WO2017149392A1 - Self-emulsifying compositions of cb2 receptor modulators - Google Patents

Self-emulsifying compositions of cb2 receptor modulators Download PDF

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Publication number
WO2017149392A1
WO2017149392A1 PCT/IB2017/000266 IB2017000266W WO2017149392A1 WO 2017149392 A1 WO2017149392 A1 WO 2017149392A1 IB 2017000266 W IB2017000266 W IB 2017000266W WO 2017149392 A1 WO2017149392 A1 WO 2017149392A1
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composition
bcp
receptor
modulator
group
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PCT/IB2017/000266
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French (fr)
Inventor
Sharon Anavi-Goffer
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Sharon Anavi-Goffer
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Priority to US16/081,105 priority Critical patent/US20190060300A1/en
Priority to EP17759334.0A priority patent/EP3423033A4/en
Publication of WO2017149392A1 publication Critical patent/WO2017149392A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is in the field of pharmaceutical compositions ' and discloses novel compositions for the oral administration of Caiwiabinoid Receptor Type 2 (CB2) modulators and optionally of an antipsychotic agent for the treatment of mental disorders,
  • CB2 Caiwiabinoid Receptor Type 2
  • Mental disorders can arise from multiple sources and affect a large percentage of the population. There are a range of different types of treatment of mental disorders and what is most suitable depends on the disorder and oft the individual.
  • Schizophrenia is mental disorder which affects about 1% of the population (Lewis ⁇ 3 ⁇ 4 L ieberman, 2000), and genetic and environmental factors underlie the eventual eruptio of the disease (Ross, 2006 ' ⁇ . Schizophrenia is often chronic, characterized by deterioration of social contact cognitive deficits, anxiety and depression, resulting in suicide in about 10% of the schizophrenic population (Lewis ⁇ 3 ⁇ 4 Liebemian, 2000).
  • TS Tourette syndrome
  • TS is characterized, by multi le motor tics and at least one vocal tic.
  • TS includes ties like blinking, coughing,, throat clearing, sniffing and facial, movements.
  • aspects of the invention relate to stable self-emnlsifying compositions comprising at least one €B2 modulator, a self-emulsifying vehicle and optionally at least one additional antipsychotic agent, methods of mak ng the compositions and methods of treatment using same for the txeaiment of mental, d s rders,
  • stable self-eraulsifyirig compositions comprising a therapeutically effective: amount of at least one CB2 receptor • modulator- in substantially pure form, a self-emulsifying vehicle and optionally a therapeutically effective amount of ai least one antipsychotic agent, for use in treating a mental disorder in a patient in need thereof.
  • the self-emulsifying (or self-emulsifiable) drug delivery systems can be liquid compositions generally used for oral deliver)'., or mere particularl designed for improved delivery of drug moieties with poor aque us solubility (see Nagaraju J. Seminar, M. Pharm. II Sem. 2010, Kakatiya University, Warangai, Department of Pharmaceutics, Uni versity College of Pharmaceutical Sciences.
  • the seLr-emulsifying drug delivery system (SEDDS) compositions enable to reduce the oral dose to correspond to the dose given by iwtraperitoneai injections or a lower dose.
  • the seif-emu fyi&g dru deliver system (SEDDS) compositions potentiate the therapeutic actions of a CB2 receptor modulator,, reducing the required do.se hence its toxicity.
  • compositions of this invention can be formulated as a stable self-emulsifying dreg delivery system (SEDDS) comprising at least one CB2 receptor modulator, optionall at least one antipsychotic agent and a .self-emulsifying vehicle comprising at least one oil, at least one surfactant with HLB ⁇ 9, at least one surfactant ⁇ with ilLB>13. at least One co-surfactant and at least one antioxidant and'Or free-radical scavenger.
  • SEDDS stable self-emulsifying dreg delivery system
  • the antioxidant and/or free-radical scavenger can be selected from vitamin E, d- alpha-tocopherol ( 1 - 10% w/w), di-alpha-tocopherol (2-i 5%w/w), dl-aipha-tocopheryi acetate (2 ⁇ .15% w/w), mixed tocopherols (alpha, beta, gama -- 1-10% w/w). d-alplia-tocopheryl acetate (2- 13% w/w), butylated hydroxyanisoje (BHA, 0.01-0.5% w/w), tocophersolan (TPGS.
  • vitamin E d- alpha-tocopherol ( 1 - 10% w/w), di-alpha-tocopherol (2-i 5%w/w), dl-aipha-tocopheryi acetate (2 ⁇ .15% w/w), mixed tocopherols (alpha, beta, gama -- 1-10% w/w
  • tocopherol PEG este succinate (2-10% w/w), vitami €, beta ⁇ amteoe., butylated hydrox toluene, butylated hydroxyanisole or other FDA-approved antioxidant listed in the FDA's Inactive Ingredients Database (IID), and combinations thereof.
  • IID Inactive Ingredients Database
  • the ratio of antioxidant/CB2 modulator is from 1 : 1 to 2:1 w/w.
  • the antioxidaiit/CB2 modulator is from hi to 3:3 w/w.
  • th ratio of anittoxtda «iCB2 modulator is from 1:1 to 4:lw/w. in some enibodimerrts
  • the ratio of aniioxidaj t B2 modulator is from .1:1 to 5:lw/w
  • the ratio of antioxidant/CB2 modulator is from 2:1 to 3:1 w/w. In some embodiments, the ratio of antioxidant/CB2 modulator is from 2:1.
  • the ratio of antioxtdant/CBl modulator is from 2:1 to 5:1 w/w. In some embodiments, the ratio of antioxidant/CB2 modulator is from 3:1 to '4:1 w/w. In some embodiments. the ratio of antioxidant B2 modulator is from 3:1 tc > 5:1 w/w. In some embodiments. the ratio of antioxidant/CB2 modulator is from 1:1 to 10: iw. ' w. In some embodiments, the ratio of antioxkiant/CB2 modulator ⁇ s from 2:1 to 10:1 w/w. in some embodiments, the rati of antioxidantCB2 modulator i s from 3:1 to 10:1 w/w..
  • the ratio of antioxidant/CB2 Modulator i S from 4:1 t 10:1 w/w. In some embodiments, the ratio of antioxidam7CB2 modulator i s from 5:1 to 10:1 w/w. In some embodiments, the ratio of antioxidantCB2 Modulator is from 6:1 to 10: 1 w/w. in some embodiments, the ratio of antioxidant/CB2 modulator is from 7:1 to 10:1 w/w. in some enrbodiments- the rati of ant-oxida»tCB2 Modulator i S from 8;1 to ⁇ ⁇ /w. In some emlxjdimeuts.
  • the ratio of antioxidant B2 modulator i s from 5:1 to 35:3 w/w. in some embodiments, the ratio of antioxidant/CB2 modulator i s from 5:1 ⁇ 40:] w/w* in some embodiments.
  • the ratio of a «tioxidaittCB2 modulator is from 10:1 to 15:1 w/w. In some embodiments. the ratio of antioxidant/CB2 modulator is from J :! t 20:1 w/w. In some embodiment, the ratio of aiitioxidani/CB2 modulator is from 10:1 to 25: w/w. in some embodiments. th ratio of antioxidani/CB2 modulator is from 10:1 to 30; 1 w/w.
  • the ratio of aitfioxidajnt/CB2 modulator is from 10:1 to 35:1 w/w. In some embodiments, the ratio of aniioxidarttCB2 modulator is from 10:1 to ⁇ 40:1 w/w. in some embodiments. the ratio of antioxidant/CB2 modulator is from I S:! to 20:1 w/w. in some embodiments, the ratio of a.Rtioxida «i/CB2 modulator is from 15:1 t 251 ⁇ ww. in sotne embodiments. th ratio of antioxidaiit/CB2 modulator is fr m 15:1 to 30:1 W/w...
  • the ratio of aniioxidaot/CB2 modulator is from 5:1 to 35: 1 w/w ' ,. In some embodiments, the ratio of atttk>x_da «t CB2 modulator is from 1.5: 1 . to (. 40; .1 w/w. In some embodiments, the ratio of antsoxidajr B2 modulator is from 20: 1 to 25: 1 w/w. la some embodiments, the ratio of causingoxidafi.t/CB2 modulator is from ,20; 1 to 30; ⁇ w/w. fil some embodiments, the ratio of causingoxida.nt/CB2 modulator is from 20:1 to 35: 1. w/w.
  • the ratio of afitiexidant BS modulator is from 20:1 to 40:1 w/w. In some embodiments, the ratio of anttoxida «t CB2 modulator is from 25: 1 t 30: 1 w/w. In some embodiments, the ratio of a «tioxidant/CB2 modulator is from 25: 1 to 35:1 w/w.. In some emboditneiits, the ratio of a «tioxidan.t CB2 modulator is from 25; 1 to 40: 1 w/w. In some embodiments, the ratio of antioxidant/CB2.
  • the ratio of a.i.tioxidant CB2 modulator is from 30: 1 to 40:1 w/w. » some embodiments, the above composition can spontaneously ; form an: oil-in- water ernuli sion upon dilution with wate containing media or body fluid.
  • the ratio of anuoxida»t/CB2 modulator such as bat not limited t 4-0-roetiiy tiiopokioi. ( H), is- from. 40; 1 t 2500; I w/w.
  • the aiiiioxidant/CB2 modulator i from 40:1 to 80; 1 w/w.
  • the ratio of anitoxida. t CB2 modulator is from 40: 1 to 100:1 w/w.
  • the ratio of aniioxidaat/CB2 modulator k from 100: 1 to 500: .1 w/w.
  • the ratio of antioxidant/CB2 modulator is from 500: 1 to 1 00:1 w/w. in some embodiments, the ratio of antioxidaru/CB2 modulator i from 1000; 1 to I5 ' 00:l /w. In some embodiments, the rati of amioxidani/CB2 modulator is from 1500:1 to 2000; iw/w. In some embodiments, the ratio of antioxidaut ' CB2 modulator is fro 2000:1 to 2500: I w/w. i some embodiments, the ratio of antioxidant/CB2 modulator is from 3:1 to 5:l.w/ .
  • the ratio of antioxidani/CB2 modulator is front 40:1 to 100: iw/w. In some embodiments, the ratio of awtioxidai.il/CB2 modulator is from 40:1 to 50; J w/w. I some embodiments;, the ratio of causingoxidai.it/CB2 modulator is from 40:1 to 60:1 w/w. In some embodiments, the ratio of anii.oxi.dant/CB2 modulator is .from, 40:1 to 80:1 w/w.
  • the ratio of aniioxidant/CB2 modulator is from 60: 1 to 500: Iw/w, In some embodiments, the ratio of antioxidant/CB2 modulator is from 80:1 to 500:1 w/w. In some embodiments, the ratio o antioxidant/CB2 modulator is from 100:1 to 500: 1 w/w. In some embodiments, the ratio of antioxidant/GB2 modulator is from 150: 1 to 250: 1 w/w. in some embodiments, the ratio of airdoxidam/CB2 modulator is front 150:1 to 280; I w/w.
  • the ratio of amioxidai.ii/CB2 modulator is from 150:1 to 300:1 w/w, In some embodiments, the ratio of antioxida»tCB2 modulator is from 200: to 500 ' : I w/w. In some embodiments., the ratio f antioxidaiit/CB2 modulator is from 300; I to 500l / . i some embodiments , the ratio of a»tioxidant/CB2 modulator is from 400:1 to 500:1 w/w. in some embodiments, the ratio of a.fttioxida3 ⁇ 4/CB2 modulator is from 600: i to 1000; Iw/w.
  • the ratio o antioxMaiii/CBS moduiator is from 700:1 to 1000:1.
  • the r tio of anti0xida»tCB2 modulator is from 1000:1 to 1400; iw/w. in some embodiments, the ratio of amio idaui/CB2 moduiator is from 1200:1 to 1400:1 w/w. in. some embodiments, th ratio of a»tioxidatitCB2 modulator is from 1200:1 to 1500; iw/w. In some embodiments, the rati of ant iox:idani/CB2 modulator is from 1300:1 to 500:1 ww. In some embodiments- the ratio of antioxidani/CB2 modulator is from 1400:1 to 1500; I w/w.
  • the ratio of amioxidarit/CB2 moduiator is from 1500:1 to 1600:1 w/w. In some embodiments, the ratio of an iioxidaai/CB2 inodu iator is from; 1 00; I to 1700:1 w/w, In some embodiments, the ratio of antioxidafflCB2 modulator is from: 1500:1 to 1800:1 w/w. In some embodiments, the ratio of antioxidatitCB2 modulator is from 1.500; ⁇ . to 1700:1 w/w. In some embodiments, the rati of amiox.ida /CB2 modulator is from .1500:1 to 1800:1 w/w.
  • the ratio of a»iioxidant/CB2 moduiator is from 1500:1 to 1900:1 w/w. in some embodiments, the ratio of antioxidam/CB2 modulator is from 1500:1 to 2000:1 w/w. l ' «. some embodiments, the ratio of ⁇ arttioxidant/CB2 ' modulator is from 1600:1 to 2000:1 w/w. in some embodiments, the ' ratio of ani.ioxida:nt/CB2 modulator is .from 1700:1 to 2000:1 w/w. In some embodiments, the rati of amioxida»t/CB2 modulator is torn 1800:1 to 2000:5 w/w.
  • the ratio of aMioxidani/CB2 moduiato is from 2000:1 to 2200:1 w/w- Is some embodiments, the ratio of a «tioxidam/CB2 modulator is from 2000:1 to 2300:1 w/w. In some embodiments, the ratio of autk>xidant/CB2 modulator is from.2000:1 to 2400:1 w/w. in some embodiments, th ratio of antiox.i ' da»t/CB2 modulator Is from.2000:1 to 2500:1 w/w. In some embodiments, the ratio of antioxida.it/CB2 modulator is from 2100:1 to 2500:1 w/w.
  • the ratio of ainioxidant/CB2 modulator is from 2200; ⁇ to 2500: 1 w/w. In some embodiments, the ratio of amioxidani/CB2 modulator is from 2300: 1 to 2500: 1 w/w. in some embodiments, the ratio of • antioxida»t/CB2. modulator is from 2400: 1 to 2500: w/w. in some embodiments, the above composition can spontafteoiisly form ⁇ an emulsion upon dilution with water containing media or body fluid.
  • compositions comprising CB2 receptor selective or highly selective agonists as sole active, methods of making the compositions and methods using CB2 receptor selective agonists for the treatment of mental disorders.
  • the CB2:CB 1 Ki ratio for high affinity ligands with Ki 1-50 «M ratio is abooi 1 :500 while the CB2:CB1 Ki for low affinity ligands with Ki 50-200 tiM ratio is about 1 :50..
  • compositions comprising as CB2 receptor selective agonist beta-earyophyltene (BCP) and optionally at least one antipsychotic agent in the vehicle of a. self-emulsifying drag delivery system (SED ' OS vehicle), methods of making the compositions .and methods using the coi.nposifi.ons for the treatment of mental disorders.
  • Some aspects of the invention relate to compositions comprising as CB2 receptor selective agonist beta-eaty pfay llene (BCP) and optionally at least one antipsychotic agent in SEDDS vehicle, methods of making the compositions and methods usin ' the compositions for the treatment of menial disorders.
  • compositions comprising as CB2 recepto selective agonist [(.1 ,2R,5ll)-2-[2 i .6-dii.r tlK>x.y-4-(2 ⁇ methyioctan-2-y
  • bieyelo[3. i.J ]hepi-3-enyl ⁇ methanol (HU-308) and optionally a least one antipsychotic agent in the vehicle of a. self-eninlsifying dfng delivery system (SEDDS), methods of making the compositions and methods using th compositions for the treatment of mental disorders.
  • SEDDS self-eninlsifying dfng delivery system
  • compositions comprising as CB2 receptor selective agonist [(I R 5 2 > 5R)-2-[2 i 6-dhnethoxy-4-(2 ⁇ inethyIoctan-2-yi) he ; nyl '-7 > ?-dime.th l ⁇ 4 ⁇ bicyclo 3. l , ' i ]hept-3-enyl] methanol (HU-308) and optionall at least one antipsychotic agent in a SEDDS vehicle, methods of making the compositions and methods using the compositions fo the treatment of mental disorders.
  • the mental disorder is schizophrenia, in some embodiments * , the schizophrenia is selected from the group consistin of paranoid schizophrenia, disorganized schizophrenia, undifferentiated schizophrenia, catatonic schizophrenia and residual sc hizophrenia. It s hould be appreciated that onset of schizophrenia can occur at any age, infanc , childhood, adolescence Of adulthood.
  • the -method, of treatment comprises treating at least one symptom of schizophrenia selected from the group consisting of a negative symp torn of schizophrenia, and/or a positive symptom of schizophrenia, both positi ve and. negative-symptoms as well as other symptoms of schizophrenia (e.g. cognitive symptoms).
  • the composition is formulated ' as an orally-admkistrahle- dosage form.
  • the oral composition is formulated in a dosage form selected from the group consisting of a capsule, a liquid composition .for oral adnikhstratiois, a syrup, a suspension, an eniuision and an ingestible solution.
  • the composition can be a- topical composition.
  • the topical composition can h formulated as a transdeittial gel, cream, patch or topical spray.
  • the composition comprises at least one CB2 receptor modulator, a self-emulsifying vehicle and optionall a therapeutically effective amount of at least one additional active agent selected from the group consisting of an. antipsychotic age t, a GPR55 modulator, at least one cognitive enhancer, at least one anti-diabetic agent, an antiinflammatory agent, an enzyme enhancer, an enzyme inhibitor, an antidepressant an anxiolytic,, a terpeoe/terpenoid and combinations thereof
  • the composition can further comprise at least one enzyme .modulator selected from the grou targeting the enzymes cyctoo.xygenase-2 (COX-2), fatt acid amide hydrolase (FAAB), inonOaeylgiyeerol lipase ( GL), a p-h drolase domain containing 6 (ABDH6 or ABBD6), «/ ⁇ hydroIase domain containing 12 (ABPH1.2), ⁇ ⁇ - hydrolase domain containing 4 (ABDH4), sn- l-diacylglyceroi lipase alpha (DAGLa!pha), sn-I- diacylglyceroi lipase beta (DAGLheia), N-acyi phosphatidylethan lamine phospholipase I (NAPE-PLD), phosphodiesterase 1 (GDEl), phospholipase C (PLC), phospholipase D (PLD)
  • COX-2
  • the composition .can. further comprise at least one antipsychotic agent.
  • the at least one antipsychotic agent can be selected from the group, consisting of benpeiidol, bromperidoi, cirop rido!, haloperkioi, timiperone, fluspirilene, penfluridol, pimozide, cepmmaske, chlorpromaz ne, cyamemazine, dixyrazme, f!uphenazine, levomepromazine, mesoridazine, perazine, p rioyazine, perphenazine, pipotiazine.
  • prochlorperazine promazine, promethazine, prothipendyl, thioproperazine, thioridazine, ttii oopera ie, tdflitproniazine, eMorprothixene, ciopenthixoi, flupeniixol, thiothixene, zudopenihixol, amisulpride, araoxapiiie, aripiprazole, dehydroaripiprazole, .asena me, earipraxine, cloz pi -, bionanserin,, Uoperidone.
  • heia- earyophyllene (8CP) as sole active agent in a ⁇ self-emulsifying vehicle in the manufacture of a composition (also known as a medicament) for treating schizophrenia in a subject in need thereof.
  • the composition is formulated for use in. the treatmem. of a human subject, in some other aspects, the composition is formulated for use in the treatment of a non- human subject.
  • the schizophrenia is selected from the group consisting of paranoid schizophrenia:, disorganized schizophrenia, undifferentiated- schizophrenia, catatonic schizophrenia and residual schizophrenia.
  • the at least one .antipsychotic agent can b coadmi istered in a single dosage form together with, the CB2 receptor modulator, In some other aspects, the at least one antipsychotic agent can be co-administered in dosage form separate from the CB2 receptor modulator.
  • the co-administration can comprise sequential or simultaneous administration, in some embodiments, the sequential administration comprises administration of the at least one antipsychotic agent prior to administration, of the CB2 receptor modulator or subsequent to administration of the CB2 receptor modulator.
  • the at least one CB2 receptor modulator in the composition of the present disclosure is selected from the group consisting of at least one GB2 receptor agonist or partial-agonist, at least one CB2 receptor antagonist o inverse agonist, at least one CB2 receptor antagonist or inverse agonist which is also a selective estrogen receptor modulator- (SERM), at least one type of CB2 receptor al!ostenc modulator aod- comfemafions. he eof
  • BCF can be one of the €B2 receptor selecti ve agonists of this invention.
  • the BCF used for implementing the teachings herein is at least about
  • the BC ' P is substantially pure (at least about 98% or about 99% by weight ⁇ E-8CP- in other aspects, the BCP used for impletn atmg the teachings herein is at least about 65%, at least, about 75%, at least abou 85% and even at least about 95% by weight - 8 CP, In some embodiments, the BCP is substantially pure (at least about 98% or about 99% by weight) Z-BCP.
  • the BCF used for irnpleuienting the teachings herein is at least about 65%, at least about 75%, at least about 85% and eve at least about 95% or about 98% by weight E-BCP and/or Z ⁇ B CP.
  • the BCP is substantiall pure (at least about 97- 99% by weight) E-ECP and/or Z-BCP.
  • the BCP used for implementing the teachings herein comprises at least about 49% E-BCP, about 1-49% Z-BCP, abou i -5% BCP oxide and about i- 15% alpha humuiene.
  • the BCP used for implementing the teachings herein comprises about 45-49% E-BCP, about 45-49% Z-BCP, about 1 -5% BCP oxide and about 1 -5% alpha humuiene.
  • BCP used for implementing the teachings herein comprises about 45-90% E-BCP, about 5-30% Z-BCP, about i -5% BCP oxide and traces alpha humuiene.
  • composition comprising: a CB2 receptor selective agonist and self-emolsifying vehicle for use n treating schizophrenia.
  • a composition comprising a CB2 receptor selective agonist and a self-emulsifying vehicle in the manufacture of a eomposj lion for treating schizophrenia in a subject in need thereo
  • a method for the treating schizophrenia in subject need thereof comprising , administering a therapeutic composition comprising a CB2 receptor selective agonist in a self-emulsifying vehicle.
  • FIG. 1 shows results deni nstra ting that oral, treatment with BCP in self-emulsifying oral formniation at adolescence reversed the effect of POP on mice in the forced-swim test
  • FIG. 2 shows that oral treatment with, treatment with BCP in self-emulsifying oral formulation at adolescence reversed the effect of PCP on activity of mice in the open field test.
  • FIGS. 3A-B show results demonstrating that oral treatment with BCP in seif-eirsuls ifying oral formulation at adolescence reversed the effect of PCP on mice in the social interaction test (Fig. 3 A) but did not affect their body weight (Fig. 3B).
  • FIG. 4 shows results demonstrating that oral treatment with BCP in oil at -adolescence did not reverse the effect of PCP on mice in th forced-swim test
  • treating or 'treatment 1 ' includes curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of
  • a "therapeutic composition*' refers to a preparation of one or more of the active ingredients with other components such as pharmaceutically -acceptabl c arriers and excipients.
  • the purpose of a therapeutic composition is to facilitate administration of an active
  • pharmaceutically acceptable earrier or ''self-emulsi ying vehicle refers to a carrier or a diluent that does not cause significant irritation to a subject, effectivel provides the acti ve ageiit(s) to the patient in need thereof and does not substantially abrogate the activity -arid ' properties of the ' administered active ingredients. An adjuvant is included unde these phrases.
  • the terra "exeipient” refer to an inert substance added to a therapeutic composition to further fac litate administration of an acti ve ingredient.
  • compositions used in implementing/the teachings herein may be formulated using techniques with which one of average skill in the art is familiar in a con ventional manner using one or more pharmaceutically-acceptabie carriers comprising excipients and adjuvants,
  • the ' 'Tlydroph.ilfc Lipophilic Balance ' 1 (1ILB) system th balance between the hydrophilse and lipophilic moieties of a surface-active molecule, is used as a basis for rational mean of selecting and classifying ' emulsifying agents or surfactants.
  • the i.O surfactant s assigned a number between I and 20 Surfactants with BLB values -of .between 3 and 6 are lipophilic and form water- in-oil emulsions, while values, of 8 to 18 indicate predominantly hydrophilic charactensii.es and the formation of o.il a-water emulsions.
  • compositions suitable for implementing; the teachings herein include compositions comprising: active ingredients in an amount effective to achieve the intended purpose (a therapeutically effective amount).
  • a therapeutically effective amount is well within the capability of those skilled in the art, for example, is initially estimated from animal models such as rats, mice, monkey or pigs.
  • SEDDS is a broad term associated with the production of emulsions with droplet, size rangin from a few nanometers to several microns, which can. be classified as self- licro- emulsifying drag deli .very systems (SMEDDS) and self-nanoentulsifying drug deliver system (SNEDDS) (Zanchetta B. et a!. Adv. Chem. Eng. 2015, 5:3).
  • SMEDDS self- licro- emulsifying drag deli .very systems
  • SNEDDS self-nanoentulsifying drug deliver system
  • SEDDS formulatio is a liquid composition.
  • SEDDS are waterless: compositions which upon, dilution with water containing media r body fluid self-emulsify forming an oil-in- water emulsion. According to the specific composition and mode of preparation, SEDDS may form, • upon, dilution with aqueous media, emulsions with different droplet sizes.
  • the present invention provides a highly effective stable oral composition
  • the term "seieciive” when used alone is meant genetically, meaning that it includes als highl selective CB2 receptor ⁇ modulator, in some embodiments, the CB2:CB1 Ki ratio for high affinity li gauds with Ki 1-50 nM ratio is about 1 .500 while the CB2;CBI Ki for low affinity !igands wit Ki 50-200 nM ratio is about 1 :50.
  • some of the CB2 receptor selective or highl selective agonists can be synthetic cannabinoids or cannabinoids of plant origin (phytocannabinoids) such as cannabis, hemp, cloves, malabathrum, West African pepper, hops, or gano, etc
  • the cannabi noids are a group of chemical compounds of v ery diverse structures.
  • the most important types of phytocaimabinoids are: cannabigerol-type (CBG), cannabi chrornene-type (CBC), cannab idiol-t pe (CBD), tetrahydrocannabinol- and cannabin l- type -(TH € S CBN), cannabielsoin-type (CBB),. iso-t6trahy ⁇ frocannabittol-iype (iso-THC), cannahicycloi-iype (CBL ⁇ ? and ca na icitran-type (CBT) ⁇
  • CBG cannabigerol-type
  • CBC cannabi chrornene-type
  • CBD cannab idiol-t pe
  • TH € S CBN cannabin l- type -(TH € S CBN)
  • cannabielsoin-type CBB
  • caiiftabitioids like CBD, CBDA, C-BDV, CBG, CBGA, CBGV, TH and ' THCV
  • Some caiiftabitioids are inhibitors of the GPiRSS Hgand .(Anav -Goffer et al. 2012).
  • THC THC.
  • THCV and CBN are non-selective CB ! and CB2 receptor ligands.
  • tact delta-9- THC is -a weak CBl and CB2 receptor partial agonis (Childers, 2006 ⁇ ., thus that in the presence
  • cannabinoids are i fact loosely defined mixtures of a cannabiiioid with, other cannabinoids, impurities, geometrical isomers and enantiomers.
  • the cannabinoid's proneness to spontaneous ' oxidation complicates even more the purity issue- -of these -substances.
  • the mental disorder to be treated by the compositions and methods described herein can iO be selected from the group consisting of schizophrenia, schizoaffective disorder, bipolar disorder 1 and 11, unipolar disorder, multiple personality disorder, psychotic disorders, depression, psychotic depression, depressive disorders, major depressiv disorder, depression associated with tic disorders, epilepsy, anxiety disorders, autistic spectrum disorder, enuresis and addiction, Asperger syndrome, op ositional defiant disorder, behavioral disturbance, agitation, psychosis/agitation associated wit Alzheimer's disease, psychosis associated- with Parkinson's disease, personality disorders, borderline personality disorder, avoidant personality disorder, aittn tion-deficit ' hyperactive disorder (ADHD, ADD, HD), mania, dementia, anorexia, anorexi nervosa, anxiety, generalized anxiety disorder, social anxiety disorder, body dtsmographie disorder, obsessive compulsive disorder, paranoid disorder, nightmares, agitation, posi
  • Cannabinoid Receptor Type 2 (CB2) receptor selecti ve agonist as sole active, methods of making the compositions and methods using CB2 receptor selecti ve agonists fo the treatment of menial disorders.
  • Some other embodiments relate to compositions comprising CB2 receptor selective agonists in combination with at least: one antipsychotic agent in a self enmisifying vehicle,
  • Othe embodiments of the invention relate to compositions comprising beta- earyophyilene (BCP) as sole CB2 receptor selective agonist, methods of making th compositions and methods usin BCP for the treatment of schizophrenia.
  • BCP beta- earyophyilene
  • the use of BCP in schizophrenia disclosed in this invention is unexpected and .surprising, as cannabi.iioi.ds are know to cause aggravation of psychosis i patients with schizophrenia.
  • TBC is known to induce a range of positive symptoms of schizophrenia (according io The Diagnostic and Statistical Manna!
  • BCP typically appears as a mixture of two isomers E-BCP and Z ⁇
  • BCP substantially inactiv sesquiterpenes such as atpha-hurnulene and derivatives such as BCP oxide
  • substantially inactiv sesquiterpenes such as atpha-hurnulene and derivatives such as BCP oxide
  • natural, sour es include a greate proportion of E-BCP th n Z- BCP.
  • the BCP includes both E-BCP and Z-BCP, alone or in combination.
  • compositions comprising ' beta- caryophyliene (BCP) in combination with risperidone, paliperidone, paliperidone palmitate, aripiprazole, quetrapine, CBD and its analogs, THCV, brexpiprazoSe and combinations thereof, •methods of making the compositions and methods using .the compositions for the treatment -of schizophrenia,
  • CB2 The Cannabinoid Receptor Type 2 (CB2) is a guanine nucleotide-b.irid.ing protei (G protein ⁇ conpled receptor that In humans is encoded by die CNR2 gene.
  • the CB2 receptor selective agonist in the compositions of this invention is selected from the group comprising BCP, [( l R.,2R. > 5R)-2-[2 J 6-d :methoxy-4-(2- m.ethy1oetan-2-y!)phenyl] -7,7-dimethy I -4-bicyclo [3, 1 , 1 Jhept-3-enyl] methanol (Ht -308), filJ- 433, eU-910, HU- 1.4.
  • RU-308 (f( Ill J 2]l,5R)-2-[2 s 6-dimfithoxy-4-(2-nie yioctan-2 ⁇ -7,7- d ' imethyi- - bicycio[3,l . l]hept-3-enyl] methanol) is a synthetic cannabinoid, . which is highly selective for die CB2 receptor.
  • BCP whose main commercial vise is as food additive, is not commercially available in pharmaceutical grade.
  • the food additive grade contains a relatively low percentage of BCP, contains impurities like BCP oxide, alpha-humulene and BCP (+) enaniiooier and i not well defined analytically.
  • the BCP impurities can have potential negative skie-elTects on the therapeinie effect of the compositions of this invention.
  • alpha- homulene is a skin, eyes and respiratory irritant, according to its
  • BCP oxide was found to be an. allergen (Skbld M, arlberg AT. Marina M, Borje A, Food Chem, Toxicol 2006 Apr;44(4):53S-4S).
  • compositions of this invention use BCP (and/or other CB2 modulators) i substantially pure form, being substantially free of BCP oxid and alphatiuniylene,
  • co positions comprising .from about 85%w w t about 99%w/w BCP and from about l %w/w to about 15%w/w humuieiie, with traces of other ingredients- like BCP-oxide.
  • compositions ⁇ .comprising from about 85%w w to about 99%w/w BCP and from about I%w/w to about bnmi ene.
  • a method of treatment of a mental disorder in a patient in need thereof by administration of a composition comprising from aboot 3 ⁇ 45 w ' w to about 99%w/ ⁇ v BCP and from .l% v/w to 153 ⁇ 4w/w humuiene... a self-eraulsifyiii .
  • a method, of treatment of a mental disorder in a patient in need thereof, by administration of a composition comprising from about 83%w to about 99%w/w BCP and from l%w/w to 15%w/w huniulene, a self-emulsifying vehicle and optionally one or more of the following: a therapeutically effective oxys* of either at leas one antipsychotic agent, at least one GPR55 modulator, at least one ani nflannuaiory agent, at least one enzyme enhancer, at least on enzyme inhibitor, at least one antidepressant, at least one anxiolytic, at least one terpene o terpenoid, at least one anti -diabetic agent, at least cognitive • enhancer- agent or any combinations of the foregoing, in some embodiments, the composition. can comprise from about 85%w/w to about 99% /w BCP and from about !%w;/w to about 13%w/
  • the -compositions ' Of this invention comprisin CP and/or other CB2 receptor selective agonists are stabilized by addition of an antioxidant and/or free-radical scavenger.
  • stable means that the quantitative composition does not significantly change over the time, during- the entire shelf-life of the composition, namely for at least 3 months, advantageously for at least 6 months, more advantageously for at least 12 months, even more advantageously for at least 24 months, ⁇ under standard conditions, in particular at a temperature ranging: for 20°G to 4G°C :and relative humidity ranging for 3-0% to 75%.
  • caryophyllene oxide level is less than 5% by weight, based on the total weight on die composition, during the entire shelf Hi of the composition, in the present invention, the composition is advantageously stable during 6 months to 1 year or during I year to 2 years under standard conditions.
  • compositions comprising BC ' P and/or other CB2 receptor selective agonists and furthe comprisin an antioxidant a free-radical scavenger or a combination of a antioxidant and a free-radical scavenger have an extended sheli-iife
  • the stable or stabilized compositions have the property to loose less than about 5% of the original compound when stored at room temperature from - about one year to about two years, in some embodiments, the stable or stabilized compositions have the property to loose less than about 10% of the original compound when stored at room temperature from, about one year to about two years.
  • the stable or stabilized compositions have the property to loose less than about 4% Of die original compound when stored at room temperature from about, One year to about two years. In some embodiments, the stable or stabilized compositions have the property to loose less than about 3% of the original compound when stored at room temperature from, about one year to about two years. I some embodiments, the stable or stabilized compositions have the property to loose less than about 2% of the original compound whe stored at room- temperature from about one year to about two years.
  • the stable or stabilized compositions have the property to loose less than abou 1% of the original compound whe stored at room temperature from about one year to about two years, in some embodiments, the stable or stabilized compositions have the property to loose from about 5% to about 10% of the original compound when stored at room temperature from about one year to about two years. In some embodiments, the stable or stabilized compositions have the property' to loose from about .1% to about 5% of the original, compound- when, stored at. room, temperature irom- a ut one year to aboiit two years.
  • One of the problems related to the use of eannahinoids, in general, and CB2 receptor agonists, In particular, is their low bioavailability.
  • oral THC- is onl 4% to 12% hioavaiiahie and its absorption is highly variable (McGilveray LJ,, Pain Res- anag. 2005 Aritumn; 10 Soppl A; 15A-22A).
  • McGilveray LJ Pain Res- anag. 2005 Aritumn; 10 Soppl A; 15A-22A.
  • BCP a C 2 selective agonist
  • PCI Application 2013/1-40342 which are incorporated herein is their entireties.
  • THC ⁇ -tetrahydrocammbinol
  • composition of this disclosure is based on a formulation of the self-emulsifying drag: delivery system (SEDDS) type.
  • SEDDS technology is based on isotropic mixtures of oils.
  • Surfactants, solvents .and eo-ssammlungs/surfactants which form- fine relatively stable oil--in-wai;er (o/w) emulsions upon aqueous- dilution owing to the gentle agitation of the gastrointestinal fluids.
  • a large number of composition alternatives have been explored (see Examples 1-1 Ijijn order to develop the most suitable- composition for oral delivery of CB2 receptor agonists in general and BCP in particular.
  • Example 1 shows a SEEDS composition that is efficient for oral administration.
  • the composition is stabilized by addition to t e: composition of an antioxidant and/or free -radical scavenger.
  • the stabilization of the composition can be necessary because of the ptoneuess of the C B.2 receptor modulators and CB2 receptor agonists to oxidation and can be achieved by addition to the composition of an antioxidant or free-radical scavenger.
  • Antioxidant or free-radical can. also potentiate the therapeutic effect of CB2 receptor modulators and CB2 receptor agonists.
  • composition formulated as a stable self- emulsifying drug delivery system comprising at least one oil, at least one surfactant HLB ⁇ 9, at least one surfactant HLB> , at least one co-surfactant,, at least one antioxidant, and/or free-radical scavenger; at least one CB2 receptor selective or highly selective agonist and optionally at least one antipsychotic agent.
  • the oil is selected from the group consisting of medium chain triglycerides, propylene glycol, dicapri!ate/dicapraie, medium chai mono-and diglycerides, aceiyiated mono-and digiyeerides and olive oil and combinations thereof.
