N-acylated fatty amino acids to reduce absorption variability in cannabinoid based compositions

Abstract

To provide a method of preparing an oral cannabinoid formulation to reduce cannabinoid absorption variability.SOLUTION: The present invention provides a method of preparing an oral cannabinoid formulation with reduced cannabinoid blood absorption variability in a subject following administration of the oral cannabinoid formulation, the method comprising adding N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and the cannabinoid to the oral formulation, in a cannabinoid / N-acylated fatty amino acid weight / weight (w / w) ratio of 1:6, 1:10, or 1:20 within the oral formulation, thereby preparing the oral cannabinoid formulation with reduced cannabinoid blood absorption variability.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 769,395, filed November 19, 2018, the entirety of which is incorporated by reference herein as if fully set forth herein.

[0002] The present disclosure provides the use of N-acylated fatty amino acids to reduce the absorption variability of cannabinoid-derived compositions. [Background technology]

[0003] Oral cannabinoid administration is generally characterized by a wide range of variability in absorption from dose to dose in the same person (intrasubject variability). This variability has long been a problem and has been discussed, for example, in Wheless et al., CNS Drugs (2019) 33:593-604; Oh et al., Clinical Pharmacology: Advances and Applications (2017) 9:9-17; Huestis, Chem Biodivers. (2007) 4(8):1770-1804; Kim & Yoon, J. Chromatogr., Sect. B. (1996) 682:55; Ohlsson et al., Clin. Pharmacol. Ther. (1980) 28:409 and Perez-Reyes et al., Clin. Pharmacol. Ther. (1973) 14:48. For example, Wheless et al. report that in pediatric epilepsy patients, the coefficient of variation (%CV) associated with absorption ranges from 103%CV to 135%CV (see Table 3). Oh et al. report that in healthy volunteers who fasted before taking an oral cannabinoid formulation (same as disclosed herein), the coefficient of variation (%CV) associated with absorption ranges from 58%CV to 60%CV (see the last two lines of Table 1). This variability is undesirable as it makes prescribing a specific dose difficult and in some cases impossible. The consequence of this dosing challenge can be a significant over- or under-medication of the patient in the treatment of the disease. The variability in absorption associated with oral cannabinoid compositions is a negative feature of their use, but has been tolerated to date due to the lack of alternatives. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Wheless et al., CNS Drugs (2019) 33:593-604 [Non-Patent Document 2] Oh et al., Clinical Pharmacology:Advances and Applications(2017)9:9-17 [Non-Patent Document 3] Huestis, Chem Biodivers.(2007)4(8):1770-1804 [Non-Patent Document 4] Kim & Yoon, J. Chromatogr., Sect. B. (1996) 682:55 [Non-Patent Document 5] Ohlsson et al., Clin.Pharmacol.Ther.(1980)28:409 [Non-Patent Document 6] Perez-Reyes et al., Clin. Pharmacol. Ther. (1973) 14:48 Summary of the Invention [Means for solving the problem]

[0005] (Summary of disclosure) The present disclosure provides the use of N-acylated fatty amino acids to reduce the absorption variability of oral cannabinoid-derived compositions. In certain embodiments, the use of N-acylated fatty amino acids reduces the absorption variability of cannabinoid-derived compositions to a coefficient of variation (%CV) of less than 45%, less than 40%CV, or less than 30%CV. In certain embodiments, the use of N-acylated fatty amino acids in oral cannabinoid compositions reduces the inter-subject variability by 2-fold in a direct comparison of an oral cannabinoid formulation containing N-acylated fatty amino acids to the same formulation without N-acylated fatty amino acids. More specifically, in terms of bioavailability (amount of cannabinoid in blood after administration), the inter-subject variability was 84% ​​when the composition did not have N-acylated fatty amino acids compared to 41% or 38% when the composition had N-acylated fatty amino acids.

[0006] As disclosed herein, the ratio of cannabinoids to N-acylated fatty amino acids in the oral formulation is important to observe the described reduction in inter-subject absorption variability. A 1:2 ratio (weight / weight (w / w)) of cannabinoids to N-acylated fatty amino acids was not effective in bringing the %CV below 45%. However, a 1:20 ratio achieved 41%CV, a 1:10 ratio achieved 26%CV to 38%CV, and a 1:6 ratio achieved 39%CV. Thus, the present disclosure provides the use of specific ratios of cannabinoids to N-acylated fatty amino acids to reduce inter-subject variability of cannabinoids to date.

[0007] Certain embodiments include selecting an N-acylated fatty amino acid and a cannabinoid in a ratio of 1:20, 1:10 or 1:6 to create an oral formulation with reduced absorption variability when administered to a subject. [Brief description of the drawings]

[0008] [Figure 1A-1] Representative cannabinoid structures are provided. [Figure 1A-2] Representative cannabinoid structures are provided. [Figure 1B-1] Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 1B-2] Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 1B-3] Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 1B-4] Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 1B-5]Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 1B-6] Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 1B-7] Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 1B-8] Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 1B-9] Additional representative structures of cannabinoids that can be synthetically derived (THC, nabilone, CBD, 7-OH-CBD, CBDV, 7-OHCBDV and Formulas I-XVI) are provided. [Figure 2-1] The modified amino acids of compounds I to XXXV are shown. [Figure 2-2] The modified amino acids of compounds I to XXXV are shown. [Figure 2-3] The modified amino acids of compounds I to XXXV are shown. [Figure 2-4] The modified amino acids of compounds I to XXXV are shown. [Figure 2-5] The modified amino acids of compounds I to XXXV are shown. [Figure 3-1]

[0033] Figure 1 shows a fatty acid amino acid of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms, R2 is H (i.e., hydrogen) or CH3 (i.e., a methyl group), and R3 is H; or a salt or free acid form thereof. [Figure 3-2]

[0033] Figure 1 shows a fatty acid amino acid of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms, R2 is H (i.e., hydrogen) or CH3 (i.e., a methyl group), and R3 is H; or a salt or free acid form thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Oral cannabinoid administration is generally characterized by a wide variation in absorption from dose to dose in the same person (intrasubject variability). This variability has long been a problem and has been discussed, for example, in Wheless et al., CNS Drugs (2019) 33:593-604; Oh et al., Clinical Pharmacology: Advances and Applications (2017) 9:9-17; Huestis, Chem Biodivers. (2007) 4(8):1770-1804; Kim & Yoon, J. Chromatogr., Sect. B. (1996) 682:55; Ohlsson et al., Clin. Pharmacol. Ther. (1980) 28:409 and Perez-Reyes et al., Clin. Pharmacol. Ther. (1973) 14:48. For example, Wheless et al. report that in pediatric epilepsy patients, the coefficient of variation (%CV) associated with absorption ranges from 103%CV to 135%CV (see Table 3). Oh et al. report that in healthy volunteers who fasted before taking an oral cannabinoid formulation (same as disclosed herein), the coefficient of variation (%CV) associated with absorption ranges from 58%CV to 60%CV (see the last two lines of Table 1). This variability is undesirable as it makes prescribing a specific dose difficult and in some cases impossible. The consequence of this dosing challenge can be a significant over- or under-medication of the patient in the treatment of the disease. The variability in absorption associated with oral cannabinoid compositions is a negative feature of their use, but has been tolerated to date due to the lack of alternatives.

[0010] The present disclosure provides the use of N-acylated fatty amino acids to reduce the absorption variability of oral cannabinoid-derived compositions. In certain embodiments, the use of N-acylated fatty amino acids reduces the absorption variability of cannabinoid-derived compositions to a coefficient of variation (%CV) of less than 45%, less than 40%CV, or less than 30%CV. In certain embodiments, the use of N-acylated fatty amino acids in oral cannabinoid compositions reduces the inter-subject variability by 2-fold in a direct comparison of an oral cannabinoid formulation containing N-acylated fatty amino acids to the same formulation without N-acylated fatty amino acids. More specifically, in terms of bioavailability (amount of cannabinoid in blood after administration), the inter-subject variability was 84% ​​when the composition did not have N-acylated fatty amino acids compared to 41% or 38% when the composition had N-acylated fatty amino acids.

[0011] As disclosed herein, the ratio of cannabinoids to N-acylated fatty amino acids in the oral formulation is important to observe the described reduction in inter-subject absorption variability. A 1:2 ratio of cannabinoids to N-acylated fatty amino acids was not effective in bringing the %CV below 45%. However, a 1:20 ratio achieved 41%CV, a 1:10 ratio achieved 26%CV to 38%CV, and a 1:6 ratio achieved 39%CV. Thus, the present disclosure provides the use of specific ratios of cannabinoids to N-acylated fatty amino acids to reduce inter-subject variability of cannabinoids to date.

[0012] In certain embodiments, the w / w ratio of cannabinoid:N-acylated fatty amino acid may be 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25. In certain embodiments, the w / w ratio of N-acylated fatty amino acid / cannabinoid is 1:6, 1:10 or 1:20. In certain embodiments, the N-acylated fatty amino acid includes sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) and the cannabinoid includes Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) or synthetic forms thereof.

[0013] Aspects of the disclosure are now described with additional options and details below: (i) cannabinoids, (ii) N-acylated fatty amino acids, (iii) oral formulations, (iv) methods of use, (v) representative embodiments, (vi) representative experimental procedures, (vii) experimental examples, and (viii) concluding section.

[0014] (i) Cannabinoids. Cannabinoids are a group of cyclic molecules derived from the cannabis plant that activate cellular cannabinoid receptors (i.e., CB1 and CB2). There are at least 85 different cannabinoids that can be isolated from cannabis. Many cannabinoids, such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), produced by the cannabis plant, have very low or no water solubility. The most notable cannabinoids are THC and CBD. Additional examples include cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabidiol (CBO), tetrahydrocannabinolic acid (THCA) and tetrahydrocannabivarinic acid (THCVA). See, for example, Figures 1A, 1B. Extracts of the cannabis plant also include flavonoid compounds, terpenes, terpenoids and synthetic, semi-synthetic or highly purified versions of any such components.

[0015] In certain embodiments, synthetic cannabinoids include chemically synthesized natural cannabinoids, and also include their analogs and derivatives.Derivatives of natural cannabinoids can include metabolites of cannabinoids disclosed in WO2015 / 198078.For example, metabolites of CBD include 7-OH-CBD, and metabolites of CBDV include 7-OH-CBDV.

