阅读说明：本技术 四氢***酚调节剂 (Tetrahydrocannabinol modulators ) 是由 J·C·拉贝尔 B·J·道格拉斯 于 2018-09-04 设计创作，主要内容包括：本公开提供大麻素组合物,其包括δ-8-四氢大麻酚(δ-8-THC)、大麻二酚(CBD)、δ-9-THG、减少δ-8-THC、δ-8-THC、11-羟基-δ-8-THC或11-羟基-δ-9-THC的分解代谢的天然产物,以及δ-8-THC和δ-9-THC的药学上协同或累加的组合。(The present disclosure provides cannabinoid compositions comprising-8-tetrahydrocannabinol (-8-THC), Cannabidiol (CBD), -9-THG, natural products that reduce catabolism of-8-THC, 11-hydroxy-8-THC, or 11-hydroxy-9-THC, and a pharmaceutically synergistic or additive combination of-8-THC and-9-THC.)

1. A composition comprising a combination of-8-THC and a non-cannabinoid natural product:

(i) wherein the non-cannabinoid natural product is capable of increasing the duration of psychoactive or non-psychoactive drug action of-8-THC as determined by co-administration of-8-THC with or without the non-cannabinoid natural product, or

(ii) Wherein the non-cannabinoid natural product is capable of increasing the duration of psychoactive or non-psychoactive drug action of-9-THC as determined by co-administration of-9-THC with or without the non-cannabinoid natural product, or

(iii) Wherein the non-cannabinoid natural product is capable of increasing the concentration of 11-hydroxy-8-THC in the bloodstream of a human subject as determined by co-administration of-8-THC with or without the non-cannabinoid natural product, or

(iv) Wherein the non-cannabinoid natural product is capable of increasing the concentration of 11-hydroxy-9-THC in the bloodstream, as determinable by co-administration of-9-THC to said human subject with or without said non-cannabinoid natural product.

2. The composition of claim 1, further comprising-9-THC.

3. The composition of claim 1, which does not comprise-9-THC.

4. The composition of claim 1, wherein the cannabinoid and the non-cannabinoid natural product are mixed together as a pharmaceutically acceptable composition for oral administration,

wherein the pharmaceutically acceptable composition for oral administration is optionally a powder, tablet, pill, capsule, slurry, suspension, or liquid composition.

5. The composition of claim 1, wherein-8-THC and the non-cannabinoid natural product are not mixed together,

wherein-8-THC is a component of a first pharmaceutically acceptable composition for oral administration, and

wherein the non-cannabinoid is a component of a second pharmaceutically acceptable composition for oral administration.

6. The composition of claim 1, further comprising at least one inhibitor of UDP-glucuronyl transferase (UGT), wherein UGT is capable of catalyzing the glucuronidation of one or both of 11-hydroxy-8-THC and 11-hydroxy-9-THC in the absence of the inhibitor,

wherein the inhibitor is optionally a substrate of UGT, capable of acting as a competitive inhibitor of at least one UGT.

7. The composition of claim 1, further comprising an inhibitor of a cytochrome P450enzyme (CYP enzyme),

wherein the CYP enzyme catalyzes the metabolism of psychoactive cannabinoids to non-psychoactive metabolites, or

Wherein the CYP enzyme catalyzes the metabolism of a non-psychoactive medically active cannabinoid to a non-psychoactive metabolite.

8. A method of administering the composition of claim 1 to a human subject, comprising the steps of:

(i) providing the composition to the human subject,

(ii) administering the composition to the human subject, or self-administering the composition by the human subject,

(iii) causing an increase in the concentration of cannabinoids of the composition in the bloodstream of the human subject, an

(iv) Wherein the administration results in a psychological or medical effect on the human subject, the effect being assessed by one or both of a questionnaire or biochemical test.

9. A pharmaceutically acceptable composition capable of oral administration to a human subject, said composition comprising-8-THC and-9-THC, wherein

(i) The applied composition causes irritation to CB1, or

(ii) The applied composition causes irritation to CB2, or

(iii) The applied composition results in greater stimulation of CB1 than does-8-THC alone, or

(iv) The applied composition results in greater stimulation of CB1 than does-9-THC alone, or

(v) The applied composition results in greater stimulation of CB2 than does-8-THC alone, or

(vi) The applied composition resulted in a greater degree of irritation of CB2 compared to-9-alone,

(vii) the-8-THC in the administered composition enhances the pharmacological activity of-9-THC in the administered composition, or

(viii) the-9-THC in the administered composition enhances the pharmacological activity of-8-THC in the administered composition.

10. A pharmacologically acceptable composition according to claim 9, comprising a tablet containing the following precise and optionally approximate amounts of-8-THC and-9-THC:

(i)10mg-8-THC and 10mg-9-THC, or

(ii)5mg-8-THC and 5mg-9-THC, or

(iii)2mg-8-THC and 2mg-9-THC, or

(iv)1mg-8-THC and 1mg-9-THC, or

(v)5mg-8-THC and 2mg-9-THC, or

(vi)5mg-8-THC and 1mg-9-THC, or

(vii)5mg-8-THC and 0.5mg-9-THC, or

(viii)2mg-8-THC and 1mg-9-THC, or

(ix)2mg-8-THC and 0.5mg-9-THC, or

(x)2mg-8-THC and 0.25mg-9-THC, or

(xi)1mg-8-THC and 1mg-9-THC, or

(xii)1mg-8-THC and 0.5mg-9-THC, or

(xiii)1mg-8-THC and 0.25mg-9-THC, or

(xiv)10-30mg-8-THC and 10mg-9-THC, or

(xv)10-30mg-8-THC and 5mg-9-THC, or

(xvi)10-30mg-8-THC and 2mg-9-THC, or

(xvii)10-30mg-8-THC and 0.5mg-9-THC, or

(xviii) More than 30mg-8-THC and 10mg-9-THC, or

(xix) More than 30mg-8-THC and 5mg-9-THC, or

(xx) More than 30mg-8-THC and 2mg-9-THC, or

(xxi) More than 30mg-8-THC and 0.5 mg-9-TMC.

11. The pharmaceutically acceptable composition of claim 9, which can be used for one or more of oral administration, intranasal administration, mucosal administration, topical administration, transdermal patch administration, or administration to a human subject by inhalation.

12. The pharmaceutically acceptable composition according to claim 9, wherein the stimulation of CB1 and the stimulation of CB2 in a human subject can be determined by administering to an animal subject a composition comprising-8-THC and-9-THC, by administering-8-alone, and by administering-9-alone, and by extrapolating the stimulation results to a human.

13. A method of administering the composition of claim 9 to a human subject, comprising the steps of:

(i) providing the composition to the human subject,

(ii) administering the composition to the human subject, or self-administering the composition by the human subject,

(iii) causing an increase in the concentration of cannabinoids of the composition in the bloodstream of the human subject, an

(iv) Wherein the administration results in a psychological or medical effect on the human subject, the effect being assessed by one or both of a questionnaire or biochemical test.

14. A method of administering a non-cannabinoid natural product to a mammal, wherein the non-cannabinoid natural product is capable of increasing the concentration of a biologically active cannabinoid in a biological fluid of a test mammal,

or wherein the non-cannabinoid natural product is capable of reducing the conversion of a biologically active cannabinoid to a non-biologically active cannabinoid in the mammal,

the method comprises the following steps:

(i) a step of administering-8-THC to said mammal,

(ii) a step of administering the non-cannabinoid natural product to the mammal, wherein a first time period is required to begin and complete administration of-8-THC, and wherein a second time period is required to begin and complete administration of the non-cannabinoid natural product,

(iii) wherein the first time period is the same as the second time period, or wherein the first time period overlaps but is not the same as the second time period, or wherein the first time period does not overlap with the second time period,

(iv) a step of obtaining at least one sample of biological fluid from said test mammal and transferring said sample to a container after completion of both said first period of time and said second period of time, and within five days after completion of both said first period of time and said second period of time,

(v) subjecting said sample to a step of an assay capable of detecting one or more biologically active compounds-8-THC, 11-hydroxy-8-THC, -9-THC, 11-hydroxy-9-THC, 7-hydroxy-8-THC, 7-hydroxy-9-THC, or capable of detecting one or more biologically inactive compounds 11-nor-9-carboxy-8-THC, 11-nor-9-carboxy-9-THC, 7-hydroxy-8-THC or 7-hydroxy-9-THC,

(vi) a step of detecting said one or more biologically active compounds and biologically inactive compounds and calculating the concentration of said one or more compounds in said biological fluid.

15. The method of claim 14, wherein the non-cannabinoid natural product:

(i) capable of increasing the concentration of a biologically active cannabinoid in a biological fluid of a test mammal, capable of being determined by an in vitro assay for a cytochrome P450enzyme, by an in vitro assay for UDP-glucuronosyltransferase (UGT) or by an in vivo test in a mammalian subject,

(ii) is capable of reducing the conversion of a biologically active cannabinoid to a biologically inactive cannabinoid in said mammal as determinable by an in vitro assay for a cytochrome P450enzyme, by an in vitro assay for UDP-glucuronosyltransferase (UGT) or by an in vivo test in a mammalian subject.

16. A composition comprising one or more of-8-THC, Cannabidiol (CBD), -7-THC, -10-THC or cannabinoid, wherein a double bond is present in a ring carbon other than at the 8-or 9-position, wherein the composition provides an amount of-9-THC equal to or less than a maximum amount of-9-THC, and wherein:

(i) the composition comprises-9-THC; or

(ii) The composition comprises a non-cannabinoid natural product capable of modulating the activity of a cytochrome P450(CYP) enzyme in a human subject, thereby producing the CYP enzyme with regulatory activity, and wherein said regulatory activity results in an increased in vivo concentration of an active metabolite of-8-THC, Cannabidiol (CBD), -7-THC, or-10-THC, or other similar THC isomers, administered in said human subject; or

(iii) The composition comprises a non-cannabinoid natural product capable of inhibiting the activity of UDP-glucuronyl transferase (UGT), and wherein the inhibited UGT results in an elevated in vivo concentration of an active metabolite of-8-THC, Cannabidiol (CBD), -7-THC or-10-THC or other similar THC isomers administered in the human subject; or

(iv) Cannabinoids with double bonds present at ring carbons other than the 8-or 9-position are not-7-THC or-10-THC but still produce active metabolites and where the double bonds located at ring carbons other than the 8-or 9-position are between carbons 9 and 11 (the double bond on the 11-methyl), carbons 7 and 6a, carbons 10 and 10a and carbons 6a and 10 a.

17. The composition of claim 16, wherein the active metabolite has one or more of psychoactive, medicinally active, and pharmacologically active.

18. A composition according to claim 16, wherein the maximum limiting concentration of-9-THC is defined by one or both of: (i) washington, oregon, california or colorado, or any other state or jurisdiction with similarly defined laws, or (ii) the national football league or other professional or non-professional sports regulatory agency's drug testing policies.

19. A composition according to claim 16, wherein the maximum defined concentration of-9-THC or a signalling metabolite thereof is an amount detectable in whole blood, plasma, urine or other bodily fluids of the human subject.

20. The composition of claim 16 comprising one or more of-8-THC, Cannabidiol (CBD), -7-THC, or-10-THC,

wherein-7-THC has psychotropic or pharmaceutical activity and wherein said activity is exerted by 11-hydroxy-7-THC, or

wherein-10-THC has psychotropic or pharmaceutical activity and wherein said activity is exerted by 11-hydroxy-10-THC, or

Wherein the other similar isomers have psychotropic or pharmaceutical activity, and wherein said activity is exerted by monohydroxy metabolites of such isomers.

Technical Field

The present disclosure relates to compositions and methods that provide increased concentrations of active cannabinoids, such as-8-tetrahydrocannabinol (-8-THC), -9-THC, Cannabidiol (CBD), and combinations thereof.

Background

The major cannabinoids from cannabis are Cannabidiol (CBD), cannabidiene (CBC), Cannabigerol (CBG), -9-trihydrocannabinol (-9-THC) and Cannabinol (CBN) (appendix et al (2008) J. Nat. prod.) -71: 1427-. A source of-8-tetrahydrocannabinol (-8-THC) is described (Owens et al (1981) clinical chemistry (Clin. chem.) 27: 619-. As to another difference between-8-THC and-9-THC, in treating glaucoma-8-THC and-9-THC have equal potency, but-8-THC has "little or no central effect", and is therefore "less psychoactive" compared to-9-THC (Cannabis Research results: 1980, National Institute of drug abuse, Research Monograph 31 (RC Peterson), pp 201-202. consistently, in a study that both-8-THC and-9-THC are effective as antiemetics, Cannabis sativa L.J.International Association of Life society, Biotechnology 76. 79 (Asrah. 1995-79); Cannabis 8-THC is a lower psychoactive cannabinoid than-9-THC (Abramov et al (1995) journal of the National Institute of drug abuse, National Institute of Research on drug abuse, National Institute of Research 31 (RC, RC Peterson), pp.201-202 Science 56: 2097-.

Clinical trials have demonstrated that cannabis or cannabis-derived formulations can ameliorate neuropathic pain in multiple sclerosis, improve appetite and sleep quality in cancer patients, reduce pain in fibromyalgia patients, and can act as antiemetics for chemotherapy-induced nausea and vomiting (see "Health Canada (2 months 2013) Information to healthcare professionals cannabis and Cannabinoids (feb.2013) Information for Health carerofessionals. cannabis (Marihuana, Marijuana) and the Cannabinoids) (pages 152 altogether)). The present disclosure addresses an unmet need for-8-THC compositions having less psychoactive than-9-THC, but still effective for medical effects such as treating glaucoma, for use as antiemetics, increasing sleep for tranquility, for use as anorectics, and the like. In addition, the present disclosure provides compositions comprising-8-THC, which cannot be detected by blood or urine tests that detect-9-THC or metabolites of-9-THC, and are limited by the dosage and packaging limitations of-9-THC.