  • th surfactant !iLB ⁇ 9 i selected: from the group consisting of oleoyi polyoxyl-6 giycerides, linoleyl polyoxy!-6 giycerides (20-40%), Polysorbaie 85 (Tween- 85) poiyoxyetiiylene (20) sorbitan trioleate (5-15%), Span-80 (sorbitan. nionooieate) (5-25%), poS.ygryce.ryi ⁇ 3 dioleate (15-35%) and glycerin rnonolinoleate ( .10-35%), and combination thereof
  • the Surfactant HLB>13 is selected from the group consisting of po ' lyoxylated. castor oil (5-25%),. PEG 40 hydrogenated castor oil, PBG 5 hydroxystearate (5- 25%) and capryiocaproyi polyoxyl -S giycerides (10-20%), PEG-20 sorbitan: nionostearate, PEG- 20 sorbitan monooieate (5-25%) and PEG 40 stearate (5-25%) and combinations thereof.
  • the co-sarfactaai is selected from the group consistin of soy lecithin (> :::: 75% phosphatidylcholine in oil 1.-10% w/w), soy lecithin PC content 5G% ' (2-1.5%), egg lecithin E-60 or E-80 (1-5%) and disieafoylph.6sphati.dy1 choline (0.5-3%), and. combinations theieof.
  • composition formulated as a stabl self- emulsifying drug delivery system comprising:
  • an oil selected from die group- consisting of medium chain triglycerides, propylene glycol dieaprilate/dieaprate, medium chain ono-and diglycerides, acetyiated mo. «o-a»d diglycerides and olive oil and combinations thereof;
  • HLB ⁇ 9 selected from the group consisting, of oleoyl polyoxyi ⁇ 6 glycerides,. Hnoieyl poiyoxyl-6 gSycerkies (20-40%), Polysorbate 85 (Tween-8.5) poiyo yethylene (20) sorbita trioleate (5-15%), Span-80 (sorbitan monoo!eate) (5-25%), polygl.yceryi-3 dioleate (1 -3.5%) and glycerin monolinoleate (10-35%), and combinations thereof;
  • a surfactant HLB>I3 selected from the group consisting- of polyoxykte castor oil (5-25%), PEG 40 hydrogenated castor oil, PEG-15 hydroxystearate (5-25%) and eapryloeapro i polyox 1 -8 glyc-erid.es (10-20%), and combination thereof;
  • a surfactant HLB 13 selected from the group consisting of PEG-20 sorbitan monostearate, PEG-20 sorbitan monooleate (5-25%) and PEG 40 stearate (5-25%) and combinations thereof;
  • an antioxidant and/or or free radical scavenger selected from the group consisting of d-aipha-tecopherol (1 -4% w/w), dl-alpha-tocophero) (25% w/w), dl-alpha-tocopheryl acetate (2-5%),.
  • mixed tocopherols (alpha, beta, ga a— 1 -4 w/w), d-a!pha-tocopheiyl acetate (2-5%), buty Sated hydroxyanisoie (BHA, 0.1-0.5%) and combinations thereof, and combinations thereof; from about 1% w/w to about 20% w/w of at least one C82 receptor agonist in Substantially pure form; and
  • composition .formulated as stable seif- e idsifying drug delivery- system (SEDDS) comprising;
  • die at least one C-B.2 receptor agonist is the composition of this disclosure is selected from, die group consisting of BCP, HU-308, HU-433, lU-910, HU-91 , CB 65, GP la, GP 2a,.
  • live at least one agent i ' a the composition of this disclosure is selected from the group consisting of an. antipsychotic agent, a GPR55 modulator, an antiinflammatory agent, an ea3 ⁇ 4yrae enhancer, an enzyme inhibitor., an. antidepressant,, an anxiolytic, a terpene or terpenoid, an. anti-diabetic agent, a cognitive enhancer agent and combinations thereof.
  • the at least one agent ia the composition of this disclosure i selected from the group consisting of a Uraonene, pinene, linalool, n racene, thujone, polypeptide-p, rosn ariruG acid, chararitin, ethyihydroxy chaicone polymer, coumarin, curcmnine, pipeone, CB1 receptor antagonists and combinations thereof
  • ibe at Least one agent in the composition of this disclosure is selected from th group consisting of the group of modulators that targeting die enzymes cycSooxygenase-2 (COX-2), fatt acid .amid hydrolase (FAAH), monoacylglycerol lipase (MGL), ⁇ ⁇ -hydrolase domain containing 6 (ABDH6 or ABHD6), hydrolase domain containing 12 (ABDH12), fl/p-hydrofase domai coMaming 4 (ARDH4).
  • COX-2 cycSooxygenase-2
  • FAAH fatt acid .amid hydrolase
  • MDL monoacylglycerol lipase
  • ABDH6 or ABHD6 ⁇ ⁇ -hydrolase domain containing 6
  • ABDH12 ⁇ ⁇ -hydrolase domain containing 12
  • ARDH4 fl/p-hydrofase domai coMaming 4
  • DAGi-alpha diaeyIglyeero
  • DAGLbeta sn-1 -diaeylglyeefol lipase beta
  • MAAE-PLD N-aeyl phosphatidyiefhaBoiaOTine phospholipase D
  • PLC phospholipase C
  • PLD phospholipase D
  • the at least one antipsychotic agent in the composition of this disclosure is selected from the group consisting of benperidol, bronipendof, droperidol, tialoperidoS, tmnperone, fluspirilene, penfluridol, pitaozi.de, acepromazine, chlorpromaz e, .
  • CBDV eannabidivarin
  • CBDpA eannabiodiolic acid
  • THCV tetrahydrocaanabivarin
  • the at least one antipsychotic agent may belong to several types or subclasses.
  • the composition described herein further comprises, in addition to a CB2 selective receptor agonist, at least one antipsychotic agent, such as, for example, a typical antipsychotic agent including, but not limited to, one or more of a b t rophenone type antipsychotic agent selected from the group consisting of haloperidol, droperidol, benperidol, trifluperidol, raelperone, lenperone, azaperone, domperidone, butyroph.eno.ne, iluanisone, penfluridol, pipaniperone, spiperone, nonaperpne, bromperidol and tiiiiiperone, diphenylbutylpjperidine type antipsychotic agent selected from the grou consisting of luspiriiene, penfluridol, pimozide, clopimozicfe, fluspirilene, penfluridol,
  • an atypical antipsychotic agent including, but not limited to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected .from the group consisting aripiprazole and its metabolites OPC- 1.4857, DM-
  • compositions comprising combinations. -of a CB2 selecti ve receptor agonist froni one of the above types or subclasses with a antipsychotic agent from one of the abo ve types or subclasses.
  • composition wherein the at least one CBS receptor agonist is he a-caryophyllene (BCP) as sole active agent.
  • BCP he a-caryophyllene
  • composition wherein the at least one CB2 receptor agonist is beta-caryophyilene (BCP) in a mixture with hiimitlene and traces of BCP oxide.
  • BCP beta-caryophyilene
  • composition herein the at leas on CB2 receptor agonist is beta-caryophyllene (BCP) and the at least one antipsychotic agent is selected from the grou consisting of risperidone, paiiperidone, paiiperidone palmitate, aripiprazole, quetiapine, CBD and its analogs, THC V, brexpiprazole and combinations thereof.
  • BCP beta-caryophyllene
  • the composition of this disclosure can be formulated for oral, topical, intranasal or rectal administration.
  • the .composition of this disclosure is formulated for oral administration, herei in the form of capsule, suspension, liquid composition for oral 5 adr nistratioo, solution, emulsion or syrup.
  • topical composition of this disclosure is formulated as a transdermal gel, cream, patc or topical spray.
  • 14A-14E show results demonstrating thai BCP treatment at adolescence reversed the effect of PCP on ambulation but did not affect body weight; line graph of body weight at PND 40-68 (14A), bar graph of female and male body weight at PMD63 (.14B) S line graph of male ambulation at PND 63 (14D), : line graph of female ambulation at PND 63 and line graph of male and female ambulation at PND • 0 63").
  • tftere is provided a composition comprising beta- caryopfiy!lene (BCP) and seif-entulsifying vehicle for use in treating schi3 ⁇ 4op renia.
  • BCP beta- caryopfiy!lene
  • beta-caryoph llene (BCP) and seli-emnlsifying vehicle in the manufaciure of a medicament for treating schizophrenia in a IS subject in need thereof.
  • such a composition is formulated for administration t a human Subject, in some em odiments, siich a com osition i foniiulated for administration to a non- human animal subject.
  • a method for treating iO schizophrenia in a subject in need thereof comprising administering a pharmaceuticaily-effective amount of ' beta-caryoph llene (BCP) to a subject in need thereof
  • BCP beta-caryoph llene
  • the subject is a human subject.
  • the subject is a non- hurnan animal.
  • compositions and methods of treatments disclosed herein are useful for treating one or more of paranoid schizophrenia, disorganized schizophrenia, undifferentiated schizophrenia, catatonic schizophrenia, and residual: schizophrenia.
  • compositions and methods of treatments disclosed, herein are useiul in the treatment oiVnegaiive symptom of schizophrenia (according to The Diagnostic and Statistical Manual of Mental Disorders (DS )).
  • compositions and methods of txeatments disclosed herein are useful in the treatment of a positive symptom of schizophrenia.
  • composition and methods of treatments disclosed herein are useful i the treatment of another symptom of schizophrenia (e.g. cognitive sy mptoms).
  • the duration of treatment according to the .method of treating schizophrenia according to aspect of the invention is any suitable duration as determined by a treatin health-care professional, typically a psychiatric doctor.
  • the CB2 receptor agonist (or specifically BCP) regimen of administration and the unit dosage administered to a mental disorder patient in need thereof can depend on the mode of administration, the efficiency of the composition and tire mental disorder to be treated.
  • injectable, nasal and transdermal compositions tend t need lower dosages- than some oral compositions.
  • some oral compositions like the self-emul ify ng composition detailed in Example I and Example 22
  • dosages comparabl or lower to intraperitoneal injectable ' compositions for example, see comparison between the effects, of BCP in the open field test after intraperitoneal injection vs. gavage administration of self-emulsifying composition in Example 1).
  • the results of intraperitoneal injectio are .described >in Example -.15 ⁇ . nd Figure 14E in U.S.
  • Patent Application 2015/0051299 and PCX Application 2013/140342 to be compared with: the results (in Figure 2 of this disclosure) of gavage administration in SE DS composition as described m Example .1. of this disclosure (Description of EXAMPLE 1511. ''Postnatal induction of schizophrenia (days 3- 15) followed by treatment of adolescent mice with BCP (postnatal days 43-61 ) and FIGS.
  • 14A-I4E show ⁇ results demonstrating that BCP treatment at adolescence reversed the effect of PCP on ' ambulation- but did not affect bod weight: line graph of body weight at PND 40-68 (14A), ar graph of female and male body weight at PND63 (14B), line graph of male ambulation at PHD 63 (14D), fine graph of female ⁇ ambul tion at PND 63 and line graph of m le and female arrtbulation at PND 5 63”)-
  • Example I and Figures 1 and 3 A of this disclosure show that n other tests, i.e. forced-swim test and social interaction test, BCP in self-emulsifying composition is als orally active at about the same dosage (5 nig/kg) as in the open field test (Example I and Figure
  • some SEDDS compositions surprisingly at much more effective than other SEDDS compositions (like in Example 16 V-01 is eff ective whereas ⁇ -02 and V-
  • oral compositions like the self-emulsifying composition detailed iri Example I surprisingly are much more effective than other oral compositions (like Example 1 — oil composition and compare between the effects of BCP in the forced swim test after gavage administration of self-emulsifying composition in Example 1 and Figure 1 versus the results after 10 gavage administration of oil compositio in Example 1.4 and Figure 4 in th s application).
  • a highly effective self-emulsifying composition of the present disclosure for the treatmen of a mental disease in a patient in need thereof wherein the administration of an oral dose of said self-emulsifying composition (see Example I) produces a therapeutic effect similar to the intraperitoneal -administration of the same dose (as IS above, Example 1511 and Figure I4E in U.S. Patent Application 2015/0051299 and PCX Application 2013/140342) and a much more effective therapeutic -effect than non-seif- einuisifying oral compositions such as oil compositions (Example 1 ).
  • the CB2 receptor modulator daily dosage administered to -a mental disorder patient .in need thereof, by any mode of administration, including but not limited iO to adinirastratioE of slownrelease/long-acttve formulations given on : daily basis, may vary from 0,01 mg/da to 50 mg day (for highl selective Hgands including but not limited to HU ⁇ 3(i8 ⁇ or from 0.1 rng/day to 500 mg/day (for less potent modulators including but not limited to BCP, MB.) fo highly effective compositions.
  • ⁇ mental disorder patient in an mod of administration including but not limited to administration t a patient in need thereof of slow-release/!ong-aetive formulations given on a daily basis, may vary from 0, 1 rug/day to 10 mg/day (for highly selective ligands including but not limited to HU- 308) or from 3 mg/day to 1000 ntg/day (for less potent modulators including but not limited t BCP, M B) for less effective compositions.
  • a highly effective composition administered daily in any .mode of administration may be given in an amount of 0.1 - .10. mg to infants (5-20 .kg), 10-20 mg to children (20-50 kg), 20-50 nig to young adults and 50- 500 mg to adults (50-100 kg).
  • a highly effective compositio administered dally in any mode of administration may be given in a amount of 0.0.1 -2 mg to -infests (5-20 kg), 2-5 mg to children. (20-50 kg), 5-1 mg to young adults and 1 - 100 mg to adults (50-100 kg ⁇ ..
  • These daily amounts will be administered in one or more discrete dosage units per day or, for highly effective compositions two or three times week.
  • the CB2 receptor modulator for highly selective ligands ⁇ . includin ' but not limited to BU-308 and for less potent modulators including but not limited t BCP, the daily dosage for less effective compositions may vary from 1. mg/day to 500 rng/day (for highl selective ligands including but not limited to HU-308) or from 1 mg/day to 1000 mg/day (for less potent modulators including bet not limited to BCP, MH) for less effective compositions.
  • the average daily amount, in any mode of administration including but not limited t administration in slow-release/long-active formulations given on a daily basis, for a human subject is in the range of from about (for highly potent modulators including but not limited to HU-308) I mg to: about 25 mg from about 25 mg to about 100 nig, from about 100 mg to about 500 mg such as about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg.
  • rag or about 100 rag, about 130 nig,. bout 150 mg, about 200 rag, about 230 mg, about 350 mg, about 330 mg, about 410 mg, about 460 mg, about 520 rag. about 640 rag, about 770 mg, about 850 rag, about 930 mg, or abottt 1000 rag (for less potent modulators including but not limited to BCP or M ) or for less effective compositions,
  • the average daily amount of CB2 receptor modulator in an mode .of administration includes but not limited t administration in a sio -release iong-aciive formulations given on a daily basis, for a human subject (especially for an adult human, weighing betwee about 40 k and about 120 kg) is in the range of from about I mg/day to about 5 mg day from about 50 rag/day to about 100 mg/day, such as about 5 mg/day, about .10 mg/day, about 30 mg/day, about 50 mg/day, about ' 70 mg/day from about 100 mg day for highly selective ligands including but not limited to ⁇ -308, and is in the range of from about 10 mg/day to about 100 mg/day from about 0 mg/day to about 1000 mg/day, such as -about 1.0 mg/day, about 50 mg/day, about 70 mg/da from about 100
  • a composition according to the teachings herein is provided as r made as a dosage form including a plurality of discrete units (e.g., discrete solids or metered liquids, sprays), especially discrete solid units such as pills (including tablets and caplets) and capsules (Including geicaps), wherei each unit - includes a CB2 receptor selective modulator or specifically BCP, HU-308 or 4 ⁇ 0-raethylho-nokio1 ( H) in the range of from about 0,05 mg t about 1000 mg, selected from about 0,05 mg, about 0.1 trig, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 30 nig, about 35 mg, about 40 mg, about 45 mg, about 50 nig, about 55 mg, about 60 nig, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 ing, about 95 mg, about 100 mg, about 200 mg, about 300 mg, about 40 mg, about 500 mg for
  • the dosage of the CB2 receptor modulator administered: t a mental disorder patient, for highly effective delay ed-release delivery compositions may vary from 100 fflg single administration (fo highly potent modulators including but not limited to MO-308 or for weekly injection) to 3000 rag/single administration (for- less potent modulators including, ut not limited to BCP, MR or for injection every 3 months).
  • a delayed- release delivery compositions administrated by injection may be given at 1.-50 nig to infants (5- 20 kg), 50-100 mg to childre (20-50 kg) and from 100-200 mg to 200-3000 mg to dults (50- 100 kg).
  • a deiayed-release deliver compositions administered by .injection should be given at 0.5-10 mg to infants (5-20 kg), 10-20 mg to children (20-50 kg) and from 20-100 m to 1 0- 1000 nig to adults (50- 100 kg).
  • the CB2 receptor modulator dosage for delay ed-release delivery' compositions (such as compositions for a slow-release, sl w-actifig form of medication prepared as a capsule or a depot injection given for example hut not limited b intramuscular injection, which are administrated every I week, once a month and to up to ever diree ⁇ months): ma vary from ⁇ nig/single administration to 500 mg/single administration for less potent modulators including but not limited to BCP or MB, and from 0.1 nig/single administration to 250 oig smgle administration for highly potent modulators, including ' but not limited to Hli-308.
  • the CB2 receptor modulator dosage for delayed release delivery com ositions may vary from 0.5 nig/single
  • the dosage for less effective long term delivery compositions ia all modes of
  • the CB2 receptor modulator dosage tor delayed release delivery compositions may vary from. mg/day to 3000 nig/day.
  • the CB2 receptor modulator dosage tor delayed release delivery compositions may var from 1 mg single administratio to 1000 mg/single administration (for highly potent, modulators including but not limited to EIJ-
  • a delayed-release delivery composition for a slow-release, slow-acting form of medication prepared as a capsule or as a depot injection given for example but not limited to
  • ⁇ 0 intramuscular injection which are administrated ev ry 1 week, once a mouth and to up to ever six months.
  • a delayed-release .delivery composition for a slow-release, slow-acting form.
  • IS injection given for example but not limited by intramitscular injection, which are admimsirated once a week, once a month, and to up to once every six months) according to some ' ⁇ embodiments may be given at an amount of 0.1 -10 mg to infants (5-20 kg), 5-20 rng to children (20-50 kg) and from 0- 100 mg to 50-1000 mg to adults (50-1 0 kg).
  • the administration regimen of delayed-release delivery i0 composition is one administration per week, to once every two weeks, to one administrat n pe month, to one administration per each other month or once every six months as required.
  • the average amount (in mg) per single administr tion of a delayed-release delivery composition mainly by injection, (once a week and up to every six months) for a human subject (especially an adult human., weighing between about 40 kg and about 120 .kg) is in the range of from about (for highly potent modulators including but not limited to HU-308) 10 ⁇ mg to about 25 rag from about 25 mg to about 100 mg, from about 100 nig to about 500 mg such as about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 m , about 65 mg, about 70 tag, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg
  • about 40 kg and about 120 kg is in the range of from about 10 mg/single administration to about 50 .mg single administration from about 50 mg single administration to about 100 mg/single administration., such as about 20 mg/single admini tration, about 30 mg/single administration , about 60 m /singie administration fro about 1 0 mg/single administration to about 1000 mg/single administration , such as about 200 mg single administration, about 300 mg/single adm srntiion, about 400 mg/single administration,, about 500 mg single a innistration, about 600 mg/singie administration, about 700 mg/single administration, about 800 mg/single administration, about 900 mg single administration, from about 1000 mg/single administration (.for highly potent modulators inchiding but not.
  • HU-308 is in the range of from about 100 mg/single administration to about 3000 mg/single administration, such as about 200 mg/single administration, about 300 nig/single administration, about 400 mg/single administration, about 5.00 .mg/single administration, about 600 mg/singie administration, about 700 mg/single adm nis ration s about 800 mg/single administration, about 900 mg/single administration, from about 1000 mg/smg!e admiRistration to about 3000 mg/single adminis&ation, suc as about.
  • modulators including but not limited to BCP or MH) or for less effecti ve compositions, in some embodiments of the method, of treating schizophrenia according to the teachings herein, .the average amount of a single administration mainly, but not limited to injection or oral administration is administered, with a frequency o between about once a. month to once every two months, to about once e en' three months, , .to about once every four months,, to abou once
  • a composition according to the teachings herein is provided as or made as a dosage form including- a plurality of discrete units (e.g., discrete solids or metered liquids, sprays, depot fbnnuiatiou for injection), especially discrete solid units such as pilis .(.including, tablets and capiets) and capsules (including . elcaps), where each unit includes a CB2
  • discrete units e.g., discrete solids or metered liquids, sprays, depot fbnnuiatiou for injection
  • discrete solid units such as pilis .(.including, tablets and capiets) and capsules (including . elcaps)
  • each unit includes a CB2
  • JO including but not limited to HU-308, and in the range of from about .100 mg to about 3000 mg, such as about 10 mg, such as about 50 mg, such as about .100 mg, such a about 250 mg, abou 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 90 mg, about 950 mg, about 1000 mg, about 1500 mg, about 2000 nig, about 2500 mg, or about 3000
  • such a dosage form is useful for single administration of tire desired average dosage per singl administration.
  • compositions of this invention may be administered by any suitable route of administration, including but not limited to oral, parenteral ,. : topical, i.O intranasal, vaginal or rectal administration.
  • suitable route of administration including but not limited to oral, parenteral ,. : topical, i.O intranasal, vaginal or rectal administration.
  • art oral composition formulated as a capsule, suspension, syrup, liquid composition for oral administration, solut n, transnmeosal lozenge, sachet or sprinkle.
  • the topical composition is formulated as a tra sdermal gel, cream, patch or topical spray.
  • the int anasal, composition is .formulated a a nasal spray,
  • the composition is a gastro-resistant oral dosage form, that is to say, an orally-admiiiistrable dosage form configured to carry the active(s) through the stomach to be released ' into contact with the digestive tract only after passage through the duodenum
  • the composition is in the form of a gastro-resistant soft gel capsule, comprising between 5 mg and about 1000 mg BCP in a self-emulsifying vehicle.
  • the composition is in the form of a gastro-resistant soft gel capsule, comprising between 0.5 mg and about. 500 mg HU-308 in a self-emulsifying vehicle.
  • Some embodiments of the method when implemented with an adult human subject, comprise orall ingesting a single such capsule twice day for at least one a month, or once every two months, to about once every three months, to about once every four months, to about once .every fiv months, to about once every ix months, so that the average daily amount: is between about 5 mg an about 500 n g BCP.
  • the composition described herein further comprises at least one antipsychotic ager , uch as., for .example, a typical antipsychotic agent including, -but not limi ted to, one or more Of -c-hlorpromaztne, haloperidol, perphenazine, pimozide or fluphenazirie, and/o an atypical antipsychotic agent including,: but not limited to, one or more of clozapine, risperidone, olanzapine., quetiapine, ziprasidone, aripiprazole, serf indole,, arnisulpride, paiiperidoiie, paliperidone palmitate, and combinations thereof.
  • a typical antipsychotic agent including, -but not limi ted to, one or more Of -c-hlorpromaztne, haloperidol, perphenazine, pimozide or fluphenazirie
  • the CB2 receptor selective agonist or for example BCP is administered together with at least one antipsychotic agent selected-.
  • a butyrophenone type antipsychotic agent selected from the group consisting of •haloperidol, droperidol* benperidol, trifluperidol, melperone, lenperone, azaperone, doin eridone.
  • a diphenyibu ylpipeiidine type antipsychotic -agent selected ' from the group consisting of luspirilene, penfluridol, pimozide, clopimozide, fluspiriiene, penfliiridol, a phenothiaziiie type antipsychotic acid agent selected from the group consisting of acepromazme, c-hiorprofnazine.
  • iloperidone !nrasidone, inelperooe, nernonapride, olanzapine, paiipersdone, palipersdone pa!mitate, perospkone, quetiapitie, remoxipride, risperidone, sertindole, sultopride, trimipraraine, ziprasidone, ⁇ 1-007, pimavanserin ( ⁇ 03 ⁇ ; 5- ⁇ 2 ⁇ antagonist), and.
  • an atypical antipsychotic agent including, but not limited to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected from, the group consisting aripipraz ie and its metabolites QPC- 14857, DM- 1458, DM- 1 51, D -1452, DM- 1454 and DCPP, brexpiprazole and RP5063 (RP500Q) and combinations thereof arid/or a.
  • an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected from, the group consisting aripipraz ie and its metabolites QPC- 14857, DM- 1458, DM- 1 51, D -1452, DM- 1454 and DCPP, brexpiprazole and RP5063 (RP500Q) and combinations thereof arid/or a.
  • eannab oid exhibiting antipsychotic activit selected from the group consisting of (XHCV— €B1 antagonist CB2 receptor partial -agonist), cannabidiol (CBD — CB l/CB2/GP : 55/ABn-CBD antagonist/inhibitor) and cannabigercil (CBG — GB1 CB2 partial agonist) and combinations thereof
  • the two active agents can be co-adrnintsiered in a single dosage form.
  • the CB.2 receptor modulator or for example BCP and the antipsychotic agent can be coadmini tered in separate dosage forms, either sequentially or simultaneously.
  • the additional antipsychotic agent may be administered prior to administration of th CB2, or the additional antipsychotic agent may be administered subsequent to administration of GB2.
  • a stable sdf-emiilsifying composition for treatment of mental disorders in a patient in need thereof cojmprisi «g a therapeutically effective amount of at least one CB2 receptor modulator in substantially pure form, a , sel&et ilsifyin vehicle and optionally a therapeutically effective amount of at least one aiitipsye otic : ⁇ agent, wherein the at least one CB2 receptor modulator and the at least one antipsychotic agent are substantiall solubifized.
  • substantially solubiBzed means that more than 90%w/w. preferably more than 95% w/w and eve more preferably .more than 99%w/w are s hibi Sized
  • the self-emulsifying composition spontaneously forms an oi.S-in-vv ; ater emulsion, typically with n average particle size belo I micron (see Example 1) upon dilution with water containing media o body fluid.
  • the average particle size of the emulsion depends on the composition comprising the self-emulsifying vehicle and: the active agent(s).
  • a se!t-envdsifyitig composition fo treatment of menial disorders in a patient in need thereof, wherein said composition is physically stable at least 2 hours during the time required for effective absorption in the gastrointestinal tract, and wherein, said composition, spontaneously' forms an oil-m-water emulsion upon dilution with water containing media or body fluid.
  • the Gi tract transition time is a function of marr factors, like gastric- emptyin rate and intestinal transit rate, but about ⁇ 0 hrs Gi stability is considered to be sufficient.
  • the drop Set (particle) size of the above emulsion is smaller than 10 mem, preferably smaller than 1 mem more preferabl smaller than 500 run, most preferably smaller than 150 nm.
  • the at least one CB2 receptor .modulator in the above composition can be selected from the group consisting of at least one CB2 receptor agonist or partial-agonist, at least one CB2 receptor antagonist or inverse agonist, at least one CB2 receptor antagonist or inverse agonist which is also a selective estrogen receptor modulator (SERM), at least one type of CB2 receptor aJlosterie modulator and co in tions thereof
  • SERM selective estrogen receptor modulator
  • the at least one C.B2 receptor agonist or partial agonist in the above composition is selected from, the group consisting of BCP, I1U-308, !-IU ⁇ 433, HU-910., MiJ ⁇ 9 I4, CB 65, GP la, GP 2a, GW 405833, JWH 015, JWH 133, AM I 24L -759,656,.
  • the at least one CB2 receptor antagonist or inverse agonist of th above composition is selected from the group consisting of A 630, JTE-907, S 14 528, COR..170, 4-0- methyihonokiol (MB), GS 12021 (4-0 ⁇ .raethylhonokiol analog), cannabinol, 01238, 01 184, analogs thereof, derivatives thereof and combinations thereof.
  • the at least one CB2 receptor alJosterjc rn.odui.aior of the above composition is selected from the group consisting of dihydrogambogic acid, garctno!ic acid, (-)- 5'-dimeih : ylheptyl-cari5Mbidi:o.l (DMH-CBD), analogs thereof, derivatives thereof and combinations thereof.
  • the at least one CB2 receptor modulator which is also a selective estrogen receptor modulator (SERM) of the above composition, is selected from the group consisting of raloxifene, hazedoxiien, iasofoxifene, tamoxifen, afimoxifene, arzoxi ene, ornic!oxifene, toremiiene, ospetnifene, analogs thereof, derivatives thereof and combinations thereof
  • SERM selective estrogen receptor modulator
  • the at least one antipsychotic agent of the above composition is selected .from the group consisting of one or more of a ' but rophe»on:e type antipsychotic agent selected from the group- consisting of ha!operidoi, droperidol, henperidol, triflnperidoi s melperone, ieriperone, azaperone, domperidone, biiiyrophenone, fiuanisone., penfluridol, piparaperone, spiperone, nonaperone, bromperidol and tiniiperone, a diphenySbiiiyipipericline type antipsychotic agent selected troffi the group consisting of iuspiolene, penfluridol, pknozide, clopimozide, fluspirilene, penfluridol, a phenothiazine type antipsychotic acid agent selected from- the grou consisting of acepromazine
  • an atypical anti s chotic agent including, but not limited to one or more of an atypical antipsychotic agent usually belongin to the P2 partial agonist types selected i om the group consisting aripiprazole and its metabolites QPC ⁇ 14857, DM-5458, DM- 1451, DM-.1452, DM- 454 and.
  • DCPP DCPP, brexpiptazole and RP5063 (RP5000) and combinations thereof and/or a oannabinoid exhibiting antipsychotic activity selected from the group consisting of tetrahydtocannabivann (THCV CB1 antagonist, CB2 receptor partial agonist), eannabklioi (C.8D CB ' I /CB2/GPR55/ABft-CB0 antagonist/inhibitor) and eannabigerol (CBG— CB1 CB2 partial agonist) and combinations thereof.
  • THCV CB1 antagonist CB2 receptor partial agonist
  • eannabklioi C.8D CB ' I /CB2/GPR55/ABft-CB0 antagonist/inhibitor
  • CBG— CB1 CB2 partial agonist eannabigerol
  • SEDDS stable -seif- erai sifying drug delivery system
  • the above composition is formulated as a stable seif- mnlsifying drug delivery system comprising:
  • an oil selected from the group consisting of .medium chain triglycerides, propylene glycol dicaprilate/dicaprate, medium chain mono-arid diglycerides, acetyiated mono-and diglycerides and olive oil and combinations thereof,
  • surfactant MLB ⁇ 9 selected irom the grou consisting of oleoyi polyoxyl-6 glycerides, lino!eyl polyoxyl-6 glycendes (20-40%); Polysorbate 85 (Tween-85) polyoxyethylene (20) sorbi an trioleate (5- 15%),
  • Span-80 (sorbitan raorsooieate) (5-25%), poiyg!yceryl-3 dioleate ( 15-35%) and glycerin rnonoHnoleaie (10-35%), from about 5% w/w to about 10 % w/w of a surfactant HLB> 13 selected from the group consisting of poiyoxylated castor oil (5-25%), PEG 40 hydrogenated castor oil, PEG- 15 hydroxystearate (5-25%) and capry!ocaproyl polyoxy!-S glyeeodes (.10-20% ⁇
  • d-alpha-tocophero! (1-4% w/w), dl-alpha-iocopherol (25% w/w), di-alpha-tocopheiyl acetate (2-5%), mixed tocopherols (alpha, beta, ga a— 1 -4% w/w), d ⁇ aipha ⁇ tocopheryl acetate (2-5%), btityiated hydro yamsole (BHA, 0.1-0.5%) and combinations thereof!
  • the above composition is formulated as a stable self-emulsifyin drug delivery system (SEDDS) comprising:
  • the at least one CB2 receptor agonist in the above com position is beta-caryophyilene (BCP) as sole active agent.
  • the at least one €82 receptor agonist in the above coraposition is beia ⁇ earv3 ⁇ 4pliyilefte (BCP) a d the at least one antipsychotic agent is selected from the . rou consisting of risperidone, paliperidone, paliperidone palmitate, aripiprazoSe, iieiiapine, CBD and its analogs, THCV, brexpipra ole and combinations thereof
  • the at least one 62 receptor agonist is beta-cawophyll ne (BCP) and the at least one antipsychotic agent is selected from the group consisting of an of extract of cannabis species comprising .10-98% CBD and its analogs and/or 10-98% THCV and its analogs and/or 10-98% CBG and its analogs and combinations thereof.
  • BCP beta-cawophyll ne
  • the at least one CB2 receptor agonist 1 the above composition is 10 [(lR-2 ,5R)-2-[2,6-to
  • the at least one CB2 receptor agonist in the above composition is HU-308 and the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidone palmitate, aripipraaole,. quetiapine, CBD and its analogs, I S THCV, brexpipraiiole and combinations thereof
  • composition ' of the instant invention is- stabilized b addition of an antioxidant or a free-radical scavenger.
  • the ratio of ant,i x.ida t/CB2 modulator such as hut not -limited: to BCP, is from 1 : 1 to 2:1 w/w. In some embodiments, the aniioxidant/ €B2 modulator ratio is from 10 1:1 to SMw w, In some embodiments, the ratio of antioxidauif/CB2 modulator is from 1 : 1 to 4: 1 w/w. in some embodiments, the ratio of anttoxidant B2 modulator is fro 1 : 1 to 5: 1 w/w.
  • th ratio of antioxidan t/CB2 modulator is from 2: 1 to 3:1 w/w hi some embodiments, the ratio of antioxidant CB2 modulator is from 2: :i to 4:1 w/w. In some embodiments, tire ratio of antioxidamVCBZ modulator is from 2: :1 to 5:lw/w, i some
  • th ratio of amioxidant CB.2 .modulator is from 3.; 1 to 4:1 w/w, I some embodiments, the rati of antioxidant/CB2 modulator is from 3: :1 ft) 5: 1 w/w. In some embodiments, the ratio of antipxidan.t CB2 modulator is front 1: ' i to i 0:1 w w. in som embodiments, the ratio of antioxidaiit CB2 modulator is from 2i . i to 10: 1 w/w. In some embodiments, the rati of antioxidant B2 modulator is from 3; 1 to 10: 1 w/w.
  • the rati of aiitioxuknt/CB.2 modulator is from : 1 to 10: Kv.- ' w. hi some embodiments, the ratio of antio>:idant/CB2 modulator is from 5: . i to 10: 1 w/w. In some embodiments. the ratio of antioxidant>'CB modulator i: s from 6: ⁇ to 10: Iw/w.. in some embodiment, the ratio of antioxida «t/CB2 modulator is from 7: 1 to 10: 1 w/w. In some embodiments. the ratio of antioxidant/CB2 modulator is from 8: 1 to 10: iw/w.
  • the rati of antioxidant/CB2 modulator is fro 9: 1 to 10; iw/w. in some embodiments,. the ratio of atttioxidant CB2 modulator is from 5:1 to 1 : Iw/w. in some embodiments. the ratio of arttioxidant"CB2 modulator i; > from 5: 1 t 20; Iw/w. In some embodiments. the ratio of antioxidant CB2 modulator is from 5: 1 t 25: iw/w. In some embodiments. the rati of ant!Oxidant/CB2 modulator is from 5: 1 to 30: iw/w.
  • the ratio of ajBi.ox.dant/CB2 modulator is from 10: 1 t 15:1 W/W: in some embodiments, the ratio of aiitioxidant/CB2 modulator is from 10: 1 t 20: i w/w. in some embodiments, the ratio of antioxidaftt/CB2 modulator is from 10; ! to 25;! w/w.
  • the ratio of antioxidajftt €B2 modulator is from 10: 1 to 30: 1 w/w. in some embodi e ts- the ratio of antioxidant/CBS modulator is from 10: 1 to 35:1 w/w. in some embodi.ments. the ratio of aiitioxida «t/CB2 modulator is from 10:1. to 40: 1 w/w. In some embodiments. the ratio of antjoxidani/CB2 modulator is from 15: 1 to 20: ⁇ w/w.. in some embodiments, the ratio of sirtioxidatt.t CB2 modulator is from 15; ! to 25' 1 w/w.
  • the ratio of antioxida.nt CB2 modulator is from 15:1 to 30:1 w/w. In some embodiments, the ratio of antioxidant/CB2 modulaior is from 15: 1 to 35: 1 w/w. in some embodiments, the ratio of antioxidant/CB2 modulator is from 15; ! t 40: I w/w. In some embodiments, the ratio of Rtioxidant/CB2 modulator i from 20; 1 t 25: i w/w. In some embodiments. the ratio of a «tioxidajtii CB2 modulator is from 20;! to 30:1. w/w. In some embodiments.
  • the ratio of antioxidaut/CB2 modulator is from 20:1 to 35: 1 w/w. in some embodiments, the ratio of antioxidani/CB2 modulator is from 20: 1 to 40:1 w/w. in some embodiments.
  • th ratio of antioxidani. B2 modulator is from 25: 1 t 30; i w/w. In some embodiments, th ratio of aiiiioxidai t C 2 modulaior is from 25; ! to 3S;.l. w/w. In some embodiments, the ratio of causingoxidant/CB2 modulator is from 25: 1 to ⁇ 40:1 w/w. In some embodiments.
  • the ratio of antioxidant/CS2 modulator is from 30:1 to 35:1 w/w. in some embodiments, the ratio of afttk>xida «t/CS2 modulator is from 30: 1 t 40: 1 w/w. in some embodiments, the above composition can spontaneously form an oii-in-water emulsion upon dilution with water containing media or body .fluid.
