BR112018015570B1 - BIOLOGICALLY ACTIVE CANNABIDIOL ANALOGUES, PHARMACEUTICAL COMPOSITION AND USE THEREOF - Google Patents

Abstract

These are biologically active cannabidiol analogues comprising a compound of formula [I] in which one of R1 or R2 or both is the residue of a chemical moiety formed by the reaction of an amino group of the amino acid ester of R1 or R2 or both with a dicarboxylic acid or a dicarboxylic acid derivative and the other R1 or R2 (in the case of mono) is the residue of a dicarboxylic acid or dicarboxylic acid derivative or Hydrogen (H) (i.e. not derived) and salts of same. These CBD analogs are useful in pain management in oncology and other clinical settings where neuropathy is presented. Furthermore, these CBD analogues are useful in blocking the addictive properties of opiates.

Description

Field of Invention

[001] The present invention is directed to the development of biologically active cannabidiol analogues with the ability to be formulated into pharmaceutical compositions, and methods of using such compositions for a pharmacological benefit. In a further embodiment of the present invention biologically active CBD analogues possessed analgesic properties alone and in combination with a sub-analgesic dose of morphine in cisplatin-induced neuropathy. Furthermore, these analogs exhibited blocking properties for opioid dependence.

Background of the Invention

[002] Cannabidiol (CBD) has a variety of pharmacological benefits, which include, without limitation, anti-inflammatory, analgesic, anticonvulsant, antipsychotic, antifibrosis, healing, antioxidant, neuroprotective, anti-infectious, anticancer and immunomodulatory effects.

[003] Cisplatin is a common chemotherapy used to treat a variety of cancers. Unfortunately, cisplatin has a dose-limiting effect in that 50 to 85% of patients develop peripheral neuropathy after 3 to 6 months of treatment. Cisplatin-induced neuropathy (CIN) presents in a “sock and glove” distribution that causes tingling paresthesia, numbness, and allodynia (Paice, 2010; Amptoulach et al., 2011). Pain management for CIN includes anticonvulsant, antidepressant, and nonsteroidal anti-inflammatory drugs. These drugs prove to be well tolerated in patients, but show little efficacy in the treatment of CIN (Wolf et al., 2008; Amptoulach et al., 2011; Miltenburg et al., 2014).

[004] Although opioids can provide effective CIN pain relief, 76 to 96% of patients report aversive side effects that include sedation, nausea and fatigue, which limits usefulness and decreases the patient's quality of life (Guindon et al. , 2008; Toth & Au, 2008). Additional concerns of opioid therapy include tolerance, dose escalation, and dependence, which can lead to withdrawal symptoms after resolution of CIN (Kim et al., 2015). Collectively, these observations suggest a need to develop innovative pharmacotherapies for CIN.

[005] Cannabinoids (CB) are used in oncology contexts to control nausea, weight loss, lack of appetite, and chemotherapy-related pain (Alexander et al., 2009). CB analgesia in both chronic and acute pain models is mediated through CB1 and CB2 receptors that are differentially expressed in the central and peripheral nervous systems (Chiou et al., 2013; Pisanti et al., 2013). An emerging body of literature supports the notion that CB systems can also modulate CIN. For example, direct and indirect CB1 and CB2 agonists attenuate tactile allodynia in rodent models of CIN ( Vera et al., 2013 ; Guindon et al., 2012 , Khasabova et al., 2012 ). However, similar to non-opioid therapies, CB compounds have modest efficacy and are of limited utility.

[006] CB1 and opioid receptors are colocalized in pain pathways. Evidence suggests that dual pharmacotherapy on these targets can enhance CB-mediated analgesic effects (Wilson-Poe et al., 2008; Hall et al., 2005; Mansour et al., 1988; Basbaum et al., 1984). For example, the CB1 agonist THC shows synergistic effects with subanalgesic doses of the mu opioid agonist morphine in a mouse model of arthritic pain (Cox et al., 2007). However, the use of any CB1 agonist in oncology settings is unlikely due to these compounds increasing the proliferation and growth of some tumor cells (Hall et al., 2005). Interestingly, other CB constituents that show low affinity for CB receptors also show synergistic effects with low dose opioids. For example, cannabidiol (CBD) shows synergistic effects with subanalgesic doses of morphine in an acute pain model (i.e., acetic acid writhing), but not against thermal pain (Walker et al., 2015). Whether a combined CBD-opioid pharmacotherapy could provide highly effective pain relief against cisplatin neuropathy is unknown.

[007] Challenges in pain control in oncology settings lead to unnecessary suffering, diminished quality of life, and in some cases, reduced life expectancy due to patients withdrawing from ongoing chemotherapy treatment. Current therapies against CIN are only modestly effective or are fully effective but poorly tolerated.

Summary of the Invention

[008] In this document, biologically active analogues of CBD are described that can be administered by a wide variety of administration routes that include, but are not limited to, orally, transdermally or transmucosally (e.g., buccal, rectally, ocular, nasal) to a mammal, such as a human, for the treatment of a medical condition such as pain, inflammation, epilepsy and eye disease, which includes, but is not limited to, treatment of retinal diseases (e.g., diabetic retinopathy and macular degeneration ).

[009] It has been found that biologically active CBD analogues containing a natural amino acid and a dicarboxylic acid chemical moiety attached to one of the hydroxyl groups (with the amino acid attached to CBD through an ester bond and the dicarboxylic acid attached to the amino group of the amino acid in an amide bond) with the other free hydroxyl group result in concentrations higher than expected in vivo. Furthermore, CBD amino acid esters (diesters) have to be reacted with a dicarboxylic acid, amide bonds with the free amine group of the cannabidiol amino acid ester, to affect in vivo bioavailability. Exemplary CBD analogues can be represented by the following formulas:

[010] The structures of CBD-divalinate-dihemisuccinate (1) CBD-mono-valinate-dihemisuccinate (2) and CBD-monovalinate-hemisuccinate (3) are shown above.

[011] In general, the analogues of the present invention can be represented by the following generic formula I:

[012] This formula I shows the structure for amino acid ester and/or dicarboxylic acid ester analogues in which R1 or R2 or both is/are the residue of a chemical moiety formed by the reaction of the amino group of the amino acid ester with a dicarboxylic acid or with a dicarboxylic acid derivative and R1 or R2 (in the case of the mono amino acid ester) is the residue of a dicarboxylic acid or dicarboxylic acid derivative or a Hydrogen (H). Both R1 and R2 could be residues of chemical moieties formed by reaction of the amine group of the amino acid ester at both sites with a dicarboxylic acid.

[013] The biologically active analogues of the invention can be formed from amino acids that include, for example, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoserine lactone and norleucine. A “dicarboxylic acid” herein means an organic acid that has two carboxyl groups (—COOH). The general molecular formula for dicarboxylic acids can be written as HO2C-R-CO2H, where R can be straight chain or branched, aliphatic or aromatic. Examples of suitable dicarboxylic acids in this invention include, but are not limited to, malonic acid, malic acid, glutaric acid, succinic acid and phthalic acid. Dicarboxylic acids are reacted with their anhydrides and reactive derivatives of dicarboxylic acids such as, for example, dicarboxylic acid halides.

[014] In a further embodiment of this invention, it has been found that biologically active CBD analogues such as those described above which include, for example, CBD-val-HS, have several attributes that suggest that biologically active CBD analogues may be useful in pain control. Firstly, CBD-val-HS has much better absorption and a longer biological half-life than CBD. Most importantly, CBD-val-HS is biologically active and fully effective as certain opioids in this murine model of CIN. Collectively, these findings strongly argue that biologically active CBD analogs be considered in pain management in oncology and, perhaps, other clinical settings in which neuropathy is presented. Furthermore, these biologically active CBD analogues have been found to have stronger activity than CBD itself in blocking the addictive properties of morphine.

[015] This suggests that a combination of these CBD derivatives with morphine and/or other opiates would have better analgesic activity than morphine and/or other opiates used alone while also preventing dependence on morphine and/or other opiates caused by its prolonged use.

Detailed Description of the Invention

[016] The present invention comprises compounds of formula I

[017] wherein one of R1 or R2 or both is/are the residue of a chemical moiety formed by the reaction of an amino group of the amino acid ester of R1 or R2 or both with a dicarboxylic acid or a dicarboxylic acid derivative and the another R1 or R2 (in the case of mono) is the residue of a dicarboxylic acid or derivative of dicarboxylic acid or Hydrogen (H), (i.e. not derived), and salts thereof.

[018] The amino acid can be, however, without restrictions, those on the list, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine , threonine, tryptophan, tyrosine and valine.

[019] The present invention further comprises biologically active compounds of formula II: wherein R'1 and R'2 or both are amino acid ester residue (or residues) and natural derivatives thereof and salts thereof.

[020] The amino acid ester (or esters) is (are) selected from, but without restriction, one of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine and derivatives thereof and salts thereof.

[021] The compounds of the present invention can be described as compounds of formula III: wherein one of R1 or R2 or both is/are an amino acid ester residue of a chemical moiety formed by the reaction of a carboxyl group of an amino acid with one or both phenolic groups of cannabidiol; or one of R1 or R2 or both is/are an ester residue of a chemical moiety formed by the reaction of a carboxyl group of a dicarboxylic acid or dicarboxylic acid derivative with one or both phenolic groups of cannabidiol; or one of R1 or R2 is the amino acid residue ester from the reaction of the phenolic group of cannabidiol with the carboxyl group of an amino acid and the other R1 or R2 is the ester residue from the reaction of the phenolic group of cannabidiol with the carboxyl of an dicarboxylic acid or dicarboxylic acid derivative; or one of R1 or R2 (in the case of mono) is hydrogen (H), (i.e. not derived) and the other R1 or R2 is an amino acid residue ester or an ester residue, and salts thereof.