Disclosure of Invention

Briefly, the present disclosure provides compositions comprising a combination of-8-THC and a non-cannabinoid natural product: (i) wherein the non-cannabinoid natural product is capable of increasing the duration of psychoactive or non-psychoactive pharmacological effect of-8-THC as determined by co-administration of-8-THC with or without the non-cannabinoid natural product, or (ii) wherein the non-cannabinoid natural product is capable of increasing the duration of psychoactive or non-psychoactive pharmacological effect of-9-THC as determined by co-administration of-9-THC with or without the non-cannabinoid natural product, or (iii) wherein the non-cannabinoid natural product is capable of increasing the concentration of 11-hydroxy-8-THC in the bloodstream of a human subject as determined by co-administration of-8-THC with or without the non-cannabinoid natural product, or (iv) wherein the non-cannabinoid natural product is capable of increasing the concentration of 11-hydroxy-9-THC in the bloodstream, can be determined by co-administering-9-THC with or without a non-cannabinoid natural product to a human subject.

The present disclosure also encompasses such compositions further comprising-9-THC, or such compositions not comprising-9-THC. Further, the above compositions are provided wherein the cannabinoid and the non-cannabinoid natural product are mixed together as a pharmaceutically acceptable composition for oral administration, wherein the pharmaceutically acceptable composition for oral administration is optionally a powder, tablet, pill, capsule, slurry, suspension, or liquid composition.

Also contemplated are the above compositions wherein-8-THC and the non-cannabinoid natural product are not mixed together, wherein-8-THC is a component of a pharmaceutically acceptable composition for oral administration, and wherein the non-cannabinoid is a component of a pharmaceutically acceptable composition for oral administration.

Additionally, the present disclosure provides the above composition further comprising at least one inhibitor of UDP-glucuronyl transferase (UGT), wherein, in the absence of the inhibitor, the UGT is capable of catalyzing glucuronidation of one or both of 11-hydroxy-8-THC and 11-hydroxy-9-THC, wherein the inhibitor is optionally a substrate for the UGT, which is capable of acting as a competitive inhibitor of the at least one UGT. Also contemplated are the above compositions further comprising at least one inhibitor of UDP-glucuronyl transferase (UGT), wherein in the absence of the inhibitor, the UGT is capable of catalyzing glucuronidation of one or both of 11-hydroxy-8-THC and 11-hydroxy-9-THC, wherein the inhibitor comprises one or more of curcumin, carvacrol, and norziconane triterpenoid saponins.

Further contemplated are the above compositions further comprising an inhibitor of a cytochrome P450enzyme (CYP enzyme), wherein the CYP enzyme catalyzes the metabolism of psychoactive cannabinoids to non-psychoactive metabolites, or wherein the CYP enzyme catalyzes the metabolism of non-psychoactive medically active cannabinoids to non-psychoactive non-medically active metabolites.

Additionally, the above compositions are provided, which comprise an inhibitor of an alcohol dehydrogenase that catalyzes the conversion of 11-hydroxy-9-THC to the corresponding carboxy aldehyde. Additionally, the above compositions are provided, which comprise an inhibitor of aldehyde dehydrogenase or aldehyde oxidase, which catalyzes the conversion of the carboxy aldehyde of 11-hydroxy-9-THC to 11-nor-9-carboxy-9-THC. Also contemplated are the above compositions comprising an inhibitor of an alcohol dehydrogenase that catalyzes the conversion of 11-hydroxy-8-THC to the corresponding carboxy aldehyde.

In another aspect, there is provided a composition as described above comprising an inhibitor of an aldehyde dehydrogenase or aldehyde oxidase that catalyzes the conversion of the carboxy aldehyde of 11-hydroxy-8-THC to 11-nor-9-carboxy-8-THC. In addition, the above composition is provided, which comprises an inhibitor that inhibits CYP3A 4-mediated conversion of-8-THC to 7-hydroxy-8-THC.

In another aspect, the present disclosure contemplates the above composition comprising an inhibitor that inhibits CYP3a 4-mediated conversion of-8-THC to 7-hydroxy-8-THC, wherein the inhibitor comprises one or more of grapefruit juice, bergamottin, peppermint oil, sesquiterpenes, and curcumin.

In psychoactive embodiments, the present disclosure provides the above composition, wherein the psychoactive effect comprises one or more of: (i) reduced Rapid Eye Movement (REM) sleep; (ii) increased deep sleep; or (iii) a decrease in seizure rate or seizure intensity. In a non-psychoactive embodiment, there is provided the above composition, wherein the non-psychoactive medical effect comprises one or more of: (i) antiemetic effect; (ii) neuroprotective effect; or (iii) a feeding deterrent effect.

In the cannabinoid receptor example, the disclosure provides a pharmaceutically-acceptable composition capable of oral administration to a human subject, the composition comprising-8-THC and-9-THC, wherein (i) the administered composition results in stimulation of CB1, or (ii) the administered composition results in stimulation of CB2, or (iii) the administered composition results in greater stimulation of CB1 as compared to the administration of-8-THC alone, or (iv) the administered composition results in greater stimulation of CB1 as compared to the administration of-9-THC alone, or (v) the administered composition results in greater stimulation of CB2 as compared to the administration of-8-THC alone, or (vi) the administered composition results in greater stimulation of CB2 as compared to the administration of-9-THC alone, (vii) (viii) the-8-THC in the administered composition enhances the pharmacological activity of-9-THC in the administered composition, or (viii) the-9-THC in the administered composition enhances the pharmacological activity of-8-THC in the administered composition.

A very high number range is provided. There is provided the above pharmacologically acceptable composition comprising a tablet containing more than 30mg-8-THC and 10-30mg-9-THC, or a first tablet containing more than 30mg-8-THC and a second tablet containing 10-30 mg-9-THC. There is provided a pharmacologically acceptable composition as described above comprising a tablet containing more than 30mg-8-THC and 2-10mg-9-THC, or a first tablet containing more than 30mg-8-THC and a second tablet containing 2-10 mg-9-THC. There is provided the above pharmacologically acceptable composition comprising a tablet containing more than 30mg-8-THC and 0.5-2.0mg-9-THC, or a first tablet containing more than 30mg-8-THC and a second tablet containing 0.5-2.0 mg-9-THC. Also included are the above pharmacologically acceptable compositions comprising a tablet containing more than 30mg-8-THC and 0.01-0.5mg-9-THC, or a first tablet containing more than 30mg-8-THC and a second tablet containing 0.01-0.5 mg-9-THC. Also provided are the above compositions, wherein the word "about" precedes each amount. In addition to the tablet embodiments, pills, capsules, powders (e.g., a first powder and a second powder), gels, lotions, slurries, liquids, aerosols, and the like are provided.

A high number range is provided. There is provided the above pharmacologically acceptable composition comprising a tablet containing 10-30mg-8-THC and 10-30mg-9-THC, or a first tablet containing 10-30mg-8-THC and a second tablet containing 10-30 mg-9-THC. There is provided the above pharmacologically acceptable composition comprising a tablet containing 10-30mg-8-THC and 2-10mg-9-THC, or a first tablet containing 10-30mg-8-THC and a second tablet containing 2-10 mg-9-THC. There is provided the above pharmacologically acceptable composition comprising a tablet comprising 10-30mg-8-THC and 0.5-2.0mg-9-THC, or a first tablet comprising 10-30mg-8-THC and a second tablet comprising 0.5-2.0 mg-9-THC. Also included are the above pharmacologically acceptable compositions comprising a tablet comprising 10-30mg-8-THC and 0.01-0.5mg-9-THC, or a first tablet comprising 10-30mg-8-THC and a second tablet comprising 0.01-0.5 mg-9-THC. Also provided are the above compositions, wherein the word "about" precedes each amount.

A moderate number range is provided. There is provided the above pharmacologically acceptable composition comprising a tablet comprising 10mg-8-THC and 10mg-9-THC, or a first tablet comprising 10mg-8-THC and a second tablet comprising 10 mg-9-THC. There is provided the above pharmacologically acceptable composition comprising a tablet containing 1.0mg-8-THC and 1.0mg-9-THC, or a first tablet containing 1.0mg-8-THC and a second tablet containing 1.0 mg-9-THC. There is provided the above pharmacologically acceptable composition comprising a tablet containing 1.0mg-8-THC and 0.5mg-9-THC, or a first tablet containing 1.0mg-8-THC and a second tablet containing 0.5 mg-9-THC. Also included are the above pharmacologically acceptable compositions comprising a tablet comprising 1.0mg-8-THC and 0.25mg-9-THC, or a first tablet comprising 1.0mg-8-THC and a second tablet comprising 0.25 mg-9-THC. Also included are the above pharmacologically acceptable compositions comprising a tablet comprising 1.0mg-8-THC and 0.125mg-9-THC, or a first tablet comprising 1.0mg-8-THC and a second tablet comprising 0.125 mg-9-THC. Also provided are the above compositions, wherein the word "about" precedes each amount.

A low number range is provided. In an embodiment having a lower amount of-9-THC, there is provided the above-described pharmacologically acceptable composition comprising a tablet comprising 4.0mg-8-THC and 0.125mg-9-THC, or a first tablet comprising 4.0mg-8-THC and a second tablet comprising 0.125mg-9-THC, or a tablet comprising 2.0mg-8-THC and 0.125mg-9-THC, or a first tablet comprising 2.0mg-8-THC and a second tablet comprising 0.125mg-9-THC, or a tablet comprising 1.0mg-8-THC and 0.125mg-9-THC, or a first tablet comprising 1.0mg-8-THC and a second tablet comprising 0.125 mg-9-THC. Also provided are the above compositions, wherein the word "about" precedes each amount.

A very low number range is provided. There is provided the above pharmacologically acceptable composition comprising a tablet containing 2.0mg-8-THC and 2.0mg-9-THC, or a first tablet containing 2.0mg-8-THC and a second tablet containing 2.0mg-9-THC, a tablet containing 2.0mg-8-THC and 1.0mg-9-THC, or a first tablet containing 2.0mg-8-THC and a second tablet containing 1.0 mg-9-THC. There is provided the above pharmacologically acceptable composition comprising a tablet containing 2.0mg-8-THC and 0.5mg-9-THC, or a first tablet containing 2.0mg-8-THC and a second tablet containing 0.5 mg-9-THC. Also included are the above pharmacologically acceptable compositions comprising a tablet comprising 2.0mg-8-THC and 0.25mg-9-THC, or a first tablet comprising 2.0mg-8-THC and a second tablet comprising 0.25 mg-9-THC. Also provided are the above compositions, wherein the word "about" precedes each amount. In addition to the tablet embodiments, pills, capsules, powders (e.g., a first powder and a second powder), gels, lotions, slurries, liquids, aerosols, and the like are provided.

Range embodiments are also provided, where a range may consist of any two consecutive values, or any three consecutive values, or any four consecutive values, etc. For example, for the disclosure above: "the above-mentioned pharmacologically acceptable composition is provided which comprises tablet … … containing 2.0mg-8-THC and 2.0mg-9-THC and tablet containing 2.0mg-8-THC and 1.0 mg-9-THC", and the range examples will be "tablet containing 2.0mg-8-THC and 1.0 to 2.0 mg-9-THC".

Also provided are the above pharmaceutically acceptable compositions, which can be used for one or more of oral administration, intranasal administration, mucosal administration, or administration to a human subject by inhalation.

Furthermore, in another aspect, there is provided the above pharmaceutically acceptable composition, wherein a greater degree of stimulation is determinable by comparing stimulation of CB1 or CB2 in: (a) administering a composition comprising-8-THC and-9-THC, (b) administering-8-THC in an amount equal to that present in the composition. Further, there is provided the above pharmaceutically acceptable composition, wherein a greater degree of stimulation can be determined by comparing stimulation of CB1 or CB2 in the following manner: (a) administering a composition comprising-8-THC and-9-THC, (b) administering-9-THC in an amount equal to that present in the composition.

In an embodiment in which the animal cannabinoid receptor data is extrapolated to human cannabinoid receptors, the disclosure provides the above-described pharmaceutically acceptable composition, wherein stimulation of CB1 and stimulation of CB2 in a human subject can be determined by administering to the animal subject a composition comprising-8-THC and-9-THC, by administering-8-alone, and by administering-9-alone, and by extrapolating the stimulation results to a human.

Also provided are methods of administering the above compositions, for example, comprising the step of providing a compound, or the step of providing a first compound and a second compound, further comprising the step of oral administration (of the compound, or both the first compound and the second compound), the step of administration by nasal inhalation (of the compound, or both the first compound and the second compound), the step of oral administration in combination with nasal inhalation (for one compound), or the step of oral administration (for the first compound) and the step of nasal administration (for the second compound).

Also, methods for making the above compositions are contemplated. Cannabidiol (CBD) embodiments are also provided.

The present disclosure provides compositions comprising a combination of-8-THC, Cannabidiol (CBD) and non-cannabinoid natural products: (i) wherein the non-cannabinoid natural product is capable of increasing the duration of psychoactive or non-psychoactive pharmacological action of-8-THC as determined by co-administration of-8-THC with or without the non-cannabinoid natural product, or (ii) wherein the non-cannabinoid natural product is capable of increasing the duration of psychoactive or non-psychoactive pharmacological action of CBD as determined by co-administration of CBD with or without the non-cannabinoid natural product, or (iii) wherein the non-cannabinoid natural product is capable of increasing the concentration of 11-hydroxy-8-THC in the bloodstream of a human subject as determined by co-administration of-8-THC with or without the non-cannabinoid natural product, or (iv) wherein the non-cannabinoid natural product is capable of increasing the concentration of 11-hydroxy-CBD in the bloodstream, can be determined by co-administering CBD with or without non-cannabinoid natural products to a human subject.

In addition, the above composition further comprising-9-THC is provided. Further, the above composition not comprising-9-THC is provided. Further, the above composition is provided wherein-8-THC, Cannabidiol (CBD) and the non-cannabinoid natural product are mixed together as a pharmaceutically acceptable composition for oral administration, wherein the pharmaceutically acceptable composition for oral administration is optionally a powder, tablet, pill, capsule, slurry, suspension or liquid composition.

Further, the above compositions are provided wherein-8-THC, CBD and non-cannabinoid natural products are not all mixed together, wherein-8-THC is a component of a first pharmaceutically acceptable composition for oral administration, wherein CBD is a component of a second pharmaceutically acceptable composition for oral administration, and wherein non-cannabinoid is a component of a third pharmaceutically acceptable composition for oral administration. Alternatively, the-8-THC and CBD may be provided together in a fourth pharmaceutically acceptable composition. Likewise, the-8-THC and the non-cannabinoid natural product may be provided together in a fifth pharmaceutically acceptable composition. In addition, the CBD and the non-cannabinoid natural product may be provided together in a sixth pharmaceutically-acceptable composition.