  • th ratio of aa tioxidant CB2 modulator is from 40: i to 2500:1 w/w
  • the a»ttoxidant/CB2 modulator is from 40: 1 to 80: 1 w/w
  • the ratio of ariiioxid3 ⁇ 4ni/CB2 modulator is from 40:1 to 100:1 w/w.
  • the ratio of amioxidani/CB2 modalator is from 100:1 to 500: /w.
  • the ratio of • anti xtdaat/C-82 modulator is from 500: ⁇ to 1000:1 w/w.
  • the ratio of antioxidant CB2 modulator is from 1000:1 to J 300: 1. w/w in so e embodiments, the ratio of an ioxidant CB2 modulator is from 1500: 1 to 2000 ⁇ : I w/w. in some embodiments, the ratio of anti ⁇ x.idaitt/CB2 modulator is from 2000.1 to 2500.. I w/w. in some mbodim nt, the ra tio of antl0xidaat CB2 modulator is from 3:1. to 5: 1 w/w.
  • the ratio of antioxidanf/CB2 modulator is from 40: 1 to 100:1 w/w. In some embodiments, the ratio of .a»tioxidaiit CB2 modulator is from 40:1 to 50: 1 w/w. In some embodiments, the ratio of a.iitio3 ⁇ 4;idant/CB2 modulator i from 40:1 to 60:1 w/w. In some embodiments, th ratio of antioxidani7CB2 modulator is tow 40:1 to 80 1 w/w. In some embodiments, the ratio of aniioxidant/CB2 modulator is from 60: 1 to 500:1 /w.
  • the ratio of aiHiosidant/CB2 .modulator is from 80: 1 to 500: 1 w/w.
  • the ratio of ariiioxidam/CB2 modulator is from 1.00:1 to 500:1. w/w.
  • the ratio of antioxidaiu7CB2 modulator i from 150: 1 to 250:1 w/w.
  • the ratio of aniiox.klani/CB2 modulator is from 150: 1 to 280: 1 w/w.
  • the ratio of a:ntioxidani/CB2 modulator is from 150: 1 to 300:1 w/w.
  • the ratio of antioxidant/CB2 modulator is from 200: 1 to 500: 1 w/w. in some embodiments, the ratio of ant:ioxidarii/CB2 modulator i from 300:1 to 500:1 w/w. In some -embodiments, ' .the ratio of aniioxidani/CB2 modulator is from 400: 1 to 500:1 w/w. In some embodiments, the ratio of amioxida»i/CB2 modulator is frona 600: 1 to 1000:1 w/w. In some embodiments, the ratio of aMioxidant/CB2 modulator is .from. 700: 1 to 1.000: 1 w/w.
  • the rati of antioxidant/CB2 modulator is from 800: i to 1000:1 /w. In some embodiments, .the- ratio of aniioxi ant/CB2 modulator is from 900: 1 to 1000: 1 w/w. In some embodiments, th ratio of antioxidani/CB2 modulator is from 1000: 1 to 1200:1 w/w.. in some embodiments, the ratio of arjiioxidant/CB2 modulator is from 1000:1 to 1300: 1 w/w. I some embodim nt the ratio of an&oxidam/CBS modulator is from 1000: 1 to 1400: 1 w/w.
  • the ⁇ .ratio of aniioxidai.tt/CB2 modulator is trom 1200:1 to 1400: 1 w/w.
  • the ratio of attttoxida»t CB2 modulator is trom 1200; ! to 1500: 1 w/w.
  • the ratio of aniioxidaiit/CB2 modulator is f om. 1300:1 to ! 500: 1 w/w.
  • the ratio of a»tioxidani CB2 modulator is from 1400: 1 to 1.500: 1 w/w.
  • the ratio of antioxidani/CB2 modulator is from 1500: 1 to 1600: 1 w/w. In some embodiments, th -ratio -of antioxidant/CBS modulator is from 1500: 1 to 1700: 1 w/w. 1» some embodiments, the- ratio of - antioxidant/CBS modulator is from 1500: 1 to 1800: 1 w/w. in some embodiments, ' the ratio of ai. «ioxidam/C'B2 modulator is from 1500: 1 to 1700 1 w/w. In. some embodiments, the ratio of antioxida-nt CB2 modulator is from 1500:1 to 1800: 1 w/w.
  • the ratio of ant:iox.idaitt/CB2 modulator is from 1500: 1 to 1900: 1 w/w. in some embodiments, the ratio of anti0xida»t/CB2 moduiaior is from 1500 1 to 2000: 1 w/w. 1» some embodiments, the ratio of antioxidant/CB2 modulator is front; 1600:1 to 2000: 1 w/w. In. some- embodiments * the ratio of a ioxidartt/CB2 modulator is from 1700: 1 to 2000: 1 w/w. In. some embodiments, the ratio of auiio.
  • ;idaiii/CB2 modulator is from 1 BOO; 1 to 2000: 1 w/w.
  • the ratio of autioxidarU/CB2 modulator is from 2000; 1 to 2200; 1 w/w.
  • the ratio of antioxidant CB2 modulator is from 2000:1 to 2300 1 w/w.
  • the ratio of aiH!0xkiaut/ 'B2 modulator is from 2000; ! to 2400: 1. w/w.
  • the ratio of antioxidant/CB2 modulator is from 2000: 1 to 2500: 1 w/w.
  • the ratio of aniioxidaiu7CB2 modulator is from 2100;!
  • the ratio of atitioxidaat CB2 modulator is from 2200: 1 to 2500: 1 w/w.
  • the ratio of antk>xidant/CB2 modulator is from 2300 1 to 2500: 1 w/w.
  • the ratio of antioxidam/CB2 modulator is from 2400.1 to 2500;! w/w. in some embodiments, the above composition cart spon aneo sly form an oil-in- water emulsion upon dilution with wate containing media o body fluid.
  • composition of the present disclosure can be formulated for oral, topical, intranasal, vagina! or rectal administratiou.
  • the oral composition of this disclosure can be formulated as a capsule, liquid composition for oral delivery, suspension, solution, emulsion or syrup.
  • the topical compositio of this disclosure can be formulated as a transdermal gel, cream, patch or topical spray.
  • the intranasal composition of this disclosure can be formulated as a nasal spray.
  • the at least one C82 receptor modulator is a CB2 selective agonist and is beta caryophyllene (BCP) in substantially pure form as sole active agent and the mental disorder is schizophreni of 5 all types, onset at any age-
  • the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidon p&lroitate, aripiprazole, uetiapine, CB ' D and its analogs, THCV, brexpip.ra ole and cO-mbinations thereof and the mental disorder is 10 schizophrenia.
  • the BCP in the above composition comprises either one of the two BCP isomers E-BCP and Z-BCP wherein in. substantiall pure form or ⁇ mixtures thereof
  • tire BCP in the above composition comprises substantially pure isomer E ⁇ CP and is substantially tree of BCP oxide and a-hiiiBiiiene.
  • the BCP in the above compositio comprises substantially pare isomer Z-BCP and is substantially free of BCP oxide and a-humuleoe.
  • a method of treatment of a mental disorder in patient in .need thereof by administration of a composition, comprising a therapeiiticalSy effecti ve amount of at least one CB2 receptor modulator in essentially pure form 10 and optionally a therapeutically elective amount of at least one antipsychotic agent in a self- emulsifying vehicle.
  • the at least, one CB2 receptor modulator in.
  • the above method of treatment is selected from the group consisting of at least one CB2 receptor agonist or partial agonist, a least one CB2 receptor antagonist or inverse agonist, at least one CB2 receptor antagonist or inverse agonist which is also a selective estrogen receptor modulator (SERM), at least one type IS of CB2 receptor allosteric modulator and combi ations thereof.
  • SERM selective estrogen receptor modulator
  • the CS2 receptor selective agonist or partial agonist in the above method of treatment i selected horn the group comprising BCP, O!J-308, HU-433, BU-910,
  • the at least one antipsychotic- agent in the above method of treatment is selected from the group consisting of one or more of a buiyrophenone type antipsychotic agent selected from the group consisting of haloperidol.
  • a dipheny!butyipiperidine type antipsychotic agent selected from the grou consisting of hfspuiiene. penfluridol, piraozi.de » .
  • a pbenothiazine type antipsychotic acid agent selected from the group consisting of acepromazine, ehlorpromazine, cyamerna lne, dkyra ine, fiuphenazine, !evomeprotnazine, mesoridazine, pera ine, perieyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyi, thioproperazine, thioridazine and trifluoperazine and i if!upr njazine, a ihioxanthene type antipsychotic: agent selected from, the group consisting of chlorprothixene, elopenthixol, ftupentixol, thiothixene and zucJopen
  • an atypical antipsychotic agent including, but not limited to one or more of a atypical antipsychotic agent usually belonging to tire 13 antagonist/inverse agonist, 5- ⁇ 2 ⁇ antagonist'lnverse agonist types selected, .from, the group consisting of amisulprlde, amoxapine, asenapirie, cariprazine, clozapine, blonanserin, iioperidone, h rasidone, nielperone, nemonapride, olanzapine, paliperidone, paliperidone palmitate.
  • perosptrone quefiapiue, iemoxipride, risperidone, seri indole, sultopride, irimipramine, ziprasidone, ⁇ -007, pimavanserin (ACP-103; 5-HT2A antagonist), and combinations thereof and/or an atypical antipsychotic- agent including, but not limited to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types ' selected from, the .group consisting aiipiprazole and.
  • a eannabinoid exhibiting antipsychotic activity selected from the group consisting of tetraln ⁇ drocannabivati.n (THCY CB I antagonist, CB2 receptor partial agonist), cannahi.diof (CBP— €Bi/CB2/GPR55/ABn-CBD antagonist/inhibitor) and cannabigerol ⁇ C8C3TM ⁇ CB1 CB2 partial agonist) and combinations thereof.
  • the mental disorder in the above method of treatment is selected from the group consisting -of schizophrenia, schizoaffective disorder, bipolar disorde I and il, unipolar disorder,, multiple personality disorder, psychotic disorders, depression, psychotic depression, depressive disorders, major depressive disorder, Tourette's syndrome, tic disorders.
  • Said schizophrenia is selected, from the group consisting of paranoid schizophrenia, disorganized schizophrenia, undifferentiated schizophrenia, catatonic schizophrenia and residual schizophrenia
  • Said schizophrenia in the above method of treattiient ea be selected from adult schizophrenia and pediatric schizophrenia and .may take the form of a negative symptom of schizophreni ., a positi ve symptom. f schizophrenia and both.
  • a method oftreattaeat of a mental, disorder ia a patient in need thereof with a composition of the present disclosure wherein the mental disorder is schizophrenia and.
  • the CB2 receptor selective agonist is beta caryoph llen (BCP) as sole active agent.
  • a method of treatment of a mental disorder in 3 ⁇ 4 patient i need thereof with a compositio of the present disclosure wherein the mental disorder is schizophrenia, the CB2 receptor selective agonist is BCP and. tire at least one antipsychotic agent is selected from the grou consisting of risperidone, paiiperidone, paliperidone palniitate, aripiprazoie, qnetiapirie, CBD and its analogs, THCV, brexpiprazo!e and combinations thereof.
  • the composition comprises a therapeutically effective amount of BCP as sol active agent in a self-emulsifying: vehicle.
  • a method of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure wherein said composition comprises a therapeutically effective amount of at least one CBS receptor selective agonist in essentially pure form and optionally a therapeutically effective- amount of at least one antipsychotic agent i a self-emulsifying- vehicle, .
  • the comp sitio is administered to a patient in need thereof front about once a month to about once .every two months, to about once every three months-, -to about once every -four months, to about once every five months, -to about once every si .months, to about once per week, twice pet week, 3 times per week, 4 times per • week, 5 times per week, 6 times per week, once per day, twice .per day or 3 times per day.
  • a method of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure wherein said composition c m ris s a therapeutically effective amount of at least one CB2 receptor selective. agonist in essentially pure form and optionally a therapeutically effective amount of at least one antipsychotic agent «r a sel.f ⁇ ei «ulsifyi.n vehicle and is administered twice per week to a patient in need thereof.
  • composition of the present disclosure wherein said composition comprises a therapeutically effective amount of at least one CB2 receptor selective agonist In essentially pure form, and optionally it therapeutically effective amount of at least one antipsychotic agent in self-emulsifying vehicle, and is administered three times a week to a patient in need thereo
  • a method, of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure wherein the therapeutically effective amount of the composition comprising BCP as sole active and a self- emulsifying vehicle is administered to a patient in need thereof from about once a month, to about once every two months, to about once every three months, to about once every four months, to about once every five months, to about once every six months, to about once per week, twice per week, 3 times per week,.4 time per week, 5 times per week, 6 times per week, onc pe day, twice per day, 3 times per da or 4 times per day .
  • a method of treatment o a mental disorder in a patient in need thereof with, a composition of the present disclosure wherein th therapeutically effective amount of the composition comprisin BCP as sole active and a setf- emuSsiiymg vehicle is administered twice per week or three- time per week to a patient in need thereof
  • a method of treatment of a mental disorder in a patient in need thereof w th a composition, in an mode of ministration, including but no limited to administration in a slow-release/kmg-aetive formulations given on a daily basis, of the present disclosure wherein the average daily amount of said BCP or iiU-308 or 4-0- me hylhonokiol (MH) administered is in a range selected from the group consisting of 0.1-1 nig, 1 -10 ma, 10-20 m3 ⁇ 4, 20-50 ma, 50-100 ma, 100-200 me or 200-iO O me, accord
  • a method of treatment of a mental disorder in a patient in need thereof with a elayed-reiease composition (such as compositions- for a slow- release, slow-acting form of medication prepared as a capsul or a depot injection given for example but not limited b intramuscular injection, which are administrated every 1 week or once a month to up to every- six months) of the present disclosure
  • a elayed-reiease composition such as compositions- for a slow- release, slow-acting form of medication prepared as a capsul or a depot injection given for example but not limited b intramuscular injection, which are administrated every 1 week or once a month to up to every- six months
  • the average jamou-nt of a single administration of said BCP administered is in a tange selected from, the group consistin of 0.1 -10 rng, 10-100 mg, 100-200 mg, 200-300 rag, 300-400 mg, 500-600 nig, 600-700 rrsg, 7OO-
  • composition of the present disclosure wherein said at least one antipsychotic agent is co-administered in a single dosage form together with said CB2 receptor modulator.
  • a method of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure wherein-said at least one antipsychotic agent is co-administered sequentially in dosage form separate from said €82 receptor selective agonist wherein in either order.
  • a method of treatment of mental disorder in a patient in need thereof with composition of this disclosure wherein the at least one CB2 receptor selecti e agonist in substantially pure form is beta caryophyllene (BCP) as sole active agent and the mental disorder is bi-po!ar disorder, onset at any age.
  • BCP beta caryophyllene
  • the at least, one ( B2 receptor seleciive agonist in swbstantiall pure form is beta caryophyilene (BCP) as sole active agent and the rnental disorder is depression, onset at any age.
  • a method of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure wherein the at least one CB2 selective receptor agonist in substantially pure form is beta caryophyilene ⁇ BCP J as sole acti ve agent and the mental disorder is arsxietv, onset at any age.
  • the above self-enmlsifymg composition wherein the at least one CB2 receptor modulator is selected from the grou consisting of at least one CB2 receptor agonist or partial agonist, at least one CB2 receptor antagonist or inverse agonist, at ⁇ 0 least one CB2 recepto antagonist or inverse agonist winch is also a selective estrogen receptor modulator (SEEM), at least one type of CB2 receptor allosteric modulator and combinations thereof
  • SEEM selective estrogen receptor modulator
  • the at least one CB2 receptor agonist or partial agonist in the above composition is selected from the group consisting of BCP, BU-308, HU-433, HU ⁇ 910, MU-914,
  • the at least one CB2 receptor antagonist or inverse agonist is Selected from the grou consisting of AM630, JTB-9Q7, $R J 44528, CQR170, 4-0- ntethylhonokiol, GS 12021 (4-Q-methyihonokiol analogue), eatHiabiaol, 01238, 01184., eannabidiol (CBD) analogs thereof, derivatives thereof and combinations thereof.
  • the at least one CB2 receptor a!losteric modulator is selected from the group consisting of dihydrogamb gic acid, garcinolic acid, (-)-5'-d.iinetbyi]ieptyl-cannabidioi (DMH-CBD) and analogs thereof, derivatives thereof and combinations thereof.
  • the at least one C82 receptor modulator which is also a selective estrogen receptor modulato is selected from the group consistin of raloxifene.
  • ba edoxiien lasofoxifene, tamoxifen, afimoxifene, arzoxifene, ormeloxifene, toremi ene, ospeinifene. analogs thereof, derivati ve thereof and combinations thereo
  • the at least one antipsychotic agent is selected from the grou consisting of one or more of a botyroph tione type antipsychotic agent selected from the grou consisting of haloperidoi, droperidoL benperidol trifluperidol., nielperone, lenperdne, azaperone.
  • a thioxanthene type antipsychotic agent selected, from the group consisting of chlorprothtxene, clopenthixol, f upentixol, thiothixene and zuclopenthixol and/or an atypical antipsychotic agent including, but not limited to one or more of ao atypical antipsychotic agent
  • IS usually belonging to the D2 antagonist/inverse agonist, 5-HT2A antagonist/inverse agonist types selected from the group consisting of araisulpride, amoxapine, asenapine, cariprazine, clozapine, blonanserin, iloperidon , Iniasidone, meiperone, ftemonapri e, olanzapine, pali per i done , paliperidone palmitate, perospirone, qaefiapine, remoxipride, risperidone, sertindole, suitopride, trirmpramine., ziprasidone, ⁇ -007, pimavanserin (ACP-103; 5-HT2A antagonist), and i0 combinations thereof, and/or an atypical, antipsychotic agent including, but not limiied to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected from the group consisting a
  • the stable self-e uisiiymg drug delivery composition of thi invention comprises at least one oil, at least one surfactant HLB ⁇ 9, at least one surfactant 11LB> 13, at least one eo-siaiactant, at least one antioxidant and'or free-radical scavenger, at least one CB2 receptor modulator and optionally an antipsychotic agent, and combinations thereof'
  • the stable self-emul ify tog drug delivery coniposition of this invention comprises:
  • a oil selected from the group consistin of medium chain triglycerides., propylene glycol, dicapri!ate/dicaprate, medium, chain mono- and di giycerides,, acetylated. mono-and digiycerides, sesame oil and olive oil and combinations thereof,
  • HLB 9 selected from the group consisting of ojeoyl polyoxyl-6 giycerides, Hnoieyl
  • a surfactant BLB>! 3 selected from the grou consisting of polyoxyiated castor oil (5-40%), PEG 40 hydrogenated casto oil, PEG-15 hydroxy sieMaie (5-25%) and caprylocaproyl poiyox.yl.-8 giycerides (10-20%).
  • surfactant HLB>13 selected 1 from, the group consisting of PEG-20 sorbiUiii mo iosiearate, PBG ⁇ 20 sorbitan monoo!eaie (5-25%) and PEG 4 siearate (5-25%),
  • an antioxidant or free .radical scavenger selected from the .group consisting of d-aipha-tocopherol (1-10% w/w), di-a!phatocopheroi (2-1.5% w/w).
  • stable self-emulsifying drug delivery compositions comprising;
  • I S from about .30% w/w to about 50% w/w oleoyi polyoxyi-6 glycendes
  • stable self-emulsifying drug delivery composition of this invention wherein the at least one CB2 receptor agonist is beta- 15 caryophyilene (BCP) as sole active agent in a self-emulsifying vehicle.
  • BCP beta- 15 caryophyilene
  • a stable .self-emulsifying drag delivery composition of this invention wherein the at least ne CB2 receptor agonist is beta- caryophyilene (BCP) and the at. least one antipsychotic agent is selected from the grou consisting of risperidone, pa!iperidone, palipcridone palnuiate, atipiprazole, quetiapine, CBD, i0 i ' HCV, CBG, brexpiprazole their derivatives and analogs and combinations thereof.
  • BCP beta- caryophyilene
  • composition o th s invention wherein the at least- ne CB2..receptor agonist is beta-caiyophylierie (BCP) and the. at least one antipsychotic agent is selected from the grou consistin of 10-98% CBD, 10-98% THCV, 10-
  • a stable self-emulsifying drug delivery composition of this invention wherein the at least one CB2 ' .receptor agonist is beta- caryophylleiie (BCP) as sole active agent in a self-emulsifying vehicle arid the mental disorder is schizophrenia of ail types, onset at any age.
  • BCP beta- caryophylleiie
  • composition, of this invention wherei the at least one CB2 receptor agonist is BCP and the at least one additional active agent is selected fr m the group consisting of a!pha-hnnjulene, copaeae, eogenol, ⁇ -eadinene, BCP oxide and combinations thereof
  • composition of this invention i which, said BCP comprises from l%w/w to 15%w/w alpha-himitilene and from 0, 1 %-2%w/w each of copaene, eugenoi, 5 ⁇ cadinene ; BCP oxide, derivatives thereof analogs thereof and combinations thereof
  • composition of this invention wherein the at least, one CB2 recepto selective agonist in substantially pure form is beta caryophyllene (BCP), the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidone palnritate, aripiprazole, quetiapine, CBD, THCV CBG, hrexpiprazole; derivatives thereof analogs thereof and combinations thereof and the menial disorder is schizophrenia.
  • BCP beta caryophyllene
  • composition of this invention wherein said BCP comprises substantially the isomer E-BCP and is optionall free of BCP oxide and a- hismnSene
  • BCP comprises the snbsiattiially pure isomer Z-BCP and is optionally free of BCP oxide and a-k nitileoe.
  • composition of this invention wherein the at least one €B2 receptor agonist is [( 1 R s 2R,5R ⁇ -2 ⁇ 2,0-dimethox I ]-
  • composition of this invention wherein the • at least one CB2 receptor agonist is HU-3Q8 and the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidone palmitate, aripiprazole, quetiapine, CBD, THCV, CBG, brexpiprazoie; derivatives thereof analog thereof and combinations thereof.
  • composition of this disclosure wherein the at least one CB2 receptor inverse agonist is 4-0 ⁇ methylhonokioI (MH), and the at least one .additional active agent is selected from the group consisting of eiigenol, caryophylien oxide and combinations thereof.
  • composition of this inventio.i wherein: the at least one CB2 receptor selective agonist is 4-0-niethylhonokiol as sole active agent and the mental disorders are tic disorders, repetiti ve beha vior disorders of al l types, onset at any age:.
  • the stable composition of this disclosure is stabilized by addition of an antioxidant, a free-radical scavenger or a combination thereof
  • composition of the instant disclosure wherei formulated for oral, parenteral, topical, intranasal, v gi al o rectal administration.
  • the above oral composition can be formulated as a spray, inhalation, capsule, suspension, solution, emulsion or syrup,
  • the above topical composition can be f rmulate as a transdermal gel, cream, patch or topical spray.
  • the above intranasal composition can be ⁇ f rmulated a a nasal spray.
  • a method of treatment of a mental disorder in a patient in need thereof by administration of a composition of this disclosure, comprising therapeuticall effective amount of at least one CB2 receptor modulator, a self-emulsifying vehicle and optionally a therapeutically effective ⁇ amount of at least one antipsychotic agent and eoinbin.ats.oriS thereof.
  • a composition of this invention comprising a therapeutically effective amount of BCP and from l 3 ⁇ 4w/w to 15% w/w aipha-huniulene and from 0J%w/w-3% w/w each of copaene, eugenol, ⁇ -cadmene, BCP oxide, caryophyllene oxide and their derivatives and analogs and combinations thereof, a self-emulsifyittg vehicle and optionally a therapeutically effecti ve amount of at least one antipsychotic agent and combination thereof
  • a method of treatment of mental disorder in a patient in .need thereof, wherein the mental, disorder is schizophrenia by administration of a composition comprising a therapeutically effective amount of BCP and from 1% to 15% alpha- bumulene and itoni 0J % ⁇ 2% each, of copaene, eugenol, ⁇ cadinene, BCP xide, caryophyllene oxide and their derivatives and analogs and combinations thereof, a self-emulsifying vehicle and Optionally therapeutically effective amount of either at least one antipsychotic agent an combinatio thereof, the CB2 receptor selective agonist is beta caryophyllene (BCP) and optionally at least one additional active agent selected from the group consisting of alpha- humuSene, copaene, eugenol ⁇ -eadiuene, BCP oxide arid combinations thereof,
  • a mental disorder in a patient in need thereof, wherein the mental disorder is hi ⁇ polar disorder, onset at; any age, by administration of a compositio comprising at least one CB2 receptor selective agonist, wbereiii the at least one CB2 receptor selective agonist is beta caryophyllene (BCP) -and optionally at least one additional active agent selected from the group consisting of alpha- humulene, copaene, eugenol, ⁇ -cadinene, BCP oxide and combinations thereof
  • BCP beta caryophyllene
  • composition comprising at least one CB2 receptor selective agonist which is beta catyophylkne (BCP) a sole active agent ami optionally at least one agent is selected iro the group consistin of alpha-huniulene, copaene, eugenol, ⁇ -eadmene, BCP oxide and com inations thereof "
  • BCP beta catyophylkne
  • composition comprising a therapeutically effective amount of BCP and at least one antipsychotic agent selected from the group consisting of risperidone, pa!iperidone, paiiperidone paimitate, aripiprazoie, qnetiapine, CBD anil its derivatives and analogs, THCV, ' CBGV bi»xpip*3 ⁇ 4201 ⁇ 4 and combinations thereof
  • a method of treatment of a mental disorder in a paiieni in need thereof by administration, of a composition of this invention Comprising at least one CB2 receptor modulator selected from the group consisting of at least one CB2 receptor agonist or partial-agonist, at least one CB2 receptor antagonist of inverse agonist, at least one CB2 rece tor antagon st or inverse agonist which is also a selective estrogen receptor modulator (SE M), at least one type of CB ' 2 receptor allosteric modulator and combinations thereof
  • a method of treatment of a .mental disorder in a patient in need thereof by administration of a composition of this invention, comprising a CB2 receptor selective agonist or partial: agonist selected from the group comprising BCP, B.U-308, Hl 433, HU 10, HU-914, CB 65, GP l a ; , GP 2a, GW 405833, iWH 015, JWH 133, AM1241, L759,656, 1,759,633, MDA .1 , SEE 601 , BML-1 0, N ⁇ alkyl.arm e, mtaniatin, diindo!yimethane (DIM) and analogs, CBG, 1 3- ydroxy-A9-tetrahydmcannahinol (1.!-OH-mC), delta-8- HC, l.
  • a method of treatment of a mental disorder i a patient in need thereof b administration of a composition of this invention, comprising CB2 receptor antagonist or inverse agonist selected from the group consisting of AM630, JTE-907, SR144528, ( )RI 70 5 4 ⁇ 0-.methylhonokioi, GS 1.202.1 (4-0-met.hylhottoktoi analog), cannabinoi, 01238, 01 184, cannabidiol (CBD); and analogs, derivatives or combinations thereof;
  • CB2 receptor antagonist or inverse agonist selected from the group consisting of AM630, JTE-907, SR144528, ( )RI 70 5 4 ⁇ 0-.methylhonokioi, GS 1.202.1 (4-0-met.hylhottoktoi analog), cannabinoi, 01238, 01 184, cannabidiol (CBD); and analogs, derivatives or combinations thereof;
  • the at least one antipsychotic agent is selected from the group consisting of on or more of a huiyrophenone type antipsychotic agent selected from the group consisting of haloperidol , droperidol, benperidoL trifluperidol, me .
  • l erone lenperone, azaperone, domperidone, ' huty phenone, penfluridol, pipamperone, spiperone, uonaperone, brompeiidol and timiperone, a diphenylbutyipiperidine type antipsychotic agent selected from the grou consisting of iuspirilene, penfluridol, pimozi.de, clopimozide, fliispiritene, -penfluridol, a phenothiaaine type antipsychotic acid agent selected from the group consisting of aceproraazine, ehlor romazme, cyanieniazine, dixyxazftie, fiuphenazine, levcmieproniazme, rnesondazine, perazme, perkyazine, perpheimzine, pipotiazine, prochlorperazine,
  • DM- 1451, DM- 1452, DM- .1454 and DCPP brexpiprazole and RP5063 ( P5000) and combination thereo and/or a cannaiiinoid exhibiting antipsychotic activity selected from the group- consisting, of tetrahydrocfuiiiabivarin (THCV— CB1, antagonist, CB2 receptor partial onis :), ca sahidiol
  • CBD B1./CB2/GPR55 ABN- €BD antagonist/inhibitor and eannabigerol ( €BG -CB 1/CB2 partial agonist): analogs thereof, derivatives thereof and combinations thereof.
  • a method of treatment of a mental disorder by administration of a composition of this invention wherein said compositio comprises, a therapeutically effective amount of at least one CB2 receptor modulator and optionally a therapeutically effective amount of at least one antipsychotic agent and combination thereof, in a seii-enMisifying vehicle and is administered to a. patient in need thereof from about once a month to about once every two months, to about once every three months, to about once every tour months, to abou once every five ' months, to about once every six: months, to about once per week, twice per week, 3 times per week. 4 times per week, 5 times per week, 6 times per week, once per day, twice per day, 3 t mes per day or 4 times per day.
  • a method of treatment of a mental disorder b administration of a composition of this, invention comprising a therapeutically effective amount of at. least one CB2 receptor modulator and optionally a therapeutically effective amount of at least one antipsychotic agent, at least one GP 55 modulator, at least one anti-inflammatory agent and combinations thereof, in a seff ⁇ emukifying vehicle, wherein the composition is administered twice per week to a patient in need thereof in an embodiment, there is provided a method of treatment of a menial disorder byadministration of a compoisition.
  • the .composition comprising a therapeutically effective amount of at least one CB receptor selective .modulator and optionally an antioxidant, a therapeutically effective amo nt of at least one antipsychotic agent and combinations thereof, in a self-emulsifying vehicle, wherein the composition is administered once per week, twice per week, three times, per week to a patient in need .hereof.
  • a method of treatment of a mental disorder by administration of a composition of this invention wherein: the composition comprises a therapeutically effective amount BCP, ⁇ 308 or Mil as sole active and a self-emulsifying vehicle, and. wherein the composition is administered to a patient in. need thereof from abou once a month to about once every two months, to about once every three months, to about once every tour months, to abou once every five months, to about once ever si months, to about once pe week, twice, pet week, .3 times per week., 4 times per week, 5 times per week, 6 times per week, once per day, twice per day, 3 times per day or 4 times ' a day.
  • a composition of this invention wherein the average daily amount of said either BCP, HU-308, 4-0-methyIhonokiol (MH) administered in any daily mode of administration, including but not limited to administration i delayed-releas formulations given on a daily basis, is in range selected from the grou consisting of 0.01 -0.1 n% 0. 1 -1 nig 1 -10 mg, 10-25 mg, 25-100 ntg, 100-1000 ⁇ nig, .according to the age arid the effectiveness of the composition.
  • a method of treatment of a mental disorder by administration of a composition of thi invention wherein the averag amount of a single administration, of a de!ayed-release delivery composition is selected from compositions for slow- release, delayed release drugs formulated as a capsule or as a depot injection given either orally or mostly by -injection, administrated once a week or once a .month to up to every six months comprising 8CP, HU-30S, or 4 ⁇ 0-»iethylhonok.io! (MB), administered in amount selected from 0.1-10 mg, 10-25 mg, 25-100 mg, 100-1000 mg or 100-3000 mg, according to patient's age and compositio " s effectiveness.
  • a compositio for the treatment of a mental disorder in a patient in need thereof wherein formulated as a stabl ' seif-emulsifying drug deli ery system comprising:
  • TPGS Tocopherol PEG ester succinate
  • TPGS Tocopherol PEG ester succinate
  • BCP was obtained from Sigma-Aldrieh (St Louis, MO, USA), catalogue Nr. W22S207 (assay not indicated) and further purified using preparative HPLC (HP 1090 series; column, PBGASIL ODS (Senshu Sci. id, 10 x250 m); solvent, 70% CfOOH; flow rate, 2.0 L/min; detection, UV 220 nmj to remov other sesquiterpenes,
  • Batch 1 Total BCP ⁇ 98%; 95% E-BCF, 3 2-BCF, 1 % BCP oxide and traces of a-knnnlene.
  • Batch 2 Total BCP - about 85%, about 13% alp.ha. ⁇ hiimn1ene, about ' !.% eopaene, about 0.3 eugenol, about 0.3% o-eadineoe and about 0.3 BCP oxide Phencychdine (PCP), Cremophor EL and DMSO were obtained from Stgma-Aldrieh (St. Louis, MO, USA). Animal model of schizophrenia:
  • mice niodel of schizo ren a was esta l shed.
  • This treatment .induces Song-lastin schizophrenic-like effects in. mice that lasted into adulthood.
  • dl-alpha tocopherol and Phosal 75SA were stored in a refrigerator.
  • dl ⁇ Alplia tocopherol and Phosal 75 S A were removed from refrigerator and allowed to reach room temperature while tightly closed.
  • Labrafil M 944CS and Polysorbate 60 were heated to 50-55 " C until each product becomes a clear and. homogenous liquid.
  • the SEDDS vehicle obtained as a ay liquid was transferred to -amber glass storage bottles and the head space was flashed with nitrogen.
  • the bottles were tightly closed, sealed and s ored in a refrigerator at-+2-8 ' C.
  • the SEDDS vehicle was stored in a refrigerator.
  • the active agent BCP was stored in a freezer.
  • the vehicle and the active were removed from storage, allowed to reach room temperature while lightly closed, then warmed to 35-40 using a water bath, The vehicle was shaken to homogenize it.
  • the oral composition obtained was slightly cloudy / opalescent.
  • the above oral composition is filled into capsules or diluted with water, as per need.
  • the waier-dilaied composition was found to be a submicrcm emulsion with average particle, size of 260 nm-and wide size distribution (50-800 nm).
  • compositions in Examples 2-11 below were prepared in a. wa similar to Exampl 1 , ..using, the quantities indicated in the Tables.
  • Sucralose in ethyl alcohol (IJSP grade) at 45 " C. Add. solution to the mixture and mix slowly for 10 minutes.. Dispense into tightly closed light protected glass bottles., preferably under nitrogen..
  • BCP (5 rng/fcg or 10 ag/kg in diluted self-emulsifying vehicle (Example I)) was 15 administered to adolescent mice (10 ui/g) by gavage twice a week (on Sunda and Wednesday) for 3 weeks (PND 43-62), a total of 6 injections.
  • Control group and PCP ⁇ .indo.ced group received by gavage the oral formulation solution without the drug.
  • mice were tested in. the open field test (PND 64-66). forced-swimming test (PHD 70-71 ) and. social interaction, test (P D 88-89),
  • mice Each mouse was placed, in a novel cage together with a ncmaggressive intruder mouse, o the same species, same- sex and a similar age. The interaction between the two- mice was recorded for 10 minutes with EthdVision. software (Moldus), Social interaction was defined by contact between the mice (tracking nose point). Reduced duration of contact behavior indicates on impairment in social interaction.
  • PIG. 1 shows that oral treatment with 5 or. 1.0 mg/l g BCP in SEDDS oral formulation: at adolescence reversed the effect of FCP on. mice in th forced-swim test. These results show tha BCP acts orally and that the SEDDS composition used is efficient for oral administration. These • results show that BCP in oral SEDDS composition is effective in reversing depression-like behavior, supporting, its use as a pharmaceutical drug for the treatment of mental diseases i which depression is one of the syinpioms (like for example bi-polar/mania-depressive disorder, depression., anxiety, ADHD, Toorette syndrome, depression associated with neurodegenerative diseases, depression that leads to metabolic diseases).
  • FIG. 1 shows that oral treatment with 5 or. 1.0 mg/l g BCP in SEDDS oral formulation: at adolescence reversed the effect of FCP on. mice in th forced-swim test.
  • FIGS. A-B show that oral treatment with 5 mg/kg BCP in SEDDS oral compositio at adolescence reversed the eiTect of PCP on mice 1 ⁇ 2 the social interaction test (3A) hut did not affect their body weight (3-B). These results show that BCP acts orally and that the composition used is efficient for oral administration. These results show that BCP ' in oral SEDDS composition is effective in reversing deficits i social interaction.
  • BCF was dilated in canola oil.
  • mice BCP (10 mg ' kg diluted in canola oil) was administered to adolescent mice (PND 4362) by gavage twice a week (on Sunday and Wednesday) for 3 weeks, a. total of gavages. Control group and PCP-iiKluced group received by gavage the oil vehicle.- After the final gavage, mice were tested in the open field test (PND 59), forced-swiraming test (PND 83) and social interaction test (PHD 88-89 ' ) ' .
  • the SEDDS vehicle of the oral composition of Example ⁇ was warmed tip separately to 52 for 15 rain, i order to prepar about 5% (g vol) Mil solution, the vehicle (380.18 mg) was added t MH (21.2 mg) directly and vortexed for 100 sec to obtain the oral composition. Then the solution was warmed up to 50 C for 10 mi T Then the solution as warmed up to 5? C for 13 mi and vortexed for 180 sec.
  • the SEDDS vehicle of the oral com.posit.ion of Example 1 was warmed u separately to 55 € for i 5 mm, In order to prepare about 1% (g/vol) Mi l solution, the vehicle (39 rug) was added to MH (4- mg) directly and vortexed for 60 sec to obtain the oral composition;. Then the solution was warmed up to 55 € for 10 mm and vortexed for- 60 see.