[0016] [ka] TIFF2024178417000002.tif196156TIFF2024178417000003.tif72168

[0017] Other examples of synthetic cannabinoids include 3-carbamoyl-2-pyridones and derivatives and / or analogs thereof disclosed in U.S. Patent Application No. 2008 / 0103139; pyrimidine derivatives and / or analogs thereof disclosed in U.S. Patent Application No. 2006 / 0293354; carenadiol and derivatives and / or analogs thereof disclosed in U.S. Patent No. 4,758,597; carbamoyl-2-pyridones and derivatives and / or analogs thereof disclosed in WO 2013 / 045115; cannabinoid carboxylic acids and derivatives and / or analogues thereof; pyrido[3,2-E][1,2,4]triazolo[4,3-C]pyrimidines and derivatives and / or analogues thereof as disclosed in WO 2008 / 118414; tetrahydro-pyrazolo[3,4-C]pyridines and derivatives and / or analogues thereof as disclosed in WO 2007 / 112399; bicyclo[3.1.1]pyridines and derivatives and / or analogues thereof as disclosed in WO 2006 / 043260; ]heptan-2-one cannabinoids and derivatives and / or analogues thereof; resorcinol and derivatives and / or analogues thereof as disclosed in WO 2005 / 0123051; dexanabinol compounds and derivatives and / or analogues thereof as disclosed in WO 2004 / 050011; cannabinomimetic lipid amide compounds and derivatives and / or analogues thereof as disclosed in WO 2000 / 032200. and analogs; nabilone, and derivatives and / or analogs thereof, as disclosed in U.S. Patent Application No. 2010 / 0168066; 2-oxoquinolone compounds, and derivatives and / or analogs thereof, as disclosed in U.S. Patent Application No. 2003 / 0191069; and 3,4-diaryl-4,5-dihydro-(h)-pyrazole-1-carboxamides, and derivatives and / or analogs thereof, as disclosed in U.S. Patent Application No. 2011 / 0137040.

[0018] In certain embodiments, 3-carbamoyl-2 pyridone and derivatives and / or analogs thereof include methyl 3-methyl-2-{[2-oxo-1-(2-oxo-ethyl)-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carbonyl]-amino}-butyrate, dimethyl 2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonyl)-amino]-succinate, and methyl 2-{[1-(3-methoxycarbonylamino-propyl)-2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carbonyl]-amino}-2-methyl-propionate.

[0019] In certain embodiments, pyrimidine derivatives and / or analogs include the compound having formula (I) (2-((2,4-dichlorophenyl)amino)-N-((tetrahydro-2H-pyran-4-yl)methyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide).

[0020] [ka] Other pyrimidine derivatives and / or analogues include 2-(3-chlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid cyclohexylmethyl-amide, 2-phenylamino-4-trifluoromethylpyrimidine-5-carboxylic acid cyclohexylmethyl-amide, 1-[2-(2,3-dichlorophenylamino)-4-trifluoromethylpyrimidin-5-yl]-1-morpholin-4-yl-methanone, 1-[2-(2,4-dichlorophenylamino)-4-trifluoromethylpyrimidin-5-yl]-1-morpholin-4-yl-methanone and 2-(3-chlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid cyclopentylamide.

[0021] In certain embodiments, carenadiol and its derivatives and / or analogs have the formula (II):

[0022] [ka] In certain embodiments, R is a lower alkyl having 1 to 9 carbon atoms, including isomeric forms such as i-butyl, n-butyl, and t-butyl. 5 H 11 Or 1,1-dimethylheptyl.

[0023] In certain embodiments, the cannabinoid carboxylic acids, and derivatives and / or analogs thereof, have the formula (III), (IV), (V) or (VI):

[0024] [ka] TIFF2024178417000007.tif64164 (in the formula, R 1 is a linear, branched or cyclic hydrocarbon residue having 1 to 12 C atoms, X + NH 4 + , monovalent, divalent or trivalent metal ions or primary, secondary, tertiary or quaternary organic ammonium ions having up to 48 C atoms, which may further carry functional groups.

[0025] Examples of polyvalent ammonium ions include N,N-dicyclohexylamine-H + and N,N-dicyclohexyl-N-ethylamine-H + X + can also be the hydrogen cation of a pharma- ceutical active substance having at least one basic nitrogen atom, such as, for example, morphine, methadone (or its enantiomers), or hydromorphone.

[0026] In certain embodiments, pyrido[3,2-E][1,2,4]triazolo[4,3-C]pyrimidines and derivatives and / or analogs thereof include 5-tert-butyl-8-(2-chlorophenyl)-9-(4-chlorophenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one, 8-(4-bromo-2-chlorophenyl)-5-tert-butyl-9-(4-chlorophenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one, 5-tert-butyl-8-(2-chlorophenyl) ... rt-butyl-9-(4-chlorophenyl)-8-(2-methylphenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one, 9-(4-bromophenyl)-5-tert-butyl-8-(2-chlorophenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one and 5-tert-butyl-8-(2-chlorophenyl)-9-(4-chlorophenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine.

[0027] In certain embodiments, the tetrahydro-pyrazolo[3,4-C]pyridine and analogs and / or derivatives thereof have the formula (VII), (VIII), (IX), (X) or (XI):

[0028] [ka] Examples of compounds having the following structure include compounds having the following structure: TIFF2024178417000009.tif192156TIFF2024178417000010.tif104168.

[0029] In certain embodiments, the bicyclo[3.1.1]heptan-2-one cannabinoids, as well as derivatives and / or analogs thereof, have the formula (XII) with specific stereochemistry:

[0030] [ka] wherein C-4 is S, the protons at C-1 and C-5 are cis relative to each other, and the protons at C-4 and C-5 are trans; R 1 is (a) O or S, and (b) C(R') 2 where R', at each occurrence, is hydrogen, cyano, -OR'', -N(R) 2 , saturated or unsaturated, linear or branched chain C 1 ~C 6 Alkyl, 1 ~C 6 Alkyl-OR'' or C 1 ~C 6 Alkyl-N(R'') 2 where R″ at each occurrence is hydrogen, C(O)R′″, C(O)N(R′″) 2 , C(S)R''', saturated or unsaturated, linear or branched chain C 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl-OR''' and C 1 ~C 6 Alkyl-N(R''') 2 where R′″ at each occurrence is hydrogen or a saturated or unsaturated, straight chain, branched or cyclic C 1 ~C 12 alkyl, or (c) NR″ or N—OR″, where R′ is as previously defined; R 2 and R 3 are each independently: (a) -R'', -OR'', -N(R) 2 , -SR'', -S(O)(O)NR'', where R'' at each occurrence is as previously defined; (b) -S(O)R b , -S(O)(O)R b where R b is hydrogen, saturated or unsaturated, linear or branched C 1 ~C 6 Alkyl, C 1 ~C 6Alkyl-OR'' and C 1 ~C 6 Alkyl-N(R'') 2 where R″ is as previously defined; or (c) —C(O)OH, —S(O)(O)OR e Or -P(O)(OR e ) 2 -OC(O)OH, -OS(O)(O)OR e , -OP(O)(OR e ) 2 , -OR d Or -OC(O)-R d chain, where R d is saturated or unsaturated, linear or branched chain C 1 ~C 6 is alkyl, R e Each occurrence represents hydrogen and R as previously defined. d is selected from the group consisting of R 4 is (a) R, where R is hydrogen, halogen, OR''', OC(O)R''', C(O)OR''', C(O)R''', OC(O)OR''', CN, N(R''') 2 , NC(O)R''', NC(O)OR''', C(O)N(R''') 2 , NC(O)N(R'') 2 and SR′″, where R′″ at each occurrence is as previously defined; (b) saturated or unsaturated, straight chain, branched or cyclic C 1 ~C 12 alkyl-R, where R is as previously defined; (c) an aromatic ring which may be further substituted at any position by R, where R is as previously defined; or (d) a saturated or unsaturated, linear, branched or cyclic C alkyl group, optionally terminated by an aromatic ring which may be further substituted as defined in (c). 1 ~C 12 Examples of compounds having the formula (I) are alkyl.

[0031] In certain embodiments, resorcinol and its derivatives and / or analogs have the formula (XIII):

[0032] [ka] (In the formula, R 1 is (a) a linear or branched alkyl chain having 7 to 12 carbon atoms; and (b) -OR 3 where R 3 is a straight or branched alkyl chain having 5 to 9 carbon atoms, optionally substituted with one phenyl group, or (c) -(CH 2 ) n -OR 4 where n is an integer from 1 to 7; R 4 is a linear alkyl chain having 1 to 5 carbon atoms; R 2 is a non-cyclic terpenoid containing 10 to 30 carbon atoms).

[0033] In certain embodiments, resorcinol and its derivatives and / or analogs include compounds having the formula (XIII), where R 1 and R 2 is as follows: R 1 is a linear alkyl chain of 5 to 8 carbon atoms optionally substituted with one methyl group; R 2 is selected from geranyl optionally substituted with one --OH and farnesyl optionally substituted with one --OH.

[0034] In certain embodiments, resorcinol and its derivatives and / or analogs have the formula (XIII): R 1 is (a) a linear or branched alkyl chain having 7 to 12 carbon atoms; and (b) -OR 3 where R 3is a linear or branched alkyl chain having 5 to 9 carbon atoms optionally substituted with one phenyl group; or (c) -(CH2)nO-R4, where n is an integer from 1 to 7 and R4 is a linear alkyl chain having 1 to 5 carbon atoms; R2 is an acyclic terpenoid containing 10 to 30 carbon atoms, with the proviso that R1 is isononyl and R2 is not geranyl.

[0035] In certain embodiments, resorcinol and its derivatives and / or analogs have the formula (XIII), 1 is (a) a linear or branched alkyl chain having 7 to 12 carbon atoms; and (b) -OR 3 is a group, where R 3 is a linear or branched alkyl chain having 5 to 9 carbon atoms or a linear or branched alkyl chain having a terminal carbon atom substituted with one phenyl group, or (c)-(CH 2 ) n -O-alkyl, where n is an integer of 1 to 7 and the alkyl group contains 1 to 5 carbon atoms.

[0036] In certain embodiments, resorcinol and its derivatives and / or analogs have the formula (XIII), 2 are acyclic terpenoid carbon chains such as geranyl, farnesyl, and related acyclic terpenes and their isomers, as well as other acyclic paraffinic or olefinic carbon chains.

[0037] In certain embodiments, resorcinol and its derivatives and / or analogs have the formula (XIII), 1 is dimethylheptyl, R 2 is geranyl).

[0038] In certain embodiments, the dexanabinol compound, as well as derivatives and / or analogs thereof, has the formula (XIV):

[0039] [ka] and having a (3S,4S) configuration and a high enantiomeric purity of at least 99.90% enantiomeric excess over the (3R,4R) enantiomer.

