JWH-120 is a sedative that acts as an agonist at both CB1 and CB2 receptors; is a potent and 173-fold selective CB2 agonist; JWH-122 is a potent and highly selective CB1 agonist; JWH-133 is a potent and selective CB2 receptor agonist. 1JWH-139 is 3-(1,1-dimethylpropyl)-6,6,9-trimethyl6a,7,10,10a-tetrahydro-6H-benzo[c]chromene; JWH-147 is It is a nafthopyrrole analgesic that acts as a cannabinoid agonist at the CB1 and CB2 receptors; JWH-148 is a moderately selective ligand for the CB2 receptor, more than 8 times more selective for the CB1 subtype. JWH-149 is a potent and highly selective CB2 agonist; JWH-161 is a CB1 ligand; JWH-164 is a potent cannabinoid agonist; JWH-166 is a potent cannabinoid agonist; , is a potent and highly selective CB2 agonist; JWH-167 is a weak cannabinoid agonist of the phenylacetylindole family; JWH-171 is an analgesic that acts as a cannabinoid receptor agonist; JWH -175 is (1-pentylindol-3-yl)naphthalen-1-ylmethane, 22 nM CB1; JWH-176 is 1([(1E)-3-pentylinden-1-yridin]methyl)naphthalene JWH-181 is a potent cannabinoid agonist; JWH-182 is a potent cannabinoid agonist with some selectivity for CB1; JWH-184 is a 1-pentyl - 1H-indole -3-yl(4-methyl)-1-naphthylmethane; JWH-185 is 1-pentyl -1H-indol -3-yl(4-methoxy - 1-naphthyl)methane; JWH-192 is , (1-(2-morpholin-4-ylethyl)indol-3-yl)-4-methylnaphthalen-1- ylmethane ; -3-yl)-4-methylnaphthalen-1-ylmethanone; JWH-194 is 2-methyl-1-pentyl-1H-indol-3-yl-(4-methyl-1-naphthyl)methane ; JWH-195 is (1-(2-morpholin-4-ylethyl)indol-3-yl)-naphthalen-1-ylmethane; JWH-196 is 2-methyl-3-(1-naphthalenyl methyl)-1-pentyl-1H-indole; JWH-197 is 2-methyl-1-pentyl-1H-indole - 3-(4-methoxy-1-naphthyl)methane; JWH-198 is (1-(2-morpholin-4-ylethyl)indol-3-yl)-4-methoxynaphthalen-1-ylmethanone; -yl)-4-methoxynaphthalen-1-ylmethane; JWH-200 is an analgesic of the aminoalkylindole family that acts as a cannabinoid receptor agonist; Analgesic from the phenylacetylindole family that acts as a cannabinoid agonist with comparable affinity; JWH-205 is 142-methyl-1-pentylindol-3-yl)-2 phenylethanone; JWH-210 is a naphthoylindole family of analgesics that acts as a potent cannabinoid agonist at CB1 and CB2 receptors; JWH-213 is a potent and highly selective CB2 agonist; JWH-229 is a 1-methoxy-3-(1',1'-dimethylhexyl)-Δ8-THC, a dibenzopyran cannabinoid that is a potent CB2 agonist; JWH-234 is a cannabinoid agonist with CB2 selectivity JWH-250 is an analgesic of the phenylacetylindole family that acts as a cannabinoid agonist of CB1 and CB2 receptors; JWH-251 is a (1-pentyl-3-(2 - methylphenylacetyl)indole) ); JWH-258 is a potent and mildly selective CB1 agonist; JWH-302 is (1-pentyl-3-(3-methoxyphenylacetyl)indole); JWH-307 is , an analgesic of the naphthoylpyrrole family, acts as a cannabinoid agonist at CB1 and CB2 receptors, and is somewhat selective for the CB2 subtype; -3(1',1'-dimethylheptyl)-9α-hydroxyhexacannabinol, has 33 times selectivity for CB2 receptors, has high CB2 receptor affinity, and has high CB1 receptor affinity. JWH-359 is a dibenzopyran cannabinoid and a potent and selective CB2 receptor agonist; JWH-387 has low affinity for 1 - pentyl -3- (4-bromo-1- JWH-398 is an analgesic in the naphthoyl indole family that acts as a potent cannabinoid agonist at CB1 and CB2 receptors; JWH-424 is a potent and moderately selective CB2 agonist with a Ki of 2.3 nM for CB1 and 2.8 nM for CB2; HU-210 is a cannabinoid that is 100-800 times more potent than natural THC from cannabis, has a longer duration of action, and has many of the same effects as natural THC. is a powerful analgesic; ajlemic acid (AB-III-56, HU-239, IP-751, CPL 7075, CT-3, resunab) is a non-psychoactive THC metabolite 11-nor-9-carboxy-THC is a cannabinoid derivative that exhibits useful analgesic and anti-inflammatory effects without inducing a subjective “ high.” HU-243 (AM-4056) is being developed as a treatment for inflammatory diseases such as neuropathic pain and arthritis, and as a treatment for rare life-threatening inflammatory diseases; HU-243 (AM-4056) Cannabinoids are potent agonists in the body; HU-308 acts as a cannabinoid agonist and is highly selective for the CB2 receptor subtype. HU-331 is a quinone anticarcinogenic compound synthesized from cannabidiol that has analgesic properties, promotes neural stem cell proliferation, and protects both liver and vascular tissues from oxidative stress through inhibition of TNF-α. HU-336 is an angiogenesis inhibitor that directly induces apoptosis of vascular endothelial cells and inhibits angiogenesis without changing the expression of pro-angiogenic cytokines and their receptors; HU-345 ( Cannabinolquinone) is a drug that can inhibit aortic ring angiogenesis more potently than its parent compound, cannabinol; CP47,497 or (C7)-CP47,497 is a cannabinoid receptor agonist. be.