  • Beta-caryophy!lene is a. dietary .cannabinoid. Proc Natl Acad Sei USA 1.05(26): 9099-9104.
  • Newell KA Deng C, Huang XF, (2006) increased cannahinoid receptor density ' in the posterior cinguiate cortex: in schizophrenia. Exp Brain Res. 172:556-60.

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Abstract

Disclosed are stable self-emulsifying compositions comprising at least one CB2 receptor modulator, a self-emulsifying vehicle and optionally at least one antipsychotic agent for use in the treatment of mental disorders, methods of preparing such compositions and methods of treating mental disorders using same. Disclosed are also stable sell -emulsifying compositions comprising beta caryophyllene (BCP) or HO-308 as sole active agent or in combination with humulene, an antipsychotic for use in the treatment of schizophrenia, methods of making such compositions and methods of treating schizophrenia rising BCP. Disclosed are also stable self- emulsifying compositions comprising 4-0-methylhonokiol (MH) as sole active agent or in combination with caryophyllene oxide, and optionally at least one antipsychotic agent for use in the treatment of tic disorders, methods of making such compositions and methods of treating Tourette syndrome using MH

Description

SEL -E tiLSlFViNG COMPOSITIONS OF
CB2 RECEPTOR MODULATORS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priorit ' to U.S. Provisional Patent Application Serial No.
62/303,508, filed on March 4, 2016, and to V&, Provisional Patent Applieation Serial, 62/303,494 filed on March , 2016, the entire contents of each of which are hereby incorporated by reference in their entirety,
FIELD OF THE INVENTIO
The present invention is in the field of pharmaceutical compositions' and discloses novel compositions for the oral administration of Caiwiabinoid Receptor Type 2 (CB2) modulators and optionally of an antipsychotic agent for the treatment of mental disorders,
BACKGROUND
Mental disorders can arise from multiple sources and affect a large percentage of the population. There are a range of different types of treatment of mental disorders and what is most suitable depends on the disorder and oft the individual.
Schizophrenia is mental disorder which affects about 1% of the population (Lewis <¾ L ieberman, 2000), and genetic and environmental factors underlie the eventual eruptio of the disease (Ross, 2006'}. Schizophrenia is often chronic, characterized by deterioration of social contact cognitive deficits, anxiety and depression, resulting in suicide in about 10% of the schizophrenic population (Lewis <¾ Liebemian, 2000).
Another important mental disorder is tic disorders, specifically, Tourette syndrome (TS), which is characterized, by multi le motor tics and at least one vocal tic. Starting at childhood, TS includes ties like blinking, coughing,, throat clearing, sniffing and facial, movements. About 1 % of the school-age children and adolescents have Toilette's,
.SUMMARY
Aspects of the invention relate to stable self-emnlsifying compositions comprising at least one€B2 modulator, a self-emulsifying vehicle and optionally at least one additional antipsychotic agent, methods of mak ng the compositions and methods of treatment using same for the txeaiment of mental, d s rders,
According to aspects illustrated therein, there is provided stable self-eraulsifyirig compositions comprising a therapeutically effective: amount of at least one CB2 receptor •modulator- in substantially pure form, a self-emulsifying vehicle and optionally a therapeutically effective amount of ai least one antipsychotic agent, for use in treating a mental disorder in a patient in need thereof. In some embodiments, the self-emulsifying (or self-emulsifiable) drug delivery systems (SEDDS) can be liquid compositions generally used for oral deliver)'., or mere particularl designed for improved delivery of drug moieties with poor aque us solubility (see Nagaraju J. Seminar, M. Pharm. II Sem. 2010, Kakatiya University, Warangai, Department of Pharmaceutics, Uni versity College of Pharmaceutical Sciences.
According to aspects of the invention, the seLr-emulsifying drug delivery system (SEDDS) compositions enable to reduce the oral dose to correspond to the dose given by iwtraperitoneai injections or a lower dose.
Accordin to other aspects- of the Invention, the seif-emu fyi&g dru deliver system (SEDDS) compositions potentiate the therapeutic actions of a CB2 receptor modulator,, reducing the required do.se hence its toxicity.
According to aspects of di invention, he compositions of this invention can be formulated as a stable self-emulsifying dreg delivery system (SEDDS) comprising at least one CB2 receptor modulator, optionall at least one antipsychotic agent and a .self-emulsifying vehicle comprising at least one oil, at least one surfactant with HLB<9, at least one surfactant ■with ilLB>13. at least One co-surfactant and at least one antioxidant and'Or free-radical scavenger. The antioxidant and/or free-radical scavenger can be selected from vitamin E, d- alpha-tocopherol ( 1 - 10% w/w), di-alpha-tocopherol (2-i 5%w/w), dl-aipha-tocopheryi acetate (2^ .15% w/w), mixed tocopherols (alpha, beta, gama -- 1-10% w/w). d-alplia-tocopheryl acetate (2- 13% w/w), butylated hydroxyanisoje (BHA, 0.01-0.5% w/w), tocophersolan (TPGS. tocopherol PEG este succinate) (2-10% w/w), vitami €, beta^amteoe., butylated hydrox toluene, butylated hydroxyanisole or other FDA-approved antioxidant listed in the FDA's Inactive Ingredients Database (IID), and combinations thereof.
In some embodiments, the ratio of antioxidant/CB2 modulator, such as but not limited to BCP, is from 1 : 1 to 2:1 w/w. In some embodiments, the antioxidaiit/CB2 modulator is from hi to 3:3 w/w. in some embodiments, th ratio of anittoxtda«iCB2 modulator is from 1:1 to 4:lw/w. in some enibodimerrts, the ratio of aniioxidaj t B2 modulator is from .1:1 to 5:lw/w, \ some embodiments. the ratio of antioxidant/CB2 modulator is from 2:1 to 3:1 w/w. In some embodiments, the ratio of antioxidant/CB2 modulator is from 2:1. it > 4:1 w/w. In some embodiments, the ratio of antioxtdant/CBl modulator is from 2:1 to 5:1 w/w. In some embodiments, the ratio of antioxidant/CB2 modulator is from 3:1 to '4:1 w/w. In some embodiments. the ratio of antioxidant B2 modulator is from 3:1 tc > 5:1 w/w. In some embodiments. the ratio of antioxidant/CB2 modulator is from 1:1 to 10: iw.'w. In some embodiments, the ratio of antioxkiant/CB2 modulator ί s from 2:1 to 10:1 w/w. in some embodiments, the rati of antioxidantCB2 modulator i s from 3:1 to 10:1 w/w.. In some embodiments. the ratio of antioxidant/CB2 Modulator i S from 4:1 t 10:1 w/w. In some embodiments, the ratio of antioxidam7CB2 modulator i s from 5:1 to 10:1 w/w. In some embodiments, the ratio of antioxidantCB2 Modulator is from 6:1 to 10: 1 w/w. in some embodiments, the ratio of antioxidant/CB2 modulator is from 7:1 to 10:1 w/w. in some enrbodiments- the rati of ant-oxida»tCB2 Modulator i S from 8;1 to ΙΟ νν/w. In some emlxjdimeuts. the ratio of antioxidantCB2 Modulator i: s from 9:1 t 1 :1 w/w. .In some embodiments. the ratio of aotioxk1ant/CB2 modulator is from 5:1 to 15:3 w/w. In some embodiments. the ratio of antk>x.k1ant/CB2 modulator 1 s from 5:1 to 20:lw/w, in some embodiments, the ratio of ant?oxidantCB2 modulator is from 5:1 t 25:1 w/w. in some embodiment, the ratio of ¾nttoxidantCB2 modulator i s from 5:1 to 30:1 w/w. In some embodiments. the ratio of antioxidant B2 modulator i s from 5:1 to 35:3 w/w. in some embodiments, the ratio of antioxidant/CB2 modulator i s from 5:1 ΐ 40:] w/w* in some embodiments. the ratio of a«tioxidaittCB2 modulator is from 10:1 to 15:1 w/w. In some embodiments. the ratio of antioxidant/CB2 modulator is from J :! t 20:1 w/w. In some embodiment, the ratio of aiitioxidani/CB2 modulator is from 10:1 to 25: w/w. in some embodiments. th ratio of antioxidani/CB2 modulator is from 10:1 to 30; 1 w/w. In some embodiments, the ratio of aitfioxidajnt/CB2 modulator is from 10:1 to 35:1 w/w. In some embodiments, the ratio of aniioxidarttCB2 modulator is from 10:1 to ■40:1 w/w. in some embodiments. the ratio of antioxidant/CB2 modulator is from I S:! to 20:1 w/w. in some embodiments, the ratio of a.Rtioxida«i/CB2 modulator is from 15:1 t 251 ■ww. in sotne embodiments. th ratio of antioxidaiit/CB2 modulator is fr m 15:1 to 30:1 W/w... In some embodiments, the ratio of aniioxidaot/CB2 modulator is from 5:1 to 35: 1 w/w',. In some embodiments, the ratio of atttk>x_da«t CB2 modulator is from 1.5: 1 . to (. 40; .1 w/w. In some embodiments, the ratio of antsoxidajr B2 modulator is from 20: 1 to 25: 1 w/w. la some embodiments, the ratio of aniioxidafi.t/CB2 modulator is from ,20; 1 to 30; ί w/w. fil some embodiments,, the ratio of aniioxida.nt/CB2 modulator is from 20:1 to 35: 1. w/w. in some embodiments,, the ratio of afitiexidant BS modulator is from 20:1 to 40:1 w/w. In some embodiments, the ratio of anttoxida«t CB2 modulator is from 25: 1 t 30: 1 w/w. In some embodiments, the ratio of a«tioxidant/CB2 modulator is from 25: 1 to 35:1 w/w.. In some emboditneiits, the ratio of a«tioxidan.t CB2 modulator is from 25; 1 to 40: 1 w/w. In some embodiments, the ratio of antioxidant/CB2. modulator is from 30:1 to 35:1 w/w,, In some embodiments, the ratio of a.i.tioxidant CB2 modulator is from 30: 1 to 40:1 w/w. » some embodiments, the above composition can spontaneously ; form an: oil-in- water ernuli sion upon dilution with wate containing media or body fluid.
In some embodiments, the ratio of anuoxida»t/CB2 modulator, such as bat not limited t 4-0-roetiiy tiiopokioi. ( H), is- from. 40; 1 t 2500; I w/w. In some enibodiments, the aiiiioxidant/CB2 modulator i from 40:1 to 80; 1 w/w. In some embodiments, the ratio of anitoxida. t CB2 modulator is from 40: 1 to 100:1 w/w. In some embodiments, the ratio of aniioxidaat/CB2 modulator k from 100: 1 to 500: .1 w/w. In some embodiments, the ratio of antioxidant/CB2 modulator is from 500: 1 to 1 00:1 w/w. in some embodiments, the ratio of antioxidaru/CB2 modulator i from 1000; 1 to I5'00:l /w. In some embodiments, the rati of amioxidani/CB2 modulator is from 1500:1 to 2000; iw/w. In some embodiments, the ratio of antioxidaut'CB2 modulator is fro 2000:1 to 2500: I w/w. i some embodiments, the ratio of antioxidant/CB2 modulator is from 3:1 to 5:l.w/ . In some embodiments, the ratio of antioxidani/CB2 modulator is front 40:1 to 100: iw/w. In some embodiments, the ratio of awtioxidai.il/CB2 modulator is from 40:1 to 50; J w/w. I some embodiments;, the ratio of aniioxidai.it/CB2 modulator is from 40:1 to 60:1 w/w. In some embodiments, the ratio of anii.oxi.dant/CB2 modulator is .from, 40:1 to 80:1 w/w. In some embodiments, the ratio of aniioxidant/CB2 modulator is from 60: 1 to 500: Iw/w, In some embodiments, the ratio of antioxidant/CB2 modulator is from 80:1 to 500:1 w/w. In some embodiments, the ratio o antioxidant/CB2 modulator is from 100:1 to 500: 1 w/w. In some embodiments, the ratio of antioxidant/GB2 modulator is from 150: 1 to 250: 1 w/w. in some embodiments, the ratio of airdoxidam/CB2 modulator is front 150:1 to 280; I w/w. In some embodiments, the ratio of amioxidai.ii/CB2 modulator is from 150:1 to 300:1 w/w, In some embodiments, the ratio of antioxida»tCB2 modulator is from 200: to 500': I w/w. In some embodiments., the ratio f antioxidaiit/CB2 modulator is from 300; I to 500l / . i some embodiments , the ratio of a»tioxidant/CB2 modulator is from 400:1 to 500:1 w/w. in some embodiments, the ratio of a.fttioxida¾/CB2 modulator is from 600: i to 1000; Iw/w. In some emb diments,; the ratio o antioxMaiii/CBS moduiator is from 700:1 to 1000:1. w/w. 1» some embodiments, the ratio o antroxidantCB2 modulator is from 800: to 000:1 w/w. in some embodimerits, the ratio of a»tioxidan.t/CB2 modulator is from.900:1 t 1000:1 w/w.. hi some embodiment, the ratio of antioxidam/CB2 modulator is from 1000:1 to 1200:1 ww. in some embodiments, the ratio of ant:iox.idaitt/CB2 modulator is from 1000:1 to 1300; iw/w. fu some embodiments, the r tio of anti0xida»tCB2 modulator is from 1000:1 to 1400; iw/w. in some embodiments, the ratio of amio idaui/CB2 moduiator is from 1200:1 to 1400:1 w/w. in. some embodiments, th ratio of a»tioxidatitCB2 modulator is from 1200:1 to 1500; iw/w. In some embodiments, the rati of ant iox:idani/CB2 modulator is from 1300:1 to 500:1 ww. In some embodiments- the ratio of antioxidani/CB2 modulator is from 1400:1 to 1500; I w/w. In some embodiments, the ratio of amioxidarit/CB2 moduiator is from 1500:1 to 1600:1 w/w. In some embodiments, the ratio of an iioxidaai/CB2 inodu iator is from; 1 00; I to 1700:1 w/w, In some embodiments, the ratio of antioxidafflCB2 modulator is from: 1500:1 to 1800:1 w/w. In some embodiments, the ratio of antioxidatitCB2 modulator is from 1.500;}. to 1700:1 w/w. In some embodiments, the rati of amiox.ida /CB2 modulator is from .1500:1 to 1800:1 w/w. In some embodiments, the ratio of a»iioxidant/CB2 moduiator is from 1500:1 to 1900:1 w/w. in some embodiments, the ratio of antioxidam/CB2 modulator is from 1500:1 to 2000:1 w/w. l'«. some embodiments, the ratio of ■arttioxidant/CB2' modulator is from 1600:1 to 2000:1 w/w. in some embodiments,, the 'ratio of ani.ioxida:nt/CB2 modulator is .from 1700:1 to 2000:1 w/w. In some embodiments, the rati of amioxida»t/CB2 modulator is torn 1800:1 to 2000:5 w/w. in some embodiments, the ratio of aMioxidani/CB2 moduiato is from 2000:1 to 2200:1 w/w- Is some embodiments, the ratio of a«tioxidam/CB2 modulator is from 2000:1 to 2300:1 w/w. In some embodiments, the ratio of autk>xidant/CB2 modulator is from.2000:1 to 2400:1 w/w. in some embodiments, th ratio of antiox.i'da»t/CB2 modulator Is from.2000:1 to 2500:1 w/w. In some embodiments, the ratio of antioxida.it/CB2 modulator is from 2100:1 to 2500:1 w/w. In some embodiments, the ratio of ainioxidant/CB2 modulator is from 2200; } to 2500: 1 w/w. In some embodiments, the ratio of amioxidani/CB2 modulator is from 2300: 1 to 2500: 1 w/w. in some embodiments, the ratio of •antioxida»t/CB2. modulator is from 2400: 1 to 2500: w/w. in some embodiments, the above composition can spontafteoiisly form · an
Figure imgf000007_0001
emulsion upon dilution with water containing media or body fluid.
Some aspects of the invention relate to compositions comprising CB2 receptor selective or highly selective agonists as sole active, methods of making the compositions and methods using CB2 receptor selective agonists for the treatment of mental disorders. In some embod ments, the CB2:CB 1 Ki ratio for high affinity ligands with Ki 1-50 «M ratio is abooi 1 :500 while the CB2:CB1 Ki for low affinity ligands with Ki 50-200 tiM ratio is about 1 :50..
Some aspects of the invention, relate lo compositions comprising as CB2 receptor selective agonist beta-earyophyltene (BCP) and optionally at least one antipsychotic agent in the vehicle of a. self-emulsifying drag delivery system (SED'OS vehicle), methods of making the compositions .and methods using the coi.nposifi.ons for the treatment of mental disorders. Some aspects of the invention relate to compositions comprising as CB2 receptor selective agonist beta-eaty pfay llene (BCP) and optionally at least one antipsychotic agent in SEDDS vehicle, methods of making the compositions and methods usin 'the compositions for the treatment of menial disorders.
Some other aspects of the invention relate to compositions comprising as CB2 recepto selective agonist [(.1 ,2R,5ll)-2-[2i.6-dii.r tlK>x.y-4-(2~methyioctan-2-y
bieyelo[3. i.J ]hepi-3-enyl} methanol (HU-308) and optionally a least one antipsychotic agent in the vehicle of a. self-eninlsifying dfng delivery system (SEDDS), methods of making the compositions and methods using th compositions for the treatment of mental disorders.
Some other aspects of the invention relate to compositions comprising as CB2 receptor selective agonist [(I R52 >5R)-2-[2i6-dhnethoxy-4-(2~inethyIoctan-2-yi) he;nyl '-7>?-dime.th l~4~ bicyclo 3. l ,'i ]hept-3-enyl] methanol (HU-308) and optionall at least one antipsychotic agent in a SEDDS vehicle, methods of making the compositions and methods using the compositions fo the treatment of mental disorders. In some embodiments, the mental disorder is schizophrenia, in some embodiments*, the schizophrenia is selected from the group consistin of paranoid schizophrenia, disorganized schizophrenia, undifferentiated schizophrenia, catatonic schizophrenia and residual sc hizophrenia. It s hould be appreciated that onset of schizophrenia can occur at any age, infanc , childhood, adolescence Of adulthood.
According to some aspects of the invention, the -method, of treatment comprises treating at least one symptom of schizophrenia selected from the group consisting of a negative symp torn of schizophrenia, and/or a positive symptom of schizophrenia, both positi ve and. negative-symptoms as well as other symptoms of schizophrenia (e.g. cognitive symptoms).
In some aspects, the composition is formulated' as an orally-admkistrahle- dosage form. The oral composition is formulated in a dosage form selected from the group consisting of a capsule, a liquid composition .for oral adnikhstratiois, a syrup, a suspension, an eniuision and an ingestible solution.
In other aspects, the composition can be a- topical composition. I« some .embodiments, the topical composition can h formulated as a transdeittial gel, cream, patch or topical spray.
In some aspects of the invention, the composition comprises at least one CB2 receptor modulator, a self-emulsifying vehicle and optionall a therapeutically effective amount of at least one additional active agent selected from the group consisting of an. antipsychotic age t, a GPR55 modulator, at least one cognitive enhancer, at least one anti-diabetic agent, an antiinflammatory agent, an enzyme enhancer, an enzyme inhibitor, an antidepressant an anxiolytic,, a terpeoe/terpenoid and combinations thereof
In some aspects of the invention, the composition can further comprise at least one enzyme .modulator selected from the grou targeting the enzymes cyctoo.xygenase-2 (COX-2), fatt acid amide hydrolase (FAAB), inonOaeylgiyeerol lipase ( GL), a p-h drolase domain containing 6 (ABDH6 or ABBD6), «/ ~hydroIase domain containing 12 (ABPH1.2), α β- hydrolase domain containing 4 (ABDH4), sn- l-diacylglyceroi lipase alpha (DAGLa!pha), sn-I- diacylglyceroi lipase beta (DAGLheia), N-acyi phosphatidylethan lamine phospholipase I (NAPE-PLD), phosphodiesterase 1 (GDEl), phospholipase C (PLC), phospholipase D (PLD) and combination thereof.
In some aspects of the invention, the composition .can. further comprise at least one antipsychotic agent. The at least one antipsychotic agent can be selected from the group, consisting of benpeiidol, bromperidoi, cirop rido!, haloperkioi, timiperone, fluspirilene, penfluridol, pimozide, cepmmaske, chlorpromaz ne, cyamemazine, dixyrazme, f!uphenazine, levomepromazine, mesoridazine, perazine, p rioyazine, perphenazine, pipotiazine. prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, ttii oopera ie, tdflitproniazine, eMorprothixene, ciopenthixoi, flupeniixol, thiothixene, zudopenihixol, amisulpride, araoxapiiie, aripiprazole, dehydroaripiprazole, .asena me, earipraxine, cloz pi -, bionanserin,, Uoperidone. lurasidoiie, eiperone, neniooapride, olanzapine, paliperkloiie, paliperidone paimitate, perospirone, quetiapine, temexiptide,
Figure imgf000009_0001
sertksdoie, soHopride, trimipramine, ziprasidone, brexpiprazole, iTI-007, pintavanse iii, P5063 (RP5O0O) eannafoidiol (CBD), camiabidivaritt (CBDV), eaonabiodiolie acid (CB A), tetahydrocannabivari (THCV), OK 4S57, DM-1458, DM4451, DM4452, DM-1454, DCPP, eannabigerol (CBG) and its analogs CBGA and CBGV and combinations thereof.
According: to some aspects of the invention, there is also provided the use of heia- earyophyllene (8CP) as sole active agent in a■self-emulsifying vehicle in the manufacture of a composition (also known as a medicament) for treating schizophrenia in a subject in need thereof. In some aspects, the composition is formulated for use in. the treatmem. of a human subject, in some other aspects, the composition is formulated for use in the treatment of a non- human subject.
In some aspects, the schizophrenia is selected from the group consisting of paranoid schizophrenia:, disorganized schizophrenia, undifferentiated- schizophrenia, catatonic schizophrenia and residual schizophrenia.
In some aspects of the invention, the at least one .antipsychotic agent can b coadmi istered in a single dosage form together with, the CB2 receptor modulator, In some other aspects, the at least one antipsychotic agent can be co-administered in dosage form separate from the CB2 receptor modulator. The co-administration can comprise sequential or simultaneous administration, in some embodiments, the sequential administration comprises administration of the at least one antipsychotic agent prior to administration, of the CB2 receptor modulator or subsequent to administration of the CB2 receptor modulator.
According to some aspects of the invention, the at least one CB2 receptor modulator in the composition of the present disclosure is selected from the group consisting of at least one GB2 receptor agonist or partial-agonist, at least one CB2 receptor antagonist o inverse agonist, at least one CB2 receptor antagonist or inverse agonist which is also a selective estrogen receptor modulator- (SERM), at least one type of CB2 receptor al!ostenc modulator aod- comfemafions. he eof
According to some aspects of the invention, BCF can be one of the€B2 receptor selecti ve agonists of this invention.
la some aspects, the BCF used for implementing the teachings herein is at least about
65%, -at least about 75%, at least about 85% and eve at least about 95% by weight E-BGP. In some embodiments, the BC'P is substantially pure (at least about 98% or about 99% by weight} E-8CP- in other aspects, the BCP used for impletn atmg the teachings herein is at least about 65%, at least, about 75%, at least abou 85% and even at least about 95% by weight - 8 CP, In some embodiments, the BCP is substantially pure (at least about 98% or about 99% by weight) Z-BCP.
in some aspects, the BCF used for irnpleuienting the teachings herein is at least about 65%, at least about 75%, at least about 85% and eve at least about 95% or about 98% by weight E-BCP and/or Z~B CP. in some embodiments,, the BCP is substantiall pure (at least about 97- 99% by weight) E-ECP and/or Z-BCP.
For example, in some aspects, the BCP used for implementing the teachings herein comprises at least about 49% E-BCP, about 1-49% Z-BCP, abou i -5% BCP oxide and about i- 15% alpha humuiene.
Fo example, in some aspects., the BCP used for implementing the teachings herein comprises about 45-49% E-BCP, about 45-49% Z-BCP, about 1 -5% BCP oxide and about 1 -5% alpha humuiene.
For example, in some aspects BCP used for implementing the teachings herein comprises about 45-90% E-BCP, about 5-30% Z-BCP, about i -5% BCP oxide and traces alpha humuiene.
According: to an aspect of the i.iivention:. there is also provided a composition comprising: a CB2 receptor selective agonist and self-emolsifying vehicle for use n treating schizophrenia.
According to an aspect of the invention, there is also provided a use of a composition comprising a CB2 receptor selective agonist and a self-emulsifying vehicle in the manufacture of a eomposj lion for treating schizophrenia in a subject in need thereo According to an aspect of the invention, there is- also provided a method for the treating schizophrenia in subject need thereof, the method comprising, administering a therapeutic composition comprising a CB2 receptor selective agonist in a self-emulsifying vehicle.
BRIEF DESCRIPTION' OF THE FIGURES
Some embodiments of the invention are described herein with reference to the accompanying .figures. The description, together with the figures, makes apparent to a person having -ordinary skill in the art how some embodiments of the invention ma be practiced. The figures are for the purpose of illustrative discussion and no attempt s made to show structural details of an embodiment in more detai l than is necessary for a fundamental understanding of th invention. Fo the sake of clarity, some objects depicted in the figures are not to scale.
FIG. 1 shows results deni nstra ting that oral, treatment with BCP in self-emulsifying oral formniation at adolescence reversed the effect of POP on mice in the forced-swim test
FIG. 2 shows that oral treatment with, treatment with BCP in self-emulsifying oral formulation at adolescence reversed the effect of PCP on activity of mice in the open field test.
FIGS. 3A-B show results demonstrating that oral treatment with BCP in seif-eirsuls ifying oral formulation at adolescence reversed the effect of PCP on mice in the social interaction test (Fig. 3 A) but did not affect their body weight (Fig. 3B).
FIG. 4 shows results demonstrating that oral treatment with BCP in oil at -adolescence did not reverse the effect of PCP on mice in th forced-swim test,
DETAILED DESCRIPTIO
Unless otherwise defined, all technical a d scientific- terms used herein have the sam meaning as commonly understood by one of ordinary skill in. the art to which the invention pertains. In case of conflict, th specification, .including definitions, takes precedence.
As used herein, the terms "comprising", "tnekiding", "having" and grammatical variants thereof are to be taken as. specifying the stated features* integers, steps or components but do not -preclude the addition of one or more additional .features, integers, steps, components or groups thereof.
As used herein, the' indefinite articles "a" and "an" mean "at least one" or "one or more" unless the context clearly dictates otherwise. As used herein, when a numerical value is preceded by the term "about", -the term '"about" is intended to indicate +J~10%<.
As used herein, the term "treating" or 'treatment1' includes curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of
5 condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition.
As used herein a "therapeutic composition*' refers to a preparation of one or more of the active ingredients with other components such as pharmaceutically -acceptabl c arriers and excipients. The purpose of a therapeutic composition is to facilitate administration of an active
10 ingredient to a subject.
The term "pharmaceutically acceptable earrier" or ''self-emulsi ying vehicle" refers to a carrier or a diluent that does not cause significant irritation to a subject, effectivel provides the acti ve ageiit(s) to the patient in need thereof and does not substantially abrogate the activity -arid' properties of the' administered active ingredients. An adjuvant is included unde these phrases.
1.5 The terra "exeipient" refer to an inert substance added to a therapeutic composition to further fac litate administration of an acti ve ingredient.
Therapeutic compositions used in implementing/the teachings herein may be formulated using techniques with which one of average skill in the art is familiar in a con ventional manner using one or more pharmaceutically-acceptabie carriers comprising excipients and adjuvants,
10 which facilitate processing of the active ingredients into a pharmaceutical, composition and generally includes mixing an amount of the active ingredients with the other components. Suitable techniques are described in "Remington's Pharmaceutical Sciences," Mack Publishing Co.. Hasten, PA, latest edition, which is incorporated herein by reference. For example, 'pharmaceutical compositions useful in implementing the teachings herein may be manufactured.'
IS by one or more processes that, are well known in the art; e.g., mixing, blending, homogenizing, dissolving, granulating, emulsifying, encapsulating, entrapping and lyophilizing processes.
The ''Tlydroph.ilfc Lipophilic Balance' 1 (1ILB) system., th balance between the hydrophilse and lipophilic moieties of a surface-active molecule, is used as a basis for rational mean of selecting and classifying' emulsifying agents or surfactants. In the B LB system the i.O surfactant s assigned a number between I and 20, Surfactants with BLB values -of .between 3 and 6 are lipophilic and form water- in-oil emulsions, while values, of 8 to 18 indicate predominantly hydrophilic charactensii.es and the formation of o.il a-water emulsions.
Pharmaceutical compositions suitable for implementing; the teachings herein include compositions comprising: active ingredients in an amount effective to achieve the intended purpose (a therapeutically effective amount).. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, for example, is initially estimated from animal models such as rats, mice, monkey or pigs.
The terms -self-emulsifying and self-emulsiftahSe, as used herein, can be used rnterdtangeably,
SEDDS is a broad term associated with the production of emulsions with droplet, size rangin from a few nanometers to several microns, which can. be classified as self- licro- emulsifying drag deli .very systems (SMEDDS) and self-nanoentulsifying drug deliver system (SNEDDS) (Zanchetta B. et a!. Adv. Chem. Eng. 2015, 5:3).
SEDDS formulatio is a liquid composition. SEDDS are waterless: compositions which upon, dilution with water containing media r body fluid self-emulsify forming an oil-in- water emulsion. According to the specific composition and mode of preparation, SEDDS may form, •upon, dilution with aqueous media, emulsions with different droplet sizes.
The present invention provides a highly effective stable oral composition comprising a therapeutically effective amount of at least one CB2 receptor seieciive or highly selective agonist in substantially pure form in a self-emtdsifying vehicle and optionally a therapeutically effeciiv amount of at least one antipsychotic agent in a sei.f-em.dsityi.ng vehicle, for use i treating: a mental disorder in a patient in need thereof. In the context of this disclosure, the term "seieciive" when used alone is meant genetically, meaning that it includes als highl selective CB2 receptor■modulator, in some embodiments, the CB2:CB1 Ki ratio for high affinity li gauds with Ki 1-50 nM ratio is about 1 .500 while the CB2;CBI Ki for low affinity !igands wit Ki 50-200 nM ratio is about 1 :50.
In some aspects of the iirvention, some of the CB2 receptor selective or highl selective agonists can be synthetic cannabinoids or cannabinoids of plant origin (phytocannabinoids) such as cannabis, hemp, cloves, malabathrum, West African pepper, hops, or gano, etc
The cannabi noids are a group of chemical compounds of v ery diverse structures. The most important types of phytocaimabinoids are: cannabigerol-type (CBG), cannabi chrornene-type (CBC), cannab idiol-t pe (CBD), tetrahydrocannabinol- and cannabin l- type -(TH€S CBN), cannabielsoin-type (CBB),. iso-t6trahy<frocannabittol-iype (iso-THC), cannahicycloi-iype (CBL}? and ca na icitran-type (CBT)÷ The most studied cannabinoids are
5 TH€5 CBD, CBG and' CBN. At least 85 different eannahinoids have been isolated from the cannabis plant. These compounds have very different affinities for the cannahinoi or non~ eannahinoid receptors. Som are neutral Uganda (no or very little affinity- to the eannabinoid receptors), some are CB l and€82 receptor agonists, some are- CB 1 arid€B2 -receptor partial agonists, some are CBl arid CB2 receptor antagonists, some a e CBl and CB2 receptor inverse-
10 agonists, some are combination thereof and only a few are specific and selective agonist or antagonists. Some caiiftabitioids (like CBD, CBDA, C-BDV, CBG, CBGA, CBGV, TH and' THCV) are inhibitors of the GPiRSS Hgand .(Anav -Goffer et al. 2012).
THC. THCV and CBN are non-selective CB ! and CB2 receptor ligands. tact delta-9- THC is -a weak CBl and CB2 receptor partial agonis (Childers, 2006}., thus that in the presence
I S of a more potent selective agonist de!ta-9-THC will antagonize its effects. CBC, CBD, :C-BDV, CBD.A, CBG, CBGV, CBGA, THCA and TI ICV have not been reported to activate the CBl or CB2 receptors with significant potency (Handbook of Cannabis, Oxford University Press, R.G. Pert wee Editor, p. 137, 2014). Summing up, unlike the CB2 receptor selective agonists of this, invention, none of the above ca-nnabmoids. are selective or highly selective -CB2 recepto
10 agonists*
Most of the commercially available cannabinoids are i fact loosely defined mixtures of a cannabiiioid with, other cannabinoids, impurities, geometrical isomers and enantiomers. The cannabinoid's proneness to spontaneous' oxidation complicates even more the purity issue- -of these -substances.
IS The affinities for two different cannabirsoid receptors (CBl- and CB2 receptors) complicate the issue of pharmacological activity. Therefore, the present disclosure uses as active agents well-defined stable highly pine CB2 receptor selective agonists, ost of the CB2 receptor agonists of this invention are potent selective CB2 receptor agonists.
The mental disorder to be treated by the compositions and methods described herein can iO be selected from the group consisting of schizophrenia, schizoaffective disorder, bipolar disorder 1 and 11, unipolar disorder, multiple personality disorder, psychotic disorders, depression, psychotic depression, depressive disorders, major depressiv disorder, depression associated with tic disorders, epilepsy, anxiety disorders, autistic spectrum disorder, enuresis and addiction, Asperger syndrome, op ositional defiant disorder, behavioral disturbance, agitation, psychosis/agitation associated wit Alzheimer's disease, psychosis associated- with Parkinson's disease, personality disorders, borderline personality disorder, avoidant personality disorder, aittn tion-deficit'hyperactive disorder (ADHD, ADD, HD), mania, dementia, anorexia, anorexi nervosa, anxiety, generalized anxiety disorder, social anxiety disorder, body dtsmographie disorder, obsessive compulsive disorder, paranoid disorder, nightmares, agitation, posi-traumatic stress disorder (PTSD), severe mood dysregiilatio.ti and Toureite's syndrome.
Some embodiments of the invention relate to compositions comprising -at least one
Cannabinoid Receptor Type 2 (CB2) receptor selecti ve agonist as sole active, methods of making the compositions and methods using CB2 receptor selecti ve agonists fo the treatment of menial disorders. Some other embodiments relate to compositions comprising CB2 receptor selective agonists in combination with at least: one antipsychotic agent in a self enmisifying vehicle,
Othe embodiments of the invention relate to compositions comprising beta- earyophyilene (BCP) as sole CB2 receptor selective agonist, methods of making th compositions and methods usin BCP for the treatment of schizophrenia. The use of BCP in schizophrenia disclosed in this invention is unexpected and .surprising, as cannabi.iioi.ds are know to cause aggravation of psychosis i patients with schizophrenia. Thus, for example, TBC is known to induce a range of positive symptoms of schizophrenia (according io The Diagnostic and Statistical Manna! of Menial Disorders (DS )), and THC treated schisophrenic patients experienced a exacerbation of symptom (Deepak Cyril D'Soum et ah Eur Arch Psychiatry Clin. Neurosci. 2009 Oct; 259(7): 413-43 1). In addition, while TH can induce anxiety in. some patients, BCP reduces anxiety.
When f u d i . nature, BCP typically appears as a mixture of two isomers E-BCP and Z~
BCP, together with substantially inactiv sesquiterpenes such as atpha-hurnulene and derivatives such as BCP oxide, Typically, natural, sour es include a greate proportion of E-BCP th n Z- BCP.
For- implementing the teachings herein, the BCP includes both E-BCP and Z-BCP, alone or in combination.
Figure imgf000016_0001
SOP ©xid® «»h**m<*i¾»e
Some other embodiments of the invention relate to compositions comprising' beta- caryophyliene (BCP) in combination with risperidone, paliperidone, paliperidone palmitate, aripiprazole, quetrapine, CBD and its analogs, THCV, brexpiprazoSe and combinations thereof, •methods of making the compositions and methods using .the compositions for the treatment -of schizophrenia,
Other embodiments of the invention relate to compositions- comprising beta- caryophyUene (BCP) as sole CB2 receptor selective, agonist, methods of 'making the- compositions and methods using BCP for the treatment of mental disorders othe than schizophrenia. Other embodiments of the invention relate to compositions comprising heta- earyophy!lene (BCP) as sole CB2 receptor selective agonist, methods of makin the compositions and methods using BCP for die treatment of mental disorders other ..than, schizophrenia, depression and anxiety.
The Cannabinoid Receptor Type 2 (CB2) is a guanine nucleotide-b.irid.ing protei (G protein }~conpled receptor that In humans is encoded by die CNR2 gene.
Recent studies have identified the eannabinoid CB2 receptor in the brain. Dp-regulation of CB2 receptor expression in he. brain dining central nervous system pathologies has been demonstrated for certain neurological, diseases.