[0040] In certain embodiments, cannabinomimetic lipid amide compounds, and derivatives and / or analogs thereof, include compounds having the formula (XV):

[0041] [ka] During the ceremony, X is one member of the group consisting of C=O and NH and Y is the other member of this group. In other words, X can be C=O and Y can be NH, or Y can be C=O and X can be NH, but X and Y cannot both be from the same group.

[0042] R 1 is H or an alkyl group. In certain embodiments, R 1 , H, CH 3 or (CH 3 ) 2 and R 2 is an alkyl, substituted alkyl, alkenyl, or alkynyl group. In certain embodiments, R 2 is CH(R)CH 2 Z, C.H. 2 CH(R)Z or CH(R)(CH 2 )nCH 2 Z, R is H, CH, CH 3 , C.H.H., C.H. 2 CF 3 or (CH 3 ) 2 Z is H, halogen, N 3 , NCS or OH, and n is selected from the group consisting of 0, 1 and 2. R3 is an alkyl, substituted alkyl, aryl, alkylaryl, O-alkyl, O-alkylaryl, cyclic and heterocyclic group. O-alkyl and O-alkylaryl refer to groups in which an oxygen atom is interposed between the carbon atom of the anandamide moiety and the substituent. 3 Exemplary groups include cyclohexyl, cyclopentyl, alkylcyclohexyl, alkylcyclopentyl, piperidinyl, morpholinyl, and pyridinyl. In certain embodiments, R 3 nC 5 H 10 Z', nC 6 H 12 Z', nC 7 H 14 Z' or 1',1'-C(CH 3 ) 2 (CH 2 ) 5 CH 2 Z', where Z' is H, halogen, CN, N 3 , NCS or OH.

[0043] In certain embodiments, the cannabinomimetic lipid amide compounds, and derivatives and / or analogs thereof, include compounds having the formula (XVI):

[0044] [ka] During the ceremony, Y is one member of the group consisting of C=O and NH, and X is the other member of this group. R 1 is H or an alkyl group. In certain embodiments, R 1 , H, CH 3 or (CH 3 ) 2 It is. R 2 is an alkyl, substituted alkyl, alkenyl, alkynyl, O-alkyl, cyclic, polycyclic, or heterocyclic group. 2 teeth,

[0045] [ka] CH=CH 2 , CH=C(CH 3 ) 2 , C≡CH, CH 2 OCH 3 , CH(R)(CH 2 )nCH 2 Z or CH 2 CH(R)(CH 2 )nZ, R is H, CH 3 or (CH 3 ) 2 Z is H, halogen, N 3 , NCS, OH or OAc, n is 0, 1 or 2; R 3 is an alkyl, substituted alkyl, aryl, alkylaryl, O-alkyl, O-alkylaryl, cyclic or heterocyclic group. 3 includes cyclohexyl, cyclopentyl, alkylcyclohexyl, alkylcyclopentyl, piperidinyl, morpholinyl, and pyridinyl. 3 nC 5 H 10 Z', nC 6 H 12 Z', nC 7 H 14 Z' or 1',1'-C(CH 3 ) 2 (CH 2 ) 5 CH 2 Z', where Z' is H, halogen, CN, N 3 , NCS or OH.

[0046] In certain embodiments, Nabilone and derivatives and / or analogues thereof have the formula (XVII):

[0047] [ka] (In the formula, R 1 ~R 36Nabilone derivatives and / or analogues include compounds having R 1 ~R 36 can refer to a compound in which at least one of the following contains deuterium. See Figure 1B for the chemical structure of Nabilone.

[0048] The cannabinoid may be a medicinal compound and / or may be provided in combination with a nutritional supplement.

[0049] (ii) N-acylated fatty amino acids. In certain embodiments, the N-acylated fatty amino acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC). Other names for SNAC include sodium-N-salicyloyl-8-aminocaprylate, monosodium 8-(N-salicyloylamino)octanoate, N-(salicyloyl)-8-aminooctanoic acid monosodium salt, monosodium N-{8-(2-hydroxybenzoyl)amino}octanoate, or sodium 8-[(2-hydroxybenzoyl)amino]octanoate. SNAC has the following structure:

[0050] [ka] Salts of SNAC may also be used as carriers.

[0051] Other forms of SNAC include the formula:

[0052] [ka] In the formula, X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation. Examples of monovalent cations include sodium and potassium. Examples of divalent cations include calcium and magnesium. Examples of organic cations include ammonium and tetramethylammonium.

[0053] Representative modified amino acids, such as N-acylated FA-aa, are provided as compounds I-XXXV (see FIG. 2). Salts of these compounds and other N-acylated FA-aa can also be used as carriers.

[0054] Many of these compounds can be readily prepared from amino acids based on the present disclosure by methods within the skill of one of ordinary skill in the art. For example, compounds I-VII are derived from aminobutyric acid. Compounds VIII-X and XXXI-XXIIV are derived from aminocaproic acid. Compounds XI-XXVI and XXXV are derived from aminocaprylic acid. For example, the modified amino acid compounds can be prepared by reacting a single amino acid with an appropriate modifying agent that reacts with a free amino moiety present in the amino acid to form an amide. Protecting groups can be used to avoid unwanted side reactions as known to those of ordinary skill in the art.

[0055] The amino acid can be dissolved in an alkaline aqueous solution of a metal hydroxide, such as sodium or potassium hydroxide, and heated at a temperature ranging from 5° C. to 70° C., preferably from 10° C. to 40° C., for a period ranging from 1 hour to 4 hours, preferably 2.5 hours. 2 The amount of alkali used per equivalent of the group is generally NH 2 The range is between 1.25 and 3 millimoles per equivalent, preferably between 1.5 and 2.25 millimoles. The pH of the solution is generally in the range between 8 and 13, preferably between 10 and 12.

[0056] Then, a suitable amino acid modifying agent is added to the amino acid solution while stirring. The temperature of the mixture is generally maintained at a temperature ranging between 5°C and 70°C, preferably between 10°C and 40°C, for a period ranging between 1 and 4 hours. The amount of amino acid modifying agent used relative to the amount of amino acid is determined by the amount of free NH 2 Generally, amino acid modifiers are based on the total NH 2 It is used in an amount ranging between 0.5 and 2.5 molar equivalents, preferably between 0.75 and 1.25 equivalents per molar equivalent of the group.

[0057] The reaction is quenched by adjusting the pH of the mixture with a suitable acid, such as concentrated hydrochloric acid, until a pH between 2 and 3 is reached. The mixture is allowed to stand at room temperature and separates to form a clear upper layer and a white or off-white precipitate. The upper layer is discarded and the modified amino acid is collected from the lower layer by filtration or decantation. The crude modified amino acid is then dissolved in water at a pH ranging between 9 and 13, preferably between 11 and 13. Insoluble material is removed by filtration and the filtrate is dried in vacuum. The yield of modified amino acid generally ranges between 30 and 60%, usually 45%.

[0058] If desired, modified amino acids may be prepared using amino acid esters, such as, for example, benzyl, methyl, or ethyl esters of the amino acid compounds. The amino acid esters dissolved in a suitable organic solvent, such as dimethylformamide, pyridine, or tetrahydrofuran, may be reacted with a suitable amino acid modifying agent at a temperature ranging between 5° C. and 70° C., preferably at 25° C., for a period ranging between 7 and 24 hours. The amount of amino acid modifying agent used for the amino acid ester is the same as described above for the amino acid. The reaction may be carried out with or without a base, such as, for example, triethylamine or diisopropylethylamine.

[0059] The reaction solvent is then removed under negative pressure and the ester functionality is removed by hydrolyzing the modified amino acid ester with a suitable alkaline solution, such as 1N sodium hydroxide, at a temperature ranging between 50°C and 80°C, preferably 70°C, for a period of time sufficient to hydrolyze the ester group and form a modified amino acid having a free carboxyl group. The hydrolysis mixture is then cooled to room temperature and acidified, for example with 25% aqueous hydrochloric acid, to a pH ranging between 2 and 2.5. The modified amino acid precipitates from the solution and is recovered by conventional means such as filtration or decantation. Benzyl esters can be removed by hydrogenation with a transition metal catalyst in an organic solvent.

[0060] The modified amino acids may be purified by recrystallization or fractionation on a solid column support. Suitable recrystallization solvent systems include acetonitrile, methanol and tetrahydrofuran. Fractionation can be performed on suitable solid column supports such as alumina using a methanol / n-propanol mixture as the mobile phase; on reverse phase column supports using a trifluoroacetic acid / acetonitrile mixture as the mobile phase; and by ion exchange chromatography using water as the mobile phase. When ion exchange chromatography is performed, a sodium chloride gradient of 0-500 mM is preferably used.

[0061] In certain embodiments, the formula

[0062] [ka] (Wherein, Y is

[0063] [ka] or SO 2 and; R 1 is C 3 ~C 24 Alkylene, C 2 ~C 20 Alkenylene, C 2 ~C 20 is aromatic, such as alkynylene, cycloalkylene, or arylene; R 2 is hydrogen, C 1 ~C 4 Alkyl or C 2 ~C 4 alkenyl; R 3 is C 1 ~C 7 Alkyl, C 3 ~C 10 cycloalkyl, aryl, thienyl, pyrrolo, or pyridyl; R 3 Optionally, one or more C 1 ~C 5 Alkyl group, C 2 ~C4 Alkenyl groups, F, Cl, OH, OR 1 , S.O. 2 , COOH, COOR 1 Or, SO 3 H) The modified amino acid having the formula

[0064] [ka] The lactam having the formula R 3 -YX(where, Y, R 1 , R 2 , and R 3 where X is a leaving group. Lactams of the above formula can be prepared, for example, by the method described in Olah et al., Synthesis, 537-538 (1979).

[0065] In certain embodiments, modified amino acids also include amino acids whose alpha amino group is acylated with a fatty acid, which can be represented by the general formula AX, where A is an alpha-amino acid residue and X is a fatty acid attached to the alpha-amino group of A by acylation. Amino acids include cationic and non-cationic amino acids. In certain embodiments, the term "non-cationic amino acid" refers to an amino acid selected from the group consisting of non-polar hydrophobic amino acids, polar uncharged amino acids, and polar acidic amino acids. In certain embodiments, the term "non-cationic amino acid" as used herein refers to an amino acid selected from the group consisting of alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tryptophan (Trp), methionine (Met), proline (Pro), sarcosine, glycine (Gly), serine (Ser), threonine (Thr), cysteine ​​(Cys), tyrosine (Tyr), asparagine (Asn), and glutamine (Gin), aspartic acid (Asp), and glutamic acid.

[0066] In certain embodiments, the acylated FA-aa comprises an alpha amino acid residue of a non-polar hydrophobic amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is an amino acid residue of a non-polar hydrophobic amino acid, and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "non-polar hydrophobic amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "non-polar hydrophobic amino acid" refers to an amino acid selected from the group consisting of alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tryptophan (Trp), methionine (Met), proline (Pro), and sarcosine.