[022] One of R1 and R2 or both is/are an amino acid ester chemical moiety that is further reacted with a dicarboxylic acid or dicarboxylic acid derivative to form an amide chemical moiety by reacting the amino group of the amino acid ester with a chemical carboxyl moiety of dicarboxylic acid or dicarboxylic acid derivative.

[023] The amino acid is any, however, without restrictions, among alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine , tryptophan, tyrosine and valine.

[024] In one embodiment of the present invention R1 or R2 or both is/are ester residue (or residues) of natural amino acids and derivatives thereof and salts thereof.

[025] Exemplary, but not exclusive, examples of the present invention include: the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD -Di- Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD- Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate or CBD- monovalinate-dihemisuccinate.

[026] The present invention further encompasses a formulation for administering a biologically active CBD analogue for the treatment of a disease condition comprising a therapeutically effective amount of at least one compound of formula I, II or III in a base or carrier. acceptable.

[027] Exemplary, but not exclusive, formulations according to the present invention are formulations such as: 1) a formulation that is a suppository formulation in an acceptable suppository base; 2) a formulation that is an oral formulation (e.g., tablet, capsule or liquid); 2) a formulation that is a transmucosal delivery formulation; 3) a formulation that is a topical ophthalmic formulation (e.g., a liquid, semi-solid, or implant) for reducing intraocular pressure and/or inflammation in the treatment of glaucoma and/or ocular uveitis in an acceptable ophthalmic carrier; 4) an external or internal depot delivery system for the eye (e.g., a pump, bioerodible device, or subcutaneously positioned depot); 5) a topical formulation for application to the skin (e.g., a lotion, gel, or ointment). Topical ophthalmic formulations may be, for example, a formulation that is a polymeric ocular film using Nano lipid particles.

[028] A further embodiment of the present invention is a formulation for administering a biologically active CBD analogue to an individual in need of treatment of a disease condition comprising a therapeutically effective amount of at least one compound by means of formula I in an acceptable base or carrier.

[029] A formulation for administering a biologically active CBD analogue to an individual in need of treatment of a disease condition comprising a therapeutically effective amount of at least one compound wherein the compound is CBD-Di-Glutaminate, CBD- Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate- Di-Hemisuccinate, CBD-Di-Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate, CBD-Mono-Valinate- Mono-Hemisuccinate, or CBD-monovalinate-dihemisuccinate in an acceptable base or carrier.

[030] The formulation may comprise a suppository formulation in an acceptable suppository base; an oral formulation; a transmucosal delivery formulation; a topical ophthalmic formulation; or an external or internal warehouse delivery system.

[031] A still further embodiment of the present invention is a method of treating pain control which comprises administering to an individual in need of such treatment an effective amount of at least one compound according to formula I. The compound used in the present method is at least one compound wherein the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate, CBD-Di- Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD- Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate or CBD-monovalinate-dihemisuccinate in an acceptable base or carrier.

[032] Pain control can be, for example, pain control in oncology or neuropathic pain control.

[033] Furthermore, the present invention relates to a method for blocking opioid addictive properties and comprises administering to an individual in need of such treatment an effective amount of at least one compound by means of formula I. Preferably the compound used in this method is at least one compound wherein the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate, CBD-Di -Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate, or CBD-monovalinate-dihemisuccinate in an acceptable base or carrier.

[034] The present invention may also encompass a method for preventing morphine dependence due to prolonged use of morphine which comprises administering to an individual in need of such treatment an effective amount of at least one compound by means of formula I or, preferably , the compound used in this method is at least one compound wherein the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di- Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate, CBD-Mono-Valinate- Mono-Hemisuccinate or CBD-monovalinate-dihemisuccinate in an acceptable base or carrier.

Brief Description of Figures

[035] Figure 1 shows plasma levels of CBD versus time following rectal administration of 6.125 mg or 4.625 mg of CBD-Val-HS in a lipophilic suppository (Wecobe W base).

[036] Figure 2 shows plasma levels of CBD following rectal administration of 7 mg of CBD-Val-HS in a hydrophilic base (PEG 1000).

[037] Figure 3 shows plasma levels of CBD-Mono-VHS versus time following rectal administration of 7.5 mg of CBD-Mono-VHS in a lipophilic suppository (Wecobe W base).

[038] Figure 4 shows plasma levels of CBD-Mono-VHS versus time following rectal administration of 7.5 mg of CBD-Mono-VHS in a hydrophilic suppository (PEG 1000 base).

[039] Figure 5 shows plasma levels of CBD-Mono-VHS versus time following oral administration of 4 mg of CBD-Mono-VHS in sesame seed oil.

[040] Figure 6a shows organ levels of CBD-Mono-VHS at 2 and 4 hours after oral administration of 4 mg of CBD-Mono-VHS.

[041] Figure 6b shows plasma levels of CBD-Mono-VHS at 2 and 4 hours after oral administration of 4 mg of CBD-Mono-VHS.

[042] Figure 7a shows the concentration of CBD and THC versus time after incubation of CBD at 37 °C at pH 1.2.

[043] Figure 7b shows the concentration of CBD versus time after incubation of CBD at 37 °C at pH 7.4.

[044] Figure 8 shows CBD-Mono-VHS concentration versus time at pHs of 1.2 and 7.4.

[045] Figure 9 shows the concentration of CBD-Di-VHS post incubation at 37 °C versus time at pHs of 1.2 and 7.4.

[046] Figure 10 shows plasma levels of CBD versus time following rectal administration of 7.5 mg CBD-HG in a lipophilic suppository (Wecobe W base).

[047] Figures 11a to 11d show organ levels of CBD and CBD-Mono-VHS 70 minutes after IP administration of two doses (30 and 60 μg) of CBD-Mono-VHS in mice: a) liver levels , b) spleen levels, c) kidney levels and d) brain levels.

[048] Figure 12 shows plasma concentration of CBD-Mono-VHS 70 minutes after IP administration of two doses (30 and 60 μg) of CBD-Mono-VHS in mice.

[049] Figure 13 shows average paw withdrawal in grams of force (+/- SEM). Dashed lines represent pre- and post-cisplatin administration protocol baseline responses prior to drug efficacy inspection. Vertical bars represent average responses on CBD-Val-HS drug efficacy inspection day. Doses are in mg/kg and delivered IP 45 minutes before testing. * denotes significant attenuation of tactile allodynia compared to the carrier group (p < 0.05). Sample sizes were n = 5 to 14.

[050] Figure 14 shows average paw withdrawal in grams of force (+/- SEM). Dashed lines represent pre- and post-cisplatin administration protocol baseline responses prior to drug efficacy inspection. Vertical bars represent average responses on CBD-Val-HS drug efficacy inspection day. Doses are in mg/kg and delivered IP 45 minutes before testing. * denotes significant attenuation of tactile allodynia compared to the carrier group (p < 0.05). Sample sizes were n = 9 to 11.

[051] Figure 15 shows the effects of CBD and CBD-val-HS on morphine place preference scores. Values represent difference in the average ratio of time (seconds) spent in the S+ chamber (paired by drug) during pre- and post-condition testing. Open bars reflect saline-treated animals and striped bars represent morphine-treated animals. *denotes significant difference in the carrier group. + denotes significant attenuation of morphine preference. Sample sizes were n = 7 to 10. CBD-Amino Acid Ester Synthesis: Example 1: CBD-Di-Glutaminate Synthesis Structure of CBD-Di-Glutaminate (CBD-Di-Gln).

A. Synthesis of CBD-diglutaminate-Boc (CBD-di-Gln-boc)

[052] CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Boc-glutamine (2.2 eq.) was dissolved in DCM and 2.2 eq. of DCC was added thereto while stirring. CBD/DMAP solution was added to Boc-glutamine/DCC solution and left to stir for 30 minutes. Thin layer chromatography (10% EtOAc/90% Hexane) indicated completion of the reaction. The product was purified using silica gel and the product was eluted (in 90% EtOAc/10% Hexane) as a pure compound.

B. Deprotection of CBD-di-Gln-boc to CBD-di-Gln

[053] CBD-di-Gln-boc was dissolved in THF while stirring. HCl(g) was bubbled through it for approximately 3 minutes while stirring. Excess HCl(g) was removed with N2(g) and the solvent was evaporated. The product was confirmed by mass spectrometry. Example 2: Synthesis of CBD-Di-Hemisuccinate: Structure of CBD-Di-Hemisuccinate (CBD-Di-HS).

[054] CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (2.2 eq.) and triethylamine were added to the CBD/DMAP solution. The reaction was stirred for 30 minutes. The product was purified using silica gel and eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 75% EtOAc/25% Hexane) as the pure compound. The product was confirmed by mass spectrometry.Example 3: Synthesis of CBD-Di-Alaninate Ester Structure of CBD-Di-Alaninate (CBD-Di-Ala).

A. Synthesis of CBD-di-Ala-boc

[055] CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Boc-alanine (2.2 eq.) was dissolved in DCM and 2.2 eq. of DCC was added thereto while stirring. The CBD/DMAP solution was added to the Boc-alanine/DCC solution and left to stir for 30 minutes. Thin layer chromatography (10% EtOAc/90% Hexane; Rf = 0.15) indicated completion of the reaction.

[056] The product was purified using silica gel and the product was eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 15% EtOAc/85% Hexane) as a pure compound.