Using topical dosage forms as described in the art, including, but not limited to, semi-solids such as ointments, creams, emulsions, microemulsions, nanoemulsions, pastes, balms, gels, lotions, mousses, etc. Can be done. These include liquid sprays such as solutions, suspensions, microsuspensions, nanosuspensions, dispersions, and nanodispersions, and liquids such as aerosols and magmas. Cannabidiol, its free base, its salts, its isomers, its amorphous forms, its crystalline forms, its co-crystalline forms, its prodrugs, its analogues, its derivatives, its synthetic forms, its biosynthetic forms, its Topical dosage forms containing active metabolites, alone or in combination, can be applied topically to the skin surface for transdermal delivery of cannabidiol.

Claims (14)

A pharmaceutical composition comprising cannabidiol (CBD), in a dosage form for transdermal delivery, comprising:
1% w/w, 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% CBD at a concentration selected from the group consisting of: w/w, 10% w/w, 11% w/w, 12% w/w, 13% w/w, 14% w/w and 15% w/w;
a solvent containing 5 % to 20 % propylene glycol;
penetration enhancer containing 1% to 20% oleic acid ;
a suspending agent comprising 2% w/w to 15% w/w silicon dioxide, and
50% w/w to 80% w/w silicone pressure sensitive adhesive
wherein the pH of said pharmaceutical composition is maintained between 4.0 and 8.0 and is in the form of a transdermal matrix patch . Furthermore, gelling agents, polymers, emollients, skin irritation reducers, buffers, pH stabilizers, solubilizers, dispersants, stabilizers, plasticizers, surfactants, antioxidants, oxidants, and these 2. A pharmaceutical composition according to claim 1, comprising an effective amount of a carrier or ingredient selected from the group consisting of a combination of: A pharmaceutical composition according to claim 2 , comprising a carrier or ingredient in the range of 0.01% to 95% w/w or w/v. in a transdermal matrix patch , which may be administered in a dosing regimen selected from the group consisting of once a week, once every 8 to about 13 days, once every two weeks, and once every 15 to about 30 days. The pharmaceutical composition according to claim 1, which is . A pharmaceutical composition according to claim 1, which can be formulated as microneedles. 2. A pharmaceutical composition according to claim 1, wherein the CBD or derivative thereof is made by a synthetic route. A method for the treatment and/or prevention and/or reduction and/or control of pain and/or inflammation, comprising:
selecting patients in need of treatment and/or prevention and/or control of pain and/or inflammation, and
Topically applying a pharmaceutical composition according to claim 1;
including methods. Transdermal matrix patches for the treatment and/or prevention and/or control of pain and/or inflammation can be used once a day, once every two days, once every three days, once every four days, once every five days. 8. The method of claim 7 , wherein the method is topically applied at a frequency selected from the group consisting of once every 6 days, once every 6 days, once a week, and once every 10 days. 8. The method of claim 7 , further wherein delivery of the active ingredient of the transdermal matrix patch is provided at a constant delivery rate over a period of time. 8. The method of claim 7 , further wherein the active ingredient of the transdermal matrix patch is provided at a stable rate of absorption over a period of time. 8. The method of claim 7 , further wherein the serum level of the active ingredient of the transdermal matrix patch is provided constant over a period of time. 8. The method of claim 7 , further comprising reducing dosage variability of the active ingredient of the transdermal matrix patch over a period of time. 8. The method of claim 7, further comprising providing a plasma concentration of the active ingredient of the transdermal matrix patch in a therapeutic range over a period of time. Topical application of transdermal matrix patches is suitable for headache, migraine, tension-type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, Drug-induced neuropathic pain, causalgia, multiregional pain syndrome types I and II, and reflex sympathetic dystrophy (RSDS), AIDS-associated pain and wasting, arthritis and rheumatism, migraine, and multiple sclerosis and paralysis. muscle spasms associated with ASD and Autism Spectrum Disorder (ASD) in pediatric patients, pain and/or inflammation in patients with liver disease, pain and/or inflammation in patients with kidney disease, liver cancer. Treatment of pain and/or inflammation selected from the group consisting of pain and/or inflammation in a patient, treatment pain and/or inflammation in a kidney cancer patient, pain and/or inflammation in a cancer patient, and combinations thereof. and/or for prevention and/ or control.