[0067] In certain embodiments, the acylated FA-aa comprises an amino acid residue of a polar uncharged amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is an amino acid residue of a polar uncharged amino acid, and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "polar uncharged amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "polar uncharged amino acid" refers to an amino acid selected from the group consisting of glycine (Gly), serine (Ser), threonine (Thr), cysteine ​​(Cys), tyrosine (Tyr), asparagine (Asn), and glutamine (Gln).

[0068] In certain embodiments, the acylated FA-aa comprises an amino acid residue of a polar acidic amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is an amino acid residue of a polar acidic amino acid, and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "polar acidic amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "polar acidic amino acid" refers to an amino acid selected from the group consisting of aspartic acid (Asp) and glutamic acid (Glu).

[0069] In certain embodiments, the amino acid residue of the acylated FA-aa comprises an amino acid residue of an amino acid that is not encoded by the genetic code. Modification of an amino acid by acylation can be readily accomplished using acylating agents known in the art to react with the free alpha-amino group of an amino acid.

[0070] In certain embodiments, the alpha-amino acids or alpha-amino acid residues referred to herein are in the L-configuration, unless otherwise stated.

[0071] In certain embodiments, the amino acid residues are in the free acid form and / or a salt thereof, such as the sodium (Na+) salt thereof.

[0072] Representative embodiments of acylated FA-aa can be represented by general Fa-aa formula I:

[0073] [ka] where R1 is an alkyl or aryl group containing 5 to 19 carbon atoms; R2 is H (i.e., hydrogen), CH 3 (i.e., a methyl group), or (CH 2 ) 3 covalently linked to R4 via a group; R3 is H or absent; R4 is an amino acid side chain or (CH 2 ) 3is covalently bonded to R2 via a group; or a salt thereof.

[0074] FA-aa can be acylated with a fatty acid comprising a substituted or unsubstituted alkyl group of 5-19 carbon atoms. In certain embodiments, the alkyl group comprises 5-17 carbon atoms. In certain embodiments, the alkyl group comprises 5-15 carbon atoms. In certain embodiments, the alkyl group comprises 5-13 carbon atoms. In certain embodiments, the alkyl group comprises 6 carbon atoms.

[0075] In certain embodiments, the acylated FA-aa is soluble at intestinal pH values, particularly in the range of pH 5.5 to 8.0, such as in the range of pH 6.5 to 7.0 In certain embodiments, the acylated FA-aa is soluble at pH below 9.0.

[0076] In certain embodiments, the acylated FA-aa has a solubility of at least 5 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 10 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 20 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 30 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 40 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 50 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 60 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 70 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 80 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 90 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 100 mg / mL. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solutions at pH values ​​one unit above and below the pKa of the FA-aa at 37° C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solutions at pH 8 at 37° C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solutions at pH values ​​one unit above and below the pI of the FA-aa at 37° C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solutions at pH values ​​one unit above and below the pI of the FA-aa at 37° C., where the FA-aa has two or more ionizable groups with opposite charges. In certain embodiments, the solubility of the FA-aa is determined at 37° C. in aqueous 50 mM sodium phosphate buffer, pH 8.0.

[0077] In certain embodiments, the acylated FA-aa is selected from the group consisting of formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms and R2 is H (i.e., hydrogen) or CH 3(i.e., a methyl group) and R3 is H], or a salt or free acid form thereof. Formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r) are shown in FIG. 3.

[0078] In certain embodiments, the acylated FA-aa is selected from the group consisting of sodium N-dodecanoyl alaninate, N-dodecanoyl-L-alanine, sodium N-dodecanoyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium N-dodecanoyl leucinate, N-dodecanoyl-L-leucine, sodium N-dodecanoyl methioninate, N-dodecanoyl-L-methionine, sodium N-dodecanoyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium N-dodecanoyl prolinate, N-dodecanoyl- L-Proline, Sodium N-Dodecanoyl Tryptophanate, N-Dodecanoyl-L-Tryptophan, Sodium N-Dodecanoyl Valinate, N-Dodecanoyl-L-Valine, Sodium N-Dodecanoyl Sarcosinate, N-Dodecanoyl-L-Sarcosine, Sodium N-Oleoyl Sarcosinate, Sodium N-Decyl Leucine, Sodium N-Decanoyl Alaninate, N-Decanoyl-L-Alanine, Sodium N-Decanoyl Leucinate, N-Decanoyl-L-Leucine, Sodium N-Decanoyl Phenylalaninate , N-decanoyl-L-phenylalanine, Sodium N-decanoylvalinate, N-decanoyl-L-valine, Sodium N-decanoylisoleucinate, N-decanoyl-L-isoleucine, Sodium N-decanoylmethioninate, N-decanoyl-L-methionine, Sodium N-decanoylprolinate, N-decanoyl-L-proline, Sodium N-decanoylthreoninate, N-decanoyl-L-threonine, Sodium N-decanoyltryptophanate, N-decanoyl-L-tryptophan, Sodium N-decanoyl N-dodecanoyl sarcosinate, N-decanoyl-L-sarcosine, N-dodecanoyl asparaginate, N-dodecanoyl-L-asparagine, sodium N-dodecanoyl aspartate, N-dodecanoyl-L-aspartic acid, sodium N-dodecanoyl cysteinate, N-dodecanoyl-L-cysteine, sodium N-dodecanoyl glutamate, N-dodecanoyl-L-glutamine, sodium N-dodecanoyl glycinate, N-dodecanoyl-L-glycine, sodium N-dodecanoyl serinate, N-dodecanoyl-L-serine,Sodium N-dodecanoylthreoninate, N-dodecanoyl-L-threonine, Sodium N-dodecanoyltyrosinate, N-dodecanoyl-L-tyrosine, Sodium N-decanoylasparaginate, N-decanoyl-L-asparagine, Sodium N-decanoylaspartic acid, N-decanoyl-L-aspartic acid, Sodium N-decanoylcysteinate, N-decanoyl-L-cysteine, Sodium N-decanoylglutamate, N-decanoyl N-decanoyl-L-glutamine, Sodium N-decanoylglycinate, N-decanoyl-L-glycine, Sodium N-decanoylserinate, N-decanoyl-L-serine, Sodium N-decanoyltyrosinate, N-decanoyl-L-tyrosine, Sodium N-dodecanoylasparaginate, Sodium N-dodecanoylglutamate, N-dodecanoyl-L-glutamic acid, Sodium N-decanoylglutamate, N-decanoyl-L-glutamic acid, Amisoft The hydroxypropyl ester may be selected from one or more of HS-11 P (sodium stearoyl glutamate), Amisoft MS-11 (sodium myristoyl glutamate), Amisoft LS-11 (sodium dodecanoyl glutamate), Amisoft CS-11 (sodium cocoyl glutamate), sodium N-cocoyl glutamate, Amisoft HS-11 P, Amisoft HS-11 P (sodium N-stearoyl glutamate), (sodium N-myristoyl glutamate), (sodium N-dodecanoyl glutamate), and Amisoft HS-11 P.

[0079] The following acylated FA-aas are commercially available:

[0080] [Table 1]

[0081] In certain embodiments, the terms "fatty acid N-acylated amino acid," "fatty acid acylated amino acid," or "acylated amino acid" are used interchangeably herein and refer to an amino acid whose alpha-amino group is acylated with a fatty acid.

[0082] (iii) Oral Formulations. Representative oral formulations include capsules, coated tablets, edibles, elixirs, emulsions, gels, gel caps, granules, gums, juices, liquids, oils, pastes, pellets, pills, powders, fast dissolving tablets, sachets, semisolids, sprays, solutions, suspensions, syrups, tablets, and the like.

[0083] Representative excipient categories include binders, buffers, chelating agents, coating agents, colorants, complexing agents, diluents (i.e., fillers), disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, release agents, surfactants, stabilizers, solubilizers, sweeteners, thickeners, wetting agents, and vehicles.

[0084] Binders are substances used to cause adhesion of powder particles during granulation. Representative binders include acacia, compressible sugars, gelatin, sucrose and derivatives thereof, maltodextrin, cellulose polymers such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and methyl cellulose, acrylic polymers such as insoluble acrylate ammonio methacrylate copolymers, polyacrylate or polymethacrylic copolymers, povidone, copovidone, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, guar gum, and polyethylene glycol.

[0085] Coloring agents can be included in the oral dosage form to impart color to the formulation. Representative coloring agents include grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, and paprika. Additional coloring agents include FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, FD&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide.

[0086] Diluents can enhance granulation of oral formulations. Exemplary diluents include microcrystalline cellulose, sucrose, dicalcium phosphate, starch, lactose, and polyols with less than 13 carbon atoms, such as mannitol, xylitol, sorbitol, maltitol, and pharma- ceutically acceptable amino acids, such as glycine.

[0087] Disintegrants may also be included in the oral formulation to facilitate dissolution. Disintegrants include permeation enhancers and wicking agents, which can draw water or saliva into the oral formulation to facilitate dissolution from the inside as well as the outside of the oral formulation. Such disintegrants, permeation enhancers and / or wicking agents that can be used include starches, such as corn starch, potato starch, pregelatinized and modified starches thereof, cellulosic agents, such as Ac-di-sol, montmorillonite clay, cross-linked PVP, sweeteners, bentonite, microcrystalline cellulose, croscarmellose sodium, alginates, sodium starch glycolate, gums, such as agar, guar, locust bean, karaya, pectin, arabic, xanthan and tragacanth, silicas with high affinity to aqueous solvents, such as colloidal silica, precipitated silica, maltodextrin, beta-cyclodextrin, polymers, such as carbopol, and cellulosic agents, such as hydroxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Dissolution of the oral formulation can be facilitated by including relatively small particle size components therein.

[0088] Representative dispersing or suspending agents include acacia, alginate, dextran, fragcanth, gelatin, hydrogenated edible fats, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, sorbitol syrup, and synthetic natural gums.

[0089] Exemplary emulsifying agents include acacia and lecithin.

[0090] Flavorants are natural or artificial compounds used to impart a pleasant flavor and often an aroma to oral preparations. Representative flavorants include natural and synthetic flavor oils, flavoring aromatics, plant, leaf, flower, and fruit extracts, and combinations thereof. Such flavorants include anise oil, cinnamon oil, vanilla, vanillin, cocoa, chocolate, natural chocolate flavor, menthol, grape, peppermint oil, wintergreen oil, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, cassia oil; citrus oils such as lemon, orange, lime, and grapefruit oil; and fruit essences such as apple, pear, peach, berry, wineberry, date, blueberry, kiwi, strawberry, raspberry, cherry, plum, pineapple, and apricot. In certain embodiments, flavoring agents that can be used include natural berry extracts and natural mixed berry flavors, as well as citric and malic acid.