Also contemplated are the above compositions further comprising at least one inhibitor of UDP-glucuronyl transferase (UGT), wherein in the absence of the inhibitor, the UGT is capable of catalyzing glucuronidation of one or both of 11-hydroxy-8-THC and CBD, wherein the inhibitor is optionally a substrate for the UGT, which is capable of acting as a competitive inhibitor for the at least one UGT. In another aspect, the above composition is provided, further comprising at least one inhibitor of UDP-glucuronyl transferase (UGT), wherein in the absence of the inhibitor, the UGT is capable of catalyzing glucuronidation of one or both of 11-hydroxy-8-THC and CBD, wherein the inhibitor comprises one or more of curcumin, carvacrol, and norziconane triterpenoid saponins.

Further contemplated are the above compositions further comprising an inhibitor of a cytochrome P450enzyme (CYP enzyme), wherein the CYP enzyme catalyzes the metabolism of psychoactive cannabinoids to non-psychoactive metabolites, or wherein the CYP enzyme catalyzes the metabolism of non-psychoactive medically active cannabinoids to non-psychoactive non-medically active metabolites. The above compositions may also be obtained comprising an inhibitor of an alcohol dehydrogenase catalyzing the conversion of 11-hydroxy-CBD to the corresponding carboxy aldehyde. Further included are the above compositions comprising an inhibitor of an aldehyde dehydrogenase or an aldehyde oxidase that catalyzes the conversion of the carboxy aldehyde of 11-hydroxy-CBD to 11-nor-9-carboxy-CBD. Additionally, the above compositions are provided which comprise an inhibitor of an alcohol dehydrogenase that catalyzes the conversion of 11-hydroxy-8-THC to the corresponding carboxy aldehyde. In another aspect, there is provided a composition as described above comprising an inhibitor of an aldehyde dehydrogenase or aldehyde oxidase that catalyzes the conversion of the carboxy aldehyde of 11-hydroxy-8-THC to 11-nor-9-carboxy-8-THC.

Also included are the above compositions comprising an inhibitor that inhibits CYP3A 4-mediated conversion of-8-THC to 7-hydroxy-8-THC. Further, the above composition is provided comprising an inhibitor that inhibits CYP3a4 mediated conversion of-8-THC to 7-hydroxy-8-THC, wherein the inhibitor comprises one or more of grapefruit juice, bergamottin, peppermint oil, sesquiterpene, and curcumin.

In psychoactive and medical effect embodiments, there is provided the above composition, wherein the psychoactive effect comprises one or more of: (i) reduced Rapid Eye Movement (REM) sleep; (ii) increased deep sleep; or (iii) a decrease in seizure rate or seizure intensity. Also provided are the above compositions, wherein the non-psychoactive medical effect comprises one or more of: (i) antiemetic effect; (ii) neuroprotective effect; or (iii) a feeding deterrent effect.

In the CB1 and CB2 embodiments, there is provided a pharmaceutically acceptable composition capable of being orally administered to a human subject, the composition comprising-8-THC and Cannabinol (CBD), wherein (i) the administered composition results in stimulation of CB1, or (ii) the administered composition results in stimulation of CB2, or (iii) the administered composition results in greater stimulation of CB1 as compared to-8-THC alone, or (iv) the administered composition results in greater stimulation of CB1 as compared to CBD alone, or (v) the administered composition results in greater stimulation of CB2 as compared to-8-THC alone, or (vi) the administered composition results in greater stimulation of CB2 as compared to CBD alone, (vii) the-8-THC in the administered composition enhances the pharmacological activity of-9-THC in the administered composition, or (viii) the CBD in the administered composition enhances the pharmacological activity of-8-THC in the administered composition.

In a combined example where-8-THC and CBD are provided simultaneously, there is provided a pharmacologically acceptable composition as described above comprising a tablet containing the following amounts of-8-THC and CBD: (i)10mg-8-THC and 10mg CBD, or (ii)5mg-8-THC and 5mg CBD, or (iii)2mg-8-THC and 2mg CBD, or (iv)1mg-8-THC and 1mg CBD, or (v)5mg-8-THC and 2mg CBD, or (vi)5mg-8-THC and 1mg CBD, or (vii)5mg-8-THC and 0.5mg CBD, or (viii)2mg-8-THC and 1mg CBD, or (ix)2mg-8-THC and 0.5mg CBD, or (x)2mg-8-THC and 0.25mg CBD, or (xi)1mg-8-THC and 1mg CBD, or (xii)1mg-8-THC and 0.5mg CBD, or (xiii)1mg-8-THC and 0.25mg CBD, or contain approximately the recited amounts of-8-THC and CBD.

Furthermore, the above-mentioned pharmaceutically acceptable compositions are contemplated, which can be used for one or more of oral administration, intranasal administration, mucosal administration, or administration to a human subject by inhalation. Also provided are the above pharmaceutically acceptable compositions, wherein a greater degree of stimulation can be determined by comparing stimulation of CB1 or CB2 in the following manner: (a) administering a composition comprising-8-THC and CBD, (b) administering-8-THC in an amount equal to that present in the composition. Furthermore, the above pharmaceutically acceptable compositions are contemplated wherein a greater degree of stimulation can be determined by comparing stimulation of CB1 or CB2 in the following manner: (a) administering a composition comprising-8-THC and CBD, (b) administering CBD in an amount equal to that present in the composition. In another aspect, there is provided the above pharmaceutically acceptable composition, wherein stimulation of CB1 and stimulation of CB2 in a human subject can be determined by administering to an animal subject a composition comprising-8-THC and a CBD, by administering-8-alone, and by administering CBD alone and by extrapolating the stimulation results to a human.

In a screening method embodiment, the present disclosure provides a method of screening non-cannabinoid natural products to identify pharmaceutically acceptable non-cannabinoid natural products capable of increasing the concentration of a biologically active cannabinoid or decreasing the concentration of an inactive cannabinoid in a biological fluid of a test mammal, the method comprising: (i) administering-8-THC plus Cannabidiol (CBD) to a test mammal, (ii) co-administering a non-cannabinoid natural product to the test mammal, wherein a first time period is required to begin and complete administration of-8-THC plus CBD, and wherein a second time period is required to begin and complete administration of the non-cannabinoid natural product, (iii) wherein the first time period is the same as the second time period, wherein the first time period overlaps with but is not the same as the second time period, or wherein the first time period does not overlap with the second time period, (iv) obtaining and transferring a sample of at least one biological fluid from the test mammal into a container after both the first time period and the second time period have been completed, and within five days after both the first time period and the second time period have been completed, (v) subjecting the sample to conditions capable of detecting one or more biologically active compounds-8-THC, a, 11-hydroxy-8-THC, CBD, 11-hydroxy-CBD, 7-hydroxy-8-THC, 7-hydroxy-CBD, or a method of detection capable of detecting one or more biologically inactive compounds 11-nor-9-carboxy-8-THC, 11-nor-9-carboxy-CBD, 7-hydroxy-8-THC or 7-hydroxy-CBD, (vi) detecting said one or more biologically active compounds and the biologically inactive compounds, and calculating the concentration of said one or more compounds in the biological fluid.

As an alternative to the disclosure above, the method provides embodiments within one day, within two days, within three days, within four days, within six days, within seven days, within eight days, within nine days, within ten days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, and so on, after both the first time period and the second time period are completed, and within five days after both the first time period and the second time period are completed.

Further, the above method is provided, further comprising administering-8-THC to a control mammal, avoiding co-administration of non-cannabinoid natural products, obtaining a sample of at least one biological fluid from the mammal within five days of the administration of-8-THC and transferring the sample to a container, subjecting the sample to an assay capable of detecting one or more compounds of-8-THC, 11-hydroxy-8-THC, CBD, 11-hydroxy-CBD, 7-hydroxy-8-THC, 7-hydroxy-CBD, 11-nor-9-carboxy-8-THC, 11-nor-9-carboxy-CBD, detecting said one or more compounds and calculating the concentration of said one or more compounds in the biological fluid, the concentration of the control mammal is compared to the concentration of the test mammal and the extent to which the non-cannabinoid affects the concentration of the one or more compounds is determined.

In other forms of the screening embodiment, there is provided the above method, wherein the test mammal is a human subject, and wherein the control mammal is a human subject. Also provided are the above methods, wherein the test mammal is a human subject, wherein the control mammal is a human subject, and wherein the test mammal is the same human subject as the control mammal.

Biological fluid embodiments are contemplated. In addition, the above method is provided, wherein the biological fluid is plasma, whole blood, serum, urine, saliva, mucus, sweat, semen, cerebrospinal fluid, or the like. Furthermore, tissue samples such as hair, skin, liver biopsies, etc. are contemplated. Methods of analysis are provided (see, e.g., White RM (2017) Drugs in hair, first part of main drug classes (Drugs in hair, part i.e. metabolism of major drug classes), "department scientific general thesis (rev.)" 29:23-55.Beasley E et al (2016) Detection and localization of cannabinoids in single hair samples by rapid derivatization and matrix-assisted laser desorption ionization mass spectrometry analysis, "analytical chemistry (analysis, 88: 10328-34. gamma. diagnosis and analysis of lipid desorption ionization activity) analysis of cannabinoids in single hair samples, monitored by analysis of Drugs in biological samples (2016) (drug in health chemical analysis, 2016) (2016) analysis of Drugs in biological analysis).

Furthermore, the above method is provided, wherein the pharmaceutically acceptable natural product is administered orally and-8-THC is administered orally, or wherein the pharmaceutically acceptable non-cannabinoid natural product is administered orally and CBD is administered orally, or wherein the pharmaceutically acceptable non-cannabinoid natural product is administered orally and-8-TRC and CBD are administered orally.

In another aspect, the above method is provided, wherein the pharmaceutically acceptable non-cannabinoid natural product comprises one or more of a terpene, carvacrol, curcumin, a CYP enzyme inhibitor, and a UGT enzyme inhibitor.

In an administration method embodiment, there is provided a method of administering one of the above compositions to a human subject, comprising the steps of: (i) providing the composition to a human subject, (ii) administering the composition to a human subject, or self-administering the composition by a human subject, (iii) increasing the concentration of cannabinoids of the composition in the blood stream of the human subject, and (iv) wherein the administration results in a psychological or medical effect on the human subject, the effect being assessed by one or both of a questionnaire or biochemical test. Embodiments of the above methods of administration are provided, comprising oral administration, or comprising nasal administration, or comprising mucosal administration (e.g., intranasal formulations or suppositories), or comprising administration by inhalation, or comprising topical administration, or any combination thereof. Topical application may be via a skin patch (see US6,444,454, US7,54,190, US8,151,987, and US8,840,921, each of which is incorporated herein by reference in its entirety), or may be via a skin lotion or cream.

Compositions are provided that increase the blood flow concentration of-8-THC or an active metabolite thereof or that increase the blood flow concentration of cannabinoids or active metabolites thereof. Active cannabinoids and their metabolites have been identified in the literature, including those with psychoactive effects, non-psychoactive medical effects and those with both psychoactive and medical effects.

A composition is provided comprising a combination of-8-THC and a non-cannabinoid natural product, wherein the non-cannabinoid natural product is capable of increasing the concentration of 11-hydroxy-8-THC in the bloodstream of a human subject as determinable by an in vitro assay which is capable of detecting the ability of the non-cannabinoid natural product to inhibit CYP enzyme-mediated metabolism of-8-THC (or an active metabolite thereof) to an inactive product, or which is capable of detecting the ability of the non-cannabinoid natural product to inhibit UDP-glucuronosyltransferase (UGT) -mediated metabolism of-8-THC (or an active metabolite thereof) to an inactive product. Additionally, compositions comprising a combination of Cannabidiol (CBD) and a non-cannabinoid natural product, wherein the non-cannabinoid natural product is capable of increasing the concentration of 11-hydroxy-CBD in the bloodstream, are provided.

Can be determined by an in vitro test that detects the ability of a non-cannabinoid natural product to inhibit CYP enzyme-mediated metabolism of CBD (or an active metabolite thereof) to an inactive product, or that detects the ability of a non-cannabinoid natural product to inhibit UDP-glucuronidase (UGT) -mediated metabolism of CBD (or an active metabolite thereof) to an inactive product.

Embodiments encompassing the THC isomer family are contemplated. There is provided a composition comprising one or more of-8-THC, Cannabidiol (CBD), -7-THC, -10-THC or cannabinoid, wherein the double bond is present in a ring carbon other than the 8-position or the 9-position, wherein the composition provides an amount of-9-THC equal to or less than a maximum defined amount of-9-THC and wherein: (i) the composition comprises-9-THC; or (ii) the composition comprises a non-cannabinoid natural product capable of modulating the activity of a cytochrome P450(CYP) enzyme in a human subject, thereby producing the CYP enzyme having modulating activity, and wherein said modulating activity results in an increased in vivo concentration of an active metabolite of-8-THC, Cannabidiol (CBD), -7-THC or-10-THC or other similar THC isomer administered in the human subject; or (iii) the composition comprises a non-cannabinoid natural product capable of inhibiting the activity of UDP-glucuronosyltransferase (UGT), and wherein the inhibited UGT results in an elevated in vivo concentration of an active metabolite of-8-THC, Cannabidiol (CBD), -7-THC or-10-THC or other similar THC isomers administered in the human subject; or (iv) cannabinoids in which the double bond is present at a ring carbon other than the 8-or 9-position are not-7-THC or-10-THC.

Embodiments are provided that encompass alternative two-key locations. A cannabinoid is provided wherein a double bond is present at a ring carbon other than at the 8-position or the 9-position, which cannabinoid is not-7-THC or-10-THC but still produces an active metabolite, and wherein the double bond at a ring carbon other than at the 8-position or the 9-position is between carbons 9 and 11 (the double bond at the 11-methyl group), carbons 7 and 6a, carbons 6a and 6, carbons 6 and 12 (the double bond at the 12-methyl group), 6 and 13 (the double bond at the 13-methyl group), carbons 10 and 10a, carbons 6a and 10a, and carbons 10a and 10 b. Also included are cannabinoids having more than one double bond, and wherein the bond is in the position shown. Compositions and methods in which the cannabinoid has a double bond at one or more of the aforementioned positions are excluded.