B. Deprotection of CBD-di-Ala-boc to CBD-di-Ala

[057] CBD-di-Ala-boc was dissolved in THF while stirring. HCl(g) was bubbled through it for approximately 3 minutes while stirring. Excess HCl(g) was removed with N2(g) and the solvent was evaporated to dryness. The product was confirmed by mass spectrometry. Example 4: Synthesis of CBD-Di-Alaninate-Di-Hemisuccinate Structure of CBD-Di-Alaninate-Di-Hemisuccinate (CBD-Di-Ala-Di-HS).

[058] CBD-Di-Ala was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (2.2 eq.) and triethylamine were added to the CBD-Di-Ala/DMAP solution. The reaction was stirred overnight. The product was purified using silica gel and eluted (in a gradient starting at 30% EtOAc/70% Hexane and increasing to 100% EtOAc/0% Hexane) as the pure compound. The product was confirmed by mass spectrometry.Example 5: Synthesis of CBD-Di-Valinate Structure of CBD-Di-Valinate (CBD-Di-Val).

A. Synthesis of CBD-di-Val-boc

[059] CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Boc-valine (2.2 eq.) was dissolved in DCM and 2.2 eq. of DCC was added thereto while stirring. CBD/DMAP solution was added to Boc-valine/DCC solution and left to stir for 5 minutes. Thin layer chromatography (10% EtOAc/90% Hexane) indicated completion of the reaction. The product was purified using silica gel and product was eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 5% EtOAc/95% Hexane) as pure compound.

B. Deprotection of CBD-di-Val-boc to CBD-di-Val

[060] CBD-di-Val-boc was dissolved in THF while stirring. HCl(g) was bubbled through it for approximately 3 minutes while stirring. Excess HCl(g) was removed with N2(g). The product was confirmed by mass spectrometry.Example 6: Synthesis of CBD-Di-Valinate-Di-HS Structure of CBD-Di-Valinate-Di-Hemisuccinate (CBD-Di-Val-Di-HS).

[061] CBD-Di-Val was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (2.2 eq.) and triethylamine were added to the CBD-Di-Val/DMAP solution. The reaction was stirred overnight. The product was purified using silica gel and eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 80% EtOAc/20% Hexane) as the pure compound. The product was confirmed by mass spectrometry.Example 7: Synthesis of CBD-Di-Hemiglutarate

[062] Structure of CBD-Di-Hemiglutarate (CBD-Di-HG).

[063] CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Glutaric anhydride (2.2 eq.) and triethylamine were added to the CBD/DMAP solution. The reaction was stirred for 30 minutes. The product was purified using silica gel and eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 40% EtOAc/60% Hexane) as the pure compound. The product was confirmed by mass spectrometry.Example 8: Synthesis of CBD-Mono-Valinate Structure of CBD-Mono-Valinate (CBD-Mono-Val).

A. Synthesis of CBD-Mono-Val-boc

[064] CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Boc-valine (1.1 eq.) was dissolved in DCM and 1.1 eq. of DCC was added thereto while stirring. CBD/DMAP solution was added to Boc-valine/DCC solution and left to stir for 5 minutes. Thin layer chromatography (10% EtOAc/90% Hexane) indicated completion of the reaction. The product was purified using silica gel and product was eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 3% EtOAc/97% Hexane) as pure compound.

B. Deprotection of CBD-Mono-Val-boc to CBD-Mono-Val

[065] CBD-Mono-Val-boc was dissolved in THF while stirring. HCl(g) was bubbled through it for approximately 2 minutes while stirring. Excess HCl(g) was removed with N2(g). The product was confirmed by mass spectrometry.Example 9: Synthesis of CBD-Mono-Valinate-Mono-Hemisuccinate

[066] Structure of CBD-Mono-Valinate-Mono-Hemisuccinate (CBD-Mono-Val-Mono-HS). C. Synthesis of CBD-mono-Val-HS

[067] CBD-Mono-Val was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (1.1 eq.) and triethylamine were added to the CBD-Mono-Val/DMAP solution. The reaction was stirred overnight. The product was purified using silica gel and eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 30% EtOAc/70% Hexane) as the pure compound. The product was confirmed by mass spectrometry.Example 10: Synthesis of CBD-monovalinate-dihemisuccinate (CBD-Mono-Val-di-HS).

CBD-Mono-Val-boc Synthesis

[068] CBD was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Boc-valine (1.1 eq.) was dissolved in DCM and 1.1 eq. of DCC was added thereto while stirring. CBD/DMAP solution was added to Boc-valine/DCC solution and left to stir for 5 minutes. Thin layer chromatography (10% EtOAc/90% Hexane) indicated completion of the reaction. The product was purified using silica gel and product was eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 3% EtOAc/97% Hexane) as pure compound.

B. Deprotection of CBD-Mono-Val-boc to CBD-Mono-Val

[069] CBD-Mono-Val-boc was dissolved in THF while stirring. HCl(g) was bubbled through it for approximately 2 minutes while stirring. Excess HCl(g) was removed with N2(g). The product was confirmed by mass spectrometry.

C. Synthesis of CBD-mono-Val-diHS

[070] CBD-Mono-Val was dissolved in DCM and catalytic amount of DMAP was added to it while stirring. Succinic anhydride (2.2 eq.) and triethylamine were added to the CBD-Mono-Val/DMAP solution. The reaction was stirred overnight. The product was purified using silica gel and eluted (in a gradient starting at 0% EtOAc/100% Hexane and increasing to 30% EtOAc/70% Hexane) as the pure compound. The product was confirmed by mass spectrometry.

Example 11: Preparation of topical ophthalmic formulations of Biologically Active CBD Analogs

[071] Formulations: 0.5% w/v equivalent of CBD in Tocrisolve emulsion.

[072] Tocrisolve Composition: W/O emulsion composed of a 1:4 ratio of soybean oil/water that is emulsified with the Pluronic F68 block copolymer. Manufacturing process for Tocrisolve emulsion: • Add precisely weighed quantity of drug to a glass vial. • Add required volume of Torcisolve crude emulsion to each vial • Swirl each vial for 5 minutes. • Apply ultrasound to each vial for 10 minutes. • Centrifuge each vial for 5 minutes at 9000 rpm at 25 °C.

[073] Collect the supernatant and analyze for CBD, CBD-Val Mono and CBD-Val-HS mono as applicable. Table 1 Shows the Solubility of CBD and CBD Analogs in Tocrisolve Emulsion. Table 1. Solubility of CBD and its analogues in Tocrisolve® emulsion.

Example 12: In Vivo Eye Tissue Levels of CBD and CBD Analogs 90 min. after Topical Application of 50 μl of Formulations Containing the Equivalent of 250 μg of CBD in Tocrisolve® Emulsion.

[074] Conscious male New Zealand albino rabbits were used. The formulations were applied topically to the rabbits' eyes (50 μl containing the equivalent of 250 μg CBD) in Tocrisolve® emulsion formulations as described in Example 11. The animals were sacrificed 90 min. after application of the drug and ocular tissues collected for analysis.

[075] Table 2 shows tissue levels (ng/g) following administration of CBD, CBD-Val-HCl and CBD-Val-HS.

[076] The data showed that while CBD and water-soluble CBD-Val-HCl showed only very low levels in the retinal choroid, CBD-Val-HS reached all tissues in high concentrations. Table 2. Ocular Tissue Concentrations of CBD, CBD-Val and CBD-Val-HS (ng/gm of tissue); 90 min Post Topical Application of CBD (0.47%), CBD-Val-HCl (0.94%) or CBD-Val-HS (1.2%) in emulsion in Tocrisolve® (Dose: 250 μg CBD; volume instilled 50 μl) respectively.ND- Below Detection Limit.

Example 13: In vivo ocular tissue levels of CBD VS other CBD analogues.

[077] The same procedure was followed as shown in Example 12. Additional CBD analogues were tested in this example. In this example tissue levels of both free CBD and intact analogue were determined. Results are shown in Table 3.

[078] Formulations: Fifty microliters of 0.5% w/v CBD in Tocrisolve emulsion (Dose: 0.25 mg)

[079] Animal model: Conscious male New Zealand albino rabbits, Study duration: 90 min. Table 3. Eye Tissue Levels of both CBD and its analogues 90 min. Following Topical Administration of Different Analogues in Tocrisolve® emulsion.

[080] The data showed that while CBD and free amino acid analogues did not show any levels in tissues, CBD-Val-HS reached both the retinal choroid and iris ciliary bodies, but did not show detectable levels of CBD. On the other hand, CBD-mono-Val-HS was detected in high concentration in the aqueous humor, retinal choroid and iris ciliary bodies. Furthermore, CBD-mono-Val-HS showed high levels of Free CBD in the retinal choroid and iris ciliary bodies.

Example 14: Comparison of CBD and CBD Analogue Levels in Ocular Tissues Following Topical Administration of the two biologically active analogues, namely, CBD-di-Val-HS and CBD-mono-Val-HS.

[081] This example is a repetition of the experiment carried out in Example 13 to show reproducibility of results.

[082] Sample preparation: Aqueous Humor, Vitreous Humor, Retinal Choroid and Iris Ciliary Bodies analyzed for parent compound as well as CBD.

[083] Formulations: Fifty microliters of 0.5% w/v Tocrisolve emulsion formulations (Dose: 0.25 mg)

[084] Animal model: Conscious male New Zealand albino rabbits, Study duration: 90 minTable 4: Ocular Tissue Concentrations of CBD and CBD Analogs 90 min Post Topical Application of CBD-Val-HS- Mono or CBD- VAL-HS in Tocrisolve® Emulsion (Dose: 250 μg; instilled volume of 50 μl) respectively. AH-aqueous humor, VH-Vitreous humor, RC-Retinal Choroid, IC-Iris Ciliary Bodies. ND-Below Detection Limit. *Only one of the animals showed 160 ng of CBD-Val-HS/g of tissue. The analogue was below quantifiable levels in the other animals.