In some emb diment :, the CB2 receptor selective agonist in the compositions of this invention .is selected from the group comprising BCP, [( l R.,2R.>5R)-2-[2J6-d :methoxy-4-(2- m.ethy1oetan-2-y!)phenyl] -7,7-dimethy I -4-bicyclo [3, 1 , 1 Jhept-3-enyl] methanol (Ht -308), filJ- 433, eU-910, HU- 1.4. CB 65, GP la, CjP 2a, QW 405833, JWB 015, JWH 133, AM 1241 , L~ 759,656. L-759,633, MDA 19, SER 601, BM.L- 190, N-alkylarnide, rutamarin, diindolylmethaoe (DIM) and combinations thereof Bera-earyophyf !ene (imns-(l ?9S)-8-meihy!ette^4,1 1 , 1 1 trjmetbylbicyc'SQ|7.2 t ]Hndec-4- ene, BCP, CAS 87-44-5) is a CB2~receptor selective agonist (Gertsch et al, 2008, Anavi-Gofier et al, 2012). BCP exhibits chirahty at positions 1 and 9 and is the 1R,9S enaniiomer, the (-) f rm,
RU-308 (f( IllJ2]l,5R)-2-[2s6-dimfithoxy-4-(2-nie yioctan-2 }-7,7- d'imethyi- - bicycio[3,l . l]hept-3-enyl] methanol) is a synthetic cannabinoid, . which is highly selective for die CB2 receptor.
The fact that prally-adnsinistered BC is absorbed by the digestive tract and becomes systemically available and its apparent substantia! notMoxicity makes BCP attractive as a potential active pharmaceutical ingredient.
However, BCP whose main commercial vise is as food additive, is not commercially available in pharmaceutical grade. The food additive grade contains a relatively low percentage of BCP, contains impurities like BCP oxide, alpha-humulene and BCP (+) enaniiooier and i not well defined analytically.
According: to Chicca A, et al (Chem. Biol. 201,4, 9, 1499-1507), BCP-oxide and alpha- tnumdene's inactivity suggest the existence of a specific ses iiiterpei e pharmacophore for CB2 receptor binding in BCP only but not in BCP-oxide and alpha iumulene.
The BCP impurities can have potential negative skie-elTects on the therapeinie effect of the compositions of this invention.
For example, alpha- homulene is a skin, eyes and respiratory irritant, according to its
MSDS. Also, BCP oxide was found to be an. allergen (Skbld M, arlberg AT. Marina M, Borje A, Food Chem, Toxicol 2006 Apr;44(4):53S-4S).
in an. embodiment, th compositions of this invention use BCP (and/or other CB2 modulators) i substantially pure form, being substantially free of BCP oxid and alphatiuniylene,
Chaves (Chaves JS, Plant Med. 2008 Nov; 74( 14): 1678-83) reporte thai aipha- humulene exhibited a rapid onset arid relatively good absorptio following oral and topical administration. These findings further contribute to an explanation of the topical and systemie anti-inflammatory and antinociceptive properties previously reported for the essential oil and fo alpha-humulene obtained from Cordia verbenacea. Humulen is irritant, but only in high doses. It is documented that BCP lias a potentiating effect on homuiene. T us, Legault p. Pliarm, Pharmacol, 2007 Dec; 59(12): 1643-7) reports a enharK-eineni of the anticancer effect of huHittlene by BCP.
It is therefore interesting to determine th activity of BCP/alpba~liumii!ene combinations, The experimental data (see examples) suggests that BCP/a!pha-hun dene combinations are therapeutically active.
Aspects of the invention relate to compositions -comprising a combination of BC P and alpha-humulene. optionally with traces of other ingredients like BCP-oxide. in -some embodifnents, there are provided co positions comprising .from about 85%w w t about 99%w/w BCP and from about l %w/w to about 15%w/w humuieiie, with traces of other ingredients- like BCP-oxide. In some embodiments, there at e provided compositions■.comprising, from about 85%w w to about 99%w/w BCP and from about I%w/w to about
Figure imgf000018_0001
bnmi ene.
In some embodiments, there is provided a method of treatment of a mental disorder in a patient in need thereof by administration of a composition comprising from aboot ¾5 w 'w to about 99%w/\v BCP and from .l% v/w to 15¾w/w humuiene... a self-eraulsifyiii . vehicle, i some embodiments, there is provided a method, of treatment of a mental disorder in a patient in need thereof, by administration of a composition comprising from about 83%w to about 99%w/w BCP and from l%w/w to 15%w/w huniulene, a self-emulsifying vehicle and optionally one or more of the following: a therapeutically effective amours* of either at leas one antipsychotic agent, at least one GPR55 modulator, at least one ani nflannuaiory agent, at least one enzyme enhancer, at least on enzyme inhibitor, at least one antidepressant, at least one anxiolytic, at least one terpene o terpenoid, at least one anti -diabetic agent, at least cognitive •enhancer- agent or any combinations of the foregoing, in some embodiments, the composition. can comprise from about 85%w/w to about 99% /w BCP and from about !%w;/w to about 13%w/w humulene, with traces of other ingredients like BCP-oxide.
One of the drawbacks of BCP is its pmneness to autoxkiatkm, Beia- aiyophy IS ene starts to oxidize immediately when air exposed, and after 5 weeks almost 50% of the original compound is consumed. ■Car ophyllene oxide was found to be the major oxidation product ((Skold M. Karlfoerg AT, Matuta M, Borje A, Food Chem. Toxicol. 2006 Apr;44(4);538-43)). The practical effect of this instability is that conventional compositions- containing the compounds have relatively short shelf liv s, thus making commercial distribution and storage difficult.
In order to maintain the parity, stability ahd the therapeutic activity, the -compositions' Of this invention, comprisin CP and/or other CB2 receptor selective agonists are stabilized by addition of an antioxidant and/or free-radical scavenger. As used herein, term "stable" means that the quantitative composition does not significantly change over the time, during- the entire shelf-life of the composition, namely for at least 3 months, advantageously for at least 6 months, more advantageously for at least 12 months, even more advantageously for at least 24 months, ■under standard conditions, in particular at a temperature ranging: for 20°G to 4G°C :and relative humidity ranging for 3-0% to 75%. In particular, caryophyllene oxide level is less than 5% by weight, based on the total weight on die composition, during the entire shelf Hi of the composition, in the present invention, the composition is advantageously stable during 6 months to 1 year or during I year to 2 years under standard conditions. In some embodiments, compositions comprising BC'P and/or other CB2 receptor selective agonists and furthe comprisin an antioxidant a free-radical scavenger or a combination of a antioxidant and a free-radical scavenger have an extended sheli-iife, In some embodiments, the stable or stabilized compositions have the property to loose less than about 5% of the original compound when stored at room temperature from - about one year to about two years, in some embodiments, the stable or stabilized compositions have the property to loose less than about 10% of the original compound when stored at room temperature from, about one year to about two years. In some embodiments, the stable or stabilized compositions have the property to loose less than about 4% Of die original compound when stored at room temperature from about, One year to about two years. In some embodiments, the stable or stabilized compositions have the property to loose less than about 3% of the original compound when stored at room temperature from, about one year to about two years. I some embodiments, the stable or stabilized compositions have the property to loose less than about 2% of the original compound whe stored at room- temperature from about one year to about two years. I some embodiments, the stable or stabilized compositions have the property to loose less than abou 1% of the original compound whe stored at room temperature from about one year to about two years, in some embodiments, the stable or stabilized compositions have the property to loose from about 5% to about 10% of the original compound when stored at room temperature from about one year to about two years. In some embodiments, the stable or stabilized compositions have the property' to loose from about .1% to about 5% of the original, compound- when, stored at. room, temperature irom- a ut one year to aboiit two years. One of the problems related to the use of eannahinoids, in general, and CB2 receptor agonists, In particular, is their low bioavailability. Thus, tor example, oral THC- is onl 4% to 12% hioavaiiahie and its absorption is highly variable (McGilveray LJ,, Pain Res- anag. 2005 Aritumn; 10 Soppl A; 15A-22A). The same is true for the oral bioavailability of BCP, a C 2 selective agonist (U.S. Patent Application 20.15/0051299 and PCI Application 2013/1-40342, which are incorporated herein is their entireties).
It should be appreciated that the reasons responsible for low bioavailability via oral route can be due to poor aqueous solubility and/or poor - chemical stability in the alkaline pH of the gastrointestinal tract.
This is wh much effort has been in vested in the improvement of the cannabinoids* oral bioavailability
For -example, current .medications rising CEO request- high CBD amounts pe patient. Echo Pharmaceuticals Ltd has developed a drug delivery technology Alitra™ in which the drug- is formulated i-n a solid composition (granulates) to improve absorption and .distribution of compounds with low water solubility. For example, a drag based on CBD was developed (Arvisol®) with 30% bioavailability improvemen
Similarly, among the main disadvantages of currently available Λ-tetrahydrocammbinol (THC) formulations are dosing difficulties due to poo pharmacokinetic characteristics. Namisol® is a novel THC A-litra™ formulation, designed to improve THC absorption ( lumper's L,E>, Br J Clin Pharmacol. 2012 Jul 74(1); 42-53.}. No such research has been carried ut on C82 receptor modulators, o CB2 receptor selective agonists in general or on BCP and liquid formulations in particular.
The composition of this disclosure is based on a formulation of the self-emulsifying drag: delivery system (SEDDS) type. The SEDDS technology is based on isotropic mixtures of oils. Surfactants, solvents .and eo-soivents/surfactants, which form- fine relatively stable oil--in-wai;er (o/w) emulsions upon aqueous- dilution owing to the gentle agitation of the gastrointestinal fluids. In this ease, there- is no granulate, but rathe liquid .compositions winch can be orally administered in sot or hard gelatin, capsules. A large number of composition alternatives have been explored (see Examples 1-1 Ijijn order to develop the most suitable- composition for oral delivery of CB2 receptor agonists in general and BCP in particular. Example 1, for example, shows a SEEDS composition that is efficient for oral administration.
A liquid composition tor oral delivery is described in Example 12.
Studies have been carried ou with water-diluted SEDDS compositions on mice (see Example 13). In. some embodiments, the composition is stabilized by addition to t e: composition of an antioxidant and/or free -radical scavenger. The stabilization of the composition can be necessary because of the ptoneuess of the C B.2 receptor modulators and CB2 receptor agonists to oxidation and can be achieved by addition to the composition of an antioxidant or free-radical scavenger. Antioxidant or free-radical can. also potentiate the therapeutic effect of CB2 receptor modulators and CB2 receptor agonists.
In some enrhodiroents, there is provided a composition formulated as a stable self- emulsifying drug delivery system (.SEDDS) comprising at least one oil, at least one surfactant HLB<9, at least one surfactant HLB> , at least one co-surfactant,, at least one antioxidant, and/or free-radical scavenger; at least one CB2 receptor selective or highly selective agonist and optionally at least one antipsychotic agent. In some embodiments, at least one CB2 receptor selective -or highly selective agonist fa in a substantially pure form.
In some embodiments, the oil is selected from the group consisting of medium chain triglycerides, propylene glycol, dicapri!ate/dicapraie, medium chai mono-and diglycerides, aceiyiated mono-and digiyeerides and olive oil and combinations thereof.
In some embodiments, th surfactant !iLB<9 i selected: from the group consisting of oleoyi polyoxyl-6 giycerides, linoleyl polyoxy!-6 giycerides (20-40%), Polysorbaie 85 (Tween- 85) poiyoxyetiiylene (20) sorbitan trioleate (5-15%), Span-80 (sorbitan. nionooieate) (5-25%), poS.ygryce.ryi~ 3 dioleate (15-35%) and glycerin rnonolinoleate ( .10-35%), and combination thereof
lit some embodiments, the Surfactant HLB>13 is selected from the group consisting of po'lyoxylated. castor oil (5-25%),. PEG 40 hydrogenated castor oil, PBG 5 hydroxystearate (5- 25%) and capryiocaproyi polyoxyl -S giycerides (10-20%), PEG-20 sorbitan: nionostearate, PEG- 20 sorbitan monooieate (5-25%) and PEG 40 stearate (5-25%) and combinations thereof. In some embodiments, the co-sarfactaai is selected from the group consistin of soy lecithin (>::::75% phosphatidylcholine in oil 1.-10% w/w), soy lecithin PC content 5G% '(2-1.5%), egg lecithin E-60 or E-80 (1-5%) and disieafoylph.6sphati.dy1 choline (0.5-3%), and. combinations theieof.
In some embodiment*, there is provided composition formulated as a stabl self- emulsifying drug delivery system. (SEDDS) comprising:
from about 10% w/w to about 50% w/w of an oil selected from die group- consisting of medium chain triglycerides, propylene glycol dieaprilate/dieaprate, medium chain ono-and diglycerides, acetyiated mo.«o-a»d diglycerides and olive oil and combinations thereof;
from about 20% w/w to about 50% w/w of a. surfactant HLB<9 selected from the group consisting, of oleoyl polyoxyi~6 glycerides,. Hnoieyl poiyoxyl-6 gSycerkies (20-40%), Polysorbate 85 (Tween-8.5) poiyo yethylene (20) sorbita trioleate (5-15%), Span-80 (sorbitan monoo!eate) (5-25%), polygl.yceryi-3 dioleate (1 -3.5%) and glycerin monolinoleate (10-35%), and combinations thereof;
from about 5% w/w to about 10% w/w of a surfactant HLB>I3 selected from the group consisting- of polyoxykte castor oil (5-25%), PEG 40 hydrogenated castor oil, PEG-15 hydroxystearate (5-25%) and eapryloeapro i polyox 1 -8 glyc-erid.es (10-20%), and combination thereof;
from about 5% w/w to about 25 w/w of a surfactant HLB 13 selected from the group consisting of PEG-20 sorbitan monostearate, PEG-20 sorbitan monooleate (5-25%) and PEG 40 stearate (5-25%) and combinations thereof;
from about 0,5% w/w to about 1 % w/w of a co-surfactant selected .from the group consisting of soy lecithin (>=75%. phosphatidylcholine in oil, 1- 10% w/w), soy · lecithin- PC content >S0% (2-15%), egg lecithin E-60 or E-80 (1-5%). and distearoyiphospliatidyk-holine (0.5-3%);
from about 0. 1% w/w to about 5 % w/w of an antioxidant and/or or free radical scavenger selected from the group consisting of d-aipha-tecopherol (1 -4% w/w), dl-alpha-tocophero) (25% w/w), dl-alpha-tocopheryl acetate (2-5%),. mixed tocopherols (alpha, beta, ga a— 1 -4 w/w), d-a!pha-tocopheiyl acetate (2-5%), buty Sated hydroxyanisoie (BHA, 0.1-0.5%) and combinations thereof, and combinations thereof; from about 1% w/w to about 20% w/w of at least one C82 receptor agonist in Substantially pure form; and
optionally from about 0.1% w/w to about 5% w/w of at least one antipsychotic agent. in some embodiments, there is provided composition .formulated as stable seif- e idsifying drug delivery- system (SEDDS) comprising;
from about 30% w/w to about 50% w w capric/caprylic- triglycerides;
from about 30% w/w to about 50% w/w oleoyl polyoxyL-6 glycerides;
from about 5% w/w to about 10 % w/w polyox lated castor oil;
from about 7% w/w to about 1.5 % w/w PEG-20 sorbitan rnonosteatate;
from, about 2% w/w to about 5 % w/ soy lecithin (75% phosphatidylcholine in oil);
.from about 1% w/w to about 3 % w/w d-aipl a tocopherol;
from about 1% w/w to about 20% w/w of at least one CB2 receptor agonist in substantially pure form; and
optionally from about 0.1 w/w to about 5% w/ of at least one antipsychotic agent. la "some embodiments, die at least one C-B.2 receptor agonist is the composition of this disclosure is selected from, die group consisting of BCP, HU-308, HU-433, lU-910, HU-91 , CB 65, GP la, GP 2a,. GW 405833, JWH 01-5, JWH 133, AM 1241 , L-759,b56, L-759,633, MDA 19, SE 60.1 , BML-4 0, N-alkylamide, utamarin, diindoiytmethaiie (DIM) and combinations thereof
In some embodiments, live at least one agent i'a the composition of this disclosure is selected from the group consisting of an. antipsychotic agent, a GPR55 modulator, an antiinflammatory agent, an ea¾yrae enhancer, an enzyme inhibitor., an. antidepressant,, an anxiolytic, a terpene or terpenoid, an. anti-diabetic agent, a cognitive enhancer agent and combinations thereof.
■In some embodiments, the at least one agent ia the composition of this disclosure i selected from the group consisting of a Uraonene, pinene, linalool, n racene, thujone, polypeptide-p, rosn ariruG acid, chararitin, ethyihydroxy chaicone polymer, coumarin, curcmnine, pipeone, CB1 receptor antagonists and combinations thereof
In sorae embodiments, ibe at Least one agent in the composition of this disclosure is selected from th group consisting of the group of modulators that targeting die enzymes cycSooxygenase-2 (COX-2), fatt acid .amid hydrolase (FAAH), monoacylglycerol lipase (MGL), α β-hydrolase domain containing 6 (ABDH6 or ABHD6), hydrolase domain containing 12 (ABDH12), fl/p-hydrofase domai coMaming 4 (ARDH4). sn-) diaeyIglyeero| lipase alpha (DAGi-alpha), sn-1 -diaeylglyeefol lipase beta (DAGLbeta), N-aeyl phosphatidyiefhaBoiaOTine phospholipase D (MAPE-PLD), phosphodiesterase 1 (GOBI), phospholipase C (PLC), phospholipase D (PLD) and combination thereof.
In some embodiments, the at least one antipsychotic agent in the composition of this disclosure is selected from the group consisting of benperidol, bronipendof, droperidol, tialoperidoS, tmnperone, fluspirilene, penfluridol, pitaozi.de, acepromazine, chlorpromaz e, . cyaniemazlne, dkyrazitie, fliiphena ine, ievomeprotaazine, mesoridazme, perazine, perieyazirje, perphenazine, pipotiaziae, prochlorperazine, promazine , promethazine, prothipeodyi, thioproperazine, thioridazine, trMuopera*in.e, triilupromazine, chforprothixefte* elopeotbixol, ilnpentixoL, thiothixene, zaelopent vtxol, amisnlprtcie, atnoxapine, aripiprazofe, dehydroaripiprazole, aseoapine, c riprazine, clozapine, blonanserin, iloperidone, hu'asidorse, meiperone, Jiemonapride, olanzapine, paliperidone, paliperidone palmltaie,. perospirene, quetiapine,, rensoxipride, risperidone, sertindole, suttopride, trimipraniine, ziprasidone, brexpiprazole, ΓΠ-007, p aavanserin, P5063 (RP500Q) camj bi.diol (CBD)». eannabidivarin (CBDV), eannabiodiolic acid (CBpA), tetrahydrocaanabivarin (THCV), OPC- 14857, D!yi-1458, DM-14S1 , D -1452, D -1454, DCPP, eannahigerol (CBG) arid its analogs CBG A and CBGV and combinations thereof.
In some embodiments, the at least one antipsychotic agent may belong to several types or subclasses.
in some embodiments, the composition described herein further comprises, in addition to a CB2 selective receptor agonist, at least one antipsychotic agent, such as, for example, a typical antipsychotic agent including, but not limited to, one or more of a b t rophenone type antipsychotic agent selected from the group consisting of haloperidol, droperidol, benperidol, trifluperidol, raelperone, lenperone, azaperone, domperidone, butyroph.eno.ne, iluanisone, penfluridol, pipaniperone, spiperone, nonaperpne, bromperidol and tiiiiiperone, diphenylbutylpjperidine type antipsychotic agent selected from the grou consisting of luspiriiene, penfluridol, pimozide, clopimozicfe, fluspirilene, penfluridol, a phenothiazine type antipsychotic acid agent selected from the group consisting of aeepromazine, chl rpromazine, cyamemaziiie, dixyrazine, fluphenazine, ievoniepromazme, mesoridazine, perazine, periciazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine and trifluoperazine and tri¾p ma¾jne» a thtoxantheiie type antipsychotic agent selected from the group consisting of c orprothixene, clopehthixol, ilirpenfool, thiothixene and miclopenthixol and/or an atypical antipsychotic agent including, but not limited to one or more of a atypical antipsychotic agent usually belonging: to the D2 antagonist/inverse agonist, 5-HT2A antagonist inverse agonist types selected .irditt. the grou consisting of amisiilpride, anioxapine, asenapme, cariprazine, clozapine, blonanserin, iloperidone, lufasidotie, meiperone, iienionapficle, olanzapine, paiiperidone, paiiperidone pafmitaie, perospirone, qtietiapine, remoxipride, risperidone, sertindole, sultopride, trimipramine, ziprasidone, ITi-007, pimavanserm (ACP-103; 5-HT2A antagonist), and combinations thereof, and/or an atypical antipsychotic agent including, but not limited to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected .from the group consisting aripiprazole and its metabolites OPC- 1.4857, DM-.145S, DM-14 1 , DM- !4525 DM- 1454 and DCPP, brexpiprazole and RP5063 ( P5000) and combinations thereof ' .and/or a cannabinoid exhibitin antipsychotic activity selected, from the group- consistin of tefcrahydrocaniuibivarin (THCV— CB1 antagonist CB2 receptor partial, agonist), cannabidipl (CBD — CB 1 /CB2 GP 55/ABn-CBD antagonist/inhibitor) and. cannabigerol (CBG — CB1/CB2 partial agonist).
In some embodiments, there are provided compositions comprising combinations. -of a CB2 selecti ve receptor agonist froni one of the above types or subclasses with a antipsychotic agent from one of the abo ve types or subclasses.
I some embodiments, there is provided a composition wherein the at least one CBS receptor agonist is he a-caryophyllene (BCP) as sole active agent.
According to some embodiments, there is provided a composition wherein the at least one CB2 receptor agonist is beta-caryophyilene (BCP) in a mixture with hiimitlene and traces of BCP oxide.
In some embodiments, there is provided a. composition herein the at leas on CB2 receptor agonist is beta-caryophyllene (BCP) and the at least one antipsychotic agent is selected from the grou consisting of risperidone, paiiperidone, paiiperidone palmitate, aripiprazole, quetiapine, CBD and its analogs, THC V, brexpiprazole and combinations thereof. In certain embodiments, the composition of this disclosure can be formulated for oral, topical, intranasal or rectal administration.
in other embodiments, the .composition of this disclosure is formulated for oral administration, herei in the form of capsule, suspension, liquid composition for oral 5 adr nistratioo, solution, emulsion or syrup.
In another embodiment, the topical composition of this disclosure is formulated as a transdermal gel, cream, patc or topical spray.
The role of CB2 receptor selective agonists, in general, and BCP, in particular, io the treatment of schizophrenia, has not previously been studied,
i 0 The effec of BCP in various compositions and modes of administration in murine model of schizophrenia, produced by administration of the N-methyl-D-aspailic acid (NMDA) antagonist, phenylcyclidine (PCI5) has been described in U.S. Patent Application 2015/0051299 and PCX Application 2013/140342 (.incorporated herein in their entireties; description of EXAMPLE 151L '"Postnatal mduction of schizophrenia (days 3- 3.5) followed by treatment of I S adolescent mice with BCP (postnatal days 43-61) and FIGS. 14A-14E' show results demonstrating thai BCP treatment at adolescence reversed the effect of PCP on ambulation but did not affect body weight; line graph of body weight at PND 40-68 (14A), bar graph of female and male body weight at PMD63 (.14B)S line graph of male ambulation at PND 63 (14D),: line graph of female ambulation at PND 63 and line graph of male and female ambulation at PND •0 63").
According to some aspects, tftere is provided a composition comprising beta- caryopfiy!lene (BCP) and seif-entulsifying vehicle for use in treating schi¾op renia.
According to some aspects, there is also provided the use of beta-caryoph llene (BCP) and seli-emnlsifying vehicle in the manufaciure of a medicament for treating schizophrenia in a IS subject in need thereof.
In some embodirnents, such a composition is formulated for administration t a human Subject, in some em odiments, siich a com osition i foniiulated for administration to a non- human animal subject.
According to softie aspects of the invention, there is also provided a method for treating iO schizophrenia in a subject in need thereof, the method comprising administering a pharmaceuticaily-effective amount of 'beta-caryoph llene (BCP) to a subject in need thereof I some embodiments, the subject is a human subject. In some embodiments, the subject is a non- hurnan animal.
The efficacy of the methods and compositions according to the teachings herein are demonstrated in the experimental section .herein below,
According to some embodiments, the compositions and methods of treatments disclosed herein are useful for treating one or more of paranoid schizophrenia, disorganized schizophrenia, undifferentiated schizophrenia, catatonic schizophrenia, and residual: schizophrenia.
In some embodiments, the compositions and methods of treatments disclosed, herein are useiul in the treatment oiVnegaiive symptom of schizophrenia (according to The Diagnostic and Statistical Manual of Mental Disorders (DS )). In some embodiments, the compositions and methods of txeatments disclosed herein are useful in the treatment of a positive symptom of schizophrenia.
In some embodiments, the composition and methods of treatments disclosed herein are useful i the treatment of another symptom of schizophrenia (e.g. cognitive sy mptoms).
The duration of treatment according to the .method of treating schizophrenia according to aspect of the invention is any suitable duration as determined by a treatin health-care professional, typically a psychiatric doctor.
The CB2 receptor agonist (or specifically BCP) regimen of administration and the unit dosage administered to a mental disorder patient in need thereof can depend on the mode of administration, the efficiency of the composition and tire mental disorder to be treated.
Thus, for example, injectable, nasal and transdermal compositions tend t need lower dosages- than some oral compositions. Also,, some oral compositions (like the self-emul ify ng composition detailed in Example I and Example 22) surprisingly require dosages comparabl or lower to intraperitoneal injectable' compositions (for example, see comparison between the effects, of BCP in the open field test after intraperitoneal injection vs. gavage administration of self-emulsifying composition in Example 1). The results of intraperitoneal injectio are .described >in Example -.15ΪΪ . nd Figure 14E in U.S. Patent Application 2015/0051299 and PCX Application 2013/140342 to be compared with: the results (in Figure 2 of this disclosure) of gavage administration in SE DS composition as described m Example .1. of this disclosure (Description of EXAMPLE 1511. ''Postnatal induction of schizophrenia (days 3- 15) followed by treatment of adolescent mice with BCP (postnatal days 43-61 ) and FIGS. 14A-I4E show■ results demonstrating that BCP treatment at adolescence reversed the effect of PCP on 'ambulation- but did not affect bod weight: line graph of body weight at PND 40-68 (14A), ar graph of female and male body weight at PND63 (14B), line graph of male ambulation at PHD 63 (14D), fine graph of female■ambul tion at PND 63 and line graph of m le and female arrtbulation at PND 5 63")-
In addition. Example I and Figures 1 and 3 A of this disclosure show that n other tests, i.e. forced-swim test and social interaction test, BCP in self-emulsifying composition is als orally active at about the same dosage (5 nig/kg) as in the open field test (Example I and Figure
2 of this disclosure), Collectively, these results show that surprisingly BCP in SEDDS seif- 10 emulsifying composition is orally active at about the same dosage as intraperitoneal injection.
In some embodiments, some SEDDS compositions surprisingly at much more effective than other SEDDS compositions (like in Example 16 V-01 is eff ective whereas Λ -02 and V-
03 are less effective). Collectively, these results show that surprisingly BCP i the specific SEDDS- .self-emulsifying composition described i Example 1 is orally active at about the same
I S dosage as iniiaperiton.eal injection.
Also, some oral compositions (like the self-emulsifying composition detailed iri Example I ) surprisingly are much more effective than other oral compositions (like Example 1 — oil composition and compare between the effects of BCP in the forced swim test after gavage administration of self-emulsifying composition in Example 1 and Figure 1 versus the results after 10 gavage administration of oil compositio in Example 1.4 and Figure 4 in th s application).
In some embodiments, there is provided a highly effective self-emulsifying composition of the present disclosure for the treatmen of a mental disease in a patient in need thereof wherein the administration of an oral dose of said self-emulsifying composition (see Example I) produces a therapeutic effect similar to the intraperitoneal -administration of the same dose (as IS above, Example 1511 and Figure I4E in U.S. Patent Application 2015/0051299 and PCX Application 2013/140342) and a much more effective therapeutic -effect than non-seif- einuisifying oral compositions such as oil compositions (Example 1 ).
Thus, in some embodiments, the CB2 receptor modulator daily dosage administered to -a mental disorder patient .in need thereof, by any mode of administration, including but not limited iO to adinirastratioE of slownrelease/long-acttve formulations given on : daily basis, may vary from 0,01 mg/da to 50 mg day (for highl selective Hgands including but not limited to HU~3(i8} or from 0.1 rng/day to 500 mg/day (for less potent modulators including but not limited to BCP, MB.) fo highly effective compositions.
In some embodiments, the CB2 receptor modulator daily dosage administered to .■ mental disorder patient in an mod of administration, including but not limited to administration t a patient in need thereof of slow-release/!ong-aetive formulations given on a daily basis, may vary from 0, 1 rug/day to 10 mg/day (for highly selective ligands including but not limited to HU- 308) or from 3 mg/day to 1000 ntg/day (for less potent modulators including but not limited t BCP, M B) for less effective compositions.
Other f ctory determining the dosage are the age of the patient and effectiveness of the composition. Thus, for BCP for example, a highly effective composition administered daily in any .mode of administration;, according io some embodiments ma be given in an amount of 0.1 - .10. mg to infants (5-20 .kg), 10-20 mg to children (20-50 kg), 20-50 nig to young adults and 50- 500 mg to adults (50-100 kg). In. some embodiments, for HU-308 for example, a highly effective compositio administered dally in any mode of administration may be given in a amount of 0.0.1 -2 mg to -infests (5-20 kg), 2-5 mg to children. (20-50 kg), 5-1 mg to young adults and 1 - 100 mg to adults (50-100 kg}.. These daily amounts will be administered in one or more discrete dosage units per day or, for highly effective compositions two or three times week.
In some embodiments, the CB2 receptor modulator, for highly selective ligands■ . includin ' but not limited to BU-308 and for less potent modulators including but not limited t BCP, the daily dosage for less effective compositions may vary from 1. mg/day to 500 rng/day (for highl selective ligands including but not limited to HU-308) or from 1 mg/day to 1000 mg/day (for less potent modulators including bet not limited to BCP, MH) for less effective compositions.
In some other embodiments of the method of treating a mental disorder (or specifically schizophrenia or a tic disorder), with CB2 receptor modulator according to the teachings herein, the average daily amount, in any mode of administration including but not limited t administration in slow-release/long-active formulations given on a daily basis, for a human subject (especially an adult human,, weighing between about 40 kg and about 120 kg) is in the range of from about (for highly potent modulators including but not limited to HU-308) I mg to: about 25 mg from about 25 mg to about 100 nig, from about 100 mg to about 500 mg such as about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg. or about 100 rag, about 130 nig,. bout 150 mg, about 200 rag, about 230 mg, about 350 mg, about 330 mg, about 410 mg, about 460 mg, about 520 rag. about 640 rag, about 770 mg, about 850 rag, about 930 mg, or abottt 1000 rag (for less potent modulators including but not limited to BCP or M ) or for less effective compositions,
la other embodiments of the method of treating menial disorder tor specifically schizophreni a tic disorder) according to the teachings herein, the average daily amount of CB2 receptor modulator in an mode .of administration includin but not limited t administration in a sio -release iong-aciive formulations given on a daily basis, for a human subject (especially for an adult human, weighing betwee about 40 k and about 120 kg) is in the range of from about I mg/day to about 5 mg day from about 50 rag/day to about 100 mg/day, such as about 5 mg/day, about .10 mg/day, about 30 mg/day, about 50 mg/day, about '70 mg/day from about 100 mg day for highly selective ligands including but not limited to Ηϋ-308, and is in the range of from about 10 mg/day to about 100 mg/day from about 0 mg/day to about 1000 mg/day, such as -about 1.0 mg/day, about 50 mg/day, about 70 mg/da from about 100 mg day to about 1000 .mg/day, such as about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600: mg/day, about 700 mg/day, about S0O mg/day, about 900 mg/day or about 1 00 mg day, for less potent modulators including but not limited to BCP or for less effective compositions, in some embodiments of the method of treating schizopmenia accordin to the teachings herein, the average daily amount is administered with a frequency of between, once per week, twice per week., 3 times per week, 4 times per week, 5 times per week, 6 times per week, once per day, twice per day, 3 times per day or 4 times per day.
In some embodiments, a composition according to the teachings herein is provided as r made as a dosage form including a plurality of discrete units (e.g., discrete solids or metered liquids, sprays), especially discrete solid units such as pills (including tablets and caplets) and capsules (Including geicaps), wherei each unit - includes a CB2 receptor selective modulator or specifically BCP, HU-308 or 4~0-raethylho-nokio1 ( H) in the range of from about 0,05 mg t about 1000 mg, selected from about 0,05 mg, about 0.1 trig, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 30 nig, about 35 mg, about 40 mg, about 45 mg, about 50 nig, about 55 mg, about 60 nig, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 ing, about 95 mg, about 100 mg, about 200 mg, about 300 mg, about 40 mg, about 500 mg for highly selective ligands including but not limited to HU-308, and in the range of from about 0.1 mg, about 0.5 mg, about I rag, about 5 mg, about 10 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 rag, about 200 mg, about 300 mg, about 400 mg, about 500, about 600 mg, about 700 mg, about 80 rag, about 900 rag, or about .000 mg for less potent modulators including but not limited t BCP or for less effective compositions, ifi some such embodiments, soclr a dosage form is■useful for the once-datiy administration of the desired average daily dosage., according to age of the patient
Irs some embodiments, the dosage of the CB2 receptor modulator administered: t a mental disorder patient, for highly effective delay ed-release delivery compositions (such as compositions for a slow-release, slow-acting .form of medication prepared as a capsule or as a depot injection given for example but no Broiled t intramuscular injection, which ar administrated every 1 week or once a month to up to ever six months) may vary from 100 fflg single administration (fo highly potent modulators including but not limited to MO-308 or for weekly injection) to 3000 rag/single administration (for- less potent modulators including, ut not limited to BCP, MR or for injection every 3 months).
Other factors determining the dosage are the age of the patient and the effectiveness of the composition. Thus, according to some embodiments, for BCP or MH for example, a delayed- release delivery compositions administrated by injection may be given at 1.-50 nig to infants (5- 20 kg), 50-100 mg to childre (20-50 kg) and from 100-200 mg to 200-3000 mg to dults (50- 100 kg). n some embodiments, for HlJ-308 for example, a deiayed-release deliver compositions administered by .injection should be given at 0.5-10 mg to infants (5-20 kg), 10-20 mg to children (20-50 kg) and from 20-100 m to 1 0- 1000 nig to adults (50- 100 kg).
In some embodiments, the CB2 receptor modulator dosage for delay ed-release delivery' compositions (such as compositions for a slow-release, sl w-actifig form of medication prepared as a capsule or a depot injection given for example hut not limited b intramuscular injection, which are administrated every I week, once a month and to up to ever diree■months): ma vary from ί nig/single administration to 500 mg/single administration for less potent modulators including but not limited to BCP or MB, and from 0.1 nig/single administration to 250 oig smgle administration for highly potent modulators, including 'but not limited to Hli-308. In some embodiments, the CB2 receptor modulator dosage for delayed release delivery com ositions (such as compositions for a slow-release, slow-acting form of medication prepared as a capsule or a depot injection given for example but not limited by intramuscular Injection,. •Which are administrated once a month and up to every si months) may vary from 0.5 nig/single
5 administration to 1000 rag/single administration (for highly potent, modulators including bu not limited, to HU-308) or from 1 mg/s ingle administration to 3000 mg/single administration (for less potent modulators including but not limited to SOP or MM).
Another factor determining the dosage is the effectiveness of the composition, In some embodiments, the dosage for less effective long term delivery compositions ia all modes of
10 administration, may vary from. mg/day to 3000 nig/day. In some embodiments, the CB2 receptor modulator dosage tor delayed release delivery compositions (such as compositions for a slow-release, slow-acting form of medication prepared as a capsule or a depot injection given for example but not limited' by intramuscular injection) may var from 1 mg single administratio to 1000 mg/single administration (for highly potent, modulators including but not limited to EIJ-
15 308} or .from 10 .mg/single administration to 3000 mg/siugle administration (for less potent modulators including but not limited to BCP or Mi l).
Another factor determining th dosage is the age of the patient. Thus, for BCP for example, a delayed-release delivery composition for a slow-release, slow-acting form of medication prepared as a capsule or as a depot injection given for example but not limited to
Ϊ0 intramuscular injection, which are administrated ev ry 1 week, once a mouth and to up to ever six months., according to some embodiments may be given at an amount of 3 -50 mg to infants (5- 20 kg), 20-100 ng to children (20-50 kg), 50-200 tug to young adults and from 1 0-300 mg to adults (50- 1 0 kg), i . some embodiments, for HU-308 for example, a delayed-release .delivery composition for a slow-release, slow-acting form. Of medication prepared as a capsule or a depot
IS injection given for example but not limited by intramitscular injection, which are admimsirated once a week, once a month, and to up to once every six months) according to some '■■embodiments may be given at an amount of 0.1 -10 mg to infants (5-20 kg), 5-20 rng to children (20-50 kg) and from 0- 100 mg to 50-1000 mg to adults (50-1 0 kg).