In some embodiments, cannabinoids are provided, wherein the double bond is a cis double bond, while in other aspects the double bond is a trans double bond. Additionally, cannabinoids are included which have multiple double bonds, where all double bonds are cis, where all double bonds are trans, or where one is cis and the other is trans, or where some are cis and others are trans.

Other examples of double bond positions are cannabinoids with a double bond between carbons 9 and 10, 8 and 9, 9 and 11 (double bond on 11-methyl), 7 and 6a, 6a and 6, 6 and 12 (double bond on 12-methyl), 6 and 13 (double bond on 13-methyl), 10 and 10a, 6a and 10a, or 10a and 10 b.

In some aspects, cannabinoids are provided, wherein the double bond is a cis double bond, while in other aspects the double bond is a trans double bond. Additionally, cannabinoids with multiple double bonds are contemplated, where all double bonds are cis, where all double bonds are trans, or where one is cis and the other is trans, or where some are cis and others are trans. In some aspects, these cannabinoids do not have any double bond at the 8-position, or any double bond at the 9-position, or any double bond at the 8-or 9-position.

The monohydroxy derivative may include cannabinoids having hydroxyl groups at the carbon numbers 1, 2, 3,4, 5, 6a, 7, 8, 9, 10, 11 (methyl), 12 (methyl), 13 (methyl), 1', 2', 3', 4' and 5 '. Cannabinoids with multiple hydroxyl groups at multiple carbon positions are contemplated. In addition, cannabinoids with two hydroxyl groups on a given carbon group are also included. Also, any composition or process having one or more of the above monohydroxy derivatives may be excluded. According to the international basic and clinical pharmacology alliance lxxix, cannabinoid receptors and their ligands, pertweee RG et al (2010): in addition to CB1, and CB1(International Union of basic and Clinical pharmacology.LXXIX. Cannabinoid receivers and the physicians: beyond CB1 and CB 1), "pharmacological reviews (Pharmacol. Rev)," 62: 588-.

Also provided are the above compositions, wherein the active metabolite has one or more of psychoactive, medicinally active, and pharmacologically active.

Including compositions subject to legal or physical limitations and related methods. There is provided any of the compositions disclosed above wherein the maximum limiting concentration of-9-THC is defined by one or both of: (i) washington, oregon, california or colorado, or any other state or jurisdiction with similarly defined laws, or (ii) the national football league or other professional or non-professional sports regulatory agency's drug testing policies.

Compositions and related methods are provided that are limited by cannabinoid concentrations (e.g., mg/L, micromolar, and ng/mg tissue). Any one or more of the above compositions are provided, wherein the maximum defined concentration of-9-THC or a signaling metabolite thereof is an amount detectable in whole blood, plasma, urine, or other bodily fluids of a human subject. Also provided are the above compositions, wherein the maximum defined concentration is equal to or less than 10 nanograms (ng)/mL, equal to or less than 5ng/mL, equal to or less than 2ng/mL, or equal to or less than 1 ng/mL. Also provided are the above compositions wherein the maximum amount of-9-THC is 1mg-9-THC, 2mg-9-THC, 5mg-9-THC or 10 mg-9-THC. In another aspect, there is provided a composition as described above comprising one or more of-8-THC, Cannabidiol (CBD), -7-THC or-10-THC, wherein-7-THC has psychoactive or pharmaceutical activity, and wherein said activity is exerted by 11-hydroxy-7-THC, or wherein-10-THC has psychoactive or pharmaceutical activity, and wherein said activity is exerted by 11-hydroxy-10-THC, or wherein other similar isomers have psychoactive or pharmaceutical activity, and wherein said activity is exerted by monohydroxy metabolites of such isomers. In another aspect, the above compositions, i.e., one-part compositions, and the above compositions that are not one-part compositions are provided.

Detailed Description

As used herein, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural forms unless the context clearly dictates otherwise. All references cited herein are incorporated by reference to the same extent as if each individual patent and published patent application was specifically and individually indicated to be incorporated by reference and was made to the accompanying drawings, figures, sequence listing, compact disc, and the like.

Concentration and amount of THC compound

The washington state liquor and cannabis committee (WSLCB) set limits on the concentration of-9-THC in the bloodstream for determining affected Driving (DUI): "what is the DUI specification? The initiative itself dictates that the "-9" THC content limit of the DUI be greater than or equal to 5 nanograms per milliliter (5ng/mL) of blood. The task of state and local law enforcement agencies is to enforce DUI restrictions. "(8 months and 3 days visit 2017). With respect to testing, the NTSA publication indicates "cannabis use by drivers is of particular concern. We tested the psychoactive substance 9-tetrahydrocannabinol, commonly known as THC; the active metabolite 11-hydroxy-9-tetrahydrocannabinol (also labeled 11-OH-THC and referred to as "hydroxy THC"); and the inactive metabolite 11-nor-9-carboxy-9-tetrahydrocannabinol (also known as "carboxy-THC" and labeled "THC-COOH"). "(national transportation safety administration (NTSA) of the department of transportation of America)" (2016.7 months.) Cannabis, Other Drugs and alcohol use by Drivers (Marijuana, Other Drugs, and alcohol by Drivers) (total page 73). In addition, the NTSA publication also mentions legal limits for THC in blood, "12 months 2012, washington started to enforce legal regulations, including … … revisions to national affected driving regulations to include the intrinsic limit of THC (5 ng/mL). "

Most of the key components of the DUI regulations and other test accuracies are used to determine the consumption of cannabis or cannabis products, with "THC" being narrowly defined to include only-9 THC, so a positive test is based only on the level of-9 THC metabolites and not metabolites of any other isomers.

The present disclosure provides compositions that have no detectable increase in blood levels of-9-THC (or-9-THC metabolite levels) compared to baseline levels when the composition is not administered. The comparison is of-9-THC concentration for a given human subject, where the subject is known not to consume (or inhale) any THC source (baseline), and where the subject has consumed a composition of the present disclosure. For baseline measurements, the human subject may be a person who has never consumed (or inhaled) any THC source, or who has not consumed any THC source within the last five weeks.

The present disclosure provides compositions and methods that result in a Cmax for a given cannabinoid, wherein the Cmax in whole blood is less than a given concentration, such as 5ng/mL, wherein the Cmax in plasma is less than a given concentration, such as 5mg/mL, or the Cmax in serum is less than a given concentration, such as 5 mg/mL.

Also provided are compositions that increase the detectable blood level of-9-THC to a maximum concentration (Cmax), and wherein Cmax is less than 5ng/mL, less than 4.8ng/mL, less than 4.6ng/mL, less than 4.4ng/mL, less than 4.2ng/mL, less than 4.0ng/mL, less than 3.8ng/mL, less than 3.6ng/mL, less than 3.4ng/mL, less than 3.2ng/mL, less than 3.0ng/mL, less than 2.8ng/mL, less than 2.6ng/mL, less than 2.4ng/mL, less than 2.2ng/mL, less than 2.0ng/mL, less than 1.8ng/mL, less than 1.6ng/mL, less than 1.4ng/mL, less than 1.2ng/mL, less than 1.0ng/mL, and the like.

As an alternative to the blood flow concentration parameter Cmax, a parameter of the area under the curve (AUC) may be used. AUC refers to the integrated area of blood concentration compared to a baseline concentration level over a given time period. The given time period may be AUG 0-24 hours or AUC 0 hours-infinity, and so on.

In alternative embodiments, the concentration limits are those from human urine, human saliva, or other fluids.

The NTSA publication references the method of Moore et al to identify and quantify-9-THC (Moore C et al (2007) Simultaneous identification of 2-carboxytetrahydrocannabinol, tetrahydrocannabinol, cannabinol and cannabidiol (Simultaneous identification of 2-carboxytetrahydrocannabinol, tetrahydrocannabinol, cannabinol and cannabidiol in oral fluid) & J.chromatograph B: Biomedical and applications (Journal of Chromatography B: Biomedical science and applications) & 852, 459-464).

Limit of dosage

The present disclosure provides portions lower than, for example, those set forth by one or more of the washington state legislation, oregon state legislation and colorado state legislation.

Washington State legislation provisions: WAC 314-55-095 cannabis portion and transaction limits. (1) For qualified patients or designated providers aged 21 and older who do not enter the medical cannabis authorization database, cannabis portion and transaction limitations are as follows: (a) and (4) single-portion preparation. The single injection of cannabis should not exceed ten milligrams of active Tetrahydrocannabinol (THC) or 9. (b) Maximum number of parts. The maximum parts of any single unit of cannabis infused product intended to be consumed or swallowed are 10 parts or 100 milligrams of active THC or 9. A single unit of hemp concentrate cannot exceed 1 gram. RCW 69.50.101(2rr) "THC concentration" refers to the percentage of-9 tetrahydrocannabinol content per dry weight of any part of the plant cannabis, or volume or weight of the cannabis product, or the combined percentage of-9 tetrahydrocannabinol and tetrahydrocannabinolic acid in any part of the plant cannabis, regardless of the moisture content. The blood limit for DUI is defined in terms of "THC concentration": RCW 46,20.308(5) if the person's blood or breath is tested one or more times after arrest and after any other applicable conditions and requirements of this section, the test results show that if the person is 21 years old or older, the person's breath or blood alcohol concentration is 0.08 or higher, or the person's blood THC concentration is 5.00 or higher, or if the person is not 21 years old, the person's breath or blood alcohol concentration is 0.02 or higher, or the person's blood THC concentration is higher than 0.00, or the person refuses to accept the test, the arresting person or other law enforcement person who has performed any tests, or the department who tests the person's blood in the case of arrest (if applicable), should … … "the present disclosure provide compositions, portions, administration methods, manufacturing methods, etc. that reach or fall below the above limits.

The oregon state legislation states: OREGON, OAR 333-. (53) "THC" refers to tetrahydrocannabinol and has the same chemical Abstract service number as-9 THC. OAR 333-. To evaluate the DUI, there is no plasma concentration limit for THC in Oregon. "the present disclosure provides compositions, amounts, methods of administration, methods of manufacture, and the like, that meet or fall below the above-recited limits.

Colorado state legislation states: colorado. r 103-definition "single serving of edible cannabis retail product" refers to edible cannabis retail products sold to consumers that contain no more than 10mg of active THC. By "standard amount of cannabis" is meant a standardized single serving of active THC. The standard amount of cannabis should not exceed 10mg of active THC. "THC" refers to tetrahydrocannabinol. The "active THC" is not defined in the regulation or rule. R602 (C). Each individually packaged edible cannabis retail product, even when contained in multiple servings, must not have a total active THC content in excess of 100 milligrams. See rule R1004-tag requirements: special requirements, edible hemp retail products. R604 (C3) standard portion of cannabis should not exceed 10mg of active THC. A hemp retail product manufacturing facility that manufactures edible hemp retail products should determine the total number of standard portions of hemp for each product it manufactures. Retail units of single edible cannabis products sold must not contain more than 100 milligrams of active THC. The DUI blood limit for CRS 42-4-13016 (TV) -9THC was 5 ng/mL. (IV) As shown in the blood analysis of the notifier, if the blood of the driver contains 5ng or more of 9-tetrahydrocannabinol per ml of whole blood at this time, it is inferred that the notifier is being affected by one or more drugs. "internet bulletin, korora official web portal, cannabis korora (2017), in the statement provides a definition of the portion quantities that each standard portion of edible cannabis retail product (one portion consisting of 10mg THC) must be individually marked, stamped or printed with new universal symbols. "

The present disclosure provides compositions, amounts, methods of administration, methods of manufacture, and the like, that meet or fall below the above-recited limits.

Cytochrome P450 modulators

To provide background information, drugs may be converted in vivo to inactive forms by cytochrome P450. Cytochrome P450 is often abbreviated as "CYP", "CYP enzyme" or "CYP isozyme". "CYP enzymes exist in various isoforms and are encoded by different genes. Each CYP isozyme acts on a specific set of substrates, and substrates specifically recognized by only one CYP enzyme are available. Some of these CYP isozymes and their probe substrates are shown below: caffeine (Caffeine) (CYP1a 2); losartan (Losartan) (CYP2C 9); omeprazole (Omeprazole) (CYP2C 19); dextromethorphan (dextromeorphan) (CYP2D 6); midazolam (Midazolam) (CYP 3A); bupropion (Bupropion) (CYP2B 6); tosylamide (Tolbutamide) (CYP2C 9); chlorzoxazone (CYP2E1) (see grangen a et al (2017) journal of chromatography B analytical techniques in biomedicine and life sciences (j.chromatogr.b.analyt.technol.biomed.life Sci.) -1040: 144-158, Snyder BD et al (2014) journal of european clinical Pharmacology (eur.j.clin.pharma.) -70: 1115; 1122; 2016 and a et al (2016) Pharmacologne frontier (Frontiers in Pharmacology.) -7: 517-525; Tran et al (2016) Pharmacologne 82: 160-167).

With respect to cannabinoids, CYP2C9 catalyzes the 11-hydroxylation of cannabinoids by human liver enzymes. Accordingly, the present disclosure provides an inducer of CYP2C9, wherein administration of the inducer of CYP2C9 increases 11-hydroxylation of co-administered cannabinoids such as-8-THC or-9-THC or derivatives thereof. For this embodiment of the disclosure, an example sequence of events is shown below. This sequence of events may involve liver, gut or liver and gut CYP enzymes:

step one, administration of a CYP2C9 inducer results in increased CYP3C9 activity in the liver.

Step two, administering-8-THC, -9-THC or a mixture of-8-THC and-9-THC.

The result is an increased conversion of the administered cannabinoid to the 11-hydroxy derivative in the liver.

With respect to CYP enzyme inducers, lumacatto (Lumacaftor) has been identified as an inducer of CYP2C9 (see lumacatto/ivacavetor (ivacaftor) combination (cystic fibrosis in patients 12 or older than 12 with F508del mutation in the CFTR gene) NDA 206-038.81 clinical reviews page 24 of 99 medical reviews page 24. dapapafenib (Dabrafenib) (melanoma with BRAF V600E mutation) NDA 202-806.39 page 17 of the review by the members of the discipline team). In addition, dapafenib has been identified as an inducer of CYP2C9 (see dapafenib (melanoma with BRAF V600E mutation) NDA 202-806.39, page 17 across the review by the subject team leader) the above documents are all from the FDA website and these documents can be accessed by typing in the drug name or NDA number.