[0091] Glidants improve the flow of powder blends during manufacturing and minimize oral dosage form weight change.Typical glidants include silicon dioxide, colloidal or fumed silica, magnesium stearate, calcium stearate, stearic acid, corn starch, and talc.

[0092] Lubricants are substances used in oral formulations that reduce friction during compression of the composition. Exemplary lubricants include stearic acid, calcium stearate, magnesium stearate, zinc stearate, talc, mineral and vegetable oils, benzoic acid, poly(ethylene glycol), glyceryl behenate, stearyl fumarate, and sodium lauryl sulfate.

[0093] Representative preservatives include methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and sorbic acid.

[0094] Representative sweeteners include aspartame, dextrose, fructose, isomerized sugar, maltodextrin, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, acesulfame potassium, sodium saccharin, stevia, sucralose, and sucrose.

[0095] Certain embodiments include swallowable compositions. Swallowable compositions are those that do not easily dissolve when placed in the mouth and can be swallowed whole without chewing or discomfort. U.S. Patent No. 5,215,754 and U.S. Patent No. 4,374,082 describe methods for preparing swallowable compositions. In certain embodiments, the swallowable composition may have a shape that does not contain sharp edges and a smooth, uniform and substantially bubble-free outer coating.

[0096] To prepare a swallowable composition, each component may be combined into an intimate mixture with a suitable carrier according to conventional compounding techniques. In certain embodiments of the swallowable composition, the surface of the composition may be coated with a polymeric film. Such film coatings have several beneficial effects. First, they increase the subject's ability to swallow the composition by reducing the adhesion of the composition to the inner surface of the mouth. Second, the film may help mask the unpleasant taste of certain ingredients. Third, the film coating may protect the composition from atmospheric degradation. Polymeric films that can be used in preparing swallowable compositions include vinyl polymers such as polyvinylpyrrolidone, polyvinyl alcohol and acetate, cellulose derivatives such as methyl and ethyl cellulose, hydroxyethyl cellulose and hydroxylpropyl methylcellulose, acrylates and methacrylates, copolymers such as vinyl-maleic and styrene-maleic types, and natural gums and resins such as zein, gelatin, shellac and acacia.

[0097] In certain embodiments, the oral formulation may include a chewable formulation. Chewable compositions have a pleasant taste and mouthfeel, are relatively soft, and break down into smaller pieces and begin to dissolve rapidly after being chewed, thereby allowing them to be swallowed substantially as a solution.

[0098] U.S. Patent No. 6,495,177 describes a method for preparing chewable compositions with improved mouthfeel.U.S. Patent No. 5,965,162 describes a kit and method for preparing edible units that disintegrate rapidly in the mouth, especially when chewed.

[0099] To create a chewable composition, certain ingredients should be included to achieve the attributes described above. For example, a chewable composition should include ingredients that create a pleasant flavor and mouthfeel, and promote relative softness and dissolution in the mouth. The following discussion describes ingredients that may help achieve these characteristics.

[0100] Sugars such as white sugar, corn syrup, sorbitol (solution), maltitol (syrup), oligosaccharides, isomaltooligosaccharides, sucrose, fructose, lactose, glucose, lycassin, xylitol, lactitol, erythritol, mannitol, isomaltose, dextrose, polydextrose, dextrin, compressible cellulose, compressible honey, compressible molasses and mixtures thereof may be added to improve mouthfeel and palatability. Fondants or gums such as gelatin, agar, gum arabic, guar gum and carrageenan may be added to improve the chewiness of the formulation. Fatty materials which can be used include vegetable oils (including coconut oil, hydrogenated palm oil, hydrogenated corn germ oil, hydrogenated castor oil, cottonseed oil, olive oil, peanut oil, palm olein oil and palm stearin oil), animal oils (including refined oils and refined lard having a melting point in the range of 30°-42° C.), cocoa butter, margarine, butter and shortening.

[0101] Alkylpolysiloxanes (polymers available commercially in a variety of molecular weight ranges and with a variety of different substitution patterns) can also be used to enhance the texture, mouthfeel, or both of the chewable composition. By "enhancing texture" it is meant that the alkylpolysiloxane improves one or more of the firmness, brittleness, and chewiness of the chewable composition compared to the same preparation that lacks the alkylpolysiloxane. By "enhancing mouthfeel" it is meant that the alkylpolysiloxane reduces the gritty texture of the chewable composition when liquefied in the mouth compared to the same preparation that lacks the alkylpolysiloxane.

[0102] Alkylpolysiloxanes generally comprise a polymer backbone containing silicon and oxygen, with one or more alkyl groups pendant from the silicon atoms of the backbone. Depending on their grade, they may further comprise silica gel. Alkylpolysiloxanes are generally viscous oils. Representative alkylpolysiloxanes that can be used in swallowable, chewable or dissolvable compositions include monoalkyl or dialkylpolysiloxanes, where the alkyl groups are C 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 123, 134, 146, 147, 152, 153, 1 ~C 6 The alkyl groups are independently selected when each occurs. A particular alkylpolysiloxane that can be used is dimethylpolysiloxane (commonly referred to as simethicone). More specifically, a granular simethicone preparation designated as Simethicone GS can be used. Simethicone GS is a preparation containing 30% Simethicone USP. Simethicone USP contains 90.5% by weight or less (CH 3 ) 3 -Si{OSi(CH 3 ) 2}CH 3 SiO 4.0% to 7.0% by weight 2 It contains in admixture with

[0103] To prevent stickiness that may occur in some chewable compositions and to facilitate conversion of the active ingredients into an emulsion or suspension upon ingestion, the composition may further include an emulsifier, such as glycerol fatty acid esters, sorbitan monostearate, sucrose fatty acid esters, lecithin, and mixtures thereof. In certain embodiments, one or more of such emulsifiers may be present in an amount of 0.01% to 5.0% by weight of the administered formulation. In certain embodiments, lower or higher levels of emulsifiers may result in no emulsification or increased waxiness.

[0104] Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product to be reconstituted with water or other suitable vehicle before use.

[0105] In addition to the above, in preparing the swallowable, chewable and / or dissolvable compositions or any other oral formulation described herein, any suitable fillers and excipients may be utilized consistent with the described purpose.

[0106] Oral formulations also include edibles. Edibles refer to any product that can be consumed as food or drink. In some cases, edibles are made by infusing plant extracts or synthetic cannabinoids into foodstuffs. Examples of edible foods suitable for use include candy, candy bars, bread, brownies, cakes, cheese, chocolate, cocoa, cookies, gummies, lollipops, mints, pastries, peanut butter, popcorn, protein bars, mochi, yogurt, etc. Although not strictly edible, gum can also be used. Examples of edible beverages include beer, juice, flavored milk, flavored water, liquor, milk, punch, milkshakes, soda, tea, and water. In certain embodiments, edibles are made by combining plant extracts or synthetic cannabinoids with ingredients used to make edibles. Examples include butter and oil. Examples of oils include coconut oil, grape seed oil, olive oil, palm oil, papaya seed oil, peanut oil, sesame oil, germinated wheat oil, wheat germ oil, or any combination thereof.

[0107] The oral formulations can be individually wrapped or packaged as multiple units in one or more packages, cans, vials, blister packs, or bottles of any size. The dosages are sized to provide a therapeutically effective amount.

[0108] In certain embodiments, the oral formulation comprises botanical matter (e.g., plant parts or extracts) or synthetic cannabinoids in at least 0.1% w / v or w / w of the oral formulation; at least 1% w / v or w / w of the oral formulation; at least 10% w / v or w / w of the oral formulation; at least 20% w / v or w / w of the oral formulation; at least 30% w / v or w / w of the oral formulation; at least 40% w / v or w / w of the oral formulation; at least 50% w / v or w / w of the oral formulation; at least 60% w / v or w / w of the oral formulation; at least 70% w / v or w / w of the oral formulation; at least 80% w / v or w / w of the oral formulation; at least 90% w / v or w / w of the oral formulation; at least 95% w / v or w / w of the oral formulation, or at least 99% w / v or w / w of the oral formulation.

[0109] In certain embodiments, the oral formulation comprises a carrier in at least 0.1% w / v or w / w of the oral formulation; at least 1% w / v or w / w of the oral formulation; at least 10% w / v or w / w of the oral formulation; at least 20% w / v or w / w of the oral formulation; at least 30% w / v or w / w of the oral formulation; at least 40% w / v or w / w of the oral formulation; at least 50% w / v or w / w of the oral formulation; at least 60% w / v or w / w of the oral formulation; at least 70% w / v or w / w of the oral formulation; at least 80% w / v or w / w of the oral formulation; at least 90% w / v or w / w of the oral formulation; at least 95% w / v or w / w of the oral formulation, or at least 99% w / v or w / w of the oral formulation.

[0110] In certain embodiments, the oral formulation comprises the excipient in at least 0.1% w / v or w / w of the oral formulation; at least 1% w / v or w / w of the oral formulation; at least 10% w / v or w / w of the oral formulation; at least 20% w / v or w / w of the oral formulation; at least 30% w / v or w / w of the oral formulation; at least 40% w / v or w / w of the oral formulation; at least 50% w / v or w / w of the oral formulation; at least 60% w / v or w / w of the oral formulation; at least 70% w / v or w / w of the oral formulation; at least 80% w / v or w / w of the oral formulation; at least 90% w / v or w / w of the oral formulation; at least 95% w / v or w / w of the oral formulation; or at least 99% w / v or w / w of the oral formulation.

[0111] In certain embodiments, 10 g of dried plant extract can be used in 150 ml of water, which can provide effective concentrations of 1-99% (w / w) plant extract, 2-80% (w / w) plant extract, and 5-50% (w / w) plant extract.

[0112] Excipients are commercially available from companies such as Aldrich Chemical Co., FMC Corp, Bayer, BASF, Alexi Fres, Witco, Mallinckrodt, Rhodia, ISP, and others.

[0113] As set forth above, the oral formulations described herein include cannabinoids and N-acylated fatty amino acids in a w / w ratio of 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25.

[0114] Representative Formulations. Solution Formulations. One or more cannabinoids and one or more N-acylated fatty amino acids are combined in an aqueous / organic solvent mixture at a w / w ratio of 1:6, 1:10 or 1:20. The resulting blend is vigorously stirred. One or more surfactants may be added to prepare the final formulation.