In some embodiments, the administration regimen of delayed-release delivery i0 composition is one administration per week, to once every two weeks, to one administrat n pe month, to one administration per each other month or once every six months as required. In some other emb dimen s of the method of treating schizophrenia according id- the teachings herein, the average amount (in mg) per single administr tion of a delayed-release delivery composition , mainly by injection, (once a week and up to every six months) for a human subject (especially an adult human., weighing between about 40 kg and about 120 .kg) is in the range of from about (for highly potent modulators including but not limited to HU-308) 10 ■mg to about 25 rag from about 25 mg to about 100 mg, from about 100 nig to about 500 mg such as about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 m , about 65 mg, about 70 tag, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg, about 130 mg, about 150 mg, about 200 mg, about 230 mg, about. 350 mg, about 330 mg, about 410 mg, about 460 mg, about 500 mg, from about 500 mg t about Ϊ000 mg, such as about 650 rug, about 730· mg, about 840 mg, about 960 mg, about 1000 mg, from about 1000 nig t about 3000 rag, such as about 1200 mg, about 1800 rag, about 230 mg, about 2500 mg or about 3000 mg (tor less potent .modulators including but not limited to CP or Mil) or for Jess effective compositions.
In other embodiments of the method of treating mental disorder (or specifically schizophrenia) according to the teachings herein, the average amount (in mg) per a single administration of a delayed-re!ease · delivery composition mainly by injection (once a week and up t ever six months) for a human subject (especially an adult . 'human, weighing between . about 40 kg and about 120 kg) is in the range of from about 10 mg/single administration to about 50 .mg single administration from about 50 mg single administration to about 100 mg/single administration., such as about 20 mg/single admini tration, about 30 mg/single administration , about 60 m /singie administration fro about 1 0 mg/single administration to about 1000 mg/single administration , such as about 200 mg single administration, about 300 mg/single adm srntiion, about 400 mg/single administration,, about 500 mg single a innistration, about 600 mg/singie administration, about 700 mg/single administration, about 800 mg/single administration, about 900 mg single administration, from about 1000 mg/single administration (.for highly potent modulators inchiding but not. limited to HU-308) and is in the range of from about 100 mg/single administration to about 3000 mg/single administration, such as about 200 mg/single administration, about 300 nig/single administration, about 400 mg/single administration, about 5.00 .mg/single administration, about 600 mg/singie administration, about 700 mg/single adm nis rations about 800 mg/single administration, about 900 mg/single administration, from about 1000 mg/smg!e admiRistration to about 3000 mg/single adminis&ation, suc as about. 1250 mg/single admin stra ion about .1600 mg sing!.e administration, about 2100 nig skgle administration, about 2400 mg/single administration, about 2700 nig/single adminisnrntion, or about: 3000 mg/single administration (for less potent
5 modulators including but not limited to BCP or MH) or for less effecti ve compositions, in some embodiments of the method, of treating schizophrenia according to the teachings herein, .the average amount of a single administration mainly, but not limited to injection or oral administration is administered, with a frequency o between about once a. month to once every two months, to about once e en' three months,, .to about once every four months,, to abou once
10 every five months,. to about once every six months.
In some embodiments, a composition according to the teachings herein is provided as or made as a dosage form including- a plurality of discrete units (e.g., discrete solids or metered liquids, sprays, depot fbnnuiatiou for injection), especially discrete solid units such as pilis .(.including, tablets and capiets) and capsules (including . elcaps), where each unit includes a CB2
I S receptor selective modulator or specifically BCP, HU-308 and 4-0-methylhonoki.ol- ( H;|. in the range of from about 10 nig to about 1000 mg, such as about .10 mg, such as about 50 nig, such as about 100 mg, such as about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, •about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1 00 mg for highly selective ligands
JO including but not limited to HU-308, and in the range of from about .100 mg to about 3000 mg, such as about 10 mg, such as about 50 mg, such as about .100 mg, such a about 250 mg, abou 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 90 mg, about 950 mg, about 1000 mg, about 1500 mg, about 2000 nig, about 2500 mg, or about 3000
IS mg for less potent modulators including but riot limited to BCP or for less effective compositions. In some such embodiments, such a dosage form is useful for single administration of tire desired average dosage per singl administration..
According to some embodiments, the compositions of this invention may be administered by any suitable route of administration, including but not limited to oral, parenteral ,. : topical, i.O intranasal, vaginal or rectal administration. According to some embodiments, there is provided art oral composition formulated as a capsule, suspension, syrup, liquid composition for oral administration, solut n, transnmeosal lozenge, sachet or sprinkle. The topical composition is formulated as a tra sdermal gel, cream, patch or topical spray. The int anasal, composition is .formulated a a nasal spray,
hi an embodimeiit, the composition, is a gastro-resistant oral dosage form, that is to say, an orally-admiiiistrable dosage form configured to carry the active(s) through the stomach to be released' into contact with the digestive tract only after passage through the duodenum As a example, in some such embodiments, the composition is in the form of a gastro-resistant soft gel capsule, comprising between 5 mg and about 1000 mg BCP in a self-emulsifying vehicle. As an example, in some such embodiments,, the composition is in the form of a gastro-resistant soft gel capsule, comprising between 0.5 mg and about. 500 mg HU-308 in a self-emulsifying vehicle. Some embodiments of the method, when implemented with an adult human subject, comprise orall ingesting a single such capsule twice day for at least one a month, or once every two months, to about once every three months, to about once every four months, to about once .every fiv months, to about once every ix months, so that the average daily amount: is between about 5 mg an about 500 n g BCP.
In some embodiments, the composition described herein further comprises at least one antipsychotic ager , uch as., for .example, a typical antipsychotic agent including, -but not limi ted to, one or more Of -c-hlorpromaztne, haloperidol, perphenazine, pimozide or fluphenazirie, and/o an atypical antipsychotic agent including,: but not limited to, one or more of clozapine, risperidone, olanzapine., quetiapine, ziprasidone, aripiprazole, serf indole,, arnisulpride, paiiperidoiie, paliperidone palmitate, and combinations thereof.
In some embodiments of the method of treatment, the CB2 receptor selective agonist or for example BCP is administered together with at least one antipsychotic agent selected-. rom one or mor of a butyrophenone type antipsychotic agent selected from the group consisting of •haloperidol, droperidol* benperidol, trifluperidol, melperone, lenperone, azaperone, doin eridone. butyrophenone, tluauLsone, -penfluridol, pipamperone, spiperone, nonaperoue, broniperido!. and timiperone, a diphenyibu ylpipeiidine type antipsychotic -agent selected 'from the group consisting of luspirilene, penfluridol, pimozide, clopimozide, fluspiriiene, penfliiridol, a phenothiaziiie type antipsychotic acid agent selected from the group consisting of acepromazme, c-hiorprofnazine. cyamernazine, dixyrazine, iluphenaziiie, levomepromazine, mesoridazine, perazineY pericy-azine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prGthipendyL thioproperazine, iblorldazme md iriiliiopera/ine and triflupromazine, athtoxanthene type antipsychotic agent selected from the- group- consisting of chio prothixerie, ciopenihixol, ftupentixo!, thiothixene and zu openthi ol and/or an atypical antipsychotic agent including, but not limited to one or more of an atypical antipsychotic -agent usually belonging to the D2 antagonist/inverse agonist, 5-HT2A antagonist/inverse agonist types selected from the group consisting of araisulpride, amoxaprne, asenapine, eanpraane, clozapine, blonanserin. iloperidone, !nrasidone, inelperooe, nernonapride, olanzapine, paiipersdone, palipersdone pa!mitate, perospkone, quetiapitie, remoxipride, risperidone, sertindole, sultopride, trimipraraine, ziprasidone, ΓΤ1-007, pimavanserin (ΑΟ 03·; 5-ΉΤ2Α antagonist), and. combinations thereof and/or an atypical antipsychotic agent including, but not limited to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected from, the group consisting aripipraz ie and its metabolites QPC- 14857, DM- 1458, DM- 1 51, D -1452, DM- 1454 and DCPP, brexpiprazole and RP5063 (RP500Q) and combinations thereof arid/or a. eannab oid exhibiting antipsychotic activit selected from the group consisting of
Figure imgf000036_0001
(XHCV—€B1 antagonist CB2 receptor partial -agonist), cannabidiol (CBD — CB l/CB2/GP: 55/ABn-CBD antagonist/inhibitor) and cannabigercil (CBG — GB1 CB2 partial agonist) and combinations thereof
In some embodiments where the CB receptor selective agonist or for example BCP and an antipsychotic agent are administered together, the two active agents can be co-adrnintsiered in a single dosage form.
In some embodiments where the BCP and an antipsychotic agent are administered together, the CB.2 receptor modulator or for example BCP and the antipsychotic agent can be coadmini tered in separate dosage forms, either sequentially or simultaneously.. For example, the additional antipsychotic agent may be administered prior to administration of th CB2, or the additional antipsychotic agent may be administered subsequent to administration of GB2.
While not wishing to be bound to any one theory, the inventor consider that it is likely that at least part, if not all, of the herein demonstrated efficacy of the CB2 receptor modulators or GB2 receptor seleciive agonists i general or BCP in particular i treating schizophrenia relates to the CB2 recepior selective agonist properties. According to aa aspect of some embodiments of the teachings herein, there is also provided the rise of a CB2 recepto selective or highly selective agonist arid a seSf-effiulsif irj vehicle in the manufacture of a medicament for treating schizophrenia in a subject in need thereof.
According to some aspects, mere is also provided method for treating schizophrenia i a subject in need, thereof, the method comprising administering a phai iiaci^itieaMy-effeeiive amount of a CB2 selective rec ptor agonist to the subject.
In some embodiments, there is provided, a stable sdf-emiilsifying composition for treatment of mental disorders in a patient in need thereof, cojmprisi«g a therapeutically effective amount of at least one CB2 receptor modulator in substantially pure form, a , sel&et ilsifyin vehicle and optionally a therapeutically effective amount of at least one aiitipsye otic :■agent, wherein the at least one CB2 receptor modulator and the at least one antipsychotic agent are substantiall solubifized. hi this context, "substantially solubiBzed" means that more than 90%w/w. preferably more than 95% w/w and eve more preferably .more than 99%w/w are s hibi Sized,
The self-emulsifying composition spontaneously forms an oi.S-in-vv;ater emulsion, typically with n average particle size belo I micron (see Example 1) upon dilution with water containing media o body fluid. The average particle size of the emulsion, depends on the composition comprising the self-emulsifying vehicle and: the active agent(s).
In some mbodiment , there is provided a se!t-envdsifyitig composition fo treatment of menial disorders in a patient in need thereof, wherein said composition is physically stable at least 2 hours during the time required for effective absorption in the gastrointestinal tract, and wherein, said composition, spontaneously' forms an oil-m-water emulsion upon dilution with water containing media or body fluid. The Gi tract transition time is a function of marr factors, like gastric- emptyin rate and intestinal transit rate, but about Ϊ0 hrs Gi stability is considered to be sufficient.
The drop Set (particle) size of the above emulsion is smaller than 10 mem, preferably smaller than 1 mem more preferabl smaller than 500 run, most preferably smaller than 150 nm.
According to some embodiments, the at least one CB2 receptor .modulator in the above composition can be selected from the group consisting of at least one CB2 receptor agonist or partial-agonist, at least one CB2 receptor antagonist or inverse agonist, at least one CB2 receptor antagonist or inverse agonist which is also a selective estrogen receptor modulator (SERM), at least one type of CB2 receptor aJlosterie modulator and co in tions thereof
In some em odiment the at least one C.B2 receptor agonist or partial agonist in the above composition is selected from, the group consisting of BCP, I1U-308, !-IU~433, HU-910., MiJ~9 I4, CB 65, GP la, GP 2a, GW 405833, JWH 015, JWH 133, AM I 24L -759,656,. L~ 759,633, MDA 1.9, SER 601 , BML-190, N-al-ky!amide, ratamarin, diindolylmethane (DIM), earmabinor (PRS I 1 ,37S), 2-arachido»oylglyceroL anandamide delta- 9- f-iC, CP55940, W 55212-2, HU210, analogs thereof, deri vatives thereof and combinations thereof.
In some embodiments, the at least one CB2 receptor antagonist or inverse agonist of th above composition is selected from the group consisting of A 630, JTE-907, S 14 528, COR..170, 4-0- methyihonokiol (MB), GS 12021 (4-0~.raethylhonokiol analog), cannabinol, 01238, 01 184, analogs thereof, derivatives thereof and combinations thereof.
In some embodiments, the at least one CB2 receptor alJosterjc rn.odui.aior of the above composition is selected from the group consisting of dihydrogambogic acid, garctno!ic acid, (-)- 5'-dimeih:ylheptyl-cari5Mbidi:o.l (DMH-CBD), analogs thereof, derivatives thereof and combinations thereof.
In some embodiments, the at least one CB2 receptor modulator which is also a selective estrogen receptor modulator (SERM) of the above composition, is selected from the group consisting of raloxifene, hazedoxiien, iasofoxifene, tamoxifen, afimoxifene, arzoxi ene, ornic!oxifene, toremiiene, ospetnifene, analogs thereof, derivatives thereof and combinations thereof
In some embodiments, the at least one antipsychotic agent of the above composition is selected .from the group consisting of one or more of a 'but rophe»on:e type antipsychotic agent selected from the group- consisting of ha!operidoi, droperidol, henperidol, triflnperidois melperone, ieriperone, azaperone, domperidone, biiiyrophenone, fiuanisone., penfluridol, piparaperone, spiperone, nonaperone, bromperidol and tiniiperone, a diphenySbiiiyipipericline type antipsychotic agent selected troffi the group consisting of iuspiolene, penfluridol, pknozide, clopimozide, fluspirilene, penfluridol, a phenothiazine type antipsychotic acid agent selected from- the grou consisting of acepromazine, ehlorproirtazme, cyamemazine, dixyrazine, tluphenazrae, Sevomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine and trifluoperazine and mflupfomazine, a thtoxant'hene type antipsychotic agent selected from the group cons st n of chlorprofhixene., clopenthixol, flupentixol., thiothixene and zueiopent x.ol and/or art atypical antipsychotic agent including, but not limited to one or more of an atypical antipsychotic agent usually belonging to the 02 antagonist/inverse agonist, 5-f-IT A antagonist/inverse agonist types selected' ftom the group consisting of amisuipri.de,. am xapine, ase-napuie, cariprazine, clozapine, blonanserin, ilaperidone, lurasi one, nielperone, nemonapriile, olanzapine, paiiperidone, paiiperidone palmitate, perosptfone, quetiapiae, remoxipnde, risperidone, sertindoie, sultopride, irimipramrae, ziprasidone, iTl-007, pimavanserin (ACP»i03; 5-HT2A. antagonist), and combinations thereof, and/or an atypical anti s chotic agent including, but not limited to one or more of an atypical antipsychotic agent usually belongin to the P2 partial agonist types selected i om the group consisting aripiprazole and its metabolites QPC~ 14857, DM-5458, DM- 1451, DM-.1452, DM- 454 and. DCPP, brexpiptazole and RP5063 (RP5000) and combinations thereof and/or a oannabinoid exhibiting antipsychotic activity selected from the group consisting of tetrahydtocannabivann (THCV CB1 antagonist, CB2 receptor partial agonist), eannabklioi (C.8D CB'I /CB2/GPR55/ABft-CB0 antagonist/inhibitor) and eannabigerol (CBG— CB1 CB2 partial agonist) and combinations thereof.
In some embodiments, the, there is provided a composition formulated as a .stable -seif- erai sifying drug delivery system (SEDDS) comprising at least one oil, at least one surfactant HLB<9, at least one surfactant HLB>13. at least one co-surfactant, at least -one.. antioxidant and/or free-radical scavenger, at least one -CB2 receptor modulato and optional ly a antipsychotic- agent and combinations thereof.
In some embodiments, the, the above composition is formulated as a stable seif- mnlsifying drug delivery system comprising:
from about 10% w/w to about 50% w/w of an oil selected from the group consisting of .medium chain triglycerides, propylene glycol dicaprilate/dicaprate, medium chain mono-arid diglycerides, acetyiated mono-and diglycerides and olive oil and combinations thereof,
from about 20% w/w to about 50% w/w of surfactant MLB<9 selected irom the grou consisting of oleoyi polyoxyl-6 glycerides, lino!eyl polyoxyl-6 glycendes (20-40%); Polysorbate 85 (Tween-85) polyoxyethylene (20) sorbi an trioleate (5- 15%),
Span-80 (sorbitan raorsooieate) (5-25%), poiyg!yceryl-3 dioleate ( 15-35%) and glycerin rnonoHnoleaie (10-35%), from about 5% w/w to about 10 % w/w of a surfactant HLB> 13 selected from the group consisting of poiyoxylated castor oil (5-25%), PEG 40 hydrogenated castor oil, PEG- 15 hydroxystearate (5-25%) and capry!ocaproyl polyoxy!-S glyeeodes (.10-20%}
froro about 5% w/w to about 25 % w/w of a surfactant HLB>13 selected■"■from the grou consisting of PEG-20 sorhitan monostearate, PEG-20 sorbitan monooleate (5-25%) and PEG 40 stearate (5-25%),
from about 0.5% w/w to about 15 % w/w of co-surfactant selected from the group consisting of soy lecithin (>=75% phosphatidylcholine in oil, 1-10% w/w), soy lecithin PC content >50% (2-15%), egg lecithin E-60 or E-8G- (1-5%) and distearoySphosphaiidykho!irie (0.5-3%),
from about 0.1% w w to about 5 % w/w of an antioxidant or free ra iear sc enger selected from the group consisting of d-alpha-tocophero!: (1-4% w/w), dl-alpha-iocopherol (25% w/w), di-alpha-tocopheiyl acetate (2-5%), mixed tocopherols (alpha, beta, ga a— 1 -4% w/w), d~aipha~tocopheryl acetate (2-5%), btityiated hydro yamsole (BHA, 0.1-0.5%) and combinations thereof!
from about |% w/w to -about. 20% w/w of at least, one€132 receptor modulator in substantially pure form and optionally
from about 0, % w/w to about 5% w/w of at least one antipsychotic agent
in some embodiments, the above composition is formulated as a stable self-emulsifyin drug delivery system (SEDDS) comprising:
from about 30% w w to about 50% w/w capric/capryiic triglycerides
from about 30% w/w to about 50% w/w oleoyl polyoxyi~6 glycerides4
from about 5% w/w to about 10 % w/w polyoxylated castor oil
from, about 7% w/w to about 15 % w/w PEG-20 sorbitan monostearate
from about 2% w/w to about 5 w/ soy lecithin (75% phosphatidylcholine in oil) from about 1 % w/w to about 3 % w/w d-alpha tocopherol
from about 1% w/w to about 20% w/w of at least One 'B2 receptor modulator in substantially pure form and optionally
from about 0.1% w/w to about 5% w/w of at least one antipsychotic agent
In some embodiments, the at least one CB2 receptor agonist in the above com position is beta-caryophyilene (BCP) as sole active agent. In some embodiments, the at least one€82 receptor agonist in the above coraposition is beia~earv¾pliyilefte (BCP) a d the at least one antipsychotic agent is selected from the . rou consisting of risperidone, paliperidone, paliperidone palmitate, aripiprazoSe, iieiiapine, CBD and its analogs, THCV, brexpipra ole and combinations thereof
5 In a further embodiment in the above composition, the at least one 62 receptor agonist is beta-cawophyll ne (BCP) and the at least one antipsychotic agent is selected from the group consisting of an of extract of cannabis species comprising .10-98% CBD and its analogs and/or 10-98% THCV and its analogs and/or 10-98% CBG and its analogs and combinations thereof.
In some embodiments, the at least one CB2 receptor agonist 1» the above composition is 10 [(lR-2 ,5R)-2-[2,6-to
bi.eyelo[3;.1 , .1 Jhept-3-enyl} methanol. (If U~308) as sole active agent.
in another embodiment, the at least one CB2 receptor agonist in the above composition is HU-308 and the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidone palmitate, aripipraaole,. quetiapine, CBD and its analogs, I S THCV, brexpipraiiole and combinations thereof
According: to an. embodiment, the composition' of the instant invention, is- stabilized b addition of an antioxidant or a free-radical scavenger.
In some embodiments, the ratio of ant,i x.ida t/CB2 modulator such as hut not -limited: to BCP, is from 1 : 1 to 2:1 w/w. In some embodiments, the aniioxidant/€B2 modulator ratio is from 10 1:1 to SMw w, In some embodiments, the ratio of antioxidauif/CB2 modulator is from 1 : 1 to 4: 1 w/w. in some embodiments, the ratio of anttoxidant B2 modulator is fro 1 : 1 to 5: 1 w/w.
I some embodiments, th ratio of antioxidan t/CB2 modulator is from 2: 1 to 3:1 w/w hi some embodiments, the ratio of antioxidant CB2 modulator is from 2: :i to 4:1 w/w. In some embodiments, tire ratio of antioxidamVCBZ modulator is from 2: :1 to 5:lw/w, i some
15 embodiments, th ratio of amioxidant CB.2 .modulator is from 3.; 1 to 4:1 w/w, I some embodiments, the rati of antioxidant/CB2 modulator is from 3: :1 ft) 5: 1 w/w. In some embodiments, the ratio of antipxidan.t CB2 modulator is front 1:' i to i 0:1 w w. in som embodiments, the ratio of antioxidaiit CB2 modulator is from 2i . i to 10: 1 w/w. In some embodiments, the rati of antioxidant B2 modulator is from 3; 1 to 10: 1 w/w. In some iO embodiments, the rati of aiitioxuknt/CB.2 modulator is from : 1 to 10: Kv.-'w. hi some embodiments, the ratio of antio>:idant/CB2 modulator is from 5: . i to 10: 1 w/w. In some embodiments. the ratio of antioxidant>'CB modulator i: s from 6: < to 10: Iw/w.. in some embodiment, the ratio of antioxida«t/CB2 modulator is from 7: 1 to 10: 1 w/w. In some embodiments. the ratio of antioxidant/CB2 modulator is from 8: 1 to 10: iw/w. tn some embodiments, the rati of antioxidant/CB2 modulator is fro 9: 1 to 10; iw/w. in some embodiments,. the ratio of atttioxidant CB2 modulator is from 5:1 to 1 : Iw/w. in some embodiments. the ratio of arttioxidant"CB2 modulator i; > from 5: 1 t 20; Iw/w. In some embodiments. the ratio of antioxidant CB2 modulator is from 5: 1 t 25: iw/w. In some embodiments. the rati of ant!Oxidant/CB2 modulator is from 5: 1 to 30: iw/w. tn some embodinients, the ratio of a«tioxidant/CB2 moduiator h ; from 5: 1 to 5: Iw/w, in some embodiments, the ratio of antioxidant/CB2 moduiator « s from 5: 1 t 40; iw/w. in some embodiments. the ratio of ajBi.ox.dant/CB2 modulator is from 10: 1 t 15:1 W/W: in some embodiments, the ratio of aiitioxidant/CB2 modulator is from 10: 1 t 20: i w/w. in some embodiments, the ratio of antioxidaftt/CB2 modulator is from 10; ! to 25;! w/w. In some embodiments, 'the ratio of antioxidajftt€B2 modulator is from 10: 1 to 30: 1 w/w. in some embodi e ts- the ratio of antioxidant/CBS modulator is from 10: 1 to 35:1 w/w. in some embodi.ments. the ratio of aiitioxida«t/CB2 modulator is from 10:1. to 40: 1 w/w. In some embodiments. the ratio of antjoxidani/CB2 modulator is from 15: 1 to 20: \ w/w.. in some embodiments, the ratio of sirtioxidatt.t CB2 modulator is from 15; ! to 25' 1 w/w. In some embodiments, the ratio of antioxida.nt CB2 modulator is from 15:1 to 30:1 w/w. In some embodiments, the ratio of antioxidant/CB2 modulaior is from 15: 1 to 35: 1 w/w. in some embodiments, the ratio of antioxidant/CB2 modulator is from 15; ! t 40: I w/w. In some embodiments, the ratio of Rtioxidant/CB2 modulator i from 20; 1 t 25: i w/w. In some embodiments. the ratio of a«tioxidajtii CB2 modulator is from 20;! to 30:1. w/w. In some embodiments. the ratio of antioxidaut/CB2 modulator is from 20:1 to 35: 1 w/w. in some embodiments, the ratio of antioxidani/CB2 modulator is from 20: 1 to 40:1 w/w. in some embodiments. th ratio of antioxidani. B2 modulator is from 25: 1 t 30; i w/w. In some embodiments, th ratio of aiiiioxidai t C 2 modulaior is from 25; ! to 3S;.l. w/w. In some embodiments, the ratio of aniioxidant/CB2 modulator is from 25: 1 to ■40:1 w/w. In some embodiments. the ratio of antioxidant/CS2 modulator is from 30:1 to 35:1 w/w. in some embodiments, the ratio of afttk>xida«t/CS2 modulator is from 30: 1 t 40: 1 w/w. in some embodiments, the above composition can spontaneously form an oii-in-water emulsion upon dilution with water containing media or body .fluid.
In some embodiments, th ratio of aa tioxidant CB2 modulator, such, as bat not limited to 4~0-mei¾ylhono¾i,ol (Mil), is from 40: i to 2500:1 w/w, I some embodiments* the a»ttoxidant/CB2 modulator is from 40: 1 to 80: 1 w/w, in some embodiments, the ratio of ariiioxid¾ni/CB2 modulator is from 40:1 to 100:1 w/w. In some embodiments, the ratio of amioxidani/CB2 modalator is from 100:1 to 500: /w. In some embodiments, the ratio of •anti xtdaat/C-82 modulator is from 500: Ϊ to 1000:1 w/w. In some embodiments, the ratio of antioxidant CB2 modulator is from 1000:1 to J 300: 1. w/w in so e embodiments, the ratio of an ioxidant CB2 modulator is from 1500: 1 to 2000·: I w/w. in some embodiments, the ratio of anti©x.idaitt/CB2 modulator is from 2000.1 to 2500.. I w/w. in some mbodim nt, the ra tio of antl0xidaat CB2 modulator is from 3:1. to 5: 1 w/w. in some embodiments, the ratio of antioxidanf/CB2 modulator is from 40: 1 to 100:1 w/w.. In some embodiments,, the ratio of .a»tioxidaiit CB2 modulator is from 40:1 to 50: 1 w/w. In some embodiments, the ratio of a.iitio¾;idant/CB2 modulator i from 40:1 to 60:1 w/w. In some embodiments, th ratio of antioxidani7CB2 modulator is tow 40:1 to 80 1 w/w. In some embodiments, the ratio of aniioxidant/CB2 modulator is from 60: 1 to 500:1 /w. In some embodiments, the ratio of aiHiosidant/CB2 .modulator is from 80: 1 to 500: 1 w/w. I some embodiments, the ratio of ariiioxidam/CB2 modulator is from 1.00:1 to 500:1. w/w. In some embodiments; the ratio of antioxidaiu7CB2 modulator i from 150: 1 to 250:1 w/w. In some embodiments, the ratio of aniiox.klani/CB2 modulator is from 150: 1 to 280: 1 w/w. In some embodiments, the ratio of a:ntioxidani/CB2 modulator is from 150: 1 to 300:1 w/w. in some embodiments, the ratio of antioxidant/CB2 modulator is from 200: 1 to 500: 1 w/w. in some embodiments, the ratio of ant:ioxidarii/CB2 modulator i from 300:1 to 500:1 w/w. In some -embodiments,, '.the ratio of aniioxidani/CB2 modulator is from 400: 1 to 500:1 w/w. In some embodiments, the ratio of amioxida»i/CB2 modulator is frona 600: 1 to 1000:1 w/w. In some embodiments, the ratio of aMioxidant/CB2 modulator is .from. 700: 1 to 1.000: 1 w/w. In some embodiments, the rati of antioxidant/CB2 modulator is from 800: i to 1000:1 /w. In some embodiments, .the- ratio of aniioxi ant/CB2 modulator is from 900: 1 to 1000: 1 w/w. In some embodiments, th ratio of antioxidani/CB2 modulator is from 1000: 1 to 1200:1 w/w.. in some embodiments, the ratio of arjiioxidant/CB2 modulator is from 1000:1 to 1300: 1 w/w. I some embodim nt the ratio of an&oxidam/CBS modulator is from 1000: 1 to 1400: 1 w/w. In some embodiments, the■ .ratio of aniioxidai.tt/CB2 modulator is trom 1200:1 to 1400: 1 w/w. hi some embod-unenfcs, the ratio of attttoxida»t CB2 modulator is trom 1200; ! to 1500: 1 w/w. in some embodiments, the ratio of aniioxidaiit/CB2 modulator is f om. 1300:1 to ! 500: 1 w/w. In. some embodiments, the ratio of a»tioxidani CB2 modulator is from 1400: 1 to 1.500: 1 w/w. In some embodiments, the ratio of antioxidani/CB2 modulator is from 1500: 1 to 1600: 1 w/w. In some embodiments,, th -ratio -of antioxidant/CBS modulator is from 1500: 1 to 1700: 1 w/w. 1» some embodiments, the- ratio of - antioxidant/CBS modulator is from 1500: 1 to 1800: 1 w/w. in some embodiments, 'the ratio of ai.«ioxidam/C'B2 modulator is from 1500: 1 to 1700 1 w/w. In. some embodiments, the ratio of antioxida-nt CB2 modulator is from 1500:1 to 1800: 1 w/w. In- some embodiments, the ratio of ant:iox.idaitt/CB2 modulator is from 1500: 1 to 1900: 1 w/w. in some embodiments, the ratio of anti0xida»t/CB2 moduiaior is from 1500 1 to 2000: 1 w/w. 1» some embodiments, the ratio of antioxidant/CB2 modulator is front; 1600:1 to 2000: 1 w/w. In. some- embodiments* the ratio of a ioxidartt/CB2 modulator is from 1700: 1 to 2000: 1 w/w. In. some embodiments, the ratio of auiio. ;idaiii/CB2 modulator is from 1 BOO; 1 to 2000: 1 w/w. In some embodiments, the ratio of autioxidarU/CB2 modulator is from 2000; 1 to 2200; 1 w/w. in some embodiments, the ratio of antioxidant CB2 modulator is from 2000:1 to 2300 1 w/w. In some embodiments, the ratio of aiH!0xkiaut/ 'B2 modulator is from 2000; ! to 2400: 1. w/w. In some embodiments, the ratio of antioxidant/CB2 modulator is from 2000: 1 to 2500: 1 w/w. In some embodiments, the ratio of aniioxidaiu7CB2 modulator is from 2100;! to 2500:1 w/w. In some embodiments, the ratio of atitioxidaat CB2 modulator is from 2200: 1 to 2500: 1 w/w. In some embodiments, the ratio of antk>xidant/CB2 modulator is from 2300 1 to 2500: 1 w/w. In some embodiments, the ratio of antioxidam/CB2 modulator is from 2400.1 to 2500;! w/w. in some embodiments,, the above composition cart spon aneo sly form an oil-in- water emulsion upon dilution with wate containing media o body fluid.
The composition of the present disclosure can be formulated for oral, topical, intranasal, vagina! or rectal administratiou.
The oral composition of this disclosure can be formulated as a capsule, liquid composition for oral delivery, suspension, solution, emulsion or syrup.
The topical compositio of this disclosure can be formulated as a transdermal gel, cream, patch or topical spray. The intranasal composition of this disclosure can be formulated as a nasal spray.
In some embodiments,, there Is provided a composition of he present disclosure wherein the at least one C82 receptor modulator is a CB2 selective agonist and is beta caryophyllene (BCP) in substantially pure form as sole active agent and the mental disorder is schizophreni of 5 all types, onset at any age- In another embodiment, the at least one CB2 receptor selective agonist in substantially pure form i beta caryophyiiene (BCP), the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidon p&lroitate, aripiprazole, uetiapine, CB'D and its analogs, THCV, brexpip.ra ole and cO-mbinations thereof and the mental disorder is 10 schizophrenia. The BCP in the above composition comprises either one of the two BCP isomers E-BCP and Z-BCP wherein in. substantiall pure form or■mixtures thereof and is substantially free of BCP oxide and a-hu.mulene.
in yet another embodiment, tire BCP in the above composition comprises substantially pure isomer E~ CP and is substantially tree of BCP oxide and a-hiiiBiiiene.
15 Ta a further emhodiment, the BCP in the above compositio comprises substantially pare isomer Z-BCP and is substantially free of BCP oxide and a-humuleoe.
According to some embodiments, there is provided a method of treatment of a mental disorder in patient in .need thereof, by administration of a composition, comprising a therapeiiticalSy effecti ve amount of at least one CB2 receptor modulator in essentially pure form 10 and optionally a therapeutically elective amount of at least one antipsychotic agent in a self- emulsifying vehicle. The at least, one CB2 receptor modulator in. the above method of treatment is selected from the group consisting of at least one CB2 receptor agonist or partial agonist, a least one CB2 receptor antagonist or inverse agonist, at least one CB2 receptor antagonist or inverse agonist which is also a selective estrogen receptor modulator (SERM), at least one type IS of CB2 receptor allosteric modulator and combi ations thereof.
In some embodiments, the CS2 receptor selective agonist or partial agonist in the above method of treatment i selected horn the group comprising BCP, O!J-308, HU-433, BU-910,
CB 65, GP la, GP 2a, GW 405833, JWH 015, JWB 133, Al VI 1241 , . 1-759,656, L7S9,6 3, iV!DA. 1 , SER 601 , BME-1 0, N-alkyiamide, rutarnarin, diindolylmethane (DIM) and i.O analogs, derivatives and combinations thereof. In some embodiments, the at least one antipsychotic- agent in the above method of treatment is selected from the group consisting of one or more of a buiyrophenone type antipsychotic agent selected from the group consisting of haloperidol. droperidol, benperidol, Irifjupcrido!, nre!perone, !enperone, azaperone, domperidone, hutyrophenone, llisanisone, penfluridol, ptpamperone, spiperone, nonaperone, hromperidoi and timiperone. a dipheny!butyipiperidine type antipsychotic agent selected from the grou consisting of hfspuiiene. penfluridol, piraozi.de». clopiraozide, r iispirilene, penfluridol, a pbenothiazine type antipsychotic acid agent selected from the group consisting of acepromazine, ehlorpromazine, cyamerna lne, dkyra ine, fiuphenazine, !evomeprotnazine, mesoridazine, pera ine, perieyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyi, thioproperazine, thioridazine and trifluoperazine and i if!upr njazine, a ihioxanthene type antipsychotic: agent selected from, the group consisting of chlorprothixene, elopenthixol, ftupentixol, thiothixene and zucJopenthixo! and/or an atypical antipsychotic agent including, but not limited to one or more of a atypical antipsychotic agent usually belonging to tire 13 antagonist/inverse agonist, 5-ΗΠΓ2Α antagonist'lnverse agonist types selected, .from, the group consisting of amisulprlde, amoxapine, asenapirie, cariprazine, clozapine, blonanserin, iioperidone, h rasidone, nielperone, nemonapride, olanzapine, paliperidone, paliperidone palmitate. perosptrone, quefiapiue, iemoxipride, risperidone, seri indole, sultopride, irimipramine, ziprasidone, ΓΠ-007, pimavanserin (ACP-103; 5-HT2A antagonist), and combinations thereof and/or an atypical antipsychotic- agent including, but not limited to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types' selected from, the .group consisting aiipiprazole and. its metabolites OPC-14857, DM-1458, DM- 1451 , DM- 1452, DM- 1454 and DCPP, brexpiprazole and P5063 (RP5000) and combinations thereof .and/or a eannabinoid exhibiting antipsychotic activity selected from the group consisting of tetraln^drocannabivati.n (THCY CB I antagonist, CB2 receptor partial agonist), cannahi.diof (CBP—€Bi/CB2/GPR55/ABn-CBD antagonist/inhibitor) and cannabigerol {C8C3™~ CB1 CB2 partial agonist) and combinations thereof.
In some embodiments, the mental disorder in the above method of treatment is selected from the group consisting -of schizophrenia, schizoaffective disorder, bipolar disorde I and il, unipolar disorder,, multiple personality disorder, psychotic disorders, depression, psychotic depression, depressive disorders, major depressive disorder, Tourette's syndrome, tic disorders. epilepsy, anxiety disorders, autistic spectrum, disorder, enuresis, addiction, withdrawal symptoms associa ed with addiction, Asperger sy a ome, oppositional defiant disorder, behavioral disturbance, agitation, psychosis/agitation associated with Alzheimer's disease, psychosis associated with Partisan's disease, personality disorders, borderline personality disorder, avoidant personality disorder, atte ion-deficit hyperactive disorder (ADHD, ADD, MD), mania, dementia, anorexia, anorexia nervosa, -anxiety, generalized anxiety disorder, social anxiety disorder, body -demographic disorder, obsessive compulsive disorder, paranoid disorder, nightmares, agitation, post-traumatic stress disorder (PTSD), severe mood dysregulation, menial disorder such as depression or anxiety that leads to metabolic diseases such as obesity and depression associated with any of the above clinical conditions. Said schizophrenia is selected, from the group consisting of paranoid schizophrenia, disorganized schizophrenia, undifferentiated schizophrenia, catatonic schizophrenia and residual schizophrenia.
Said schizophrenia in the above method of treattiient ea be selected from adult schizophrenia and pediatric schizophrenia and .may take the form of a negative symptom of schizophreni ., a positi ve symptom. f schizophrenia and both.
In some embodiments, there is provided a method oftreattaeat of a mental, disorder ia a patient in need thereof with a composition of the present disclosure, wherein the mental disorder is schizophrenia and. the CB2 receptor selective agonist is beta caryoph llen (BCP) as sole active agent.
