WO2021232156A1

WO2021232156A1 - Cannabinoid pharmaceutical composition

Info

Publication number: WO2021232156A1
Application number: PCT/CA2021/050681
Authority: WO
Inventors: Molly Shoichet; Michael J. Cooke
Original assignee: Amacathera Inc.
Priority date: 2020-05-19
Filing date: 2021-05-19
Publication date: 2021-11-25

Abstract

A pharmaceutical composition comprises: a hydrogel comprising a gel polymer matrix comprising hyaluronan or a derivative thereof and methylcellulose or a derivative thereof; and a cannabinoid, wherein the cannabinoid is dispersed in the hydrogel. Also provided are methods of treating multiple sclerosis and/or Parkinson's disease and/or pain, treating or preventing nausea or anxiety, or stimulating appetite using a therapeutically effective amount of the pharmaceutical composition. Compositions may be administered orally or injected.

Description

CANNABINOID PHARMACEUTICAL COMPOSITION

This application claims priority to United States application number 63/027,054 filed May 19, 2020.

TECHNICAL FIELD [0001] This invention relates to cannabinoid pharmaceutical compositions and methods of administering cannabinoid products.

BACKGROUND OF THE ART

[0002] Cannabinoids (e.g. phytocannabinoids including cannabidiol, and synthetic cannabinoids) are an emerging class of therapeutics for a number of diseases. The poor localization and bioavailability of these compounds limits their efficacy. Sustained and alternative delivery strategies are needed to improve efficacy of these compounds.

BRIEF SUMMARY

[0003] In one embodiment, there is provided a pharmaceutical composition comprising: a hydrogel comprising a gel polymer matrix comprising between 0.5 wt% and 6 wt% hyaluronan or a derivative thereof and between 0.5 wt% and 10 wt% methylcellulose or a derivative thereof based on the total weight of the hydrogel; and a cannabinoid. In one embodiment, the cannabinoid is encapsulated in a biocompatible polymer and dispersed in the hydrogel. In one embodiment, the cannabinoid is not encapsulated in a polymer and is dispersed directly in to the hydrogel. In one embodiment, the pharmaceutical composition is formulated for oral administration. [0004] In one embodiment, the composition is formulated for administration by injection and comprises between 0.5 wt% and 2.8 wt% hyaluronan or derivative thereof and between 0.5 wt% and 4.0 wt% methylcellulose or derivative thereof based on the total weight of the hydrogel.

[0005] The biocompatible polymer may also be biodegradable and, in one embodiment, is poly(lactic-co-glycolic acid). [0006] The methylcellulose or derivative thereof suitably has a molecular weight between

2,000 g/mol and 500,000 g/mol and the hyaluronan or derivative thereof suitably has a molecular weight between 100,000 g/mol and 3,000,000 g/mol. [0007] In one embodiment, the methylcellulose or derivative thereof has viscosity above 400 cP.

[0008] In one embodiment, the composition comprises between 0.1 and 40 percent by weight cannabinoid relative to the combined weight of the hydrogel comprising hyaluronan or derivative thereof and the methylcellulose or derivative thereof, the encapsulating polymer when present and the cannabinoid.

[0009] In one embodiment, the pharmaceutical composition is a sustained release composition.

[0010] Also provided is a method of treating or preventing nausea, such as nausea caused by chemotherapy, comprising administering a therapeutically effective amount of the pharmaceutical composition as disclosed herein to a subject in need thereof.

[0011] Also provided is a method of treating or preventing anxiety comprising administering a therapeutically effective amount of the pharmaceutical composition as disclosed to a subject in need thereof. [0012] Also provided is a method of stimulating appetite comprising administering a therapeutically effective amount of the pharmaceutical composition as disclosed to a subject in need thereof. In one embodiment, the subject has cancer and/or AIDS.

[0013] Also provided is a method of treating multiple sclerosis and/or Parkinson’s disease comprising administering a therapeutically effective amount of the pharmaceutical composition as disclosed to a subject in need thereof.

[0014] Also provided is a method of treating inflammation, such as inflammation caused by rheumatoid arthritis comprising administering a therapeutically effective amount of the pharmaceutical composition as disclosed to a subject in need thereof.

[0015] Also provided is a method of treating diseases that are currently treated with viscosupplementation, such as osteoarthritis comprising administering a therapeutically effective amount of the pharmaceutical composition as disclosed to a subject in need thereof.

[0016] Also provided is a method of treating pain.

[0017] Also provided is use or use in the manufacture of a medicament of compositions disclosed herein for the treatment or prevention of nausea (including nausea caused by chemotherapy); or anxiety. Also provided is use or use in the manufacture of a medicament of compositions disclosed herein for stimulating appetite; treating multiple sclerosis and/or Parkinson’s disease; treating inflammation (including inflammation caused by rheumatoid arthritis); treating diseases that are currently treated with viscosupplementation (including osteoarthritis); and treating pain.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows the release profile of a cannabidiol analog after encapsulation in PLGA particles and dispersion in 1.4:3 HAMC, shown as cumulative mass released.