With further regard to the cannabinoids, CYP3A4 catalyses the conversion of-8-THC to the 7-hydroxy derivative of-8-THC, thereby reducing the concentration of-8-THC in the liver. The result of a reduction in-8-THC in the liver is a reduction in the conversion of-8-THC to 11-hydroxy-8-THC. Accordingly, the present disclosure provides compositions and methods for increasing 11-hydroxy-8-THC by co-administering a CYP3a4 inhibitor and-8-THC to a human subject. The CYP3a4 inhibitor may be an inhibitor that is not a CYP3a4 substrate, or it may be a CYP3a4 inhibitor that is inhibited by competitive inhibition as a CYP3a4 substrate. See Watanabe, Yamaori, Funahashi (2007) in Life Sciences (Life Sciences) 80: 1415-1419).

The present disclosure provides compositions and methods for inhibiting CYP3a4, the result of which is reduced destruction of-8-THC through CYP3a4 mediated catalysis of-8-THC to 7-hydroxy-8-THC. This is summarized as the following steps:

step one, administering an inhibitor of CYP3a 4. CYP3a4 inhibitors include grapefruit juice, bergamottin, dihydroxybergamottin, ketoconazole (ketoconazole), itraconazole (itraconazole), clarithromycin (clarithromycin), erythromycin (erythromycin), atanavir (atanavir), and ritonavir (ritonavir) (see package label.stivarga (regorafenib) tablets, oral.2012, 9 months (15 pages.) see also carbotinib (Cabozantinib) (thyroid cancer) NDA 203-756.106 pages 34-35 of the clinical pharmacology review, from the FDA website). Bergamottin and dihydroxy bergamottin are chemicals that inhibit CYP3a4 in grapefruit juice, resulting in elevated plasma levels of any drugs that are normally metabolized by CYP3a4 (see Lin HL et al (2012) drug metabolism and disposition (drug meta. dispos.) 40: 998-.

Step two-8-THC or some other THC compound is administered as a substrate for CYP3a 4.

The result is an increase in the concentration of any administered-8-THC in the liver, wherein the increase is due to a hindered hepatic conversion of the administered cannabinoid to the 7-hydroxy derivative.

Sesquiterpenes and curcumines as CYP3A4, CYP2C9 and CYP1A2 inhibitors

Other CYP enzyme inhibitors are as follows. Ten sesquiterpenes (1-10) and two curcuminoids (11 and 12) were isolated and identified from Curcuma aromatica Salisb (Curcuma aromatica). The inhibition effect of the sesquiterpene (4S,5S) - (+) -germacrone-4, 5-epoxide (7) on certain CYP subtypes is obviously stronger than or similar to curcumin (11) and demethoxycurcumin (12); for CYP3a4 inhibition, 7(IC (50) ═ 1.0 ± 0.2 μ M) >12(IC (50) ═ 7.0 ± 1.7 μ M) >11(IC (50) ═ 14.9 ± 1.4 μ M); for CYP2C9 inhibition, 12(IC (50) ═ 1.4+0.2 μ M) >11(IC (50) ═ 6.0 ± 1.4 μ M) >7(IC (50) ═ 7.6 ± 2.5 μ M); and 7(IC (50) ═ 33.2 ± 3.6 μ M) ═ 12(1C (50) ═ 34.0 ± 14.2 μ M) >11(IC (50) >100 μ M) for CYP1a2 inhibitory action. The most interesting inhibitor compounds are sesquiterpene 7 and curcumin 11 and 12(Bamba et al (2011) Natural drugs (Natural pharmaceuticals) 65: 583-.

The present disclosure provides compositions and methods for co-administration of-8-THC with one or more of sesquiterpene 7, curcumin 11 and curcumin 12. In addition, the present disclosure provides compositions and methods for co-administration of-9-THC with sesquiterpenes 7, curcumin 11 and curcumin 12. Co-administration may take the form of a powder, pill, tablet, slurry or liquid composition in which the THC compound and the sesquiterpene (or curcumin compound) are mixed together. Also, co-administration may take the form of a number of different powders, pills, tablets, slurries or liquid compositions in which the THC compound and the sesquiterpene (or curcumin compound) are not mixed together.

UDP-glucuronyltransferase (UGT) modulators

UDP-glucuronyltransferase (UGT) enzymes catalyze the attachment of glucuronic acid moieties to various drugs. This association promotes their excretion. UGT enzymes can catalyze the attachment of the glucuronic acid moiety to the hydroxyl, carboxyl, amino, or sulfhydryl groups of a compound of interest (see Fujiwara R et al (2016) Structure and protein-protein interactions of human UDP-glucuronidase (structures and protein interactions of human UDP-glucosyltransferases), pharmacology front-edge (front.) interpretation 2016).

The present disclosure provides inhibitors of UGT enzyme that prevent the binding of glucuronic acid to-8-THC or 11-hydroxy-8-THC, or to-9-THC or 11-hydroxy-9-THC, wherein the prevention of binding results in an increase in the concentration of these cannabinoids in humans. The inhibitor may be a substrate for the UGT enzyme (competitive inhibition). For example, 11-hydroxy-9-THC is a substrate for UGT1A1, as well as UGT1A9 (see Mazur, Lichti, Prathcr (2009) Drug Metabolism and disposal 37: 1496-1504). Both Canagliflozin (CNF) and Dapagliflozin (DPF) inhibit UGT1A1 and UGT1A9(Pattanawongsa et al (2015) drug metabolism and treatment 43: 1468-. Bilirubin inhibits UGT1A1, carvacrol inhibits UGT1A9(Zeng, Shi, Zhao et al (2016) (public science library Integrated services (PLOS ONE)) DOI 10.1371 (page 21)). Mefenamic acid inhibits UGT1A9(Kasichayanula, Liu, Griffin et al (2012) Diabetes, Obesity and metabolism (Diabetes and metabolism) 15: 280-283). The present disclosure provides compositions and methods for enhancing the concentration of cannabinoids in vivo, where the cannabinoids may be-8-THC, -9-THC, 11-hydroxy-8-THC, 11-hydroxy-9-THC and related derivatives. The compositions and methods employ one or more inhibitors of UGT enzymes, such as canagliflozin or dapagliflozin. This embodiment can be described by the following steps:

administering a UGT enzyme inhibitor or UGT enzyme substrate.

UGT1A9 inhibitors include ginkgo flavonoids (ginkgo flavanoids), quercetin (quercitrin), and kaempferol (kaempferol) (see Mohamed and Frye (2010) drug metabolism and disposition 38: 270-275). UGT1A9 substrates may function in vivo to reduce glucuronidation of UGT1A 9-mediated THC, including scopoletin (scopoletin), 4-methylumbelliferone (4-methylumbelliferone), anthralic acid (anthraflavic acid), 7-hydroxyflavone, naringin, and 5, 7-dihydroxyflavone (Albert et al (1999) Endocrinol 140: 3292-. UGT1a1 inhibitors include valerian, cranberry (quercetin), echinacea, and grape seed (resveratrol). UGT1A9 inhibitors include cranberry (quercetin), ginkgo, UGT1A9 substrates include grape seed (resveratrol) and ginkgo flavonoids (Mohamed and Frye (2011) & medicinal plants (Planta Med) & 77:311- & 321). The substrate is expected to reduce UGT mediated cannabinoid binding.

Step two, administering-8-THC or some other THC compound as a substrate for the same UGT enzyme.

The result is an increase in the concentration of any administered-8-THC in the liver, wherein the increase is due to the hindered glucuronidation of the administered cannabinoid.

Co-application examples

Without implying any limitation, "co-administration" includes oral administration of two different compounds, i.e., in the form of two different powders, two different pills, two different tablets, two different slurries, or two different liquids, simultaneously, or with a time interval of less than 5 hours, or with a time interval of less than 1 hour, or with a time interval of less than 10 minutes. Alternatively, "co-administration" may take the form of administering a first composition and a second composition, wherein the first composition does not have the same formulation as the second composition (here, the first formulation may be a powder, the second formulation may be a pill, or the first formulation may be a slurry, the second may be a tablet, and so on).

"co-administration" may also include any co-administration in which a first compound has a first Cmax (ng/mL or micromolar) in plasma, wherein a second compound has a second Cmax (ng/mL or micromolar) in plasma. For any chemical or compound absorbed by the gut, it is expected that the compound will have a Cmax (occurring at a time defined as tmax), and the compound will also have C (10% max), C (20% max), C (50% max), etc., with C (10% max) defined as occurring at a time after tmax, with blood concentrations of ten percent of Cmax. Using this definition, "co-administration" can be defined as an oral dosing regimen wherein the concentration of the first compound in the bloodstream and the concentration of the second compound in the bloodstream are such that the C (≧ 10% max) of the first compound coincides with the C (≧ 10max) of the second compound. Note the sign (≧) of "greater than or equal to".

"co-administration" may also include administration of a first compound and a second compound, where there is an overlap of biochemical effects. According to this definition, if there is an overlap of biochemical effects, irrespective of the overlap of plasma concentrations of the first and second compounds, this constitutes "co-administration". The present disclosure encompasses the co-administration of-8-THC, or-9-THC, or a combination of-8-THC and-9-THC with an inducer of CYP2C 9. CYP2C9 catalyzes 11-hydroxylation of THC (Watanabe et al (2007) Life sciences 80: 1415-. Inducers of CYP2C9 include hyperforin (hyperforin), the active compound in st.

The present disclosure provides compositions comprising-8-THC and st. Additionally, the present disclosure provides compositions comprising-9-THC and st. Additionally, the present disclosure provides a composition comprising-8-THC plus-9-THC and st.

Carvacrol, curcumin, triterpenoid saponin and other natural products

"carvacrol is a monoterpene phenol produced by aromatic plants, including thyme and oregano. Carvacrol is currently used at low concentrations as a food flavoring ingredient "(sunsets, Coccimiglio and aliport (2015): biological activity and Toxicological activities of Carvacrol): 55: 304-. Carvacrol inhibits UGT1a9, wherein carvacrol inhibits the activity of 4-methylumbelliferone (test substrate) glucuronidation, wherein this activity decreases to 20% of the maximum activity at 200 micromolar carvacrol (Dong et al (2012) phytotherapy study (phytother. res.), (26: 86-90). Mazur et al (2009) drug metabolism and disposition 37:1496-1504 showed the effects of UGT3A9 and UGT1A10 in the consumption of pharmacologically active cannabinoids in vivo, indicating that oxidation of "-9-THC to THC-OH results in UGT1A9 and UGT1A10 being active on cannabinoids. FIGS. 2 and 6A of Mazur supra show that THC-OH is a substrate for UGT1A9 and UGT1A 10. THC-OH is "11-hydroxy- -9-THC". Another publication states that "CBN and 11-OH-THC are predominantly metabolized by the extrahepatic isoform UGT1A10, with Km values of 55 and 16 micromoles, respectively" (Radominska-Pandya et al (2008) Human hepatic and extrahepatic UDP-glucuronosyl-transferase (UGT) involved in the metabolism of cannabinoids) (Human hepatotic and exogenous UDP-glucuronosyl-transferase (UGTs) enzymes involved in the metabolism of the cannabinoids J.E.J.Laboration of Cannabinoids J.E.J. (EB FASJ.), journal of the American society for laboratory and biology (supplement 711.4).

With respect to curcumin, "curcumin … … had no known toxicity … … even when administered at 2% of the rat diet-our … … evidence suggests that it inhibits the phosphorylation requirements of … … UGT" (Basu, Ciotti, Hwang (2004) journal of biochemistry (j. biol. chem.)) 279: 1429-. Further with respect to curcumin, "parallel loss and recovery of UGT1a1 activity and phosphoserine content after curcumin treatment indicates that mouse isoenzymes such as human UGT … … perform the required phosphorylation" (Basu et al (2007) communication of biochemical and biophysical studies (biochem. biophysis. res. commun.) 360: 7-13). UGT1A10 activity is also dependent on phosphorylation (Basu et al (2004) J. Biochem. 279: 28320-28329). In short, the ability of curcumin to inhibit this phosphorylation results in the inhibition of multiple UGT isozymes.

As regards triterpenoid saponins, nor-oleanane triterpenoid saponins from Clausena lansium (Stauntonia brachycantha) have been found to inhibit UGT1A10 and UGT1A1(Liu et al (2016) phytotherapy (Fitoterapia) 112: 56-64).

The present disclosure provides compositions and methods for inhibiting glucuronidation of 11-hydroxy-8-THC, 11-hydroxy-9-THC, or 11-hydroxy-8-THC and 11-hydroxy-9-THC, wherein the compositions primarily inhibit intestinal UGT enzyme, wherein the compositions primarily inhibit liver UGT enzyme, or wherein the compositions both inhibit intestinal and liver UGT enzyme. Compositions and methods comprising carvacrol, curcumin, deszizanol triterpenoid saponins, or any combination thereof are provided.

The amount of each of these natural products administered orally can be, for example, about 0.1mg, about 0.2mg, about 0.5mg, about 1.0mg, about 2mg, about 5mg, about 10mg, about 50mg, about 100mg, about 200mg, about 500mg, about 1,000mg, about 5g, about 10g, etc., of any given natural product, pharmaceutically acceptable derivative of natural product, or pharmaceutically acceptable compound of non-natural product.

After oral administration of the compound, "pharmacologically acceptable" may manifest as no nausea, no vomiting, no neutropenia, no elevated serum bilirubin, no elevated serum liver enzymes, and the like. "derivatives" encompass methylated, phosphorylated, sulfated, formylated, compounds that bind to mannose, sialic acid, glucose, fucose and the like. Derivatives that confer greater solubility to a cannabinoid, terpene, or another natural product include glycinyl esters, dialkyl glycinyl esters, dimethyl glycinyl esters, diethyl glycinyl esters, amino esters, phosphate esters, and trialkyl ammonium glycines, derivatives, amino acid esters of nitrogen-containing heterocycles such as 4-morpholino acetic acid and butyric acid, and derivatives of 4- (4-methylpiperazinyl) acetic acid and butyric acid, including hydrobromide.

The present disclosure provides a type of THC that does not result in a positive test for a blood/urine-9-THC test or a field wakefulness test designed for analysis of-9-THC metabolites. Further, the present disclosure provides a type of THC that is not limited by each serving/package of-9-THC. The present disclosure provides prodrugs of 11-OH-8 THC (when ingested). The prodrug may be-8-THC or the prodrug may be-8-THC modified by covalent attachment of a chemical moiety which increases the solubility of-8-THC in water. Preferably, the covalently bound moiety is hydrolysable in vivo, thereby providing-8-THC.