[085] The data in Table 4 show similar results to those shown in Example 13 and prove that CBD-Mono-Val-HS is a superior analogue for penetration into the different tissues of the eye. When biologically active analogues are designed so that R1 and R2 are natural amino acid residues (e.g., CBD-di-Val) or a dicarboxylic acid (e.g., CBD-di-HS) esters or the amino acid amide ester with a dicarboxylic acid (e.g. CBD-di-Val-di-HS), penetration into ocular tissues is not adequate.

[086] Only when the analogue is an amino acid monoester with the amino acid nitrogen in an amide bond with a dicarboxylic acid was the desired penetration into the inner chambers of the eye achieved.

Example 15: Bioavailability of CBD From Suppository Formulations Containing CBD-di-Val-di-HS (CBD-Val-HS)

[087] CBD-Val-HS was formulated in both lipophilic (Wecobe W base) and hydrophilic (PEG 1000 base) suppository formulations. The formulations were administered to cannulated mice (100 mg of suppository per mouse) and blood samples were collected, centrifuged, and the plasma separated for LC/MS/MS analysis. The amount of CBD in plasma samples was quantified. The amount of CBD-Val-HS in plasma samples was not quantified.

[088] Figure 1 shows CBD plasma levels versus time following administration of 6.125 mg or 4.625 mg CBD-Val-HS in a lipophilic suppository (Wecobe W base).

[089] Figure 2 shows plasma levels of CBD following administration of 7 mg CBD-Val-HS in a hydrophilic base (PEG 1000).

[090] Higher levels of CBD were achieved from a hydrophilic base containing CBD-Va-HS than when the same analogue was delivered through a lipophilic base.

Example 16: Bioavailability of CBD-Mono-Val-Mono-Hemisuccinate (CBD-Mono-VHS) from a Lipophilic Suppository Formulation (Wecobee M).

[091] CBD-Mono-Val-Mono-HS was formulated in Wecobee M suppository base (a lipophilic triglyceride base) in 75 mg/ml of melted base. The study was performed in a cannulated mouse model. Three animals each received 100 μl of the semisolid formulation for a 7.5 mg rectal dose of CBD-Mono-VHS. This is followed by collecting blood samples (250 μl) at each data point (0, 0.25, 0.5, 1, 2, 4, 6, and 24 h). The blood was centrifuged and the plasma was used for LC-MS/MS analysis. The results are shown in Table 5 and Figure 3. Table 5. CBD-Mono-VHS Plasma Concentration for Individual Animals Over Time Post Administration of (Wecobee M) in Mice

Example 17: Bioavailability of CBD-Mono-Val-Mono-Hemisuccinate (CBD-Mono-VHS) from a hydrophilic suppository formulation (Polyethylene glycol 1000, PEG 1000).

[092] CBD-Mono-Val-Mono-HS was formulated in PEG 1000 suppository base (a hydrophilic suppository base) in 75 mg/ml of melted base. The study was performed in a cannulated mouse model. Three animals each received 100 μl of the semisolid formulation for a 7.5 mg rectal dose of CBD-Mono-VHS. This is followed by collecting blood samples (250 μl) at each data point (0, 0.25, 0.5, 1, 2, 4, 6, and 24 h). The blood was centrifuged and the plasma was used for LC-MS/MS analysis. The results are shown in Table 6 and Figure 4. Table 6. Plasma Concentration of CBD-Mono-VHS for Individual Animals Over Time Post Administration of 7.5 mg of Drug in a Hydrophilic Suppository Form (PEG 1000) in Mice

Example 18. Oral Bioavailability of CBD-Mono-Val-Mono-Hemisuccinate (CBD-Mono-VHS)

[093] CBD-Mono-VHS was formulated in a sesame seed oil formulation (Welch, Holme and Clark Co. lot #39375) composed of 40 mg/ml of drug substance solution/ml. Animals (cannulated mice, n = 4) were dosed with 100 μl of the oil solution by oral gavage. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were centrifuged and plasma was analyzed for CBD-Mono-VHS. Table 7 and Figure 5 show the results, with very high blood levels remaining significant (> 10 ng/ml) at 24 hours after dosing. Table 7. CBD-Mono-VHS Plasma Concentration for Individual Animals Post Administration Oral dose of 4 mg/animal of the drug

Example 19. Organ Distribution of CBD-Mono-VHS after Oral Administration

[094] To determine whether CBD-Mono-VHS reaches the organs and especially the brain, two cannulated mice were administered the same dose as those in Example 18. One mouse was sacrificed at 2 hours after dosing and the other at 4 hours after dosing and the organs were harvested (brain, liver, and spleen) as well as blood for analysis. Table 8a shows organ levels of CBD-Mono-VHS at 2 and 4 h after oral dosing (4 mg/animal) while Table 8b shows plasma levels. The data is represented in Figures 6a and 6b.

[095] Plasma levels were consistent with the data from Example 18 and organs showed high levels of the drug indicating effective bioavailability. Table 8a. Organ levels of CBD-Mono-VHS at 2 and 4 hours after Oral Dosage with 4 mg/animal. Table 8b. Plasma Levels at 2 and 4 hours After Oral Dosage with 4 mg/animal of CBD-Mono-VHS.

Example 20. Stability of CBD-Mono-Val-Mono-Hemisuccinate (CBD-Mono-VHS) in Simulated Gastric Juice and Intestinal Juice

[096] It is known that CBD converts, at least partially, to Δ9-THC (the psychoactive component of cannabis) and to other cannabinoids under acidic stomach conditions. (Watanabe, K., Itokawa, Y., Yamaori, S., Funahashi, T., Kimura, T., Kaji, T., Usami, N., Yamamoto, I., 2007; Conversion of cannabidiol to Δ9-tetrahydrocannabinol and related cannabinoids in artificial gastric juice, and their pharmalogical effects in mice, Forensic Toxicol, 25, 16 to 21. and Merrick, J., Lane, B., Sebree, T., Yaksh, T., O'Neill, C ., Banks, S., 2016; Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid, Cannabis and Cannabinoid Research, 1.1, 102 to 112). This results in side effects that are proportional to the degree of conversion.

[097] The stability of CBD and CBD analogues (CBD-Mono-VHS and CBD-Di-VHS) was evaluated under acidic and alkaline conditions to simulate exposure to gastric and intestinal fluids. The procedure is outlined as follows:

[098] 1. 5 mg/ml stock solution of CBD, CBD-Mono-Val-Mono HS, CBD-Di-Val-Di HS was prepared.

[099] 2. Simulated Gastric Fluid (pH 1.2) + 1% (SDS) was prepared and kept in a water bath at 37 °C.

[100] 3. Physiological buffer (pH 7.4) + 1% SDS was prepared and kept in a water bath at 37 °C.

[101] 4. 100 μl of stock CBD, CBD-Mono-Val-Mono HS or CBD-Di-Val-Di-HS in acetonitrile (equivalent to 500 μg) was added to separate vials containing 5 ml of each of pH 1.2 and 7.4.

[102] 5. At each time point, 100 μl of the solution was withdrawn.

[103] 6. 900 μl of acetonitrile was added to each sample.

[104] 7. All samples were centrifuged at 4 °C and 13,000 rpm.

[105] 8. 100 μl of the supernatant was removed; to this 100 μl of supernatant, 900 μl of acetonitrile was added and placed in LC vials for analysis.

[106] Tables 9, 10 and 11, and Figures 7a, 7b, 18 and 19 show the results.

[107] CBD converts to Δ9-THC under acidic conditions while CBD analogues of this invention do not produce Δ9-THC. Table 9. Concentration (ng/ml) of CBD and Δ9-THC, at Different Incubation Times at 37 °C and at pHs of 1.2 and 7.4 Acid (pH 1.2) Base (pH 7.4)

[108] Conclusion: CBD is partially converted to THC under the acidic conditions of gastric juice, but is stable under the physiological pH of 7.4. Table 10. Concentration (ng/ml) of CBD-Mono-Val-Mono-HS at Different Time Points Post Incubation at pHs of 1.2 and 7.4 at 37 °C

[109] Conclusion: CBD-Mono-VHS is stable under both acidic conditions (gastric juice) and intestinal juice conditions (pH 7.4). Table 11. Concentration (ng/ml) of CBD-Di-Val-Di-HS at Different Time Points Post Incubation at pHs of 1.2 and 7.4 at 37 °C

[110] Conclusion: CBD-DiVal-DiHS is stable under acidic juice conditions and under physiological intestinal juice conditions (pH 7.4).

Example 21. Bioavailability of CBD from Suppository Formulations Containing CBD-Hemiglutarate (CBD-HG)

[111] CBD-Hemiglutarate was formulated in a lipophilic suppository base (Wecobee M) at 75 mg/ml melt base. Doses of 100 μl of the formulation were administered rectally (equivalent to 7.5 mg dose/animal) to cannulated mice (n = 4). Blood samples (0.25 ml) were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after dosing. After blood centrifugation, plasma was collected (100 μl) and subjected to LC-MS/MS analysis for CBD. The amount of CBD-HG in plasma has not been determined. Table 12 and Figure 10 show the results. Table 12. CBD Plasma Concentration Following Rectal Administration of CBD-Hemiglutarate (7.5 mg Dose) in a Lipophilic Suppository Formulation

Example 22. Plasma and Organ Concentrations of CBD and CBD-Mono-VHS Following IP Administration of CBD-Mono-VHS in Mice

[112] CBD-Mono-VHS was administered intraperitoneally to mice in 2 doses (30 μg and 60 μg CBD equivalent/mouse). Seventy minutes after dosing the animals (3 mice in each dose group), all animals were sacrificed. Blood, as well as organs (liver, spleen, kidney, and brain), were collected for LC-MS/MS analysis of their content of both CBD and CBD-Mono-VHS.