DETAILED DESCRIPTION

[0019] Cannabinoids, such as tetrahydrocannabinol and cannabidiol, are a class of compounds, a number of which are in use or are candidates for use as therapeutics for a number of diseases such as: pain, anxiety, nausea, multiple sclerosis, Parkinson’s disease, depression and inflammatory diseases.

[0020] Cannabinoids can be extracted from cannabis (phytocannabinoid) or synthesized. Cannabinoids act through interactions with the endocannabinoid system (e.g. cannabinoid receptors). FDA-approved cannabinoid-based products exist for chemotherapy-associated nausea. Cannabidiol (CBD) is of interest due to its many pharmacological effects without associated psychoactivity. However, the use of cannabidiol is limited by poor bioavailability when delivered orally (6%) or by inhalation (31%) [Ohlsson A., Lindgren J.E., Andersson S., Agurell S., Gillespie H., Hollister L.E., Single-dose kinetics of deuterium-lablled cannabidiol in man after smoking and intravenous administration. Biomed. Environ. Mass. Spectrom., 1986. 13(2): p. 77- 83; Agurell S., Halldin M., Lindgren J.E., Ohlsson A., Widman M., Gillespie H., Hollister L., Pharmacokinetics and metabolism of delta 1-tetrahydrocannbinol and other cannabinoid with emphasis on man. Pharmacological Reviews, 1986. 38(1): p.21-43]

[0021] While there are many forms of CBD available on the market, these strategies focus on oral, inhalation, transmucosal or transdermal administration. There are currently no regulated sustained-release products. [0022] Other challenges associated with CBD pharmaceutical formulations are CBD’s poor solubility in aqueous solutions and bioavailability. In particular, the combination of poor solubility, a low dissolution rate in gastrointestinal fluids and high first-pass liver metabolism means that CBD formulations have poor oral bioavailability. [0023] In order to address this poor bioavailability, high doses are required, which contributes to waste as well as the potential for adverse effects.

[0024] According to an embodiment of the present invention, there is provided a pharmaceutical composition comprising: a hydrogel comprising a gel polymer matrix comprising hyaluronan and methylcellulose and a cannabinoid dispersed in the hydrogel. In one embodiment, the cannabinoid is encapsulated in a biocompatible polymer. Suitably, the encapsulation material increases the solubility of the cannabinoid thereby decreasing the amount to drug required. In one embodiment, the composition includes between 0.5 wt% and 6 wt% hyaluronan and between 0.5 wt% and 10 wt% methylcellulose based on the total weight of the hydrogel.

[0025] In one embodiment, the pharmaceutical compositions as described herein are formulated into capsules for oral administration.

[0026] As used herein "cannabinoid" refers to any of the class of chemical compounds referred to as cannabinoids that act on cannabinoid receptors and modulate activity of the endocannabinoid system. “Cannabinoid” can also include combinations of different cannabinoids.

[0027] Known cannabinoids include THC (tetrahydrocannabinol); THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL (cannabicyclol); CBV (cannabivarin); THCV (tetrahydrocannabivarin); CBDV (cannabidivarin); CBCV (cannabichromevarin); CBGV (cannabigerovarin); CBGM (cannabigerol monomethyl ether); CBE (cannabielsoin); and CBT (cannabicitran). Combinations of cannabinoids include Sativex, which is a combination of CBD and THC.

[0028] In one embodiment, there is provided a composition comprising a HAMC hydrogel and a cannabinoid.

[0029] Hyaluronic acid (or hyaluronan) (HA) and derivatives of HA may be employed. HA is a linear polysaccharide composed of repeating disaccharide units of N-acetyl-glucosamine and D-glucuronic acid. HA is degraded enzymatically by hyaluronidase, which can be produced by cells. Its polymeric chains, of lengths of 10-15 thousand disaccharides, form random coils with large spheroidal hydrated volumes of up to 400-500 nm in diameter. Reactions can occur at the carboxyl group or the hydroxyl group of HA and also at the amino group when the N-acetyl group is removed.

[0030] Pharmaceutical grade HA is available in a wide variety of molecular weights, in the range of between about 100,000 and about 3,000,000 g/mol. In one embodiment the composition comprises HA in the range of 500,000 and 2,500,000 g/mol, in one embodiment in the range of 1,000,000 and 2,000,000 g/mol, and in a preferred embodiment in the range of 1,400,000 to 1,600,000 g/mol.

[0031] The other polymer component of the hydrogel is methylcellulose (MC). MC is an example of a temperature sensitive gel, or a thermally reversible gel, that gels upon increase in temperature. When the degree of substitution of hydroxyl groups with methyl groups is between 1.4 and 1.9 per monomer unit, MC has inverse thermal gelling properties whereby it gels upon an increase of temperature. As the temperature increases, the methyl groups of MC form hydrophobic interactions and water molecules are released from interacting with MC, thereby forming a gel.

[0032] The MC may have a molecular weight in the range of between about 2,000 and about 1,000,000 g/mol, In one embodiment the composition comprises MC in the range of 10,000 and 500,000 g/mol, in one embodiment in the range of 100,000 to 400,000 g/mol, and in one embodiment in the range of 200,000 to 300,000 g/mol.