In some embodiments, there is provided a method of treatment of a mental disorder in ¾ patient i need thereof with a compositio of the present disclosure, wherein the mental disorder is schizophrenia, the CB2 receptor selective agonist is BCP and. tire at least one antipsychotic agent is selected from the grou consisting of risperidone, paiiperidone, paliperidone palniitate, aripiprazoie, qnetiapirie, CBD and its analogs, THCV, brexpiprazo!e and combinations thereof In some embodiments, there is provided a method of treatment of a mental disorder in a patient in need thereof with the composition of the present disclosure, wherein the composition comprises a therapeutically effective amount of BCP as sol active agent in a self-emulsifying: vehicle.
According, to some embodiments, there is provided, a method of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure, wherein said composition comprises a therapeutically effective amount of at least one CBS receptor selective agonist in essentially pure form and optionally a therapeutically effective- amount of at least one antipsychotic agent i a self-emulsifying- vehicle, .wherein the comp sitio is administered to a patient in need thereof front about once a month to about once .every two months, to about once every three months-, -to about once every -four months, to about once every five months, -to about once every si .months, to about once per week, twice pet week, 3 times per week, 4 times per •week, 5 times per week, 6 times per week, once per day, twice .per day or 3 times per day.
According to another embodiment, there is provided a method of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure, wherein said composition c m ris s a therapeutically effective amount of at least one CB2 receptor selective. agonist in essentially pure form and optionally a therapeutically effective amount of at least one antipsychotic agent «r a sel.f~ei«ulsifyi.n vehicle and is administered twice per week to a patient in need thereof. Similarly, there is provided a- method of treatment of mental disorder in a patient in need thereof ith the composition of the present disclosure, wherein said composition comprises a therapeutically effective amount of at least one CB2 receptor selective agonist In essentially pure form, and optionally it therapeutically effective amount of at least one antipsychotic agent in self-emulsifying vehicle, and is administered three times a week to a patient in need thereo
According to another embodiment, there is provided a method, of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure wherein the therapeutically effective amount of the composition comprising BCP as sole active and a self- emulsifying vehicle is administered to a patient in need thereof from about once a month, to about once every two months, to about once every three months, to about once every four months, to about once every five months, to about once every six months, to about once per week, twice per week, 3 times per week,.4 time per week, 5 times per week, 6 times per week, onc pe day, twice per day, 3 times per da or 4 times per day .
According to an embodiment, there is provided a method of treatment o a mental disorder in a patient in need thereof with, a composition of the present disclosure. 'Wherein th therapeutically effective amount of the composition comprisin BCP as sole active and a setf- emuSsiiymg vehicle is administered twice per week or three- time per week to a patient in need thereof In an■■embodiment, there is provided a method of treatment of a mental disorder in a patient in need thereof w th a composition, in an mode of ministration, including but no limited to administration in a slow-release/kmg-aetive formulations given on a daily basis, of the present disclosure wherein the average daily amount of said BCP or iiU-308 or 4-0- me hylhonokiol (MH) administered is in a range selected from the group consisting of 0.1-1 nig, 1 -10 ma, 10-20 m¾, 20-50 ma, 50-100 ma, 100-200 me or 200-iO O me, accord iim to the patient's age and composition's effectiveness.
In an embodiment, there is provided a method of treatment of a mental disorder in a patient in need thereof with a elayed-reiease composition (such as compositions- for a slow- release, slow-acting form of medication prepared as a capsul or a depot injection given for example but not limited b intramuscular injection, which are administrated every 1 week or once a month to up to every- six months) of the present disclosure wherein the average jamou-nt of a single administration of said BCP administered is in a tange selected from, the group consistin of 0.1 -10 rng, 10-100 mg, 100-200 mg, 200-300 rag, 300-400 mg, 500-600 nig, 600-700 rrsg, 7OO-S0O mg or 800-1000 mg, 1000-1500 mg, 1000-2000 g? 2000-3000 mg, according to patient's age and composition's effectiveness. According to an embodiment, there is provided a method of treatment of a mental disorder in a patient in need thereof with composition of the present disclosure, wherein said at least one antipsychotic agent is co-administered in a single dosage form together with said CB2 receptor modulator.
According: to another embodiment there is provided a method of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure,., wherein-said at least one antipsychotic agent is co-administered sequentially in dosage form separate from said €82 receptor selective agonist wherein in either order.
In some embodiments, there is provided the us of a therapeutically effective amount -o at least one CB2 receptor modulator in substantiall pure .form i a seif-emnSsifying vehicle and optionally of a therapeutically effective- amount of at least one antipsychotic agent in. the mairtifacture of a composition for treating a mental disorder in a subject in need thereof.
In some embodiments, there is provided: a method of treatment of mental disorder in a patient in need thereof with composition of this disclosure, wherein the at least one CB2 receptor selecti e agonist in substantially pure form is beta caryophyllene (BCP) as sole active agent and the mental disorder is bi-po!ar disorder, onset at any age. In some embodiments, there is provided a method of treatment of a mental disorder in a patien t in need thereof with a composition of the present disclosure wherein the at least, one ( B2 receptor seleciive agonist in swbstantiall pure form is beta caryophyilene (BCP) as sole active agent and the rnental disorder is depression, onset at any age.
5 According to some embodiments, there is provided a method of treatment of a mental disorder in a patient in need thereof with a composition of the present disclosure, wherein the at least one CB2 selective receptor agonist in substantially pure form is beta caryophyilene ί BCP J as sole acti ve agent and the mental disorder is arsxietv, onset at any age.
In some embodiments;, there is provided a stable self-effiiilsifying composition for
10 treatment of mental disorders in a patient in need thereof, comprising a therapeutically effecti ve amount of at least one CB2 recepto .modulator, a self-emidsrfying vehicle and optionally a therapeutically -effective amount of at least one additional active agent selected from the -group consisting of an antipsychotic agent and combinations thereof, wherein the active agents are substantially solubiiized
15 The above self-emulsifying composition, upon dilution with water containing media, or body fluid spontaneously forms an. oil-in- water emulsion.
In some embodiments, there is provided the above self-enmlsifymg composition, wherein the at least one CB2 receptor modulator is selected from the grou consisting of at least one CB2 receptor agonist or partial agonist, at least one CB2 receptor antagonist or inverse agonist, at Ϊ0 least one CB2 recepto antagonist or inverse agonist winch is also a selective estrogen receptor modulator (SEEM), at least one type of CB2 receptor allosteric modulator and combinations thereof
In some embodiments, the at least one CB2 receptor agonist or partial agonist in the above composition is selected from the group consisting of BCP, BU-308, HU-433, HU~910, MU-914,
IS OB 65, GP la, GP 2a, GW 405833, JWH 01 , JWH 133, AMI 241, L759,656, 1,-759,633, MDA.
19, SER 601 , BML- 190, -alkylaniide, rofamarin, diiodoiyl ethane (DIM), cannahinor fP S- 21 1 ,375), 2-arac :donoylglyceroi, anandamide, CP55940, ddta-9-TBC, W1N55212¾ etJ- 10, cannabigerol (CBG), i i-liydroxy-A9-tetrahyc!rocannabinol (l l-QH-THC), deIta-8-THC, 1 1 - OM-clelta-S-THCV, ajnlernic acid, delta-S-THC-! i-oic acid, cannabinol (CBN), caimabilactones, i0 AMI 71.4, AM 1710; analogs thereof, derivatives thereof, metabolites thereof and combinations thereof In some erabodiraents, the at least one CB2 receptor antagonist or inverse agonist is Selected from the grou consisting of AM630, JTB-9Q7, $R J 44528, CQR170, 4-0- ntethylhonokiol, GS 12021 (4-Q-methyihonokiol analogue), eatHiabiaol, 01238, 01184., eannabidiol (CBD) analogs thereof, derivatives thereof and combinations thereof.
5 In some embodiments, the at least one CB2 receptor a!losteric modulator is selected from the group consisting of dihydrogamb gic acid, garcinolic acid, (-)-5'-d.iinetbyi]ieptyl-cannabidioi (DMH-CBD) and analogs thereof, derivatives thereof and combinations thereof.
In some embodiments, the at least one C82 receptor modulator which is also a selective estrogen receptor modulato (SB¾M) is selected from the group consistin of raloxifene.
10 ba edoxiien, lasofoxifene, tamoxifen, afimoxifene, arzoxifene, ormeloxifene, toremi ene, ospeinifene. analogs thereof, derivati ve thereof and combinations thereo
In some embodiments, the at least one antipsychotic agent is selected from the grou consisting of one or more of a botyroph tione type antipsychotic agent selected from the grou consisting of haloperidoi, droperidoL benperidol trifluperidol., nielperone, lenperdne, azaperone.
I S donipendone, binyrophenone. fluanisone, penfluridol, pipa perone, spiperone* nonaperene, bromperidoi and timiperone, a diphemdbutylpi.peridine type antipsychotic agent .selected from: the group consisting of tospirilene, penfluridol, pimozide, clopmiozide, fluspirilene, penfluridol, a phenot nazine type antipsychotic acid agent selected front the grou consisting of acepromazine, chlorpromazine, cyametnazine, dixyrazine, fluphenazine, levohieprbniazme,
10 inesoridazine, petazine, perieyazine, perphenazine, pipotiaznie, prochlorperazine, promazine, proinetbazine, prothipendyh thioproperazine, thioridazine and trifluoperazine and irjftupromaxine, a thioxanthene type antipsychotic agent selected, from the group consisting of chlorprothtxene, clopenthixol, f upentixol, thiothixene and zuclopenthixol and/or an atypical antipsychotic agent including, but not limited to one or more of ao atypical antipsychotic agent
IS usually belonging to the D2 antagonist/inverse agonist, 5-HT2A antagonist/inverse agonist types selected from the group consisting of araisulpride, amoxapine, asenapine, cariprazine, clozapine, blonanserin, iloperidon , Iniasidone, meiperone, ftemonapri e, olanzapine, pali per i done , paliperidone palmitate, perospirone, qaefiapine, remoxipride, risperidone, sertindole, suitopride, trirmpramine., ziprasidone, ΓΤΙ-007, pimavanserin (ACP-103; 5-HT2A antagonist), and i0 combinations thereof, and/or an atypical, antipsychotic agent including, but not limiied to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected from the group consisting a ipiprazole and its metabolites OFC-34857, DM4458, DM- 1451 , DM- 1452, DM- 1454 and DCPP, re piprazo!e and R P5063 (RP5000) and combinations thereof and/or a cannabinoid, exhibiting antipsychotic activity selected from the group consisting of ietiahydrocanuabivarln (TH V— CBl antagonist, CB2 receptor partial agonist), camiabidio! .(CBD CB3 /CB2/GPli55/ABn-CBD antagonist/inhibitor) and cannabigerol (CBG CB1/CB2 partial agonist), and their analogs and derivatives and combinations thereof.
In some embodiments, the stable self-e uisiiymg drug delivery composition of thi invention comprises at least one oil, at least one surfactant HLB<9, at least one surfactant 11LB> 13, at least one eo-siaiactant, at least one antioxidant and'or free-radical scavenger, at least one CB2 receptor modulator and optionally an antipsychotic agent, and combinations thereof'
In some embodiments, the stable self-emul ify tog drug delivery coniposition of this invention comprises:
from about 1 % w/w to abou 50% w/w of a oil selected from the group consistin of medium chain triglycerides., propylene glycol, dicapri!ate/dicaprate, medium, chain mono- and di giycerides,, acetylated. mono-and digiycerides, sesame oil and olive oil and combinations thereof,
from about 20% w/ to about 50% w/w of surfactant HLB 9 selected from the group consisting of ojeoyl polyoxyl-6 giycerides, Hnoieyl |)oi.yoxyi-6 giycerides (20-40%), Poly sorbate 85 (Tween-85) polyoxyethylene (20-40%), sorbitan trioleate (5-15%), Span-80 (sorbitan monooleate) (5-25%), poly gl eery 1-3 dioleate (15-35%) and glycerin mono!tooleate (10-35%), Polysorbate SO (Tween-80) polyoxyethylene (20-40%), Poly sor ate 60 (Tween-60) polyoxyethylene (20-40%),
from about 5% w/w to about 50 % w/w of a surfactant BLB>! 3 selected from the grou consisting of polyoxyiated castor oil (5-40%), PEG 40 hydrogenated casto oil, PEG-15 hydroxy sieMaie (5-25%) and caprylocaproyl poiyox.yl.-8 giycerides (10-20%).
from about 5% w/w to about 25 % w/w of surfactant HLB>13 selected1 from, the group consisting of PEG-20 sorbiUiii mo iosiearate, PBG~20 sorbitan monoo!eaie (5-25%) and PEG 4 siearate (5-25%),
from about 0.5% w/w to about 15 % w/w of co-surfactant selected from, the grou consisting of any lecithin (2- 15%w/w):, soy lecithin (>=75 phosphatidylcholine in oil, 1 -10 w/w), so lecithin- PC content 50% (2-15%w/w), egg lecithin B-60 or 0 -5%w7w) and.
Figure imgf000053_0001
from about 0. % w/w to about 5 % w/w of an antioxidant or free .radical scavenger selected from the .group consisting of d-aipha-tocopherol (1-10% w/w), di-a!phatocopheroi (2-1.5% w/w).
5 dl-alpha-ioeopheryi acetate (2- l 5%w/w), mixed tocopherols (alpha., beta, gam 1 -10% w/w), d-aipha~tocopheryl acetate (2-15%w/w), hutylated hydroxyanisole (B iA, O.Qi-0,5%w/w), ioeophersolan CTPGS, tocopherol PEG ester succinate) (2- 1 %w/w) and combinations thereof, from about 1 % w/ to about 10 % w w of ethyl alcohol,
from about i% w/w to about 20% w/w of at least one CB2 receptor modulator in 10 substantially pure form and. optionally from: about ft, 1% w/w to about 5% w/w of at least one antips choti c agent
In an embodiment, there are provided stable self-emulsifying drug delivery compositions, comprising;
from about 30% w/w to about 50% w/w eaprie/caprylic triglycerides
I S from about .30% w/w to about 50% w/w oleoyi polyoxyi-6 glycendes
from about 5% w/w to aboat 35 % w/w pol oxylated castor oil
from about 7% w/w to about 15 % w/w PBG-20 sorbitan monostearate
from about 2% w/w to about 10 % w/w soy lecithin (75% phosphatidylcholine in .oil) from about i% w/w to about 15 % w/w d-alph tocopherol and/or tocopherol acetate 10 from about 1% w/w to about 20% w/w of at least one CB receptor modulator and
optionally
from about 0.1% w/w to about 5% w/w of at least one an t ipsychotic agen t.
In another embodiment, there is provided stable self-emulsifying drug delivery composition of this invention, wherein the at least one CB2 receptor agonist is beta- 15 caryophyilene (BCP) as sole active agent in a self-emulsifying vehicle.
In yet another embodiment, there is provided a stable .self-emulsifying drag delivery composition of this invention., wherein the at least ne CB2 receptor agonist is beta- caryophyilene (BCP) and the at. least one antipsychotic agent is selected from the grou consisting of risperidone, pa!iperidone, palipcridone palnuiate, atipiprazole, quetiapine, CBD, i0 i'HCV, CBG, brexpiprazole their derivatives and analogs and combinations thereof. According to some embodiments, there is provided a composition o th s invention,: wherein the at least- ne CB2..receptor agonist is beta-caiyophylierie (BCP) and the. at least one antipsychotic agent is selected from the grou consistin of 10-98% CBD, 10-98% THCV, 10-
98% CBG and combinations thereof.
I another embodiment, there is provided a stable self-emulsifying drug delivery composition of this invention, wherein the at least one CB2 '.receptor agonist is beta- caryophylleiie (BCP) as sole active agent in a self-emulsifying vehicle arid the mental disorder is schizophrenia of ail types, onset at any age.
According to an embodiment,, there is provided a composition, of this invention, wherei the at least one CB2 receptor agonist is BCP and the at least one additional active agent is selected fr m the group consisting of a!pha-hnnjulene, copaeae, eogenol, δ-eadinene, BCP oxide and combinations thereof
According to another emb diment* there is provided a composition of this invention, i which, said BCP comprises from l%w/w to 15%w/w alpha-himitilene and from 0, 1 %-2%w/w each of copaene, eugenoi, 5~cadinene; BCP oxide, derivatives thereof analogs thereof and combinations thereof
In some embodiments, there is provided a composition of this invention, wherein the at least, one CB2 recepto selective agonist in substantially pure form is beta caryophyllene (BCP), the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidone palnritate, aripiprazole, quetiapine, CBD, THCV CBG, hrexpiprazole; derivatives thereof analogs thereof and combinations thereof and the menial disorder is schizophrenia.
In .some other embodiments, there is provided a composition of an of claims 12- 18, wherein said BCP comprises either one of the two BCP isomers E-BCP and Z-BCP in substantiall pure form or mixtures thereof and wherein substan iaily free of BCP oxide and a.~ humulene.
According to an embodiment., there is provided a composition of this invention, wherein said BCP comprises substantially the isomer E-BCP and is optionall free of BCP oxide and a- hismnSene, According to another embodiment, there is provided a composition of this invention, wherein said BCP comprises the snbsiattiially pure isomer Z-BCP and is optionally free of BCP oxide and a-k nitileoe.
In some embodiments there is provided, a composition of this invention, wherein the at least one€B2 receptor agonist is [( 1 Rs2R,5R}-2^2,0-dimethox I ]-
7,7~d nefh l~4- bicyclo[3, 1.1 Jbept-3-env ] methanol (HU-30S) as sole active agent.
In some other embodiments there is provided a composition of this invention, wherein the • at least one CB2 receptor agonist is HU-3Q8 and the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidone palmitate, aripiprazole, quetiapine, CBD, THCV, CBG, brexpiprazoie; derivatives thereof analog thereof and combinations thereof.
According to some embodiments, there is provided a composition of this disclosure, wherein the at least one CB2 receptor inverse agonist is 4-0~methylhonokioI (MH), and the at least one .additional active agent is selected from the group consisting of eiigenol, caryophylien oxide and combinations thereof.
In some embodiments;, there is provided a composition of this inventio.i wherein: the at least one CB2 receptor selective agonist is 4-0-niethylhonokiol as sole active agent and the mental disorders are tic disorders, repetiti ve beha vior disorders of al l types, onset at any age:.
In some embodiments, the stable composition of this disclosure is stabilized by addition of an antioxidant, a free-radical scavenger or a combination thereof
In an embodiment, there is provided a composition of the instant disclosure, wherei formulated for oral, parenteral, topical, intranasal, v gi al o rectal administration.
The above oral composition can be formulated as a spray, inhalation, capsule, suspension, solution, emulsion or syrup,
The above topical composition can be f rmulate as a transdermal gel, cream, patch or topical spray.
The above intranasal composition can be■ f rmulated a a nasal spray.
In some embodiments, there is provided a method of treatment of a mental disorder in a patient in need thereof, by administration of a composition of this disclosure, comprising therapeuticall effective amount of at least one CB2 receptor modulator, a self-emulsifying vehicle and optionally a therapeutically effective■ amount of at least one antipsychotic agent and eoinbin.ats.oriS thereof.
In another embodiment, there is provided method of treatment of a mental disorder in a patient in need thereof, by' administration of a composition of this invention, comprising a therapeutically effective amount of BCP and from l ¾w/w to 15% w/w aipha-huniulene and from 0J%w/w-3% w/w each of copaene, eugenol, δ-cadmene, BCP oxide, caryophyllene oxide and their derivatives and analogs and combinations thereof, a self-emulsifyittg vehicle and optionally a therapeutically effecti ve amount of at least one antipsychotic agent and combination thereof
According to an embodiment, there is provided a method of treatment of mental disorder in a patient in .need thereof, wherein the mental, disorder is schizophrenia, by administration of a composition comprising a therapeutically effective amount of BCP and from 1% to 15% alpha- bumulene and itoni 0J %~2% each, of copaene, eugenol, §~cadinene, BCP xide, caryophyllene oxide and their derivatives and analogs and combinations thereof, a self-emulsifying vehicle and Optionally therapeutically effective amount of either at least one antipsychotic agent an combinatio thereof, the CB2 receptor selective agonist is beta caryophyllene (BCP) and optionally at least one additional active agent selected from the group consisting of alpha- humuSene, copaene, eugenol δ-eadiuene, BCP oxide arid combinations thereof,
According to another embodiment, there is provided method of treatment of a mental disorder in a patient in need thereof, wherein the mental disorder is hi~polar disorder, onset at; any age, by administration of a compositio comprising at least one CB2 receptor selective agonist, wbereiii the at least one CB2 receptor selective agonist is beta caryophyllene (BCP) -and optionally at least one additional active agent selected from the group consisting of alpha- humulene, copaene, eugenol, δ-cadinene, BCP oxide and combinations thereof
Accordin to another embodiment, there is provided a method, of treatment of a .mental disorder in a patient in need thereof wherein the mental disorder is depression, onset at any age by administration of a composi tion comprising at least one CB2 receptor se lecti ve agon ist which is beta caryophyllene (BCP) and. optionally at least one additional active agent alpha-humulene, copaene, eugenol, δ-cadinene, BCP oxide and combinations thereof.
According to another embodiment, there is provided a method of treatment of a mental disorder in patient in need thereof, wherein the mental disorder is anxiety, onset at any age, by administration of a. composition comprising at least one CB2 receptor selective agonist which is beta catyophylkne (BCP) a sole active agent ami optionally at least one agent is selected iro the group consistin of alpha-huniulene, copaene, eugenol, δ-eadmene, BCP oxide and com inations thereof"
In an embodiment, there is provided a method of■treatment, of a mental disorder in a patient in need thereof, by administration of composition comprising a therapeutically effective amount of BCP and at least one antipsychotic agent selected from the group consisting of risperidone, pa!iperidone, paiiperidone paimitate, aripiprazoie, qnetiapine, CBD anil its derivatives and analogs, THCV, 'CBGV bi»xpip*¾20¼ and combinations thereof
In another embodiment, there is provided a method of treatment of a mental disorder in a paiieni in need thereof by administration, of a composition of this invention, Comprising at least one CB2 receptor modulator selected from the group consisting of at least one CB2 receptor agonist or partial-agonist, at least one CB2 receptor antagonist of inverse agonist, at least one CB2 rece tor antagon st or inverse agonist which is also a selective estrogen receptor modulator (SE M), at least one type of CB'2 receptor allosteric modulator and combinations thereof
in another embodiment, there is provided a method of treatment of a .mental disorder in a patient in need, thereof by administration of a composition of this invention, comprising a CB2 receptor selective agonist or partial: agonist selected from the group comprising BCP, B.U-308, Hl 433, HU 10, HU-914, CB 65, GP l a;, GP 2a, GW 405833, iWH 015, JWH 133, AM1241, L759,656, 1,759,633, MDA .1 , SEE 601 , BML-1 0, N~alkyl.arm e, mtaniatin, diindo!yimethane (DIM) and analogs, CBG, 1 3- ydroxy-A9-tetrahydmcannahinol (1.!-OH-mC), delta-8- HC, l. l~OH-de!ta-8~THCV, ajalenne acid, deIta~8-THC~i i-oic acid, cannabi.no I. cannabilacrones, AM 1714, AM I 710; and analogs, derivatives and combinations thereof
In yet -another' embodiment, there is provided a method of treatment of a mental disorder i a patient in need thereof, b administration of a composition of this invention, comprising CB2 receptor antagonist or inverse agonist selected from the group consisting of AM630, JTE-907, SR144528, ( )RI 705 4~0-.methylhonokioi, GS 1.202.1 (4-0-met.hylhottoktoi analog), cannabinoi, 01238, 01 184, cannabidiol (CBD); and analogs, derivatives or combinations thereof;
In some embodiments, there is provided a. method of treatment of this disclosure, wherei the at least one antipsychotic agent is selected from the group consisting of on or more of a huiyrophenone type antipsychotic agent selected from the group consisting of haloperidol , droperidol, benperidoL trifluperidol, me.l erone, lenperone, azaperone, domperidone, 'huty phenone,
Figure imgf000058_0001
penfluridol, pipamperone, spiperone, uonaperone, brompeiidol and timiperone, a diphenylbutyipiperidine type antipsychotic agent selected from the grou consisting of iuspirilene, penfluridol, pimozi.de, clopimozide, fliispiritene, -penfluridol, a phenothiaaine type antipsychotic acid agent selected from the group consisting of aceproraazine, ehlor romazme, cyanieniazine, dixyxazftie, fiuphenazine, levcmieproniazme, rnesondazine, perazme, perkyazine, perpheimzine, pipotiazine, prochlorperazine, promazine, prometha ine, proihipendyl, thioproperazine, thioridazine and trifluoperazine and tritliipromazine, a thioxanfhene type antipsychotic agent selected fr m the group consisting of chlorprothixene, clopenthixol, flupentixol, thiothixene and ziic!openthixol and/or an atypical antipsychotic agent including, but not limited to one or more of an atypical, antipsychotic agent usually belonging to the D2 autagouist 'in verse agonist, 5-HT2A antagonist/inverse agonist types selected from the group consisting of amisolpride, arnoxapine, asenapiue, cariprazine, clozapine, blonanserin, iloperidone, lurasidone, elperone, nemonap.ride} olanzapine, paiiperidone, paliperidorte patmitate, perospirone, iietiapme, remcndpride, risperidone, sertindoie, suitopride, trimipramine, ziprasidone, IT1-Q07, pimavanserm (AO .03; 5-HT2A arviagomst), and combinations thereof, and/or an atypical antipsychotic agent including, but not limited to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected from the group consisting aripipfazole and its metabolites OPG- 14857, DM- 145-8. DM- 1451, DM- 1452, DM- .1454 and DCPP, brexpiprazole and RP5063 ( P5000) and combination thereo and/or a cannaiiinoid exhibiting antipsychotic activity selected from the group- consisting, of tetrahydrocfuiiiabivarin (THCV— CB1, antagonist, CB2 receptor partial onis :), ca sahidiol
(CBD B1./CB2/GPR55 ABN-€BD antagonist/inhibitor) and eannabigerol (€BG -CB 1/CB2 partial agonist): analogs thereof, derivatives thereof and combinations thereof.
In another embodiment, there is provided a method of treatment of a mental disorder in a patient in need thereof, b administration of a composition of this invention, wherein the disease r mental disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, bipolar disorder I and II, unipolar disorder, multiple- personality disorder, psychotic disorders, depression, psychotic depression, depressive disorders, major depressive disorder, stereotypic: movement disorder, autism spectrum disorders, obsessive -compulsive disorde (O D), bacterial-induced tic disorder, pediatric autoimmune- neuropsychiatric disorders associated with streptococcal infections (PANDAS), chorea (Sydesiham's chore (SC), chorea .minor, chord ravid rum,, drug-kvduced chorea), drug-induced repetitive behaviors, ■akaihisia, dyskinesias, Wernicke-Korsakoff syndrome, Touretie' s syndrome, tic disorders, epilepsy, anxiet disorders, autistic spectrum disorder, enuresis, addiction, withdrawal symptoms associated with addiction, Asperger syndrome, oppositional defiant disorder behavioral disturbance, agitation, psychosis/agitation associated with Alzheimer's disease, psychosi associated with Parkinson's disease, psychosis associated with drug of abuse, psychosis associated with psychedelic drug abuse, LSD-induced psychosis, steroid-induced schizophrenia, steroid-induced psychosis, Capgras- syndrome; Fregoli syndrome; Cotard, personality disorders, borderline personality disorder, avoidant personality disorder, attention-deflcit/hyperacti e disorder (ADHD, ADD, HD), mania, dementia, anorexia, anorexia nervosa, anxiety, generalized anxiety disorder, social anxiety disorder, body disroographic disorder, obsessive compulsive disorder, paranoid disorder, nightmares, agitation, post-traumatic stress disorder (PTSP), severe mood d singulation, developmental coordination disorder, stereotypic movement disorder, bacterial-induced tic disorder, pediatric aittoirnroone neuropsyclnairic disorders associated with •streptococcal infections (PANDAS), chorea (Sydenham's chorea (SC), chorea minor, chorea gravidarum, drug-indaced chorea), drug-induced repetitive behaviors, akathisia, dyskinesias, Wernicke-Korsakoff syndrome, neufoinilainmatory diseases, neitrodegenetati ve diseases, liver associated-diseases, hepetatis, alcohol-related liver disease, fibromyalgia, gastrointestinal diseases, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cancer, .menial disorder .such as depression or anxiety that leads to metabolic diseases such as obesity and depression associated, with an of the above clinical conditions and cognitive deficits associated with any of the above clinical conditions and combinations thereof, wherein the disease is an acu te, transient or chronic disease,
In another embodiment, there is provided a method of treatment of a mental disorder in a patient in need thereof, by administration of a composition of this invention, wherein said mental disorder is schizophrenia and wherein said schizophrenia includes an symptom arid its onset is at any age.
In some embodiments, there i provided a method of treatment of a mental disorder by administration of a composition of this invention, wherein said compositio comprises, a therapeutically effective amount of at least one CB2 receptor modulator and optionally a therapeutically effective amount of at least one antipsychotic agent and combination thereof, in a seii-enMisifying vehicle and is administered to a. patient in need thereof from about once a month to about once every two months, to about once every three months, to about once every tour months, to abou once every five 'months, to about once every six: months, to about once per week, twice per week, 3 times per week. 4 times per week, 5 times per week, 6 times per week, once per day, twice per day, 3 t mes per day or 4 times per day.
In some other embodiments, there is provided a method of treatment of a mental disorder b administration of a composition of this, invention:, the composition comprising a therapeutically effective amount of at. least one CB2 receptor modulator and optionally a therapeutically effective amount of at least one antipsychotic agent, at least one GP 55 modulator, at least one anti-inflammatory agent and combinations thereof, in a seff^emukifying vehicle, wherein the composition is administered twice per week to a patient in need thereof in an embodiment, there is provided a method of treatment of a menial disorder byadministration of a compoisition. of this invention., the .composition comprising a therapeutically effective amount of at least one CB receptor selective .modulator and optionally an antioxidant, a therapeutically effective amo nt of at least one antipsychotic agent and combinations thereof, in a self-emulsifying vehicle, wherein the composition is administered once per week, twice per week, three times, per week to a patient in need .hereof.
In some embodiments, there is provided a method of treatment of a mental disorder by administration of a composition of this invention, wherein: the composition comprises a therapeutically effective amount BCP, ίίϋ~308 or Mil as sole active and a self-emulsifying vehicle, and. wherein the composition is administered to a patient in. need thereof from abou once a month to about once every two months, to about once every three months, to about once every tour months, to abou once every five months, to about once ever si months, to about once pe week, twice, pet week, .3 times per week., 4 times per week, 5 times per week, 6 times per week, once per day, twice per day, 3 times per day or 4 times' a day.
In some embodiments, there is provided method of treatment of mental disorder by administration of a composition of this invention, wherein the average daily amount of said either BCP, HU-308, 4-0-methyIhonokiol (MH) administered in any daily mode of administration, including but not limited to administration i delayed-releas formulations given on a daily basis, is in range selected from the grou consisting of 0.01 -0.1 n% 0. 1 -1 nig 1 -10 mg, 10-25 mg, 25-100 ntg, 100-1000· nig, .according to the age arid the effectiveness of the composition.
In some embodiments, there is provided a method of treatment of a mental disorder by administration of a composition of thi invention, wherein the averag amount of a single administration, of a de!ayed-release delivery composition is selected from compositions for slow- release, delayed release drugs formulated as a capsule or as a depot injection given either orally or mostly by -injection, administrated once a week or once a .month to up to every six months comprising 8CP, HU-30S, or 4~0-»iethylhonok.io! (MB), administered in amount selected from 0.1-10 mg, 10-25 mg, 25-100 mg, 100-1000 mg or 100-3000 mg, according to patient's age and compositio " s effectiveness.
"in some other embod ments., there is provided a method of treatment of a mental disorder by administration of a composition of this invention, wherein said at least one antipsychotic agent and combinations- thereof, is co-administered in single dosag for together with said CO 2 receptor modulator.
According to an embodiment, there is provided a. method of treatment of a mental disorder by administration of a composition of this invention t a paiient In need thereof, wherein the at least one antipsychotic agent, is co-administered, sequentially in dosage form separat -from said CB2 receptor selective agonist in either order.
In some embodiments, there is provided a use -of a therapeutically' effective- amount':©? -at least one CB2 receptor modulator in substantially pure form in a self-emulsifying vehicle and optionally of a therapeutically effective amount of at least one antipsychotic agent, in the ■mamifacture of a composition for treating a mental disorder in subject in need, thereof
In some other embodiments, there is provided a compositio for the treatment of a mental disorder in a patient in need thereof, wherein formulated as a stabl ' seif-emulsifying drug deli ery system comprising:
from about 0.01 % w/w to about 0.2 % w butylated hydroxytoluene,
from about 1 % w/ to about 40 % w/w Tween~60 (Poi sorisUs 60 NF),
from about 1 % w/w to about 40 % w/w Tween-80 (Poiysorbate 80 NF),
from about 1% w/w to about 15 ¾ w/w Span $0 (Sorbitan monooleate) NF,
from about 1% w/w to about 15 ¾ w/w Tocophersolan (TPGS, Tocopherol PEG ester succinate), from about i% w w to about 30 % w/w Labrafil l 44 CS,
from about 1% w/w to about 15 % w/w Lecithin (PhosphoHpori 80),
from about i% w/ to about 15 · % w/w .Ethyl alcohol anhydrous, and■■optionally from about 0.1 % w/w to about 5% w/w of at least o«e antipsychotic agent.
Exernplary embodiments of. the teachings herein are discussed hereiri below with reference to specific materials, methods and examples. The material, methods and examples discussed herein are illustrative and not intended to be limiting. In some embodiments, methods and materials similar or equivalent to those described herein are used In the practice o testing of embodiments of the invention, it is to be understood that the invention is not necessarily limited in it application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the' drawings. The invention is capable of other embodimen ts or of being practiced or carr ied out in various ways.
EXAMPLES'
Materials and methods
BCP was obtained from Sigma-Aldrieh (St Louis, MO, USA), catalogue Nr. W22S207 (assay not indicated) and further purified using preparative HPLC (HP 1090 series; column, PBGASIL ODS (Senshu Sci. id, 10 x250 m); solvent, 70% CfOOH; flow rate, 2.0 L/min; detection, UV 220 nmj to remov other sesquiterpenes,
Purified BCP hatches were analyzed by G€~ S analysis;
Batch 1 : Total BCP ■ 98%; 95% E-BCF, 3 2-BCF, 1 % BCP oxide and traces of a-knnnlene. Batch 2: Total BCP - about 85%, about 13% alp.ha.~hiimn1ene, about '!.% eopaene, about 0.3 eugenol, about 0.3% o-eadineoe and about 0.3 BCP oxide Phencychdine (PCP), Cremophor EL and DMSO were obtained from Stgma-Aldrieh (St. Louis, MO, USA). Animal model of schizophrenia:
The mouse niodel of schizo ren a was esta l shed.. Phency idine (PC'P)* an MD .-antagonist which, induces- Schizophrenia and psychotic effects in hunsans, was administered to murine pups {injection of 5 rng/kg in saline) on .postnatal, days 3, 5, 7, 9,. 1 1.,. 13, and 16 (or 3 times a week, on alternated days, - for 2 weeks). This treatment .induces Song-lastin schizophrenic-like effects in. mice that lasted into adulthood. The therapeutic effects of hetacaryophytlene, dietary eannabinoid and CB2 receptor selective gonist, in accordance with the teachings herein were evaluated.
Exam le 1
Oral 16% BCP composition in a. SEDDS (self-em dsirymg drug delivery system) vehicle.
Preparation: of the S EDDS vehicle
Vehicle
Figure imgf000063_0001
The ingredients dl-alpha tocopherol and Phosal 75SA were stored in a refrigerator. dl~Alplia tocopherol and Phosal 75 S A were removed from refrigerator and allowed to reach room temperature while tightly closed.
Labrafil M 944CS and Polysorbate 60 were heated to 50-55 "C until each product becomes a clear and. homogenous liquid.
The following ingredients were weighed into 200 ml glass beaker weigh in th following order: dl-alpha Tocopherol (i .760 g Phosal 75SA (3:245 g), oliiphor EL (7.975 g% Polysorbate 60 (12.98 g), Labrafil MI 44CS (41 ,800 g) and Caprle/eaprylie triglycerides (42.245 g). ----- Total: 1 10.00 g (A- 0.962 g/ml), The beaker was covered and heated to 45-50 'C o«ii! all ingredients ate completely melted. The obtained liquid was mixed using a magnetic stirrer at Me ium / low speed until a homogenous liquid SEDDS vehicle was formed (10-20 minutes).
The SEDDS vehicle obtained as a ay liquid was transferred to -amber glass storage bottles and the head space was flashed with nitrogen. The bottles were tightly closed, sealed and s ored in a refrigerator at-+2-8'C.
Preparation of the BCP oral composition in a SEDDS vehicle
Composition (1 % BCP)
Figure imgf000064_0001
The SEDDS vehicle was stored in a refrigerator. The active agent BCP was stored in a freezer. The vehicle and the active were removed from storage, allowed to reach room temperature while lightly closed, then warmed to 35-40 using a water bath, The vehicle was shaken to homogenize it.