[113] Table 13 shows the total CBD-Mono-VHS content of each organ for each animal for both doses with mean and standard deviation, while Table 14 shows the total CBD content. Also shown is the concentration of CBD-Mono-VHS in plasma 70 minutes after dosing.

[114] The results are also depicted in Figures 11a (liver), Figure 11b (spleen), Figure 11c (kidney), Figure 11d (brain), and Figure 12 (plasma concentration (ng/ml)) for individual animals from each dose.

[115] Conclusion: IP administration of CBD-Mono-VHS in mice resulted in high concentrations of the drug in all organs tested in a dose-proportional manner. Most importantly, the compound crosses the blood brain barrier, a significant finding in the use of this compound for the treatment of CNS-based disease conditions. Table 13. Total Drug Load (in ng) of CBD-Mono-Val-Mono- HS in Different Organs and Plasma Concentrations (ng/ml) 70 Minutes Post IP Administration of Two Dose Levels (30 and 60 μg/animal) of the Drug *Organ levels are total CBD-Mono-VHS content in the entire organ while plasma content is in ng/ml. Table 14. Total Drug Load (in ng) of CBD in Different Organs and Plasma Concentrations (ng/ml) 70 Minutes Post IP Administration of Two Dose Levels (30 and 60 μg/animal) of the Drug

[116] In a further embodiment of the present invention the inventors explored whether cannabidiol (CBD) or biologically active CBD analogues possessed analgesic properties alone and in combination with a sub-analgesic dose of morphine in a mouse model of cisplatin-induced neuropathy. Mice received 2.3 mg/kg of cisplatin and IP Ringers solution on 12 alternate days. An electronic Von Frey quantified the development of tactile allodynia before, during, and after the protocol and cisplatin and served as the endpoint for analgesic inspection. Test articles administered alone or in combination included, carrier, morphine (0.5 and 2.5 mg/kg) and CBD (1.0 and 2.0 mg/kg in Experiment 1) or a CBD analog (1. 0 to 4.0 mg/kg in Experiment 2) and were given IP 45 min before the test. Six dosages of cisplatin produced robust tactile allodynia that was attenuated by 2.5 mg/kg morphine. CBD produced a modest attenuation of tactile allodynia that was potentiated by subanalgesic doses of morphine. The biologically active CBD analogue produced robust attenuation of tactile allodynia equivalent to morphine; this effect was reproduced at lower doses when administered in combination with subanalgesic doses of morphine. These findings suggest that a biologically active CBD analog may be an effective pain management strategy for neuropathy associated with chemotherapy in oncology settings.

Example 23: Efficacy of CBD in a Cisplatin-Induced Tactile Allodynia Model Individuals

[117] Male C57BL/6 mice (25 to 30 g; Envigo; Indianópolis, IN) were housed 5 per soft-lined polycarbonate container in a temperature- and humidity-controlled vivarium. Mice were maintained under a 12-hour light/dark cycle with the light on at 06:00. Food and water were available ad libitum. Animals were acclimatized to the vivarium 1 week before experimental manipulations. All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Mississippi (Protocols 13-017 and 15-022).

Behavioral Measures

[118] An electronic von Frey (eVF; Topcat Metrology Ltd; Little Downham, UK) quantified the development of tactile allodynia during CIN induction and served as the endpoint in analgesic inspection. Animals were placed in an elevated clean Plexiglas box (3.81 x 11.43 x 11.43 cm) with a metal rod floor. After a 15 min acclimation period, a von Frey filament was applied to the midplantar region of the hind paw and removed thresholds were recorded. Filaments were applied to left and right hind paws alternately at 3 min intervals for a total of 4 measurements per paw. The average score from these 8 tests served as the dependent measure.

Test Articles

[119] Cisplatin (Tocris; Ellisville, MO) was dissolved in 0.9% saline to produce dosages of 2.3 mg/kg/ml. Lactated Ringer's solution (0.25 ml; Abbott Laboratories; Chicago, IL) was used to hydrate mice to prevent kidney and liver damage associated with repeated administration of cisplatin. Morphine sulfate (Research Biochemicals International; Natick, MA) was dissolved in 0.9% saline to produce dosages of 0.1 and 2.5 mg/kg/ml. Solutions of 1.0 and 2.0 mg/kg/ml of CBD (ELI laboratories; Oxford, MS), dissolved in 5% ethanol, 5% Cremofor and injectable water. All test articles were administered intraperitoneally (IP).

Cisplatin Induction and Drug Efficacy Inspection Procedure

[120] Mice received 6 IP injections of cisplatin (2.3 mg/kg/ml) on alternate days with Lactated Ringer's Solution on intervening days for a period of 12 days. Baseline eVF measurements were taken prior to study entry to ensure balanced group assignments. To monitor the progression of tactile allodynia additional eVF measurements were taken on Day 3 and 6 of Ringers prior to daily injections. On Ringers Day 6, eVF measurements revealed significantly lower paw withdrawal thresholds, indicative of neuropathy. Drug efficacy inspection was conducted 2 days later to minimize the potential effect that repeated eVF assay may have on our CIN outcome. Mice were counterbalanced and assigned to drug groups. All test compounds were delivered IP 45 minutes before the eVF assay.

Results and discussion

[121] The effects of the various test articles on cisplatin-induced tactile allodynia are summarized in Figure 13. Baseline eVF responses before and after cisplatin administration are shown as dashed lines. Following the cisplatin induction protocol, all mice showed lower response thresholds indicative of tactile allodynia. A 1-way ANOVA of these data revealed a significant decrease in paw withdrawal following the cisplatin protocol, F (1,71) = 136.03, p < 0.0001.

[122] On drug efficacy inspection day, carrier-treated mice will continue to show tactile allodynia. A subanalgesic dose of morphine (0.1 mg/kg) did not affect eVF responses while 2.5 mg/kg of morphine completely attenuated tactile allodynia. CBD produced modest attenuation of CIN at 1.0 but not at doses of 2.0 mg/kg. The subanalgesic dose of morphine given in combination with 2.0 mg/kg CBD attenuated tactile allodynia comparable to 2.5 mg/kg morphine. This synergistic CBD-opioid effect was not further improved with 2.5 mg/kg morphine.

[123] A 1-way ANOVA of these data revealed a significant main effect for Drug, F (7,71) = 15.72, p < 0.0001. Fisher's LSD demonstrated that mean withdrawal thresholds were significantly higher than the carrier at 2.5 mg/kg morphine, 1.0 mg/kg CBD, 0.1 mg/kg morphine in combination with 1.0 and 2 .0 mg/kg CBD, and 2.5 mg/kg morphine in combination with 2.0 mg/kg CBD groups (ps< 0.0001).

[124] These results demonstrated that a protocol of 6 doses of 2.3 mg/kg cisplatin over a period of 12 days leads to robust tactile allodynia in mice, a characteristic sign of chemotherapy-induced neuropathy. Furthermore, tactile allodynia persisted for several days after the last administration of cisplatin as evidenced by continued reduced paw withdrawal thresholds in carrier-treated mice on the drug efficacy inspection day. These findings are consistent with the literature that these and other cisplatin administration protocols produce CIN in rodents (Park et al., 2012; Guidon et al., 2012).

[125] Mice receiving 2.5 mg/kg morphine exhibited robust attenuation of tactile allodynia. This finding is consistent with the literature that opioid agonists produce analgesia in a wide variety of pain models that includes CIN (Guidon et al., 2012). Mice receiving 1.0 mg/kg CBD exhibited a modest but significant attenuation of tactile allodynia. A higher dose of CBD was ineffective in the model. A subanalgesic dose of morphine (0.1 mg/kg) did not additionally alter the antiallodynic properties of 1.0 mg/kg of CBD administered alone. However, this subanalgesic dose of morphine greatly improved the efficacy of 2.0 mg/kg CBD, producing an effect equivalent to that of a 2.5 mg/kg dose of morphine alone. Finally, the effective morphine dose of 2.5 mg/kg did not additionally potentiate the 2.0 mg/kg CBD. Collectively, these findings demonstrate that the modest efficacy of CBD can be greatly improved with subanalgesic doses of an opioid agonist.

Example 24: Efficacy of CBD-Mono-VHS in a Cisplatin-Induced Tactile Allodynia Model: Methods

[126] Subjects, cisplatin injection protocol conduct, and behavioral measures were as described in Example 23. As before, morphine sulfate was dissolved in 0.9% saline to produce dosages of 0.1 and 2.5 mg/kg/ml. Cannabidiol-mono-val-mono-hemisuccinate (CBD-Mono-VHS; ELI laboratories; Oxford, MS) 1.0 to 4.0 mg/kg/ml were dissolved in 5% ethanol, 5% Cremofor and injectable water and are dose equivalent in terms of CBD equivalent. Full doses of CBD-Mono-VHS were 1.6 to 6.4 mg/kg. All test articles were administered intraperitoneally (IP). All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Mississippi (Protocol 15-022).

Results and discussion

[127] Inspection of efficacy of these test articles in cisplatin-induced tactile allodynia are summarized in Figure 14. Baseline eVF responses before and after cisplatin administration are shown as dashed lines. Following the cisplatin induction protocol, all mice showed lower response thresholds indicative of tactile allodynia. A 1-way ANOVA of these data revealed a significant decrease in paw withdrawal following the cisplatin protocol, F (1,99) = 601.36, p < 0.0001.