[0115] Suspension formulations (oral solutions). One or more cannabinoids and one or more N-acylated fatty amino acids are combined in a w / w ratio of 1:6, 1:10 or 1:20 in water, an aqueous / organic solvent mixture or an organic solvent mixture. The resulting blend can be stirred into a suspension.

[0116] Solution formulations. One or more cannabinoids and one or more absorption enhancers are combined in an aqueous / organic solvent mixture at a w / w ratio of 1:6, 1:10 or 1:20. The resulting blend is vigorously stirred. One or more surfactants may be added to prepare the final formulation.

[0117] Suspension formulations (oral solutions): One or more cannabinoids and one or more absorption enhancers are combined in a w / w ratio of 1:6, 1:10 or 1:20 in water, an aqueous / organic solvent mixture or an organic solvent mixture. The resulting blend can be stirred into a suspension.

[0118] Gelcap Compositions. Suspension or solution formulations can be filled into gelcaps to contain up to 1 g of cannabinoids. The gelcaps can be treated with an enteric coat or can be used without a coating.

[0119] Capsules (e.g., gelatin-based or vegetarian). Powders containing one or more cannabinoids and one or more N-acylated fatty amino acids can be prepared using wet granulation techniques. The resulting dry powders can contain cannabinoids and N-acylated fatty amino acids in a (w:w) ratio of 1:6, 1:10 or 1:20. The powders can be filled into commercially available capsules.

[0120] Tablet / Capsule Compositions. Solution and suspension formulations can be dried by evaporation, freeze-drying or spray-drying. The resulting dried product can be combined with tableting excipients and compressed into tablets or capsules containing up to 1 g of cannabis. Alternatively, the dried product can be filled into capsules.

[0121] Additional information can be found in WADE & WALLER, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (2nd ed., 1994) and Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990. Furthermore, formulations can be prepared to meet sterility, pyrogenicity, general safety and purity standards required by the USFDA and / or relevant regulatory authorities of other foreign countries.

[0122] (iv) Methods of Use. The oral compositions disclosed herein can be used to treat subjects, including humans, veterinary animals (dogs, cats, reptiles, birds, etc.), livestock (horses, cows, goats, pigs, chickens, etc.), and research animals (monkeys, rats, mice, fish, etc.). Treating a subject includes providing a therapeutically effective amount. A therapeutically effective amount includes an amount that provides an effective, prophylactic and / or therapeutic treatment.

[0123] An "effective amount" is the amount of a composition necessary to produce a desired physiological change in a subject. Effective amounts are often administered for testing purposes. Representative effective amounts disclosed herein can reduce pain perception (neuropathic pain, acute pain, visceral pain) in animal models, stimulate appetite in animal models, reduce seizures (e.g., epileptic seizures) in animal models, reverse bone loss in animal models, reduce migraine headaches (constrict cranial blood vessels) in animal models, treat addiction in animal models, reduce anxiety in animal models, and / or reduce asthma symptoms in animal models.

[0124] "Prophylactic treatment" includes treatment administered to a subject who does not exhibit signs or symptoms of a disease or nutritional deficiency, or who exhibits only early signs or symptoms of a disease or nutritional deficiency, for the purpose of minimizing, inhibiting, or reducing the risk of further developing the disease or nutritional deficiency. Thus, prophylactic treatment serves as a preventative measure against the onset of a disease or nutritional deficiency.

[0125] As an example of preventative treatment, the oral formulations disclosed herein can be administered to a subject at risk of developing a migraine headache. Effective preventative treatment of migraine headaches is indicated when the number of migraines experienced by the subject per month is reduced by at least 10%, or in certain embodiments, by 25%.

[0126] As another example of preventive treatment, the oral formulations disclosed herein can be administered to subjects at risk of having epileptic seizures. Effective preventive treatment of epileptic seizures occurs when the number of seizures per month is reduced by at least 10%, or in certain embodiments, by 25%.

[0127] As another example of prophylactic treatment, the oral formulations disclosed herein can be administered to subjects at risk of suffering from neuropathic pain. Effective prophylactic treatment of neuropathic pain occurs when the incidence of neuropathic pain is reduced by at least 10%, or in certain embodiments, 25%, as measured by standard subjective or objective pain assessments.

[0128] As another example of prophylactic treatment, the oral formulations disclosed herein can be administered to subjects at risk of developing breakthrough pain. Effective prophylactic treatment of breakthrough pain is indicated when the occurrence of breakthrough pain is reduced by 10%, and in certain embodiments, by 25%, according to standard subjective or objective pain assessments.

[0129] As another example of prophylactic treatment, the oral formulations disclosed herein can be administered to subjects at risk of developing chemotherapy-induced nausea and vomiting (CINV). Effective prophylactic treatment of CINV occurs when CINV is reduced by 10%, and in certain embodiments, by 25%, as measured by standard subjective or objective CINV assessments.

[0130] As an example of preventative treatment of nutritional deficiencies, the oral formulations disclosed herein can be administered to subjects at risk of developing rickets due to vitamin C deficiency, anemia due to lack of iron in the diet, and / or bone loss due to calcium deficiency. Effective preventative treatment of these conditions occurs when these conditions are avoided or delayed due to nutritional supplementation with the oral formulations disclosed herein.

[0131] "Therapeutic treatment" includes treatment administered to a subject having a disease or nutritional deficiency, which is administered to the subject with the intent of curing or reducing the severity of the disease or nutritional deficiency.

[0132] As an example of therapeutic treatment, the oral formulations disclosed herein can be administered to a subject suffering from migraine headaches. Effective therapeutic treatment of migraine headaches is manifested when the severity of the headache is completely reduced or alleviated, as measured by standard subjective or objective headache assessments, and / or the headache resolves more quickly.

[0133] Another example of therapeutic treatment includes administration of an oral formulation disclosed herein to a subject experiencing CINV. Therapeutic treatment of CINV is manifested when vomiting is reduced or ceases (or ceases more quickly) or nausea is alleviated, as measured by standard subjective or objective CINV assessments.

[0134] Another example of a therapeutic treatment involves administration of the disclosed oral formulations to a subject with osteoporosis. Effective therapeutic treatment of osteoporosis occurs when bone density increases by 10%, and in certain embodiments, by 25%.

[0135] Another example of therapeutic treatment involves administration of an oral formulation disclosed herein to a subject with anxiety. Effective therapeutic treatment of anxiety is manifested when there is a complete and / or more rapid reduction or alleviation of the severity of anxiety as measured by standard subjective or objective anxiety assessments.

[0136] Another example of a therapeutic treatment comprises administering an oral formulation disclosed herein to a subject with multiple sclerosis. Effective therapeutic treatment of multiple sclerosis is manifested by a 10%, and in certain embodiments, a 25% improvement in score on a standard walking test.

[0137] As an example of therapeutic treatment of nutritional deficiencies, the oral formulations disclosed herein can be administered to subjects with rickets due to vitamin C deficiency, anemia due to iron deficiency in the diet, and / or bone loss due to calcium deficiency. Effective therapeutic treatment of these conditions occurs when these conditions are reduced or resolved due to nutritional supplementation with the oral formulations disclosed herein.

[0138] Therapeutic treatments can be distinguished from effective amounts based on the presence or absence of the study component upon administration, however, as will be appreciated by those of skill in the art, there may be overlap in effective amounts, prophylactic treatments and therapeutic treatments in human clinical trials.

[0139] For administration, a therapeutically effective amount (also referred to herein as a dosage) can be estimated initially based on the results of in vitro assays and / or animal model studies. Such information can be used to more accurately determine useful dosages in intended subjects.

[0140] The actual dosage administered to a particular subject can be determined by the subject, a physician, veterinarian or researcher, taking into account parameters such as physical, physiological and psychological factors, including the subject's target, weight, condition, previous or concurrent therapeutic interventions, and / or idiopathic diseases.

[0141] Useful dosages can range from 0.1 to 5 μg / kg or 0.5 to 1 μg / kg. In another non-limiting embodiment, dosages can range from 1 μg / kg, 5 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg, 100 μg / kg, 150μg / kg, 200μg / kg, 250μg / kg, 350μg / kg, 400μg / kg, 450μg / kg, 500μg / kg, 550μg / kg, 600μg / kg, 650μg / kg, 700 μg / kg, 750 μg / kg, 800 μg / kg, 850 μg / kg, 900 μg / kg, 950 μg / kg, 1000 μg / kg, 0.1-5 mg / kg or 0.5-1 mg / kg. In another non-limiting embodiment, the dosage is 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, The compound may contain more than 100 mg / kg, 100 mg / kg, 150 mg / kg, 200 mg / kg, 250 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, 500 mg / kg, 550 mg / kg, 600 mg / kg, 650 mg / kg, 700 mg / kg, 750 mg / kg, 800 mg / kg, 850 mg / kg, 900 mg / kg, 950 mg / kg, 1000 mg / kg or more.

[0142] Using the methods and oral formulations disclosed herein, the variability in absorption otherwise observed is reduced to, for example, less than 50% CV, less than 40%, or less than 30%.

[0143] A therapeutically effective amount can be achieved by administration of single or multiple doses over the course of a treatment regimen (e.g., every hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 9 hours, every 12 hours, every 18 hours, every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, or once a month).

[0144] One or more active agents can be administered simultaneously or within a selected time window, such as within 10 minutes, 1 hour, 3 hours, 10 hours, 15 hours, 24 hours, or 48 hours, or when the complementary active agent is within a clinically relevant therapeutic window.

[0145] (v) Representative embodiments.

[0146] 1. A method for preparing an oral cannabinoid formulation having reduced cannabinoid blood absorption variability in a subject, comprising adding a cannabinoid and an effective amount of an N-acylated fatty amino acid or salt thereof to the oral formulation.

[0147] 2. The method of embodiment 1, wherein the effective amount of the N-acylated fatty amino acid or salt thereof provides a weight / weight (w / w) ratio of cannabinoid / N-acylated fatty amino acid or salt thereof in the oral formulation of 1:4 to 1:25.

[0148] 3. The method of embodiment 1, wherein the effective amount of the N-acylated fatty amino acid or salt thereof provides a weight / weight (w / w) ratio of cannabinoid to N-acylated fatty amino acid or salt thereof in the oral formulation of 1:6, 1:10 or 1:20.