Transporter proteins

The present disclosure provides inhibitors for reducing cannabinoid export from cells, resulting in excretion from the human body. In some cases, drug transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (RCRP), and organic anion transporters (OAT1, OAT2, OAT3) are used to mediate drug transport into cells, and in other cases, to mediate drug transport out of cells. The transport out of the cell may reach the plasma, bile duct for excretion from the body, or transport from the renal tubular cells to the urine for excretion from the body. P-glycoprotein (Pgp) and BCRP can transport cannabinoids from cells into the bloodstream (see Spiro et al (2012) public science library integrated 7: e 35937). Accordingly, the present disclosure provides compositions and methods for inhibiting drug transporters that mediate the efflux of cannabinoids from the cell, and more preferably, for inhibiting drug transporters that mediate the efflux from the intestinal cell to the intestinal lumen (see Fakhoury et al (2005) drug metabolism and disposition 33:1603 1607; Bow et al (2008) drug metabolism and disposition 36: 198-.

The present disclosure provides compositions and methods for administering one or more cannabinoids and one or more compounds that inhibit the efflux of cannabinoids from a cell. One or more compounds may inhibit P-glycoprotein, BCRP or an OAT transporter (OAT1, OAT2, OAT 3). Inhibitors of P-gp or BCRP include verapamil (verapamil), dexverapamil (dexverapamil) and zosuquidar (zosuquidar), as well as natural products such as terpenes, flavonoids and coumarins (Abdullah, A1-Abd, E1-diene et al (2015) J.advanced Res.) (6: 45-62). Terpenes that inhibit drug transporters include farnesol a (farnesiferol a), galbanic acid (galbanic acid), limonoids (e.g., obanone), diterpenes (e.g., jatrophane (jatrophane) and tropane (lathyrane)) and sesquiterpenes (e.g., dihydro- β -agarofuran). The transport protein inhibiting flavonoids include epigallocatechin-3-gallate, 8-isopentenylnaringenin, baicalein (baicalein), kaempferol (from grape), and naringenin (from grape). Coumarins that inhibit drug transporters include furocoumarins. The present disclosure provides compositions and methods summarized by the following methods:

administering an inhibitor of a drug transporter that mediates efflux of a cannabinoid from an intestinal cell, a hepatocyte, or a renal tubular cell. P-glycoprotein inhibitors include azolotra, valsalva (valspodar), elacridar (elacridar), kava-kava (kava-kava) extracts, kavalactone (kavalactone), fibrates (fibrates), progestins (see Weiss et al (2006): drug metabolism and disposition 34: 203-207). Curcumin is a P-glycoprotein inhibitor (Neerati et al (2013) J. cancer Sci. The.) 5: 313-319).

Step two-8-THC or some other THC compound is administered as a substrate for the same transporter.

The result is an increase in the concentration of any administered-8-THC in the blood and liver, wherein this increase is due to the obstruction of efflux and thus the prevention of clearance from the body.

Identifying compounds that inhibit cannabinoid catabolism, wherein said compounds can be administered orally

Compounds that inhibit cannabinoid catabolism include CYP enzyme inhibitors, CYP enzyme substrates, UGT enzyme inhibitors, UGT enzyme substrates, P-gp inhibitors, and P-gp substrates. These types of substrates are inhibited by competitive inhibition. For assays involving assays for detecting CYP enzyme activity using microsomes as the enzyme source, the Promega corporation provides the following methodological information. A large amount of protein or phospholipid from a microparticle preparation may bind non-specifically to the drug or inhibitor, resulting in a decrease in effective concentration, and Km and Ki values are overestimated (Technical Bulletin)

Assys promegacorp, Madison, WI). Preparations of CYP enzymes are commercially available from Corning, Sigma-Aldrich, Life Technologies, Xenotech, Cypex, New England Biolabs, Oxford Biomedical Research, BioReclamatoIVT, and Moltox, Inc.

Corning

In the form of microsomes engineered to contain recombinant CYP enzymes, recombinant UGT enzymes or other drug metabolizing enzymes of the microsomal fraction of the liver (Stresser et al (2013) useEnzyme application Note 467, Corning, Inc., Tewksbury, Mass., for Cytochrome P450Enzyme localization in drug discovery (Cytochrome P450Enzyme Mapping in drug discoveryEnzymesApplication Note 467,Corning,Inc.,Tewksbury,MA)》)。

More information on the reagents and methods is available regarding CYP enzymes and UDP-glucuronidase (UGT) (see, e.g., Li et al 2015 High-throughput cytochrome P450cocktail inhibition assay for assessing drug-drug and drug-plant interactions 43: 1670-1678; Lee et al 2015 incubation and liquid chromatography tandem mass spectrometry used to simultaneously screen for activity of 5 cytochrome P450 and 4 uridine 5' -diphosphate-glucuronidase in human liver (Single ingredient of reactions of microorganisms of the same family of drugs) 11146: 1117. see, e.g., Li et al 1117. High-throughput cytochrome P450cocktail inhibition assay for assessing drug-drug and drug-plant interactions 42. the screening methods for drug-protein inhibition assay and drug-protein metabolism assay for drug-protein interaction In vitro analysis of 6 UDP-glucuronidase isoforms (In vitro assay of sixUDP-glucuronidase isoforms In human liver microsomes, using collectives of probe substructures and liquid chromatography-tandem mass spectrometry) In human liver microsomes, drug metabolism and disposition 42: 1803-1810; walsky et al (2012) optimization analysis of human UDP-glucuronyltransferase (UGT) Activity: the concentration of the propylaenine was varied and used to screen UGT inhibitors (optimized assays for human UDP-glucosylsyltransferase (UGT) activities: alternative assay for determination of drugs and treatment, 40: 1051-.

Terpenes that inhibited CYP enzymes were screened (BD Biosciences assay). BDPooled human liver microsomes take the form of human liver microsomes, which contain a number of cytochrome P450 enzymes, most notably CYP1a2, CYP2C9, CYP2C19, CYP2D6, and CYP3a 4. Terpenes or other candidate compounds can be screened for their ability to inhibit CYP enzymes as follows. The set-up of the screening assay provides direct information on the impact of terpenes on CYP enzyme-mediated catabolism of selected cannabinoids (e.g. -8-THC). The assay mixture may contain

Pooled human liver microsomes plus-8-THC plus terpenes, e.g. lemonLimonene.

Alternatively, the assay mixture may contain a mixture of Gentest-pooled human liver microsomes plus-8-THC plus terpene in the form of a mixture of two, three, four, five, six or seven terpenes selected from the group consisting of alpha-bisabolol, borneol, camphene, camphor, beta-caryophyllene, -3-carene, caryophyllene oxide, alpha-cedrene, beta-eucalyptol, fenchyl alcohol, geraniol, guaiacol, alpha-luprene, isoborneol, limonene, linalool, menthol, myrcene, nerol, cis-ocimene, trans-ocimene, alpha-phellandrene, beta-pinene, sabinene, alpha-terpinene, alpha-guaifene, caryophyllene, farnesene, germacrene B, and mixtures thereof, Guaia-1 (10), 11-diene, trans-2-abienol, cnidium-3, 7(11) -diene, eucalyptol-7 (11) -en-4-ol and valencene. Preferred terpenes are disclosed by US2015/0152018 to Raber and Elzinga, the entire contents of which are incorporated herein.

The ability of terpenes to inhibit CYP enzyme mediated cannabinoid catabolism can be determined quantitatively after incubation with +/-added terpene (or +/-terpene mixture). Quantification can be performed using High Pressure Liquid Chromatography (HPLC).

Terpenes that inhibited CYP enzymes were screened (Promega assay). The present disclosure provides reagents and methods for identifying compounds of interest that inhibit CYP enzymes that catabolize cannabinoids. For example, reagents and methods are provided for identifying terpenes (or mixtures of selected terpenes) that inhibit CYP enzyme-mediated catabolism of-8-THC. Described below

Terpenes that inhibit CYP enzymes can be identified by assays that use standard substrates (substrates not cannabinoids; supplied by Promega). Convenient to useAnalysis, in which Promega substrates are used, identifies terpenes of interest, which can be assayed using isolated human liver microsomes or isolated CYP enzymes. Here, the experimental setup was to test the target terpene when the substrate was-8-THCThe inhibitory action of (1). Inhibition was determined by HPLC analysis of-8-THC incubated with +/-terpenes.

The assay provides a luminometric method of measuring CYP enzyme activity. This assay tests the effect of drugs or other compounds on CYP enzyme activity. All of these assays can be used for cell-free CYP inhibition studies. Many of these assays are also useful in cell-based CYP-induced assays. Promega provides

A substrate. These are CYP enzyme substrates, which are luciferin precursors, i.e., [ (4S) -4, 5-dihydro-2- (6 '-hydroxy-2' -benzothiazolyl) -4-thiazolecarboxylic acid, a derivative of luciferin]. The derivatives are converted to luciferin products by CYP enzymes. d-luciferin is formed and detected in a second reaction with luciferin detection reagent from Promega. The amount of light produced in the second reaction is proportional to the CYP activity (Promega Corp, Madison, Wis.).

Examples of inhibition of the conversion of 11-hydroxy-8-THC or 11-hydroxy-9-THC to 11-nor-8-carboxy-THC

The present disclosure provides compositions that inhibit the conversion of 11-hydroxy-8-THC or 11-hydroxy-9-THC to inactive 11-nor-8-carboxy-THC compounds. This example is based on the hypothesis that 11-hydroxy THC is oxidized to carboxyaldehyde by an alcohol dehydrogenase and further oxidized to carboxylic acid catalyzed by an aldehyde dehydrogenase or an aldehyde oxidase (Patrick Callery doctor, 2017, email on 8/15).

If the terpene or other compound is a CYP enzyme inhibitor, the evaluation is carried out

The following table from BD Biosciences lists standard compounds as standard CYP enzyme inhibitors and CYP enzyme substrates. Where a terpene of the present disclosure is found to have a Km similar to one of the CYP enzyme substrates, or where a terpene of the present disclosure is found to have a Ki similar to one of the CYP enzyme inhibitors, then the terpene may be considered an inhibitor. Additionally, where the terpenes of the present disclosure are found to have a Km that is lower (or much lower) than the Km of one of the CYP enzyme substrates, or where the terpenes of the present disclosure are found to have a Ki that is lower (or much lower) than the Ki of one of the CYP enzyme inhibitors, then the terpenes can be considered inhibitors. The above statements are directed to the case where the CYP enzyme substrate is a cannabinoid (e.g., -8-THC). In the case where terpene is the substrate, it may be a competitive inhibitor. Where a terpene is the inhibitor rather than the substrate, and where a terpene has an inhibitory effect, then it may be a direct inhibitor.

TABLE 1 CYP isozymes

Cannabinoid

One or more of the following cannabinoids may be included in the compositions of the present disclosure. Alternatively, one or more of the following cannabinoids may be excluded (omitted) from the compositions and methods of the present disclosure. Cannabinoids and related compounds include, for example, cannabigerol; cannabichromene; a dihydroxycannabinol; cannabidiol; cannabinol; cannabis sativa ellison (cannabielsosin), cannabidiol; cannabinol; -8-tetrahydrocannabinol; -9-tetrahydrocannabinol; cannabichromanone; cannabinoids; cannabidicarbocycloalkanes; 10-oxo-6 a10 a-tetrahydrocannabinol; cannabichromanone; -7-isotetrahydrocannabinol; CBLVA; CBV; CBEVA-B; CBCVA; -9-THCVA; CBDVA; CBGVA; divalinnic acid (divarinolic acid); quercetin; kaempferol; dihydrokaempferol; dihydroquercetin; cannabinoids B; isovitexin; apigenin; naringenin; eriodictyol; luteolin; orientin; genistein; vitexin; a cannabilene; 3,4' -dihydroxy-5-methoxybibenzyl; dihydroresveratrol; 3,4' -dihydroxy-5, 3' -dimethoxy-5 ' -isoprenyl; 1, cannabistilbene; cannabistilbene 11 a; cannabistilbene 11 b; cannabiphenanthrene 1; cannabiphenanthrene 2; cannabispirone; iso-cannabispirone; cannabispiroenone-a; cannabispiroenone-B; cannabispirodienone; alpha-cannabinol; beta-cannabinol; acetyl-cannabinol; 7-hydroxy-5-methoxyindan-1-spirocyclohexane; 5-hydroxy-7-methoxyindan-1-spirocyclohexane; myristic acid, palmitic acid, oleic acid, stearic acid, linoleic acid, linolenic acid, arachidic acid, eicosenoic acid, behenic acid, lignoceric acid, 5, 7-dihydroxyindan-1-cyclohexane; cannabispirodienone; 3,4' -dihydroxy-5-methoxybibenzyl; a cannabilene; cannabispirone; cannabiphenanthrene 1; cannabiphenanthrene 2; alpha-cannabinol; acetyl-cannabinol; vomifoliol; dihydroemetic alcohol; beta-ionone; dihydroactinidiolide; equisetine; equisetine base; (+) -cannabinine; dehydrated cannabinoids; dihydrotheophylline; cannabinamide-a; cannabinamide-B; cannabinamide-C; cannabinamide-D; (ii) a croamide; cannabinamide-E; cannabinamide-F; Cannabinamide-G, etc. (see, e.g., Flores-Sanchez and Verpoorte (2008) Secondary metabolism of Cannabis; (Secondary metabolism in Cannabis); phytochemistry reviews (phytochem. Rev.); DOI10.1007/s 11101-008-) -9094-4).

Measuring cannabinoids

Cannabinoids can be isolated, purified, analysed and quantified by a variety of techniques. Useful apparatus and methods include, for example, gas chromatography, HPLC (high pressure liquid chromatography, high performance liquid chromatography), mass spectrometry, time-of-flight mass spectrometry, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). Separation and analysis equipment is commercially available from Waters corp., Milford, MA; agilent, Foster City, CA; applied Biosystems, Foster City, CA; and Bio-radcorp, Hercules, CA.