[128] On the drug efficacy inspection day, carrier-treated mice continued to show tactile allodynia. A subanalgesic dose of morphine (0.1 mg/kg) did not affect eVF responses while 2.5 mg/kg of morphine completely attenuated tactile allodynia. CBD-Mono-VHS given alone produced a dose-dependent attenuation of tactile allodynia that equaled 2.5 mg/kg morphine at 3.0 and 4.0 mg/kg. The combination of a subanalgesic dose of morphine and CBD-Mono-VHS shifted this dose response curve to the left where 2.0 mg/kg of CBD-Mono-VHS attenuated tactile allodynia equal to 2.5 mg/kg of morphine.

[129] Consistent with these findings, a 1-way ANOVA of these data revealed a significant effect for Drug, F (10,99) = 9.76, p < 0.0001. Fisher's LSD demonstrated that mean withdrawal thresholds were significantly higher compared to the carrier in 2.0 to 4.0 mg/kg CBD-Mono-VHS and drug combination groups of 0.1 mg/kg morphine and 1. 0 to 4.0 mg/kg CBD-Mono-VHS groups (ps< 0.0001).

[130] These results are consistent with those of Example 23 and show that this cisplatin administration protocol produces robust tactile allodynia in mice, a characteristic sign of chemotherapy-induced neuropathy. This tactile allodynia persisted for several days as evidenced by continued reduced paw withdrawal thresholds in carrier-treated mice on the day of drug efficacy inspection.

[131] As in Example 23, mice receiving 2.5 mg/kg morphine exhibited robust attenuation of tactile allodynia. CBD-Mono-VHS produced robust dose-dependent attenuation of tactile allodynia equivalent to 2.5 mg/kg morphine at doses of 3.0 and 4.0 mg/kg. Furthermore, this CBD-Mono-VHS dose response function was shifted to the left by the addition of a subanalgesic dose of morphine. This drug combination achieved a maximum effect at a dose of 2.0 mg/kg CBD-Mono-VHS which was as effective as 2.5 mg/kg morphine alone. Collectively, these findings demonstrated that 1) CBD-Mono-VHS alone produces robust opioid-equal analgesia against CIN and 2) these effects of CBD-Mono-VHS can be achieved at lower doses when combined with subanalgesic doses of an opioid agonist.

Example 25: Abuse-deterrent effects of CBD and CBD-val-HS in an addiction model Method Individuals

[132] Male C57BL/6 mice (25 to 30 g) were group housed (n = 5) in a soft-lined polycarbonate container in a temperature- and humidity-controlled vivarium. Mice were maintained under a 12:12 hour light/dark cycle with lights on at 06:00. Food and water were available ad libitum. Mice were acclimated to the nursery colony location one week prior to behavioral testing. All experimental procedures were approved on May 18, 2015 by the Institutional Animal Care Committee at the University of Mississippi (Protocol #15-022).

Device

[133] Five-place preference chambers (Model MED-CPP-3013; Med Associates, St. Albans, VT) were used for these experiments. Each chamber has two distinct stimulus conditioning chambers (white versus black walls and wire rod or metal mesh floor; 16.75 .70 cm; gray in color with a soft solid floor). Guillotine doors allowed confinement/access to individual chambers.

Procedure

[134] The groups in this study formed a 2x6 factorial design that combined 2 levels of morphine and 6 levels of CBD and CBD-val-HS. Morphine sulfate (Research Biomedical International; Natick, MA) was dissolved in 0.9% saline to produce a dosage of 2.5 mg/ml. Cannabidiol solutions (>98% purity) of 2.5, 5.0, 10.0, 20.0 mg/kg/ml and a single dose of CBD-val-HS of 10.0 mg/kg/ml (ELI Laboratories; Oxford, MS) were dissolved in 5% ethanol, 5% Cremofor and injectable water. Mice received double IP administrations of test compounds.

[135] Before behavioral testing, animals were allowed to acclimatize to the testing space for at least 30 minutes. The CPP procedure consists of four phases: 1) a 15-min device habituation test, 2) a 15-min test to establish baseline CPP scores, 3) six 45-min drug conditioning tests, and 4 ) a 15-min test to establish post-conditioning CPP scores. During drug-free habituation, baseline, and final preference tests, animals were placed in the gray starting chamber for a 5-min adaptation period. Following the adaptation period, the guillotine doors were raised allowing access to the entire device. The testing apparatus was carefully cleaned with 70% ethanol solution after each test.

[136] CPP scores were determined by and led to the establishment of the S+ chamber for drug conditioning so that S+ was assigned to the non-preferred compartment. From these CPP scores, baseline and postconditioning scores were calculated as Preference scores were calculated by taking subtraction of postconditioning and baseline CPP scores with positive values reflecting reward and negative values reflecting aversion.

Statistical Analysis

[137] Data were analyzed using SPSS software with the use of two-way ANOVA (between groups) and one-way ANOVA (between groups) for simple effects analyzes followed by planned comparisons (Fisher's LSD) for differences in groups with significance at p < 0.05.

Results

[138] The effects of Cannabidiol and CBD-val-HS on Morphine-conditioned place preference scores are summarized in Figure 15. The preference scores were close to zero in the control group (carrier + saline) which indicates that there was little change in baseline and postconditioning CPP scores. Animals treated with morphine showed higher preference scores compared to the control group. Among the saline groups, CBD and CBD-val-HS showed neither place preference nor aversion. Among the Morphine groups, preference scores decreased in a CBD dose-dependent manner that approached significance at 10 mg/kg CBD. Furthermore, CBD-val-HS at 10.0 mg/kg completely and significantly abolished morphine place preference.

[139] A two-way ANOVA revealed a significant main effect for Morphine F (1,91) = 24.57, p < 0.001 and a significant main effect for Cannabidiol F (5,91) = 2.843, p = 0.021. The Cannabidiol x Morphine interaction was not significant F (5,91) = 1.50, p = 0.197. To determine whether morphine had a place preference, a one-way ANOVA of Carrier groups was conducted and revealed a significant effect for Morphine F (1,15) = 15.69, p < 0.001. To test whether CBD possessed rewarding or aversive properties, a one-way ANOVA between Saline groups found no significant treatment effect F (5,45) = 1.311, p = 0.276. To determine whether CBD attenuated opioid reward, a one-way ANOVA on Morphine groups was performed and found a significant treatment effect F (5,43) = 2.984, p = 0.021.

[140] Planned comparisons between the morphine groups found preference scores at 10.0 mg/kg CBD that approached significance (p = 0.051) while CBD-val-HS had significantly lower preference scores than the carrier CBD (p = 0.005).

Conclusion

[141] CBD-Mono-VHS significantly blocked (P=0.005) the addictive effects of morphine at 10 mg/kg while CBD at the same dose showed a tendency to block the addictive effects of morphine (P=0.051).

Brief Description of the Formulations of the Invention

[142] The formulations of the present invention comprise a therapeutically effective amount of at least one biologically active cannabidiol analogue composition of the formula in which R1 is a natural amino acid residue, and salts/derivatives thereof in an acceptable suppository base. Biologically active cannabidiol analogs essentially consist of biologically active cannabidiol analogs disclosed above.

[143] The suppository formulation of this invention can be suppository formulations in which the suppository base is a hydrophilic base or a lipophilic base. The suppository formulation may advantageously comprise the suppository base formulation which is a hydrophilic base such as polyethylene glycol 1000.

[144] The present invention also relates to a topical ophthalmic formulation of biologically active cannabidiol analogues for reducing intraocular pressure and/or inflammation in the treatment of glaucoma or ocular inflammatory conditions, respectively. The formulation comprises a therapeutically effective amount of the present biologically active cannabidiol analogues and salts thereof in an ophthalmic acceptable carrier.

[145] A further embodiment of the invention relates to a Transmucosal Delivery Hot Melt Extrusion (HME) Patch formulation for the treatment of any disease condition responsive to CBD. The formulation comprises a therapeutically effective amount of at least one compound of the present biologically active cannabidiol analogue compositions.

[146] Suppository bases can be classified by their physical characteristics into two main categories and a third heterogeneous group: (a) fatty or oleaginous bases, (b) water-soluble or water-miscible bases, and (c) heterogeneous bases, in general combinations of lipophilic and hydrophilic substances.

[147] Among the fatty or oleaginous materials used in suppository bases are cocoa butter and many hydrogenated fatty acids from vegetable oils, such as palm kernel oil and cottonseed oil. Additionally, fat-based compounds containing combinations of glycerin with higher molecular weight fatty acids, such as palmitic and stearic acids, can be found in fat bases. Such compounds, such as glyceryl monostearate and glyceryl monopalmitate, are examples of this type of agent. The bases in many commercial products employ varying combinations of these types of materials to achieve the desired hardness under shipping and storage conditions and the desired quality of subjecting to body temperature to release their medications. Some bases are prepared with emulsified fatty materials or with an emulsifying agent present to induce emulsification when the suppository contacts aqueous body fluids. These types of bases are arbitrarily placed in the third or heterogeneous group of bases.

[148] Coconut Butter, NF, is defined as the fat obtained from the roasted seed of Theobroma cacao. At room temperature, it is a yellowish white solid that has a faint, pleasant chocolate-like odor. Chemically, it is a triglyceride (combination of glycerin and one or different fatty acids) primarily of oleopalmitostearin and oleodiestearin.

[149] Other bases in this category include commercial products such as Fattibase (triglycerides from palm, palm kernel and coconut oils with self-emulsifying glyceryl monostearate and polyoxyl stearate), Wecobee bases (triglycerides derived from coconut oil) and bases Witepsol (triglycerides of C12-C18 saturated fatty acids with varying portions of the corresponding partial glycerides).