SEDDS vehicle (84.0 g) was weighed into an Erienmeye '■flask, with, stopper and BCP (16.0 g) was added to it The flask was closed and mixed using a magnetic stirrer for 10- 15 minutes at low speed, until a homogenous mixture was foroied*
The oral composition obtained was slightly cloudy / opalescent.
The above oral composition is filled into capsules or diluted with water, as per need.
Particle Size Analysis
Particle size was measured at 25 C using dynamic light scattering analyzer ¾etasi¾er Nan© ZS (Malvern, instruments Ltd., UK) after dilution of the sample of Example 1 (16% BCP) with saline 1 ; 1 00, Results for intensity are presented on Chart 1. Chart I --■ Particle size analysis --■ 'Example ! (1 % BCP)
Results
Diam. (rim) % Intensity Width, (nm)
Z~Average (d, .iiffi): 212 Peak 1 :257 98,0 130
Pdl: 0.260 Peak 2:5020 2.0 597
The waier-dilaied composition was found to be a submicrcm emulsion with average particle, size of 260 nm-and wide size distribution (50-800 nm).
The compositions in Examples 2-11 below were prepared in a. wa similar to Exampl 1 , ..using, the quantities indicated in the Tables.
Prophetic Examples 2-4
Vehicle and compositions tube A.
Figure imgf000065_0001
Prophetic Examples 5-6
Vehicle and com ositi ns type B
Figure imgf000065_0002
BCP .0 0.0 '5.87 I 1 .0 958 iss
3090 00 36771 100 5178 100
Dilution■ with water media "* ' * + + + + +
Pro hetic Examples 7-1
Figure imgf000066_0002
Prophetic xam pie 12
Liquid Composiion for Oral Administratio
For i teas oon (5,0 g.; approx.5 mi) contains
Figure imgf000066_0001
Figure imgf000067_0001
Preparat on;
Melt Pol sorbate 60 and Solntol HS- 1 at 45 C and combine surfactants m an appropriate vessel. Add MCT oil, Labrafii, Lecithin arid Tocopherol mix slowly until homogenous mixture is obtained. Cool the mixture to room temperature,
5 Add beia-earyophyllene and mix. slowly for 10 minutes.
Separately dissolve Sucralose in ethyl alcohol (IJSP grade) at 45"C. Add. solution to the mixture and mix slowly for 10 minutes.. Dispense into tightly closed light protected glass bottles., preferably under nitrogen..
Example 13
S O II. POSTNA TAl INDUCTION OF SCHIZOPHRENIA iDAYS 3-15) FOLLOWED BY ORAL
TR A mr OF Aix)iE c r MICE wimBCp SEDDS.
METHOD
Preparation of diluted oral SHOPS vehicle wife BCP for adrnkmiration by gavage,..
Sterile double-distilled water (D W) was warmed for 10 mm in a pre-watmed tbsrmobath (3 - !5 38'C)r 'The SEDDS vehicle of the oral composition of Example 1 was wanned up separately to 35-38 C for 10 mm. In order to prepare BCP (5 mg/.tnlj for a final dose of 10 rng/kg, BC (5 mg) was added directly into the vehicle (1 till) and vortexed for 1 to obtain the oral composition. Then the wanned sterile DDW (4 ml) at 35-38 C was added at a ratio of 1:5 oral composition: DDW dilution and the diluted composition was vortexed for 1 min. "in order to 10 prepare BCP for a final dose of 5 mg kg, 500 μί of BCP at 5 rng/nil were diluted with 500 μ] SEDDS vehicle (1 :2 dilution). Then the wa med sterile DDW (4 nil) at 35-38 "C was -added -at a ratio of 1 ;5 oral composition. DDW dilution, arid the diluted composition was vortexed for 1 min.
BCP (5 rng/fcg or 10 ag/kg in diluted self-emulsifying vehicle (Example I)) was 15 administered to adolescent mice (10 ui/g) by gavage twice a week (on Sunda and Wednesday) for 3 weeks (PND 43-62), a total of 6 injections. Control group and PCP~.indo.ced group received by gavage the oral formulation solution without the drug. After the final BCP injection,, mice were tested in. the open field test (PND 64-66). forced-swimming test (PHD 70-71 ) and. social interaction, test (P D 88-89),
Faroed-swimming test
Training was conducted for 6 min a day efore the test Each mouse was placed into a transparent glass cylinder filled with fresh water at 25CC. On the test day, the total duration/i equency of immobility and climbing wa counted every 2 minutes for 6 minutes. An increase in frequency of climbing serves as a inde of increased despair.
Open fie id test
Each mouse was placed into the center of a clear open Plexsglas Chamber (40 era * 32 cm * 30 cm) which its floor was divided to squares of 4 cm. X 5 em. Testing was performed i the presence of a bright white light. Ambulation behavior was manually counted for 8 mm and data were collected in 2 mitt intervals.
Social interaction test in a novel environment
Each mouse was placed, in a novel cage together with a ncmaggressive intruder mouse, o the same species, same- sex and a similar age. The interaction between the two- mice was recorded for 10 minutes with EthdVision. software (Moldus), Social interaction was defined by contact between the mice (tracking nose point). Reduced duration of contact behavior indicates on impairment in social interaction.
Results
PIG. 1 shows that oral treatment with 5 or. 1.0 mg/l g BCP in SEDDS oral formulation: at adolescence reversed the effect of FCP on. mice in th forced-swim test. These results show tha BCP acts orally and that the SEDDS composition used is efficient for oral administration. These •results show that BCP in oral SEDDS composition is effective in reversing depression-like behavior, supporting, its use as a pharmaceutical drug for the treatment of mental diseases i which depression is one of the syinpioms (like for example bi-polar/mania-depressive disorder, depression., anxiety, ADHD, Toorette syndrome, depression associated with neurodegenerative diseases, depression that leads to metabolic diseases). FIG. 2 of this disclosure shows that oral treatment with 5 mg/kg BCP in SEDDS oral formulation- at adolescence reversed die eiTect of PCP on activit of mice in the open field tes These results sho that BCP acts orally and that the composition used is efficient for oral administration. Comparison of the results in FIG 2 in this disclosure with the results in Figures 14C-E in the U.S. Patent Application No. US 2015-0051299, shows that BCP in oral SEDDS composition is effective at the same dose as it has been shown for i.p. route of .administration,, which is surprisingly good.
FIGS. A-B show that oral treatment with 5 mg/kg BCP in SEDDS oral compositio at adolescence reversed the eiTect of PCP on mice ½ the social interaction test (3A) hut did not affect their body weight (3-B). These results show that BCP acts orally and that the composition used is efficient for oral administration. These results show that BCP' in oral SEDDS composition is effective in reversing deficits i social interaction.
Example 14
in POSTNATAL INDUCTION OF SCHIZOPHRENIA fpAYS s-iS) FOLLOWED BY ORAL
'TREATMENT OF ADOLESCENT MICE WITH BCP oil
METHODS
Preparation of diluted oral formulation- of BCP for administration by gavag
BCF was dilated in canola oil.
BCP (10 mg'kg diluted in canola oil) was administered to adolescent mice (PND 4362) by gavage twice a week (on Sunday and Wednesday) for 3 weeks, a. total of gavages. Control group and PCP-iiKluced group received by gavage the oil vehicle.- After the final gavage, mice were tested in the open field test (PND 59), forced-swiraming test (PND 83) and social interaction test (PHD 88-89')'.
Forced'Swimming test
Training was conducted for 6 min a day before the test. Each mouse was placed into a transparent glass cylinder filled with fresh water at 25*C. On the test day, the total dmation/frequency of immobility and climbing was counted every 2 minutes for .6 minutes. An increased immobility is an index of learning and habituation,, therefore a positive behavioral adaptation With- a stressful condition. Results
PIG* 4 sho s that oral treatment with ! 0 tng kg BCP in. oil composition did not, reverse the -effect of 5 tng/kg 'POP OR the frequency of immobility of mice in the forced swim test. These results show that BCP in SEDDS composition is effective while BCP in oil was ineffective on reversing the frequency of climbing hi the forced-swim test. These results sho w that BCP in SEDDS oral composition surprisingly work much better than other oral compositions.
Example 15
Preparation of MH in SEDDS vehicle,
3. The SEDDS vehicle of the Oral composition of Exampl 1 was wanned up separately to 42 C for 13 mm. in order to prepare about 5% (g/vol) MH solution, the vehicle (380 rug) was added to MH (22, S mg) directly and vortexed for 60 sec to obtain the oral composition,
2. The SEDDS vehicle of the oral composition of Example ί was warmed tip separately to 52 for 15 rain, i order to prepar about 5% (g vol) Mil solution, the vehicle (380.18 mg) was added t MH (21.2 mg) directly and vortexed for 100 sec to obtain the oral composition.. Then the solution was wanned up to 50 C for 10 mi T Then the solution as wanned up to 5? C for 13 mi and vortexed for 180 sec.
.3. The SEDDS vehicle of the oral com.posit.ion of Example 1 was warmed u separately to 55€ for i 5 mm, In order to prepare about 1% (g/vol) Mi l solution, the vehicle (39 rug) was added to MH (4- mg) directly and vortexed for 60 sec to obtain the oral composition;. Then the solution was warmed up to 55€ for 10 mm and vortexed for- 60 see.
Results
1. MH. did not dissolve in SEDDS. Two phases were evident.
2. MH did not dissolve in SEDDS. Tw phases were evident. Warming up to 50°C did not dissolve the Mi l. Warming up to 57°C dissolved the MB, and phases disappeared,
3. MH did not dissolve in SEDDS. However, MM dissolved in SEDDS after warming to 55°C; affording one homogeneous phase. Example J 6
The soiwl oii of 4-0-tnethy hO»Okioi (MB) was prepared in oral fcroiuiaiion according to Table I below.
Results
MB dissolved in V-01 or in V-02 or in V-03. No phases were evident.
Table !
Figure imgf000071_0001
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Claims

A. stable seif-etaaisifyiag. composition for treatment of mental disorders in a patient in need thereof, comprising;
a therapeutically effective amount of at least one C 82 receptor modulator, a self-emulsifying vehicle, and
optionally' a therapeutically effective amount of at least one antipsychotic agent, wherein at least one CB2 receptor modulator and the optional at least one antipsychotic agent are substantially solubilized.
The seif-enftslsifyirtg com siti n of claim 1 , wherein, upon dilution with water containin media or body fluid said composition spontaneo sly forms an oil-in- water emulsion,
The composition of claim I , wherein the at least one CB2 receptor- modulator is selected from the group consisting of at least one CB2 receptor agonist or partial agonist, at least one CB2 receptor antagonist or inverse agonist, at. least one CB2 receptor antagonist: inverse agonist that is a selective estrogen receptor modulator (SERM), at least one type of CB2 receptor allosterie' modniaior and combinations thereof
The composition of claim 3, wherein the at least one CB2 receptor agonist o partial agonist is selected from' the group consisting of BCP, HU-308, HU-433, HU-910, Mil- 914, CB 65, OP la, GP 2a, GW 405833, JWB 015, JWH 133, A I241, ' 1,759,656, L- 739,633, · ΜΌΑ 19, SER 601 , BML-I90, N-aSfcylaraide, mtaraarin, diindolyhnethane (DIM), cannabinor (PRS-2H ,375), 2-arachidonoy (.glycerol, atjandamide, GP5S940, d lta- 9~THC, W1N552. 2-2, HU-2J0, eannabigerol (CBG), l l-hydroxy-49- tetiahydrocannabittoi (11 -OH-THC), defa-8-XBC, n-OH-delta-S-TMCV, ajulemic acid, delia-8~THG- l 1 -ok acid, eannabinol (CBN), eannabiiaetones, A M ' 71 , A 1710; analogs thereof, deri vati ves thereof, metabolites thereof and combinati ons thereof The composition of claim. 3, -wherein the at least one CB2 receptor antagonist or inverse agonist is selected from the group consisting of A 630, J'TE-907, SR 44528, COR! 70, 4-0-metliylhonokioh GS 1.2021 (4-0-ffiethy honokiol analogue), eannabinol, 01238, 0.1 1 S4,. cannabidioi (CBD). analogs thereof, derivatives thereof and: combinations? thereof. The composition, of claim 3, wherein the at least one CB2 receptor aSlosteric modulator i selected from the -group consisting of dihydtogamhogte acid, garcinolic acid, (-)-5 ~ dijweihylheptyl-caftnabidiol (DMH-CBD), analogs thereof, derivatives thereof and combinations thereof.
The composition of claim 3, wbere the at least one CB2 receptor modulator is selected from ti group consisting of raloxifene, hazedoxifen, lasofoxifeue, tamoxifen, afmioxsiene, arzoxifene, ormeioxifene, torerolferie, ospemifene and analogs thereof, derivatives thereof and combinations thereof.
The composition of claim 1 , wherein the at least one antipsychotic agent is a birtyrophenone type antipsychotic agent, an atypical antipsychotic agent or a combination thereof.
wherein the butyrophenone type antipsychotic agent is selected f om the group consisting of haloperidol, droperidol, benperidoL trifluperidol, melperone, lertperone, agaperone, dontperidone, hutyropherjone, fhtanisone, penfluridol, piparoperone, spiperone, nonaperone, hrornperJdoI and timiperone, a diphenylhutyipipefidine type antipsychotic agent selected from the group consisting of l.uspiri!.e»ey penfluridol, pimozid , ciopii»oz3Edes fiuspirilene, penfluridol, a phenoiMazine typ antipsychotic acid agent selected from th group consistin of aeeprornazirte, ehiorpromazioe, cyamemazine, dixyrazine, fliiphenazine, 1evonieproniaziner mesoridazine,. perazine, periciazine, perphenazine, ptpotiazine, prochlorperazine, r mazine, promethazine, prothipendyf thioproperazine,, thioridazine and trifluoperazine and triflupromazine, a tkioxanthene type antipsychotic agent selected from, the group consisting: of chlorprotliixene, efopentkixol, flupentixof thiothixene and zuelopenthixoi, and combinations thereof
wherein the atypical antipsychotic agent is an atypical antipsychotic agent belonging to the D2 antagonist/inverse agonist or 5-BT2A antagonist/inverse agonist types and is selected from the group as isti g of amiso!pride, amoxapine, asenapine, cariprazsne, clozapine, blonanserin, iloperidoue, lorasidone, melperone, nenionapride, olanzapine, pahperidone, paliperidone paSmitate^ perospirone, qyetiapine, remoxi ride, risperidone, sertindole, sultoprtde, rriniipramine, ziprasidone, Ffi-007, pimavanseri (ACP-103; S-HT2A antagonist), and combinations thereof,
wherei the atypical antipsychotic agent is an atypical antipsychotic agen belonging to the Ό2 partial agonist types and is selected from the grou consisting aripjprazole and. its metabolites OPC- 14857, DM-1458, DM- 1451 , DM-1452, DM- 1454 and DCPPS brexpiprazole and P5063 (RP5000) and combiaatioas thereof and/or a eannabinoi exhibiting antipsychotic activity selected from the group- consisting of teirabydrocannahivaoB (THC-V— C-Bl antagonist, CB2 receptor partial, agonist), carmabidioi (CBD -CBl/€B2/CrPR55/ABn~CBD aniagonist/inhibitor) and eannabigerol
(C-BG— CB1 /CB2 partial agonist), and: their analogs and derivatives and combinations thereof.
The composition of any of claims 1 -8, wherein the composition is formulated as a stable self-emulsifying drug delivery system and wherein the composition comprises at least on oil, at least one surfactant HLB< , at least one surfactant HLB>13, at least one co- surfactant5 at least one antioxidant o free-radical scavenger, at least one CB2 receptor modulator and coinb.inatio.ns thereof and. optionally an antipsychotic agent.
The composition of an of claims 1-8, wherein the corn position is formulated as a. stable self-emulsifying drug del er)' system and wherein the composition comprises:
fro 10%· w w t 50% w/w of n oil selected from fire group consisting of medium chain triglycerides,- propylene glycol dicapri!ate/dkaprate.,. medium chain mono- and diglycerides, acetylated mono-arid diglycerides-,. sesame oil and olive oil and combinations thereof
from 20% w/w to 50% w/w of a. surfactant HLB selected from the group consisting of oie yl polyoxyi~6 glycerides, lmoiey! polyoxyl-6 glycerides (20- 40%), Pofysorbate 85 (Tween~85} polyoxyethyiene (:2O-40%w/ )., sorbitan trioleate {5-15% w/w), Span~S0 (sorbitan mo iooleate) (5-25% /w). polyglyee.ryi-3 dioleate (15-35% w/w) and glycerin monoiinoieate ( 10-35% w/w), Polysorbate SO (Tweeii-80 polyoxyethyiene (20-40% w/w), Polysorbate 60 (Tween~60) polyoxyethylene (.20-40% w/w), and eombinaiions thereof from 5% w/w to 50 % w/w of a surfactant HLB> I 3 selected from the group co.nsisiiftg o poly ylated castor oil (5-40% w/w), PEG 40 liydrogen ted castor oil, PEG- 15 hydroxystearate (5-25% w/w), caprylocaproyl polyoxyl-S glycerides ( 10-20% -w/w) and combinations thereof, f om 5% w/w to 25 % w/w of a. surfactant HLB>13 selected, from the group consisting of PEG-20 sorhi an rrtonostearate, PEG-20 sotbitan menooleate (5~ 25%), PEG 40 steatate (5-25% w/w) and combinations thereof,
from 0.5% w/ to 15 % w/w of a co-siirfactant selected from the group consisting- -of aimy lecithin (2-15% w/w), soy lecithin (>75% w/w phosphatidylcholine in oil, 1- 10% w/w), soy lecithin PC content >S0% (2-15% w/w), egg lecidim E-60 (1 - 5 w/w , egg lecithin E-80 ( 1-5% w/w), distearoylphosplra idylcboliae (0,5-3% w/w) and combinations thereof,
from 0J% w/ to 5 % w/w of an antioxidant or free radical scavenger selected from the group consisting of d-a!pha-tocopherol (1 -10% w/w), dl-alphatocopherol (2- 5%w/w), dl-a!pha-toeopfieryi acetate (2-1.5% w/w), .inked tocopherols (alpha, beta, gama 1 *10% w/w), d-a1pha~toeopheryl acetate (2-15%- w/w), butylated hydroxyanisole (BilA, 0,01 -0,5% w/w), iocophersoian (TPGS, tocopherol PEG ester saccmate) {2-10% w/w) and combinations thereof,
{torn, about 1 % w/ to about 0 % w/w of eth l alcoh l,
■ from 1 % w/w to 20% w/w of at least one CB2 receptor ' modulator in substantially pure form, and
optionally from 0,1%. w/w to 5% w/w of at -least one antipsychotic agent.
The composition of claim 10, wherein the■ composition is formulated as a stable seif- emulsi-fying drug delivery system and wherein the composition, comprises;
.from 30% w/ to 50% w/w -eapric/caprylic triglycerides,
from 30% w/w to 50% w/w oleoyl po!yoxyl~6 glycerid.es,
from 5% w/w to 35 % w/w poiyoxySated castor oil,
from 7% w/w to 1 % w w PEG-20 sorhitan monostearate,
from 2% w/w to 10 % w/w soy lecithin (75 phosphatidylcholine n oil),
from 1 % w w to 15 % w/w d-alpha tocopherol and/or tocopherol acetate,
from .1 % w/w to 20% w/w of at least: one CB2 receptor modulator, and
optionally from 0.1 % w/w to 5% w/w of at least one antipsychotic agent.
The composition of claim 4, wherein the at least one CB2 receptor agonist is heta- earyophyl!eae (BCP) as sole active agent in a self-emulsifying vehicle. The composition of claim 4, wherein the at least one CB2 receptor agonist is beta- caryophySlene (BCP) and the at least on antipsychotic agent is selected from the group consisting of risperidone, paiiperidorie, paliperidohe pahiiitate, aripiprazo e, quetlapine, CBD, TI!CV, CBG, hrexpiprazo!e, derivatives thereof, analogs thereof and combinations thereof.
The composition of claim 4, wherein the at least one CB2 receptor agonist is beta- caryophyllene (BCP) and the at least one antipsychotic agent is selected from the group consistin of 10-98% CBD, 10-98% w/w THCV, 10-98% w/w CBG and combinations thereof
The composition of claim 4„ wherein the at least one CB2 receptor agonist is BCP and the at least one additional active agent selected from the group consisting of al ha^Mmde e, eopaene, eugenol, δ-cadinene, BCP oxide and combinations thereof.
The composition of claim 1 wherei said BCP comprises from 1% to 15% alpha- iutmulene and .from 0.1 %~2% w/w each of copaene, eugenol, 5~cadinene, BCP' oxide and their derivatives and analogs and combinations thereof'
The composition of claim 4, wherein the at least one CB2 receptor selective agonist in substantially pur form is beta caryophyllene (BCP), the a least one antipsychotie agent is selected from the group consisting of risperidone, pal iperidones paliperidone palms late, aripiprazole, quetiapine, CBD, THCV CBG, brexpiprazole, derivatives thereof, analogs thereof and combinations thereof
The composition of any of claims 32- 17, wherein the BCP- comprises E-BCP isomer, Z~ BCP isomer, or a combination of E-BCP and Z--.BCP isomers in substantially pure form and wherein the E-BCP isomer and the Z-BCP isomers are substantially free of BCP oxide and alpha -humulene.
The compositio o any of claims 1.2-17, wherein the BCP comprises substantially p»re isomer E-BCP and wherein the E-BCP isomer is optionally free of BCP oxide and alpha- hmmdene.
The composition of any of claims 12-17, wherein the BCP comprises substantially -pure isomer Z-BCP and is optionally free of BCP oxide and alpha -Inniidene. The composition of claim 4, wherein the at least one CB2 receptor agonist is
Figure imgf000079_0001
btcyclop, 1. i ]hept-'3-enyI] methanol (HU-308) as sole active agent.
The composition of claim 4, wherein the at least one CBZ receptor agonist is U-308' and the at least one antipsychotic agent is selected from the group consisting of risperidone, paliperidone, paliperidone paimilate, aripipra ole, quetiapme, CBD, THCV, CBG, brexpiprazole, derivati ves thereof, -analogs thereof and combinations thereof.
The composition of claim 5, wherein the at least one CB2 receptor inverse agonist is 4-0- methylhonokioi, and the at least one additional ac ve agent selected from the grou consisting of eugenoi, caryophyilene oxide and combinations thereof
The composition of claim 4, wherein me at least one CB2 receptor selective agonist is 4~
O-memylhonokio!. as sole active agent.
The composition, of claim 1 , wherein the compositio is stabilized' by addition of aft antioxidant, a free-radical scavenger or a combination thereof
The composition o 'claim. 1, wherei the composition is formulated, for oral , parenteral, •topical, intranasal, vaginal or rectal administration..
The oral compositio of claim 1 , wherein the composition is formulated as a spray, inhalation, capsule, suspension, solution, emulsion or syrup.
The topical composition of claim 1 , wherein the composition is formulated as transdermal gef cream, patch or topical spray.
The intranasal composition of claim I., wherein the composition, is formulated as a nasal spray.
A method of treatment of a mental disorder in a patient in need thereof, by. administration of a composition comprising therapeutically effective am unt of at least one CB2 receptor modulator, a self-e ukifying vehicle and optionally a therapeutically■■effective amount of at least one antipsychotic agent.
A. method of treatment of a mental disorder in. a patient in need thereof by administration of a composition comprising therapeutically effective amount of at least one CB2 receptor modulator, wherein the at least one CB2 receptor modulator is bet caryophyilene (BCF), a self-einolsifymg vehicle, optionally at least one active agent comprising from 1% to 15% w/w a!pha-hnmulene,. from Q, \%~2% w/w of copaene, from ΟΛ-%-2% w of engenol, from 0-J%-2% w w ofS-cadiftene, from 0.1 %-2% /w of BO5 oxide, from 0.1%-2% of earyopfiyilene oxide,, derivatives ther of, analogs thereof, and combinations thereof, and optionally a therapeutically effective amount of at least one antipsychotic agent
The method, of claim 30 wherein the at least one CB2 receptor selective agonist is a substantially pure form of beta car Ophyllene (B€f*), the composition comprising at Least one antipsychotic agent, wherein the at least one antipsychotic agent is selected front the group consisting of risperidone, paliperidone, paliperidone pahuitate, aripiprazole, queiiapine, CBD, THCV CBG, brexpiprazole, derivatives thereof, analogs thereof and combinations thereof" and wherein the mental disorder is schizophrenia.
The method of treatment of claim 31 , wherein the mental disorder is schizophrenia.
The .method .of treatment, oi claim 3.Ϊ , wherein the mental disorder is hi -polar disorder, onset at any age.
The method of treatment of claim 31 , wherein the mental disorder is depression,, onset at any age.
The .method of treatment of any of claims 31-35, wherein the at least one aniipsychoiic agent is selected, from the group consisting of risperidone, paliperidone, paliperidone palmiiate, aripiprazoSe., quetiapine, CBD, derivatives thereof and analogs thereof, THCV".
CSGV, brexpiprazole and combinations thereof.
The method of claim 36 wherein the mental disorder is schizophrenia,
The method of treatment of claim 33 , wherein the at least one CB2 selective receptor agonisi: is beta, caiyophyllene (BCP) as sole active agent and the mental disorder is anxiety , onset at any age.
The method of treatment of claim 31, wherein the at least one CB2 selective receptor agonist is beta caryophy!kne (BCP) as sole active agent and the mental disorder is schizophrenia of all types, onset at an age.
The method of treatment of any of claims 30-35., wherein the at least one CB2 receptor modulator is selected from the group consisting of at least one CB2 receptor agonist or partial-agonist, at least one CB2 receptor antagonist or inverse agonist, at least one CB2 receptor antagonist or inverse agonist selective estrogen receptor modulator (SERM), at least one type of CB2 receptor aliosteoc anodnlaior and combinations thereof The method of treatment of claim 40, wherein the CB2 receptor selective agonist or partial, agonist is selected from the group comprising BCP, HlJ-308, B!J-433, Ηϋ910, U-914, CB 65, OP 1%. GP 2a, GW 405833, JWH 015, JWH 133, AM 1241 , L759,6565 t-75¾633s .DA. 19, SE 601 , BML- 190, N-alli.yJarolde, anamarin, diindolyioietban (D M) and analogs, CBG, 1 1-hydroxy-A9-tetrahydrocan«abinoI (1 l-OH-THC), de'iia-8- THQ t i-QH-de1ta-8-THCV, ajolemic add, delia-8-THC-l 1-oic acid, cannabinoi, cattnahi lactones, AM 1714, AMI 7.10, analogs thereof, derivatives thereof and combinations thereof.
The method of treatment of claim 4G, wherein the CB2 receptor antagonist or invers agonist is selected from the group consisting of AM630, JTE-907, SR 144528, COR 170, 4-0-ine ylhoiiokiol OS 12021 (4-0-met yiho.noki.ol analog), cannabinoi, 01238, 01 184, eannabidioS (CB'D), analogs thereof, derivatives thereof and combinations thereof.
The method of treatment of any of claims 30-35, wherein the at least one antipsychotic agent is selected from the group consisting of one or more of a biriyTophenone type antipsychotic agent, selected r m the group consisting of haloperidol., droperidol, benpeiido!j trifluperidol, nielperoiie, ienperone, a aperone, domperidone, butyiOphenone, fluanisone, penfluridol, pipamperone, spiperone, nonaperone, broraperidol and iimiperone,. a diphenylbuiylp-peridi-ie type antipsychotic agent selected fro the group consisting of kispirilene, penfluridol, pimozide, clopimozide, fluspirilene, penfluridol, piienofhk ine type antipsychotic acid agent selected fronv the group consisting of aceprOrnaziiie, ehlorpromazine, cyame azme, dixyrazine, fluplrenazine, iev tneproaiaztne, n¾es ttdazwe, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendy 1, thioproperazine, thioridazine and trifluoperazine · and' iriflnproniazine, a thioxanthene type antipsychotic agent selected from he g up consisting of chlorprotJhixene, clopenthixol:i flupeniixol.,. thiothixene and zticlopenihixol and or an atypical antipsychotic agent including, but not limited to one or more of an. atypical antipsychotic agent usually belongin to the D2 an|¾go«ist/inver«e agonist, 5-ΉΤ2Α antagonist/inverse agonist types selected, from the group consistin of anusulpride, amoxapine, asenapine, cariprazine, clozapine, blonanserin, iloperidone, lurasidone, melperone, nemonapride, olanzapine, pa!iperidone, paliperid'one pairmtate, perospirone, quetiapme, rerhoxipride, risperidone, seftlndole, suitopride, tiimipranrine, ^iprasidone, Ι"Π-Ο07? piniavanserin (ACP-103; S- IT2A airtagoaist), and combinations- the eof, and/or an atypical antipsychotic agent including, but not-limited to one or more of an atypical antipsychotic agent usually belonging to the D2 partial agonist types selected from the group consisting an iazoie and its .raetabo!ftes OPC-M857, DM- 1458, OM-145L DM-I452, DM- 1454 and DCPP, brexpiprazole and P5063- (RPSGOD) and combinations thereof and/or a cannahinoid exhibiting antipsychotic activity selected from the group consisting of tetrahydroeannahivarin (THCV CB1. antagonist, CB2 receptor partial agonist), cannabidiol (CBD------CBl/CB2/GPi 55/ABH-CBD antagonist/inhibitor) and cannabige.ro! fCB( ------CBl /CB2 partial agonist);, and: their analogs and derivatives and combinations thereof.
A method of treatment of any of the claims 30-35 > wherein the disease or me tal' disorde is selected from the group consisting of sdiizophrenia, schizoaffective- disorder, bipolar disorder I and H, unipolar disorder, multiple personalit disorder, psychotic disorders, depression, psychotic depression, depressive disorders, major depressive disorder, stereotypic movement disorder, au ism spectrum disorders, obsessive-compalsive disorder (OCD), bacterial-induced' tic disorder, pediatric autoimmune neuropsychiatrtc disorders associated wit streptococcal infections (PANDAS), chorea -(Sydenham's chorea (SC), chorea minor, chorea gravidarum, drug-induced chorea), drug-induced repetitive behaviors, akathisia,. dyskinesias, 'Wernicke-Korsakoff syndrome, To-urette' s syndrome, tic disorders, epilepsy, anxiety disorders, autistic spectrum disorder, enuresis, addiction, withdrawal symptoms associated with addiction, Asperger syndrome, oppositional defiant disorder, behavioral disturbance, ag ation, p ychosis/agiiaticm associaied with. Alzheimer's disease, psychosis associated with Parkinson's disease, psychosis associated with drug of abuse, psychosis associated with psychedelic drug abuse, LSD-induced psychosis, steroid-induced schizophrenia, ster id- induced psychosis, Capgras syndrome; Fregoli syndrome; Cotard, personality disorders, borderline personality disorder, avoidant personality disorder, atteMion--(ieficit/hyperactive disorder (ADHD, ADD, HD), mania, dementia, anorexia, anorexia nervosa, anxiety, generalized anxiety disorder, social anxiety disorder, body dismographic disorder, obsessive compulsive disorder, paranoid disorder, nightmares, agitation, posttraumatic stress disorder (PTSD), severe mood dysregulation, developmental coordination disorder,
SI stereot pic movement disorder, bactertal-indiiced tic disorder, pediatric autoimmune neuropsychiatrie disorders associated with streptococcal infections (PANDAS):, chorea (Sydenham's chorea (SC), chorea minor, chorea gravidarum, drug-induced chorea), drug- induced repetitive behaviors, akathisia, dyskinesias, Weniicke-KorsakofT sw^i ome, neirroinfianiffiatory diseases, neurodegenerative diseases, liver associated-diseases, hepatitis, alcohol-related liver disease, fibromyalgia, gastrointestinal diseases, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cancer, depression or anxiety that leads to metabolic diseases, depression associated with any of the above clinical conditions, cognitive deficits associated with any of the above clinical conditions and combinations thereof, wherein the disorder is acute, transient or chronic disease. The method of treatment of any of claims 30-35., wherein said mental disorder is schizophrenia and wherein said schizophrenia includes any symptom, and its onset is at any age.
The method of treatment of any of claims 30-35, wherein a composition comprising: a therapeutically effective amount of at least one CB2 receptor modulator -and ptionally a therapeutically effective amount of at least one antipsychotic agent, m a self-emulsify ing vehicle is administered to a patient in need thereof from once a month to once every two months, to once every three .months, to once every four months, to once ever five months, to once every- six months, to once per week, twice per week, 3 times per week, times per week, 5 times per week, 6 times per week, once per day, twice per day, 3 times per day or 4 times per day.
The method of treatment of any of clai ms 30-35, wherein composition comprising a therapeutically effective amount of at least one CB2 receptor modulator and optionally a therapeutically .effective amount of at least one antipsychotic agent, at least one GP S5 modulator, at least one antiinflammatory agent and combination thereof, in self- emulsifying vehicle is administered twice per week to a patient in need thereof.
The method of treatment of any of claims 30-35, wherein a composition comprising therapeutically effective amount of at least one CB2 receptor selective modulator and optionally an antioxidant, a therapeutically effecti ve amount of at least one antipsychotic agent and combination thereof in a self-nanoemulsifying vehicle is administered: once per week, twice per week, three times per week to a patient in need thereo The method of treatm nt of any of claims 30-35, wherein 'the therapeutically effective amount of a composition comprising BCP, BIJ-308 o 4-0-inethylhonokiol (MH) as sole active agent and seltemulsifyjn vehicle is administered to a patient in need thereof from once a mon th to once every two months to once every three months, to once every four months, to once every five months, to once every six months, to: once per week, twice per week, 3 times per week, 4 times per week; 5 times per week, 6 times per week, once per day, twice per day, 3 times per day or 4 times a day.
The method of treatment of claim 49, wherein the average daily amount of BCP, HU- 308, or 4-0~meihylhonokiol (Mil) administered in any daily mode of administration, including but not limited to administration in delayed release formulations given o a daily basis, is in a range selected from the group consisting of 0,01 -0,1 mg, 0, 1 -1 mg 1- 10 mg, 10-25 mg, 25- 1.00 mg, 100-1000 mg, according to the age and the effectiveness of the composition.
The method of treatment of claim 50, wherei the average daily amount of highl selecti ve ligands such as HU-308 fon rfated. in the highl effective ccnnposuion of claim. 1 is in a range selected from 0.01 mg/day to 50 .mg/day or from 0.1 mg/day to 500 nig/day ibr less potent modulators including but not limited to BOP, MHS according to age.
The method of treatment of claim 50, wherein th average daily amount of highly selective ligands includin but not limited to HIK .08 formulated in. a less effective composition (non-SEDDS) is in a range selected from 0.3 mg/day to .100 mg/day or from 1 mg/day to 1.000 mg/da for less potent modulators including but not limited to BCP. MH), according to age.
The method of treatment of claim 49, wherein the average amount of a single administration of sustained release delivery compositions is selected from compositions for slow-release, delayed release drugs formulated as a capsule or as a depot injectio given either orally or by injection, administrated once a week o once a month, to u to every six months comprising BCP, HU-308,. or 4-0-iriethylhonokiol (MH)f administered in an amount selected from 0,1 -10 mg, 10-25 mg, 25-100 mg, 100-1000 nig or 100-3000 mg, according to patient's age and composition's effectiveness. The method of treatment of claim 53, wherein the average amount of single adniii sixation. of a sustained release deliver composition, is in a range selected' rom 100 mg smgle administration for highly potent modulators including but not limited to HU- 308 or for weekly injection to 3000 tag/single administrations fo less potent modulators including but not limited to BCP, MH or for injection every 3 months, accordin to a e. The method of treatment of claim S3, wherein the average amount is in a rang selected from 0.5 mg/single administration to .1000 mg/single administration for highly potem modulators including but: not limited to Ml. - 308 administered once a month and tip to every six months or from .1 mg single administration to 3000 mg/single admiriistratio for less potent modulators including but not limited to BCP or MH administrated, once a month nd up to every six months and according to age.
The method of treatment of any of -claims 30-35, wherein the at least one antipsychotic agent is co-administered in a single dosage form together with said CB2 receptor modulator.
The method of treatment of any of claims 30-35,. wherein the at least one antipsychotic agent is co~adniinistered sequentially in a dosag form separate from said CB2 receptor selective agonist wherein in either order.
Use of a therapeutically effective amount of at least one CB2 receptor modulator in substantially pore form in a self-emulsifying vehicle and optionally of a therapeutically effective amount of at least one antipsychotic agent, in the m nufa tur of a composition for treating a mental disorder in a subject, in need thereof.
The composition of clai 10S wherein the composition is formulated' as a stable -self- emulsifying drug deliver system and wherein the composition comprises:
from 0, 1 % w/w to 0.2 % w/vv feurylated hydroxy toluene,
from. l%w/w to 40 % w/w Tween-60 (Polysorbate 60 NF),
from 1 % w/w to 40 % w/ Tween-80 (Polysorbate SO NF),
from \% w w t 15 % w w Span 80 (S rfeitan onooleate) NF,
from 1% w/w to 1 % w/w Toeophersolaii (TPGS, Tocopherol PEG ester succinate), from. 1 % w/w to 30 % w/w Labrafil Ml 44 CS,
from l% /w to 15 % w w Lecithin (Phospholipon 80),
-from 1% w/w to 15 % w/w Ethyl alcohol anhydrous, and, optionally from 0. { % w/w to 5% w/w of at least one antipsychotic agent.
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