[0149] 4. Oral formulations: 50 mg of cannabinoid and 300 mg of N-acylated fatty amino acid or its salt, 10 mg of cannabinoid and 100 mg of N-acylated fatty amino acid or its salt, 10 mg of cannabinoid and 200 mg of N-acylated fatty amino acid or its salt, 50 mg of a cannabinoid and 500 mg of an N-acylated fatty amino acid or salt thereof, or 30 mg of cannabinoids and 300 mg of N-acylated fatty amino acids or salts thereof The method of any of embodiments 1 to 3, comprising:

[0150] 5. Oral formulations: 50 mg of cannabidiol (CBD) and 300 mg of an N-acylated fatty amino acid or salt thereof, 10 mg of Δ9-tetrahydrocannabinol (THC) and 100 mg of an N-acylated fatty amino acid or salt thereof, 10 mg THC and 200 mg N-acylated fatty amino acid or its salt, 50 mg of CBD and 500 mg of an N-acylated fatty amino acid or salt thereof, or 30mg CBD and 300mg N-acylated fatty amino acids or salts thereof The method of any of embodiments 1 to 4, comprising:

[0151] 6. Oral formulations: 50 mg of cannabinoids and 300 mg of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), 10mg cannabinoids and 100mg SNAC, 10mg cannabinoids and 200mg SNAC, 50mg of cannabinoids and 500mg of SNAC, or 30mg cannabinoids and 300mg SNAC The method of any of embodiments 1 to 4, comprising:

[0152] 7. Oral formulations: 50mg CBD and 300mg SNAC, 10mg THC and 100mg SNAC, 10mg THC and 200mg SNAC, 50mg CBD and 500mg SNAC, or 30mg CBD & 300mg SNAC The method of any of embodiments 1 to 4, comprising:

[0153] 8. The method of any of embodiments 1-7, wherein the oral formulation comprises a powder.

[0154] 9. The method of embodiment 8, wherein the powder is formed by wet granulation.

[0155] 10. The method of any of embodiments 1-9, wherein the oral formulation comprises a gelatin capsule.

[0156] 11. The method of any of embodiments 1-10, wherein the oral formulation comprises a powder formed by wet granulation, the powder being within a gelatin capsule.

[0157] 12. The method of any of embodiments 1-7, wherein the oral formulation comprises an oral solution.

[0158] 13. The method of any of embodiments 1-12, wherein the reduced cannabinoid blood absorption variability results in a coefficient of variation (%CV) of <50%, less than 40%, or less than 30%.

[0159] 14. The method of any of embodiments 1-13, wherein the absorption comprises gastrointestinal absorption into the blood.

[0160] 15. Cannabinoids are found in Calophyllum brasiliense, Calophyllum caledonicum, Calophyllum inophyllum, Calophyllum soulattri, Uncaria tomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis, sinensis, Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia sinensis, Krameria triandra, Punica granatum, Viburnum plicatum, Nicotiana tabacum, Duboisia hopwoodii, Asclepias syriaca, Curcuma longa, Cannabis sativa, Cannabis indica, Cannabis ruderalis ruderalis and / or Acer spp. or extracts thereof.

[0161] 16. The method of any of embodiments 1-4, 6 or 8-14, wherein the cannabinoid is derived from Cannabis sativa, Cannabis ruderalis or Cannabis indica.

[0162] 17. The method of any of embodiments 1-4, 6 or 8-16, wherein the cannabinoids comprise Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabidiol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA) and / or mixtures thereof.

[0163] 18. The method of any of embodiments 1-17, wherein the cannabinoid comprises a plant-derived cannabinoid or a synthetic cannabinoid.

[0164] 19. The method of any of embodiments 1-18, wherein the oral formulation comprises a flavonoid compound, a terpene or a terpenoid.

[0165] 20. The method of any of embodiments 1-5 or 8-19, wherein the N-acylated fatty amino acid comprises one or more of compounds I-XXXV (Figure 2) or compounds a-r (Figure 3).

[0166] 21. The method of any of embodiments 1-5 or 8-19, wherein the N-acylated fatty amino acid comprises monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate, or N-(salicyloyl)-8-aminocaprylic acid.

[0167] 22. N-acylated fatty amino acid or its salt,

[0168] [ka] 20. The method of any of embodiments 1-5 or 8-19, including wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.

[0169] 23. The method of embodiment 22, wherein the monovalent cation is sodium or potassium.

[0170] 24. The method of embodiment 22 or 23, wherein the metal cation is calcium or magnesium.

[0171] 25. The method of any of embodiments 22-24, wherein the organic cation is ammonium or tetramethylammonium.

[0172] 26. The method of any of embodiments 22-25, wherein X is H.

[0173] 27. The method of any of embodiments 22-25, wherein X is a monovalent cation, including sodium or potassium.

[0174] 28. The method of any of embodiments 22-25, wherein X is a divalent metal cation, including calcium or magnesium.

[0175] 29. The method of any of embodiments 22-25, wherein X is an organic cation, including ammonium or tetramethylammonium.

[0176] 30. The method of any of embodiments 22-29, wherein Z is H.

[0177] 31. The method of any of embodiments 22-29, wherein Z is a monovalent cation, including sodium or potassium.

[0178] 32. The method of any of embodiments 22-29, wherein Z is a divalent cation comprising calcium or magnesium.

[0179] 33. The method of any of embodiments 22-25, wherein X is H and Z is H.

[0180] 34. The method of any of embodiments 22-25, wherein X is H and Z is sodium.

[0181] 35. The method of any of embodiments 22-25, wherein X is sodium and Z is sodium.

[0182] 36. The method of any of embodiments 1-35, wherein the oral formulation is a pharmaceutical composition.

[0183] 37. The method of any of embodiments 1-35, wherein the oral formulation is a nutritional supplement.

[0184] 38. Oral formulations are used in the following conditions: acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), rigidity, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome , cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headaches, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infections, digestive disorders, glaucoma, glioma, Graves' disease, heart disease, hepatitis, herpes, Huntington's disease, high blood pressure, lethargy, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia , liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS), proximal myotonic ... 37. The method of any of embodiments 1-36, wherein the method is utilized to treat symptoms of chronic myocardial infarction, chronic pulmonary disease, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles, sickle cell disease, stroke, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorders (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, and withdrawal.

[0185] 39. Use of an N-acylated fatty amino acid as disclosed herein to reduce inter-subject variability in cannabinoid uptake following ingestion of an oral formulation containing a cannabinoid.

[0186] 40. An oral dosage form formed according to the method of any of embodiments 1-38.

[0187] (vi) Representative Experimental Procedure. Participants may be administered a commercially available cannabis extract in an ethanol solution. The concentrate may contain 8 mg of THC per dose. This dose may be selected because it contains a high percentage of THC and produces a noticeable effect on the user-reported "euphoria." Aqueous ethanol may be used as a solvent since it effectively dissolves the cannabis extract, as well as SNAC.

[0188] In the experimental procedure, each participant will mix the cannabis concentrate with 15 ml (one tablespoon) of aqueous ethanol and immediately swallow the mixture. This treatment will constitute the control treatment. In the test treatment, each participant will mix the cannabis concentrate with a premixed solution of aqueous ethanol and 200 mg of SNAC and immediately swallow the dissolved mixture.

[0189] Blood samples can be taken from participants at post-dose time points and the amount of cannabis in the blood sample can be measured.

[0190] (vii) Experimental Examples [Example 1] Participant Selection: Body Mass Index (BMI) 18 to 30.0 kg / m 2 Healthy men and women between the ages of 21 and 55 years and weighing at least 50 kg were eligible to participate. None of the female participants were pregnant or breastfeeding. Participants were allowed to have used cannabis in the past, but were not allowed to currently use cannabis more than three times per week or within 6 days of dosing, as confirmed by CDB blood testing.

[0191] Formulation: Three powders containing CBD and SNAC were prepared using wet granulation techniques. The resulting dry powders contained CBD and SNAC in ratios of 1:2, 1:6, and 1:10 (w:w), respectively. The powders were filled into gelatin capsules prior to administration.

[0192] Methods: Participants were randomized into treatment groups and received the following treatments. All participants were to receive all treatments with a minimum of 1 week washout between treatments. Treatments included 50mg CBD / 100mg SNAC (1:2 ratio); 50mg CBD / 300mg SNAC (1:6 ratio); 50mg CBD / 500mg SNAC (1:10 ratio); 30mg CBD / 300mg SNAC (1:10 ratio); and 150mg CBD / 300mg SNAC (1:2 ratio).

[0193] Participants were fasted for at least 10 hours prior to dosing of study treatment. Water was permitted up to 1 hour prior to dosing, then started ad libitum 2 hours after dosing. Food was permitted 4 hours after dosing. Treatment was administered with 2 oz of water. Blood samples were collected pre-dose and at 5, 10, 15, 30, 45, 60, 90, 120, 240, 480, and 720 minutes after dosing. Blood samples were analyzed for concentrations of CBD and its main metabolite, 7-COOH CBD, in a commercial laboratory using a validated liquid chromatography-mass spectrometry (LC-MS) method.

[0194] Results: AUC0-last or area under the plasma concentration time curve from time zero to the last measurement was calculated for each of the administered treatments (Table 2). Treatments with 1:6 and 1:10 (w:w) ratios of CBD:SNAC demonstrated reduced variability, expressed as coefficient of variation (%CV), compared to treatment with 1:2 CBD:SNAC.

[0195] [Table 2]

[0196] [Example 2] Participant selection: Body mass index (BMI) 18 to 30.0 kg / m 2Healthy men and women between the ages of 21 and 55 years and weighing at least 50 kg were eligible to participate. None of the female participants were pregnant or breastfeeding. Participants were allowed to have used cannabis in the past, but were not allowed to currently use it more than three times per week or within 6 days of dosing, as confirmed by urine testing for THC.

[0197] Methods: Participants were randomized into treatment groups to receive the following treatments. All participants were to receive all treatments with a minimum of 1 week washout between treatments. Treatments included an oral solution containing 10 mg THC (no SNAC); an oral solution containing 10 mg THC and 100 mg SNAC; and an oral solution containing 10 mg THC and 200 mg SNAC.

[0198] Participants were fasted for at least 10 hours prior to study treatment administration. Water was permitted until 1 hour prior to dosing, then started ad libitum 2 hours after dosing. Food was permitted 4 hours after dosing. Blood samples were collected pre-dose and at 5, 10, 15, 30, 45, 60, 90, 120, 240, 480, and 720 minutes after dosing. Blood samples were analyzed for concentrations of THC and its major metabolite, 11-OH THC, in a commercial laboratory using a validated liquid chromatography-mass spectrometry (LC-MS) method.

[0199] Results: AUC0-last or area under the plasma concentration time curve from time zero to the last measurement was calculated for each of the treatments administered (Table 3). Treatments with 1:10 and 1:20 (w:w) ratios of THC:SNAC demonstrated reduced variability, expressed as coefficient of variation (%CV), compared to the control treatment without SNAC.