The present disclosure provides for on-line monitoring of purification, i.e., quantification of THC and quantification of impurities. The on-line monitoring may be performed by a UPLC method or other methods. Ultra Performance Liquid Chromatography (UPLC) is similar to HPLC except that UPLC uses smaller particles and higher pressure in the column bed. The particles may be less than 2 microns in diameter and the pressure may be approximately 15,000 psi. UPLC also uses higher flow rates and can provide excellent resolution and run time in less than 30 seconds (Wren and tchelchoff (2006): journal of chromatography a (j. chromatography a.): 1119: 140-) -146; Swartz, M.E. (5.2005): Redefined Separation Science defined). The use of UPLC in cannabinoids has been described (see Jamey et al (2008) journal of analytical Toxicology 32: 349;. 354; Badawi et al (2009) forthcomingBed Chemistry (Clinical Chemistry.) 55: 2004-. Suitable UPLC chromatography columns for cannabinoid analysis include, for exampleUPLC HST 3C 18 andUPLCBEH C18 chromatography column (Waters, Milford, Mass.). Other methods for detecting cannabinoids include, for example, Infrared (IR) spectroscopy, Gas Chromatography Mass Spectrometry (GCMS), and electrospray tandem mass spectrometry (ESI-MS/MS) (Ernst et al (2012) international medical science (Forensic sci. int.) 222: 216-.

Numbering system for various cannabinoids

The present disclosure uses the compounds of the international base and clinical pharmacology alliance lxxix. cannabinoid receptor and its ligands by pertweee RG et al (2010): except for CB1 and CB1, pharmacological review, 62: 588-. With respect to the different numbering systems of the same compound, AVIV (US 2004/0110827) indicates that: it is noted that for historical reasons, these cannabinoid analogs are still named under the previous nomenclature, with the terpene ring being the basis of the numbering system. The chiral centers of the THC-type cannabinoids are then at carbon atoms 3 and 4. The accepted nomenclature is now based on the phenol ring as the starting point for the numbering. Thus, the THC previously referred to as-1-THC was later renamed to-9-THC, similarly, -6-THC was renamed to-8-THC, and the chiral centers were located at carbons 6a and 10 a. "AVIV also has comments on enantiomers: "-9-THC was established by Mechoulam R. et al in 1967 and was found to have (-) - (3R,4R) stereochemistry. Later, it was found that the psychoactive properties of cannabinoids are present in the natural (3R,4R) OH series, whereas the opposite enantiomeric synthetic series (3S,4S) do not have these adverse effects. "

According to Chulgin's parlance, the most widely used numbering system identifies the terpene and aromatic nature of two different parts of the cannabinoid. Here, the terpene is numbered from a ring carbon bearing a branched methyl group and is numbered 7, and then the remaining three carbons of the isopropyl group are numbered sequentially. The advantage of this numbering system is that it is applicable whether the centre ring is closed or open. Other numbering systems are the biphenyl numbering system, the chemical abstracts system (substituted dibenzopyran numbering) and the tode numbering system (pyran numbering) (see Chulgin AT (1969) recent developments in cannabis chemistry, journal of psychopharmaceuticals (j. psychopharmaceutical Drugs), page 397-.

Terpenes

The present disclosure provides endogenous or exogenous (intentionally added) terpenes as components of cannabinoid compositions. Biochemical properties of terpenes, including receptor binding, can be assessed using labeled terpenes and labeled ligands, where terpenes affect the binding properties of the labeled ligands. Useful labels include radioactive labels, epitope tags, fluorescent dyes, electron-dense reagents, substrates or enzymes, such as used in enzyme-linked immunoassays, or fluorine-mimicking (fluoroete) (see, e.g., Rozinov and Nolan (1998) Chem. biol. (chem. biol.). 5: 713-728).

Terpenes modify and modulate the effects of THC and other cannabinoids and affect the overall pharmaceutical properties of a particular species. Physiological effects can be detected when inhaled from ambient air, resulting in serum levels in the single digit ng/mL range (see US2015/0080265 to Elzinga and Raber, which is incorporated herein by reference in its entirety). Terpenes exhibit unique therapeutic effects and may contribute to the overall effect of medicinal cannabis. The synergistic effects of terpenes and cannabinoids may be responsible for providing an effective treatment for pain, anxiety, epilepsy, inflammation, depression and infection (McPartand and Russo (2001) J.Cannabis Ther 1: 103-.

The term "concomitant effects" refers to the synergistic effect of a combination of cannabinoids and terpenes on physiology (Russo (2011) J.Pharmacol. (Brit. J.Pharmacol.) -163: 1344-1364; Corral (2001) J.Cannabis therapeutics, Vol.1, No. 3-4). Terpenes have been described in cannabis. See Flores-Sanchez and Verpoorfe (2008) phytochemistry review 7:615-639, US2015/0080265 to Elzinga and Raber and US2015/0152018 to Raber and Elzinga, each of which is incorporated herein in its entirety.

Dosage embodiments

In embodiments, a dose for oral administration contains about 0.1mg prodrug, about 0.2mg prodrug, about 0.3mg prodrug, about 0.4mg prodrug, about 0.5mg prodrug, about 1.0mg prodrug, about 2.0mg prodrug, about 3.0mg prodrug, about 4.0mg prodrug, about 5.0mg prodrug, about 6.0mg prodrug, about 7.0mg prodrug, about 8.0mg prodrug, about 9.0mg prodrug, about 10mg prodrug, about 20mg prodrug, about 30mg prodrug, about 40mg prodrug, about 50mg prodrug, about 60mg prodrug, about 70mg prodrug, about 80mg prodrug, about 90mg prodrug, about 100mg prodrug, about 150mg, about 200mg prodrug, about 250mg prodrug, about 300mg prodrug, about 350mg prodrug, about 400mg prodrug, about 500mg prodrug, and the like. Any range consisting of a combination of any two of these amounts is also provided.

In an exclusive embodiment, it may be excluded to provide less than any of these amounts or to provide any oral dose greater than any of these amounts.

In embodiments, dosages for oral administration are also provided that contain 0.1-0.5mg prodrug, 0.5-1.0mg prodrug, 2.0-5.0mg prodrug, 5.0-10.0mg prodrug, 10-20mg prodrug, 20-50mg prodrug, 50-100mg prodrug, 100-200mg prodrug, 200-500mg prodrug, 500-1000mg prodrug, and the like, or any range consisting of a combination or sum of any or all of these ranges. In an exclusive embodiment, it may be excluded to provide less than any of these amounts or to provide any oral dose greater than any of these amounts.

-8-THC/-9-THC ratio example

This provides a small range where the present disclosure provides an orally acceptable composition that is orally acceptable to a human subject, and where the composition is provided in the following weight/weight ratios [ -8-THC ]/[ -9-THC ]: 5mg/2.5mg, 5mg/2.0mg, 5mg/1.5mg, 5mg/1.25mg, 5mg/1.0mg, 5mg/0.75mg, 5mg/0.5mg, 5mg/0.25 mg. Also provided are 2.5mg/2.5mg, 2.5mg/2.0mg, 2.5mg/1.5mg, 2.5mg/1.25mg, 2.5mg/1.0mg, 2.5mg/0.75mg, 2.5mg/0.5mg, 2.5mg/0.25 mg.

Also included are embodiments of "about", wherein each of the ratios is preceded by the term "about". Further included are the exclusive examples wherein each of the stated ratios is preceded by the phrase "wherein weight/weight ratios of the following are excluded" or "wherein weight/weight ratios of the following are excluded. "

Other ranges for small amounts include the following weight/weight ratios [ -8-THC ]/[ -9-THC ]: 2mg/2.5mg, 2mg/2.0mg, 2mg/1.5mg, 2mg/1.25mg, 2mg/1.0mg, 2mg/0.75mg, 2mg/0.5mg, 2mg/0.25 mg. Also provided are 1.5mg/2.5mg, 1.5mg/2.0mg, 1.5mg/1.5mg, 1.5mg/1.25mg, 1.5mg/1.0mg, 1.5mg/0.75mg, 1.5mg/0.5mg, 1.5mg/0.25 mg. The following weight/weight ratios [ -8-THC ]/[ -9-THC ] are further provided: 1.0mg/2.5mg, 1.0mg/2.0mg, 1.0mg/1.5mg, 1.0mg/1.25mg, 1.0mg/1.0mg, 1.0mg/0.75mg, 1.0mg/0.5mg, 1.0mg/0.25 mg. The following weight/weight ratios [ -8-THC ]/[ -9-THC ] are also provided: 0.5mg/2.5mg, 0.5mg/2.0mg, 0.5mg/1.5mg, 0.5mg/1.25mg, 0.5mg/1.0mg, 0.5mg/0.75mg, 0.5mg/0.5mg, 0.5mg/0.25 mg.

Also included are embodiments of "about", wherein each of the ratios is preceded by the term "about". Further included are the exclusive examples wherein each of the stated ratios is preceded by the phrase "wherein weight/weight ratios of the following are excluded" or "wherein weight/weight ratios of the following are excluded. "

The present disclosure provides an orally acceptable composition that is orally acceptable to a human subject, and wherein the composition is provided at a weight/weight ratio of [ -8-THC ]/[ -9-THC ] as follows: 5mg/5mg, 10mg/5mg, 15mg/5mg, 20mg/5mg, 25mg/5mg, 30mg/5mg, 35mg/5mg, 40mg/5mg, 45mg/5mg, 50mg/5mg, 60mg/5mg, 70mg/5mg, 80mg/5mg, 90mg/5mg, 100mg/5mg, 120mg/5mg, 140mg/5mg, 150mg/5mg, 160mg/5mg, 180mg/5mg, 200mg/5mg, and the like.

Also included are embodiments of "about", wherein each of the ratios is preceded by the term "about". Further included are the exclusive examples wherein each of the stated ratios is preceded by the phrase "wherein weight/weight ratios of the following are excluded" or "wherein weight/weight ratios of the following are excluded. "

This provides a greater range than the amounts disclosed above. The present disclosure provides an orally acceptable composition that is orally acceptable to a human subject, and wherein the composition is provided at a weight/weight ratio of [ -8-THC ]/[ -9-THC ] as follows: 5mg/10mg, 10mg/10mg, 15mg/10mg, 20mg/10mg, 25mg/10mg, 30mg/10mg, 35mg/10mg, 40mg/10mg, 45mg/10mg, 50mg/10mg, 60mg/10mg, 70mg/10mg, 80mg/10mg, 90mg/10mg, 100mg/10mg, 120mg/10mg, 140mg/10mg, 150mg/10mg, 160mg/10mg, 180mg/10mg, 200mg/10mg, and the like.

Also included are embodiments of "about", wherein each of the ratios is preceded by the term "about". Further included are the exclusive examples wherein each of the stated ratios is preceded by the phrase "wherein weight/weight ratios of the following are excluded" or "wherein weight/weight ratios of the following are excluded. "

This provides a greater amount of range. The present disclosure provides an orally acceptable composition that is orally acceptable to a human subject, and wherein the composition is provided at a weight/weight ratio of [ -8-THC ]/[ -9-THC ] as follows: 5mg/20mg, 10mg/20mg, 15mg/20mg, 20mg/20mg, 25mg/20mg, 30mg/20mg, 35mg/20mg, 40mg/20mg, 45mg/20mg, 50mg/20mg, 60mg/20mg, 70mg/20mg, 80mg/20mg, 90mg/20mg, 100mg/20mg, 120mg/20mg, 140mg/20mg, 150mg/20mg, 160mg/20mg, 180mg/20mg, 200mg/10mg, and the like.

Also included are embodiments of "about", wherein each of the ratios is preceded by the term "about". Further included are the exclusive examples wherein each of the stated ratios is preceded by the phrase "wherein weight/weight ratios of the following are excluded" or "wherein weight/weight ratios of the following are excluded. "

With respect to compositions that do not contain any-9-THC, the present disclosure provides an orally acceptable composition that is orally acceptable to a human subject, wherein the composition comprises-8-THC or a-8-THC derivative, or a combination of-8-THC plus-8-THC derivative, but does not include any detectable-9-THC. The composition may contain, for example, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg or 1000 mg-8-THC.

In "about" embodiments, the composition may contain, for example, about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 15mg, about 20mg, about 30mg, about 40mg, about 50mg, 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, or about 1000 mg-8-THC.

With respect to compositions that do not contain any-9-THC derivative, the present disclosure provides an orally acceptable composition that is orally acceptable to a human subject, wherein the composition comprises-8-THC or a-8-THC derivative, or a combination of-8-THC plus-8-THC derivative, but does not include any detectable-9-THC derivative. In embodiments, the limit of detectability may be 1,000,000 picograms (pg), 500,000pg, 200,000pg, 100,000pg, 50,000pg, 20,000pg, 10,000pg, 5,000pg, 2,000pg, 1,000pg, 500pg, 200pg, 100pg, 50pg, 20pg, 10pg, and the like. Detection can be performed using High Pressure Liquid Chromatography (HPLC), Gas Chromatography (GC), mass spectrometry, GC-mass spectrometry, MALDI-TOF (see, e.g., Gottardo R et al (2012) Direct screening of herbal blends of newly synthesized cannabinoids by MALDI-TOF MS [ journal of Mass Spectrometry (J. Mass Spectrum) ] 47:141-146 ], Hall BJ et al (1998) Determination of cannabinoids in water and human saliva by solid phase micro-extraction and quadrupole ion trap gas chromatography/mass spectrometry (Determination of cannabis in water and human saliva solid-phase chromatography/mass spectrometry 1798).

In embodiments, the present disclosure provides one or more doses that are oral, topical, intravenous (iv), intranasal mucosal, intraperitoneal (ip), rectal, or any combination of their routes.

Prodrug embodiments

-8-THC is a prodrug suitable for conversion in vivo to 11-hydroxy-8-THC. The present disclosure provides prodrugs that are convertible in humans to 11-hydroxy-8-THC. -8-THC has a desired psychological effect on a human subject and 11-hydroxy-8-THC also has a desired psychological effect on a human subject, wherein the effect of 11-hydroxy-8-THC is greater than the effect of-8-THC. Other suitable prodrugs are derivatives of-8-THC that are hydroxylated, phosphorylated, methylated, acetylated, glycosylated, and the like. Furthermore, suitable prodrugs are derivatives of-8-THC, which contain a moiety that is hydrolysable by enzymes expressed by the following human cells: such as intestinal cells, pancreatic exocrine cells, or hepatocytes.