[150] The main members of water-soluble and water-miscible suppository bases are glycerinated gelatin and polyethylene glycols. Glycerinated gelatin suppositories can be prepared by dissolving granular gelatin (20%) in glycerin (70%) and adding water or a solution or suspension of the medication (10%).

[151] Polyethylene glycols are polymers of ethylene oxide and water prepared for various chain lengths, molecular weights and physical states. They are available in different molecular weight ranges, the most commonly used being polyethylene glycol 300, 400, 600, 1,000, 1,500, 1,540, 3,350, 4,000, 6,000 and 8,000. The numerical designations refer to the average molecular weight of each of the polymers. Polyethylene glycols that have average molecular weights of 300, 400 and 600 are clear colorless liquids. Those that have average molecular weights greater than 1,000 are white, wax-like solids whose hardness increases with an increase in molecular weight. Melting ranges for polyethylene glycols follow:

[152] Various combinations of these polyethylene glycols can be combined by fusion, using two or more of the various types to achieve a suppository base of the desired consistency and characteristics.

[153] In the heterogeneous group of suppository bases are mixtures of oilseeds and water-soluble or water-miscible materials. These materials can be chemical or physical mixtures. Some are pre-formed emulsions, generally of the water-in-oil type, or they may be capable of dispersing in aqueous fluids. One such substance is polyoxyl stearate 40, a surface-active agent that is used in several commercial suppository bases. Polyoxyl stearate 40 is a mixture of monostearate and distearate esters of polyoxyethylene diols and free glycols mixed together, with the average polymer length being equivalent to about 40 oxyethylene units. The substance is a white to light bronze waxy solid that is soluble in water. Its melting point is generally 39°C to 45°C (102°F to 113°F). Other surface-active agents useful in preparing suppository bases also fall within this broad grouping. Mixtures of many fat bases (which include cocoa butter) with emulsifying agents capable of forming water-in-oil emulsions have been prepared. These bases retain water or aqueous solutions and are said to be hydrophilic.

[154] The preferred suppository bases in the present invention are water-soluble or water-miscible bases.

[155] The transmucosal device film or films (in the case of coextrusion or overlay) generally comprise at least one water-soluble, water-expandable or water-insoluble thermoplastic polymer. The thermoplastic polymer used to prepare the HME film may include, but is not limited to, polyethylene oxide (PolyOx®), polyvinylpyrrolidone (Kollidon®), hydroxypropyl cellulose (Klucel®), ethyl cellulose, methylcellulose, alkylcelluloses, veegum clays, alginates , PVP, alginic acid, calcium carboxymethyl cellulose, microcrystalline cellulose (e.g. Avicel™), potassium polyacrylate (e.g. Amberlite™), sodium alginate, corn starch, potato starch, pregelatinized starch, modified starch, agents cellulosics, montmorillonite clays (e.g., bentonite), gums, agar, locust bean gum, karaia gum, pecitin, tragacanth, and other matrix formers known to those skilled in the art.

[156] This matrix may optionally contain a bioadhesive (such as a Carbopol, polycarbophil, chitosan or others known to those skilled in the art — to further improve the bioadhesiveness of the cannabinoid itself) or a bioadhesive layer may be laminated onto the film. matrix or patch containing the cannabinoid. Furthermore, an impermeable support layer can be incorporated to ensure unidirectional flow of the drug through the patient's mucosa. In some cases, a rate-controlling film or membrane may also be laminated or sprayed onto the cannabinoid-containing matrix to further control the rate of release of the actives.

[157] The transmucosal preparation will preferably contain a “penetration enhancer” (which can also be referred to as an absorption enhancer or permeability enhancer). Such penetration enhancers may include bile salts such as sodium deoxycholate, sodium glycodeoxycholate, sodium taurocholate and sodium glycocholate, surfactants such as sodium lauryl sulfate, Polysorbate 80, laureth-9, benzalkonium chloride, cetylpyridinium chloride and polyoxyethylene monoalkyl ethers, such as the BRIJ® and MYRJ® series. Additional penetration enhancers for inclusion in the embodiment include benzoic acids such as sodium salicylate and methoxy salicylate, fatty acids such as lauric acid, oleic acid, undecanoic acid and methyl oleate, fatty alcohols such as octanol and nonanol, laurocapram, polyols, propylene glycol and glycerin, cyclodextrins, sulfoxides such as dimethyl sulfoxide and dodecyl methyl sulfoxide, terpenes such as menthol, thymol and limonene, urea, chitosan and other natural and synthetic polymers.

[158] The hot melt extruded or hot melt molded matrix may also comprise bioadhesives such as water-soluble or water-swellable polymers derived from acrylic acid or a pharmaceutically acceptable salt thereof, such as polyacrylic acid polymers, which include carbomers, polycarbophils and/or water-soluble salts of a copolymer of methyl vinyl ether and maleic acid or anhydride (Gantrez MS-955).

[159] The transmucosal preparation may also comprise one or more pH-adjusting agents to improve stability and solubility. Furthermore, pH modifying agents can control cannabinoid release and improve bioadhesion. A pH adjusting agent may include, by way of example and without limitation, an organic acid or base, an alpha-hydroxy acid, or a beta-hydroxy acid. Suitable agents include tartaric acid, citric acid, fumaric acid, succinic acid and others known to those of ordinary skill in the art.

[160] The transmucosal preparation may also comprise one or more crosslinking agents to reduce matrix erosion time, control cannabinoid release or improve bioadhesion. A crosslinking agent may include, by way of example and without limitation, an organic acid, an alpha-hydroxy acid, or a beta-hemolytic-hydroxy acid. Suitable crosslinking agents include tartaric acid, citric acid, fumaric acid, succinic acid and others known to those of ordinary skill in the art.

[161] The transmucosal preparation may also contain other components that modify the extrusion, molding or casting characteristics or physical properties of the matrix. These other components are well known to those of ordinary skill in the pharmaceutical sciences and include, for example, polyethylene, xylitol, sucrose, surface active agents, others known to those skilled in the art, and combinations thereof.

[162] The transmucosal preparation of the present invention may also include superdisintegrants or absorbents. Examples of these are sodium starch glycolate (Explotab™, Primojel™) and croscarmellose sodium (Ac-Di-Sol®). Other suitable absorbents include cross-linked PVP (Polyplasdone™ , karaia gum, pectin, tragacanth, and other disintegrants known to those of ordinary skill in the art.

[163] The transmucosal preparation of the invention may include a chelating agent. Suitable chelating agents include EDTA, polycarboxylic acids, polyamines, derivatives thereof, and others known to those of ordinary skill in the art.

[164] The transmucosal preparation of the invention may include a surfactant. Suitable surfactants include sucrose stearate, Vitamin E derivatives, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and others known to those of ordinary skill in the art.

[165] The transmucosal preparation of the invention may include a preservative. Preservatives include compounds used to prevent the growth of microorganisms. Suitable preservatives include, by way of example and without limitation, benzalkonium chloride, propyl paraben, methyl paraben, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, sorbic acid, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal and others known to persons of common skill in the technique.

[166] As used herein, the term "flavorant", "flavor" or "fragrance" is intended to mean a compound used to impart a pleasant taste and often odor to a pharmaceutical preparation, in addition to natural flavorants, many synthetic flavorants are also used. Such compounds include, by way of example and without limitation, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin and others known to those of ordinary skill in the art. Flavors incorporated in the composition can be chosen from synthetic flavor oils and aromatic flavors and/or natural oils, extracts of plants, leaves, flowers, fruits and so on and combinations thereof. These may include wintergreen oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, and cassia oil. In addition, they are useful as vanilla flavors, citrus oils, which include lemon, orange, lime and grapefruit, and fruit essences, which include grape, apple, pear, peach, strawberry, raspberry, cherry, plum, apricot, and so on. against. Flavors that have been found to be particularly useful include commercially available flavors of orange, grape, cherry, and chewing gum flavors and mixtures thereof. The amount of flavoring may depend on several factors, which include the desired organoleptic effect.

[167] As used herein, the term "colorant" is intended to mean a compound used to impart color to solid pharmaceutical preparations. Such compounds include, by way of example and without limitation, 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, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red. Other suitable colorants include titanium dioxide and natural coloring agents such as grape extract, beet red powder, carmine, saffron, paprika, and others known to those of ordinary skill in the art.

[168] The transmucosal preparation of the invention may include an antioxidant to prevent deterioration of preparations by oxidation. Such compounds include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), hydrophosphoric acid, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate and sodium metabisulfate and others known to people of common skill in the technique. Other suitable antioxidants include, for example, vitamin C, sodium bisulfite, vitamin E and its derivatives, propyl gallate, a sulfite derivative, and others known to those of ordinary skill in the art.

[169] The transmucosal preparation of the invention may contain a release rate modifier. Suitable release rate modifiers include hydroxypropyl cellulose (HPC), poly(ethylene oxide) (PEO), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose, cellulosic polymers, acrylic polymers, fat, waxes, lipids, or a combination thereof. In some embodiments, the release rate modifier is polycarbophil, carbomer, or a polysaccharide.

[170] The ingredients and chemicals used to produce the transmucosal preparation used in this invention are of acceptable quality, preferably pharmaceutically acceptable quality. The transmucosal preparation containing biologically active cannabidiol analogues is homogeneous and pharmaceutically acceptable.

[171] The transmucosal preparation of the invention may include stabilizers to protect against hydrolysis. Such stabilizers may include cyclodextrins, chelating agents and surfactants.

[172] The topical ophthalmic formulation can be solutions, emulsions, lipid nanoparticles or matrix films. Other formulations known to a person skilled in the art may also be used. Lipid nanoparticles, emulsions and matrix films are the most preferred formulations.