[0200] [Table 3]

[0201] The results of Examples 1 and 2 demonstrated that oral formulations of cannabinoids and N-acylated fatty amino acids reduced inter-subject variability in AUC when the ratio of cannabinoid:N-acylated fatty amino acid ranged from 1:6 to 1:20. Reduced variability can result in a %CV of less than 50%, less than 40%, or less than 30%, resulting in a two-fold reduction in variability.

[0202] (vii) Concluding paragraph. As will be appreciated by those skilled in the art, each embodiment disclosed herein can comprise, consist essentially of, or consist of its specific stated elements, steps, ingredients, or components. Thus, the terms "include" or "including" should be understood to mean "comprise, consist, or consist essentially of." The transitional terms "comprise" or "comprises" mean includes, but is not limited to, and permit the inclusion of even major amounts of elements, steps, ingredients, or components not specifically recited. The transitional phrase "consisting of" excludes elements, steps, ingredients, or components not specifically recited. The transitional phrase "consisting essentially of" limits the scope of the embodiment to those elements, steps, ingredients, or components that are specifically recited and that do not materially affect the embodiment. A significant effect would result in a statistically significant increase in absorbance variability and / or a %CV value of greater than 50%.

[0203] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weights, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and without any intention of limiting the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by using ordinary rounding approaches. Where further clarity is needed, the term "about" when used in conjunction with a stated numerical value or range has the meaning that one of ordinary skill in the art would expect, i.e., a value that is somewhat greater or somewhat less than the stated value or range, a value within ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±11% of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1% of the stated value.

[0204] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible, however, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0205] The terms "a," "an," "the," and similar modifiers used in describing the present invention (particularly in the claims that follow) should be understood to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended as a shorthand alternative to individually referring to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if set forth individually. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") recited herein is intended merely to facilitate a better understanding of the invention, and is not intended to impose limitations on the scope of the invention as recited in the claims. No language in the specification should be construed to refer to any element essential to the practice of the invention, even if not recited in the claims.

[0206] Groups of alternative elements or embodiments of the invention disclosed herein should not be considered limiting. Each group member may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is understood that one or more members of a group may be included in or omitted from a group for convenience and / or patentability. When such inclusion or omission occurs, the specification is considered to include the group as modified to meet the recitation requirements of all Markush groups used in the appended claims.

[0207] Certain embodiments of the present invention have been described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will be apparent to those of skill in the art upon reading the foregoing description. The inventors expect that such variations will be utilized by those of skill in the art, and the inventors intend that the invention be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of any possible variations of the elements described above is encompassed by the present invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0208] Additionally, numerous patents, publications, journal articles and other documents ("references") are referenced throughout this specification. Each of these references is individually incorporated herein by reference for the teachings contained therein.

[0209] In closing, it should be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be used are within the scope of the invention. Thus, by way of example, and not of limitation, other aspects of the invention may be utilized in accordance with the teachings herein. Thus, the invention is not limited to what has been precisely shown and described above.

[0210] The details shown in this specification are for the purpose of illustrating the preferred embodiments of the present invention only, by way of example, and are provided to illustrate what is believed to be the most useful and easily understood explanation of the principles and conceptual aspects of various embodiments of the present invention. In this regard, it is not intended to show the structural details of the present invention in more detail than is necessary for a fundamental understanding of the present invention, but rather the description, taken together with the drawings and / or examples, will make clear to those skilled in the art how some forms of the present invention may be embodied in practice.

[0211] The definitions and explanations used in this disclosure are meant and intended to control in future constructions unless clearly and unambiguously modified in the following examples, or when application of the meaning would render any construction meaningless or essentially meaningless. If construction of the term renders it meaningless or essentially meaningless, the definition should be derived from a dictionary known to those skilled in the art, such as Webster's Dictionary, 3rd Edition, or the Oxford Dictionary of Biochemistry and Molecular Biology (Ed. Anthony Smith, Oxford University Press, Oxford, 2004).

Claims

1. 1. A method for preparing an oral cannabinoid formulation having reduced cannabinoid blood absorption variability in a subject following administration of the oral cannabinoid formulation, the method comprising adding N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) and a cannabinoid to an oral formulation in a weight / weight (w / w) ratio of cannabinoid / N-acylated fatty amino acid of 1:6, 1:10 or 1:20 within the oral formulation, thereby preparing an oral cannabinoid formulation having reduced cannabinoid blood absorption variability.

2. A method for preparing an oral cannabinoid formulation having reduced variability in cannabinoid blood absorption in a subject, comprising adding a cannabinoid and an effective amount of an N-acylated fatty amino acid or a salt thereof to the oral formulation.

3. 3. The method of claim 2, wherein the effective amount of the N-acylated fatty amino acid or salt thereof provides a weight / weight (w / w) ratio of cannabinoid to N-acylated fatty amino acid or salt thereof in the oral formulation of from 1:4 to 1:

25.

4. 3. The method of claim 2, wherein the effective amount of the N-acylated fatty amino acid or salt thereof provides a weight / weight (w / w) ratio of cannabinoid to N-acylated fatty amino acid or salt thereof in the oral formulation of 1:6, 1:10 or 1:

20.

5. The oral formulation is 50 mg of a cannabinoid and 300 mg of an N-acylated fatty amino acid or a salt thereof; 10 mg of a cannabinoid and 100 mg of an N-acylated fatty amino acid or a salt thereof; 10 mg of a cannabinoid and 200 mg of an N-acylated fatty amino acid or a salt thereof; 50 mg of a cannabinoid and 500 mg of an N-acylated fatty amino acid or a salt thereof, or 30 mg of cannabinoid and 300 mg of N-acylated fatty amino acid or its salt The method of claim 2 , comprising:

6. The oral formulation is 50 mg of cannabidiol (CBD) and 300 mg of an N-acylated fatty amino acid or a salt thereof; 10 mg of Δ9-tetrahydrocannabinol (THC) and 100 mg of an N-acylated fatty amino acid or a salt thereof; 10 mg of THC and 200 mg of an N-acylated fatty amino acid or a salt thereof; 50 mg of CBD and 500 mg of an N-acylated fatty amino acid or a salt thereof, or 30 mg of CBD and 300 mg of N-acylated fatty amino acid or its salt The method of claim 2 , comprising:

7. The oral formulation is 50 mg of cannabinoids and 300 mg of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), 10 mg of cannabinoids and 100 mg of SNAC, 10 mg of cannabinoids and 200 mg of SNAC, 50 mg of cannabinoids and 500 mg of SNAC, or 30 mg cannabinoids and 300 mg SNAC The method of claim 2 , comprising:

8. The oral formulation is 50 mg CBD and 300 mg SNAC, 10 mg THC and 100 mg SNAC, 10 mg THC and 200 mg SNAC, 50 mg CBD and 500 mg SNAC, or 30mg CBD and 300mg SNAC The method of claim 2 , comprising:

9. The method of claim 2 , wherein the oral formulation comprises a powder.

10. 10. The method of claim 9, wherein the powder is formed by wet granulation.

11. 3. The method of claim 2, wherein the oral formulation comprises a gelatin capsule.

12. 3. The method of claim 2, wherein the oral formulation comprises a powder formed by wet granulation, the powder being within a gelatin capsule.

13. The method of claim 2 , wherein the oral formulation comprises an oral solution.

14. 3. The method of claim 2, wherein the reduced cannabinoid blood absorption variability results in a coefficient of variation (%CV) of <50%, less than 40% or less than 30%.

15. The method of claim 2 , wherein the absorption comprises gastrointestinal absorption into the blood.

16. Cannabinoids are found in Calophyllum brasiliens, Calophyllum caledonicum, Calophyllum inophyllum, Calophyllum soultri, Uncaria tomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendula officinalis, and other cannabinoid-rich plants. officinalis, Usnea barbata, Ligusticum porteri-osha, Gaulteria procumbens, Camellia sinensis, Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia sinensis, Krameria triandra, 3. The method of claim 2, wherein the active ingredient is derived from Cannabis sativa, Cannabis indica, Cannabis ruderalis and / or Acer spp. or extracts thereof.

17. 3. The method of claim 2, wherein the cannabinoid is derived from Cannabis sativa, Cannabis ruderalis or Cannabis indica.

18. 3. The method of claim 2, wherein the cannabinoids comprise Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiol acid (CBDA), cannabinol propyl variant (CBNV), cannabiditriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA) and / or mixtures thereof.

19. 3. The method of claim 2, wherein the cannabinoid comprises a plant-derived cannabinoid or a synthetic cannabinoid.

20. The method of claim 2 , wherein the oral formulation comprises a flavonoid compound, a terpene or a terpenoid.

21. 3. The method of claim 2, wherein the N-acylated fatty amino acid comprises one or more of compounds I-XXXV (Figure 2) or compounds a-r (Figure 3).

22. 3. The method of claim 2, wherein the N-acylated fatty amino acid comprises monosodium N-salicyloyl-8-aminocaprylate, disodium N-salicyloyl-8-aminocaprylate or N-(salicyloyl)-8-aminocaprylic acid.

23. N-acylated fatty amino acid or a salt thereof 【Chemistry 1】 3. The method of claim 2, comprising the formula: wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.

24. 24. The method of claim 23, wherein the monovalent cation is sodium or potassium.

25. 24. The method of claim 23, wherein the metal cation is calcium or magnesium.

26. 24. The method of claim 23, wherein the organic cation is ammonium or tetramethylammonium.

27. 24. The method of claim 23, wherein X is H.

28. 24. The method of claim 23, wherein X is a monovalent cation comprising sodium or potassium.

29. 24. The method of claim 23, wherein X is a divalent metal cation comprising calcium or magnesium.

30. 24. The method of claim 23, wherein X is an organic cation comprising ammonium or tetramethylammonium.

31. 24. The method of claim 23, wherein Z is H.

32. 24. The method of claim 23, wherein Z is a monovalent cation comprising sodium or potassium.

33. 24. The method of claim 23, wherein Z is a divalent cation comprising calcium or magnesium.

34. 24. The method of claim 23, wherein X is H and Z is H.

35. 24. The method of claim 23, wherein X is H and Z is sodium.

36. 24. The method of claim 23, wherein X is sodium and Z is sodium.

37. The method of claim 2 , wherein the oral formulation is a pharmaceutical composition.

38. 3. The method of claim 2, wherein the oral formulation is a nutritional supplement.

39. Oral formulations are used to treat acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), rigidity, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, Cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headaches, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infections, digestive disorders, glaucoma, glioma, Graves' disease, heart disease, hepatitis, herpes, Huntington's disease, high blood pressure, lethargy, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), and anxiety.

3. The method of claim 2, utilized to treat symptoms of drowsiness, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles, sickle cell disease, seizures, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome and withdrawal.

40. 40. An oral dosage form formed according to the method of any one of claims 1 to 39.

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