Other chemical examples

The present disclosure provides compositions comprising non-naturally occurring cannabinoid compounds from cannabis plants and related methods. -8-THC and 11-hydroxy-8-THC are not naturally produced by the cannabis plant. The present disclosure provides compositions and methods that can selectively preclude in vitro (laboratory bench) allylic oxidation reactions of cannabinoids. Moreover, in some embodiments, the disclosure may exclude compositions that do not contain a double bond at the 8-position of any cannabinoid. The present disclosure provides compositions and methods that provide mixtures of oxidation products produced in the body, wherein, optionally, the mixtures of oxidation products have different positions, different chiralities, or have different positions and different chiralities. In an exclusive embodiment, the present disclosure provides in vitro compositions and methods comprising-8-THC but not 11-hydroxy-8-TBC. In addition, in vitro compositions and methods comprising-8-THC and 11-hydroxy-8-THC are provided, wherein the ratio of ((-8-THC)/(11-hydroxy-8-THC)) is at least 1/1/, at least 2/1, at least 4/1, at least 8/1, at least 10/1, at least 20/1, at least 50/1, at least 100/1, at least 200/1, etc. on a molar basis. In one aspect, the composition is a pharmaceutical composition that is present outside the human body and is capable of being administered to a human subject, or is present outside the human body and is outside any plant cell and is capable of being administered to a human subject, or is present outside the human body and is not in contact with any plant cell and is capable of being administered to a human subject.

Receptor binding methods

Cannabinoid receptors include CB1 and CB 2. CB1 and CB2 are members of the G protein-coupled receptor family. The ligands of CB1 include-9-tetrahydrocannabinol (-9-THC) and the endogenous ligand N-arachidonic acid ethanolamide (AEA; arachidonic acid ethanolamide). In addition to CB1 and CB2, cannabinoids may also bind to "receptors" (such as various ion channels, such as the vanilloid (TRPV) receptor) and nuclear receptors (such as the peroxisome proliferator-activated receptor (PPAR)) (Console-Bram et al (2012): neuropsychol and biopsychiatric progression (prog.neuropsycho-pharmacol.biol.psychiatry.) -38: 4-15; US2015/008025 by Elzinga and Raber, which is incorporated herein by reference in its entirety). Biochemical properties of terpenes, including receptor binding, can be assessed using labeled terpenes and labeled ligands, where terpenes affect the binding properties of the labeled ligands. Useful markers include³²P、³³P、³⁵S、¹⁴C、³H、¹²⁵I. Stable isotopes, epitope tags, fluorescent dyes, electron-dense reagents, substrates or enzymes, such as those used in enzyme-linked immunoassays, or fluorine-like (see, e.g., Rozinov and Nolan (1998) Chem. biol. 5: 713-728).

The following data (Table 2) on cells expressing the human CB1 receptor or the human CB2 receptor provide a suitable background, context and starting point for understanding the CB1 and CB2 receptors (Radwan et al (2015) J Natural products 78: 1271-1276; Hayakawa et al (2010) Pharmaceuticals (Pharmaceuticals) 3: 2197-2212). Radioligand binding assays were performed to test binding affinity for various cannabinoid compounds. For example, Compound 3 binds tightly to CB1 and CB2, where the binding is comparable to-8-THC or-9-THC. Compound 3 is a partial agonist of both receptors.

TABLE 2

-8-THC and 11-hydroxy-8-THC are each agonists of CB1. Additionally, -9-THC and 11-hydroxy-9-THC are each agonists of CB1. Corresponding information is available for 11-hydroxy-8-THC and 11-hydroxy-9-THC of CB 2.

The present disclosure provides compositions comprising a mixture of-8-THC and-9-THC, wherein the-8-THC amplifies a signal caused by the-9-THC. Additionally, a composition comprising a mixture of-8-THC and-9-THC is provided, wherein the-9-THC amplifies the signal caused by the-8-THC.

The present disclosure provides compositions comprising a mixture of-8-THC derivatives and-9-THC, wherein the-8-THC derivatives amplify the signal induced by-9-THC. Additionally, a composition comprising a mixture of a-8-THC derivative and-9-THC is provided, wherein the-9-THC amplifies the signal caused by the-8-THC derivative.

The present disclosure provides compositions comprising a mixture of-8-THC and-9-THC derivatives, wherein-8-THC amplifies the signal caused by the-9-THC derivative. Additionally, a composition comprising a mixture of-8-THC and a-9-THC derivative is provided, wherein the-9-THC derivative amplifies the signal induced by-8-THC.

Treatment of human subjects

This involves traumatic brain injury. The present disclosure provides prodrugs of 11-hydroxy-8-THC, wherein administration is by oral ingestion. This is for the treatment or prevention of traumatic brain injury or chronic traumatic brain disorder (CTE). -8 has a double bond in the same position as dexanabinol. Hepatic enzyme oxidation of-8-THC produces 11-hydroxy-8-THC.

Hops (Humulus lupulus l. cannabaceae) and extracted compounds are useful in the treatment of anxiety and insomnia, mild pain relief, dyspepsia, inflammation or liver damage (Weiskirchen et al (2015) leading edge of physiology (Front physiology) 6:140.doi: 10.3389).

Cannabis species with higher CBD levels show greater efficacy against insomnia than Indian Cannabis (Cannabis indica), whereas Cannabis (Cannabis sativa) has greater efficacy against nightmare (Beiendoriuk et al (2015) addiction behavior (additive Behaviors.) 50: 178-181). Also, Indian hemp shows greater efficacy in improving energy and appetite than hemp (Corral (2001) J.Cannabis therapeutics, Vol.1, stages 3-4). Cannabis or extracts thereof have been shown to be effective in preventing or reducing pain, sleep disorders and muscle spasms (see, e.g., Rog et al (2005) Neurology 65: 812-.

Inhalation embodiment

Aerosol and dry powder formulations for inhalation are available. See Mitchell, Nagel, Wicrseroa and Doyle (2003), article 54 (page 9) in AAPS pharmaceutical technology (AAPS PharmSciTech.) (4); asai et al (2016) study of drugs (pharm. Res.) 33: 487-497; kopsch et al (2017) J.Pharm, Int.J.; 529: 589-596; fishier and Sznitman (2017), Inhalation (Inhalation) 11: 21-25. Vaporizers are available from, for example, Storz and Bickel (Turtlingen, Germany), Arizer Tech (Waterloo, Canada), Organicex (Las Vegas, NV), and Elemental Technologies (Seattle, WA).

Psychological examples and methods

The present disclosure provides compositions and methods for avoiding the psychoactive effects of-9-THC. Reasons for avoiding the psychoactive effects of-9-THC include: in typical medical treatments, mental activity is considered as an adverse side effect; and mental activities are sometimes adverse events associated with social norms, as have been recorded for drinking and intoxication (see Robin and Johnson (1996) attitudes and concomitance cross-pressures: adolescent Drug alcohol abuse (attentude and peer cross-over), journal of anti-Drug abuse education (j. Drug Educ) 26:69-99, rom (2009) contamination, social inequality, and drinking and Drug abuse (Stigma), Drug and alcohol review (Drug alcohol rev.) 24: 143. 155). The following relates to the non-psychoactive effects of-8-THC. -8-THC has useful physiological activity other than psychotropic activity mediated through CB receptors. It is valuable to decouple these two types of CB receptors. In a preferred embodiment, the present disclosure provides compositions and methods having both: (1) non-psychoactive effects, and (2) psychoactive effects. To illustrate this preferred embodiment, the composition of the invention has reduced or reduced detectability of psychotropic activity compared to-9-THC. In the case of a prodrug (for example, the prodrug is-8-THC), the case is-8-THC lacks psychotropic activity, but the metabolite of-8-THC (the metabolite is 11-hydroxy-8-THC) does have psychotropic activity.

The present disclosure provides compositions and methods having psychoactive effects that occur when-8-THC or a derivative thereof is administered alone and then converted to 11-hydroxy-8-THC in vivo, wherein the non-psychoactive effects are one or more of: (1) relaxing; (2) a health condition; and (3) a reduction in REM and an increase in deep sleep.

Additionally, the present disclosure provides compositions and methods having a non-psychoactive effect that occurs when-8-THC or a derivative thereof is administered alone and then converted to 11-hydroxy-8-THC in vivo, wherein the non-psychoactive effect is one or more of: (1) increase sleep, (2) neuroprotection and (3) anorexia.

(1) Increase sleep. Sleep well in human subjects can be assessed by the behavioral risk factor monitoring system (BRFSS) sleep problem (Jungquist et al (2016) (12: 1585) -. Devine et al (2005) Pharmacoeeconomical (Pharmacoelomics.) 23:889-912 describe various tools for assessing sleep in humans: a basic Nordic sleep questionnaire, a Ritz sleep assessment questionnaire, a medical outcome study-sleep problem metric, a Pittsburgh sleep diary, a Pittsburgh sleep quality index, a self-assessed sleep questionnaire, and a sleep dissatisfaction questionnaire; functional outcomes of sleep questionnaires, quality of life and sleep-wake activity scales for insomnia patients, medical outcome studies-sleep problem metrics, and pittsburgh sleep quality index. Administration may be oral, inhalation, nasal, mucosal injection, infusion, or any combination thereof. Polysomnography, electroencephalography, sleep latency, and binocular can be used to measure sleep parameters such as REM and various sleep stages (see, e.g., Lucey et al (2016) journal of sleep research (j. sleep. res.) 25:625 635; Vacas et al (2016) 123:206- & 212 for anesthesia and analgesia.

(2) And (4) neuroprotection. Neuroprotection includes one or more of protection against seizures, epilepsy, neurotoxicity, mechanical trauma, and neuronal injury. There are methods to assess neuroprotection. See, e.g., Maas et al (2006) Lancet neurology (Lancet neuron.) 5: 38-45; hukkelhoven et al (2005)22:1025- > 1039; dijkers (1997) journal of head Trauma recovery (J.head Trauma Rehab.) 12: 74-91; rogawski (1993) Trends in pharmacology and sciences 14: 325-331; McIntosh (1993) journal of nerve trauma (J. Neurotrauma.) 10: 215-243. These methods include the Barthel index and Glasgow results scale.

(3) Anorexia. The effects of anorectic agents administered to human subjects can be assessed, for example, by the three-element diet questionnaire (TFEQ-R18, TFEQ-R21), the netherlands' diet behavior questionnaire, and the scale of loss of diet (see capperi et al (2009) journal of international obesity (int.j.obesy.) -33: 611-620; Kim et al (2014) behavior of diet (eat. behavior.) -15: 87-90; Makris et al (2004) Appetite (Appetite.) -42: 185-195). Administration may be oral, inhalation, nasal mucosa, injection, infusion, or any combination thereof.

Questionnaires and patient reported results

A questionnaire for assessing the psychological or medical impact of cannabinoids may be provided. See, e.g., Porter et al (2013) parent survey reports on the use of cannabidiol-rich cannabis in pediatric treatment-resistant Epilepsy (Report of a patient study of cannabidiol-enriched cannabis use in pediatric treatment-resistant Epilepsy), "Epilepsy behavior (Epilepsy Behav.) 29: 574-; goreick et al (2013) Effect of all-weather oral THC on chronic daily male marijuana smokers (Around-the-clock oral THC effects on sleep in large chronic days) J.S. J.Addit. (am. J.Addit.) 22: 510-514; trigo et al (2016) Effect of fixed-dose or self-adjusting-dose Sativex on cannabis withdrawal and craving (Effects of fixed or selected-delayed dosages of Sativex on cannabis with draw and craving.) < Drug Alcohol dependence (Drug Alcohol dependence) 161: 298-; and Ramesh et al (2013), Marijuana's dose-dependent effects in data Marijuana smokers, Marijuana's experiment-dependent effects in Clinical Psychopharmacology, 21: 287-293.

NMDA receptor assays and other assays

The present disclosure encompasses laboratory techniques for measuring neuroprotection, (1) NMDA receptor binding assays; (2) block NMDA toxicity in tissue culture; (3) preventing low-pressure anemia in mice; (4) improving the closed craniocerebral injury of rats; (5) occlusion of the middle cerebral artery; (6) four vessel occlusions in rats, 7) cell culture assays to assess the effect of cannabinoids on NMDA-induced cytotoxicity using neuronal and glial cells and head trauma assays, as disclosed in Mechoulan US6,096,740, which is incorporated herein by reference in its entirety. Filbert et al provided a method for assessing neuroprotection using hematoxylin and eosin histology, which revealed, for example, a reduction in piriformis neuronal damage (Filbert et al (1999) annual press, N.Y. Acad.Sci.). 890:505- > 514). Radwan et al provide a "mouse tetrad assay" to measure "exercise capacity, stiffness, body temperature and nociception" (Radwan, ElSohly, El-Alfy, Ahmed (2015) & Isolation and screening of small amounts of cannabinoids from high-performance cannabis saliva. & J Nature products 78: 1271-. Mouse tetrad analysis was described by Pertwee RG (2005) pharmacological actions of Cannabinoids (pharmacological actions of Cannabinoids.) 168: 1-51. Binding assays for CB-1 receptors and for CB-2 receptors were used as described in Husni, McCurdy, Radwan et al (2014), J.Med.chem.Res.) -23: 4295-. Epilepsy latency analysis and seizure duration analysis are described in detail by Feigenbaum et al (1989) Proc. Natl. Acad. Sci. USA 86: 9584-.

The present disclosure provides compositions having activity at cannabinoid receptors, which allow therapeutic properties similar to-9-THC without associated psychoactive properties. These ingredients include anti-appetite agents, anti-epileptic agents, inflammatory modulators, neuroprotective agents (same NMDA antagonist activity as expected for dexanabinol [ HU-211 ]), anti-encephalopathic agents in combination with CBD, anti-glaucoma agents (reduced mental activity due to-8 THC content compared to-9). Also provided are-9-THC modulators that increase the duration of the-9-THC effect, or alter the characteristics of-9-THC activity. It may be modified that the duration of-9-THC activity is increased, for example by at least 20%, at least 50%, at least 100% (double), at least 150%, at least 200%, etc. The present disclosure provides compositions for use as ingredients in non-toxic cannabis products, such as alcohol-free beer.

The invention is not limited by the compositions, reagents, methods, diagnostics, laboratory data, etc. of the present disclosure. Furthermore, the invention is not limited by any of the preferred embodiments disclosed herein.