[173] Solutions: Solution formulations will typically require solubilizers in view of the low solubility of cannabinoids. Examples of solubilizers that can be used in ophthalmic formulations include surfactants that form micellar solutions (since the active ingredient is trapped in micelles) and complex forming agents or combinations thereof. Surfactants commonly used in ophthalmic formulations include polyoxyethylene sorbates (e.g., Tween® 20 and Tween® 80), polyoxylic hydrogenated castor oils (e.g., Cremphor® EL and Cremophor® RH 40), Tyloxapol®, polyoxoethylene ethers (series Brij®) and alkoxylated fatty acid esters (Myrj® series), sorbitan esters (Span® series) and others known to a person skilled in the art. Cyclodextrins, such as hydroxypropyl betacyclodextrin and randomly methylated beta cyclodextrins, are commonly used to improve solubility through inclusion of complex formation. Solubilizers can be used alone or in combination.

[174] Emulsions: An emulsion is a system consisting of two immiscible liquid phases (oil and water), one of which is dispersed through the other as fine droplets, and the system is stabilized by a third component, the emulsifying agent. Emulsions are inherently unstable, and emulsifiers are essential for both their initial formation and long-term stability. Emulsions can be oil-in-water emulsions (oil phase dispersed in the water phase) or water-in-oil emulsions (water phase dispersed in the oil phase). A variety of other systems such as oil-in-water-in-oil emulsions and water-in-oil-in-water emulsions are also known in the art. The oil phase may consist of oils such as soybean oil, castor oil, sesame oil and olive oil. Various emulsion stabilizers or emulsifying agents are known in the art and include surfactants and phospholipids. Examples of surfactant emulsifiers include polyoxyethylene sorbates (e.g. Tween® 20 and Tween® 80), polyoxylic hydrogenated castor oils (e.g. Cremphor® EL and Cremophor® RH 40), Tyloxapol®, polyoxyethylene ethers (Brij® series ) and alkoxylated fatty acid esters (Myrj® series), sorbitan esters (Span® series) and others known to a person skilled in the art. Examples of phospholipids that can be used as emulsion stabilizers include phospholipids (e.g., phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol).

[175] Lipid nanoparticles: Colloidal dispersions of solid lipid nanoparticles (SLNs) or nanostructured lipid carriers (NLCs) containing the therapeutic agent can also be used. In these systems, the drug is loaded into the lipid phase, which is then dispersed in the aqueous phase. In the design of SLNs, only lipids that are solid at room temperature are used whereas with NLCs a combination of solid (e.g. Compritol®, Precirol®) and liquid (e.g. Miglyol®) lipids are used. Furthermore, stabilizers such as surfactants and other components such as glycerin and propylene glycol can also be used alone and in combination.

[176] Matrix films: Matrix films prepared using melt-extrusion or melt-cast technology can also be used. The films comprise a thermoplastic polymer as the carrier of the active ingredient. The thermoplastic polymer used may include, but is not limited to, polyethylene oxide (PolyOx®), polyvinylpyrrolidone (Kollidon®), hydroxypropyl cellulose (Klucel®), ethyl cellulose, methylcellulose, alkylcelluloses, veegum clays, alginates, PVP, alginic acid, calcium carboxymethylcellulose, microcrystalline cellulose (e.g. Avicel™), potassium polacrylate (e.g. Amberlite™), sodium alginate, corn starch, potato starch, pregelatinized starch, modified starch, cellulosic agents, montmorillonite (e.g., bentonite), gums, agar, locust bean gum, karaia gum, pecitin, tragacanth, and other matrix formers known to those skilled in the art. The matrix film may also comprise bioadhesives such as water-soluble or water-swellable polymers derived from acrylic acid or a pharmaceutically acceptable salt thereof, such as polyacrylic acid polymers, which include carbomers, polycarbophils and/or water-soluble salts. of a copolymer of methyl vinyl ether and maleic acid or anhydride (Gantrez MS-955).

[177] Topical ophthalmic compositions may include additional or alternative polymeric ingredients and/or viscosity agents to increase stability and/or retention on the ocular surface. Examples include carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, xanthan gum, hyaluronic acid, any combinations thereof or the like.

[178] Topical ophthalmic compositions may include a preservative. Potential preservatives include quaternary ammonium compounds such as benzalkonium chloride, hydrogen peroxide and other ophthalmic preservatives/preservative systems known in the art.

[179] Other additives such as buffering and tonicity-adjusting agents may also be included in topical ophthalmic formulations. Examples of buffering agents include citrate, borate, and acetate buffers. Tonicity-adjusting agents may include, for example, sodium chloride and potassium chloride. Furthermore, stabilizers (e.g., antioxidants and chelating agents) and penetration enhancers, e.g., benzalkonium chloride, saponins, fatty acids, polyoxyethylene fatty ethers, fatty acid alkyl esters, pyrrolidones, polyvinylpyrrolidone, pyruvian acids, pyroglutamic acids and your mixes, among others, can also be included.

[180] The above description is only representative of embodiments and illustrative examples. For the convenience of the reader, the above description has focused on a limited number of examples representative of all possible embodiments, examples that teach the principles of the invention. The description was not intended to exhaustively enumerate all possible variations or even combinations of those variations described. Alternative embodiments may not have been disclosed for a particular portion of the invention, or alternative embodiments not further described that may be available for a portion, should not be considered a waiver of those alternative embodiments. A person of ordinary skill in the art will appreciate that many of those undescribed embodiments involve differences in technology and materials rather than differences in the application of the principles of the invention. Accordingly, the invention is not intended to be limited to less than the scope set forth in the following and equivalent claims. References Alexander A, Smith, PF Rosengren, RJ. Cannabinoids in the treatment of cancer. Cancer Letters 2009; 285:6 to 12. Amptoulach S, Tsavaris N. Neurotoxicity caused by the treatment with platinum analogues. Chemotherapy Research and Practice. 2011; Article ID 843019. Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annual Review of Neuroscience. 1984; 7: 309 to 338). Chiou LC, Hu SS, Ho Y. Targeting the cannabinoid system for pain relief? Act Anaesthesiologica Taiwanica. 2013; 51:161 to 170. Cox ML, Haller VL, Welch SP. Synergy between Δ9-tetrahydrocannabinol and morphine in the arthritic rat. European Journal of Pharmacology. 2007; 567: 125 to 130). Guindon J, Lai Y, Takacs SM, Bradshaw HB, Hohmann AG. Changes in endocannabinoid tone following chemotherapy- induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment. Pharmacological Research. 2012; 67, 94 to 109. Hall W, Christie M, Currow D. Cannabinoids and cancer: causation, remediation, and palliation. The Lancet. 2005; 6:35 to 42. Khasabova IA, Khasabov S, Paz J, Rose C, Simone DA. Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. Neurobiology of Disease. 2012; 32, 7091 to 7101. Kim, JH, Dougherty PM, Abdi S. Basic science and clinical management of painful and non-painful chemotherapy-related neuropathy. Gynecologic Oncology. 2015; 136:453 to 459. Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ. Anatomy of CNS opioid receptors. Trends in Neuroscience. 1988; 11: 308 to 314. Miltenburg NC, Booger W. Chemotherapy-induced neuropathy: a comprehensive survey. Cancer Treatment Reviews. 2014; 40:872 to 882. Neelakantan H, Tallarida RJ, Reishcenbach ZW, Tuma RF, Ward SJ, Walker EA. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. Behavioral Pharmacology. 2014; 26:304 to 314. Paice JA. Chronic treatment-related pain in cancer survivors. Pain. 2010; 152:84 to 89. Park HJ, Stokes JA, Pirie E, Skahen J, Shtaerman Y, Yaksh TL. Persistent hyperalgesia in the cisplatin-treated mouse as defined by threshold measures, the conditioned place preference paradigm, and the changes in dorsal root ganglia activated transcription factor 3: the effects of gabapentin, ketorolac, and entanercept. Anesthesia and Analgesia. 2012; 116:224 to 231. Pisanti S, Picardi P, D’Alessandro A, Laezza C, Bifulco M. The endocannabinoid signaling system in cancer. Trends in Pharmacological Sciences. 2013; 34, 273 to 282. Toth C., Au S. A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy. Pain. 2008; 138:657 to 666. Vera G, Cabezos PA, Martin MI, Abalo R. Characterization of cannabinoid-induced relief of neuropathic pain in a rat model of cisplatin-induced neuropathy. Pharmacology, Biochemistry and Behavior. 2013; 105, 205 to 212. Wilson-Poe AR, Pocius E, Herschbach M, Morgan MM. The periaqueductal gray contributes to bi-directional enhancement of antinociception between morphine and cannabinoids. Pharmacology, Biochemistry and Behavior. 2013; 103: 444 to 449. Wolf S., Barton D., Kottschade L., Grothey A., Lopriniz C. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. European Journal of Cancer. 2008; 44:1507 to 1515.

Claims (4)

1. Cannabidiol analogue biologically characterized by the fact that the analogue is: CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate-Di-Hemisuccinate, CBD-Mono-Valinate-Mono-Hemisuccinate, or CBD-Mono-Valinate-Di-Hemisuccinate. 2. Pharmaceutical composition characterized by the fact that it comprises a biologically active cannabidiol analogue, as defined in claim 1, and a pharmaceutically acceptable carrier. 3. Use of a biologically active cannabidiol analogue, as defined in claim 1, characterized by the fact that it is for the preparation of a composition for analgesic treatment. 4. Use of a biologically active cannabidiol analogue, as defined in claim 1, characterized by the fact that it is for the preparation of a composition in combination with a sub-analgesic dose of morphine for the treatment of cisplatin-induced neuropathy.