[0033] It is possible to alter the rate of resorption of the composite by changing the hydrophobicity of HA or the derivative thereof. More specifically, an altered rate of resorption may be provided by the addition of at least one functional group to the HA or the derivative thereof or MC or the derivative thereof selected from the group consisting of carboxylic acid, primary amine, aldehyde, hydrazide, maleimide, thiol, furan, alkyne, azide, alkene, urethane, and primary alcohol.

[0034] In one embodiment, the cannabinoid is encapsulated in a biocompatible polymer. As used herein, "biocompatible" means substantially free from deleterious effects on living systems or tissues. The biocompatible polymer is suitably also biodegradable.

[0035] In one embodiment, the cannabinoid is not encapsulated in a polymer and is dispersed directly in to the hydrogel. [0036] Biocompatible and biodegradable polymers suitable for encapsulation of active pharmaceutical ingredients include, for example, polyesters such as poly(lactic-co-glycolic acid) (PLGA), poly (e-caprolactone) (PCL); polyanhydrides; and natural polymers or derivatives thereof, which may be proteins (e.g. gelatin or collagen) or polysaccharides (e.g. hyaluronan, starch, dextran, alginate, and chitosan). In one embodiment, the polymer is a polyester, in one embodiment PLGA.

[0037] Methods for microencapsulation of drugs are also known to those of skill in the art and include emulsion-solvent evaporation, spray drying and in situ polymerization.

[0038] Pharmaceutical compositions as described herein may suitably be prepared through the physical blending of HA and MC in solution, in one embodiment in phosphate buffered saline (PBS). After MC and HA are dispersed in PBS and allowed to dissolve, the cannabinoid, suitably encapsulated in particle form, may be dispersed in HAMC. The compositions may be sterilized by autoclave, gamma sterilization, filter sterilization or steam sterilization. Compositions are suitably stored at a range of 4°C to room temperature.

[0039] In one embodiment, the composition comprises between 0.1 and 40 percent by weight cannabinoid relative to the combined weight of the hydrogel comprising HA or derivative thereof and the MC or derivative thereof, the encapsulating polymer when the cannabinoid is used in encapsulated form, and the cannabinoid. In some embodiments, up to 20% or up to 30% by weight relative to the combined weight of the HAMC gel, the encapsulating polymer (e.g. PLGA) where applicable, and the cannabinoid. As an exemplary embodiment, a suitable cannabinoid loading may be 300 mg/mL.

[0040] Dispersing the cannabinoid in a hydrogel comprising a physical blend of HA and MC and further encapsulation of the cannabinoid within polymeric microparticles (e.g. PLGA) provides for sustained release and/or improved bioavailability.

[0041] In one embodiment, “sustained release” refers to a release that is prolonged over an extended period of time compared to the non-sustained release formulation. The PK profile of a sustained release formulation will show a reduced Cmax with an AUC similar or greater than the non-sustained release formulation.

[0042] In one embodiment, a single administered dose of a sustained release hydrogel composition as described herein provides effects for a period of greater than 24 hours, in one embodiment greater than 48 hours, in one embodiment greater than 72 hours, and in one embodiment, between 24 and 120 hours.

[0043] In one embodiment, the pharmaceutical compositions as disclosed herein are formulated for oral administration.

[0044] The pharmaceutical compositions described herein may be combined with any pharmaceutically acceptable carrier or excipient. As used herein, a “pharmaceutically acceptable carrier” or “excipient” can be a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle selected to facilitate delivery of the pharmaceutical composition to a subject. The excipient may be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with the other components of the pharmaceutical composition. Examples of pharmaceutically acceptable carriers include one or more of water, saline, buffer, PBS, glycerol, ethanol and the like, as well as combinations thereof. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the pharmacological agent.

[0045] In some embodiments, the pharmaceutically acceptable carrier is PBS or saline.

[0046] As used herein, “therapeutically effective amount” refers to an amount effective, at dosages and for a particular period of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the pharmacological agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the pharmacological agent to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the pharmacological agent are outweighed by the therapeutically beneficial effects.

[0047] As used herein “subject” refers to an animal being administered a cannabinoid, in one embodiment a mammal, in one embodiment a human patient. As used herein “treatment” and grammatical variations thereof refers to administering a composition of the present invention to subject to prevent (completely or in part) or ameliorate a disease or condition or a symptom thereof. The treatment may require administration of multiple doses, which may be at regular intervals. [0048] In one embodiment, there is provided a method of treating or preventing nausea comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein. In one embodiment, the nausea is caused by chemotherapy.

[0049] In one embodiment, there is provided a method of treating anxiety comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein.

[0050] In one embodiment, there is provided a method of stimulating appetite comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein to a subject. In one embodiment, the subject has cancer and/or AIDS. [0051] In one embodiment, there is provided a method of treating multiple sclerosis or

Parkinson’s disease comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein.

[0052] In one embodiment, there is provided a method of treating pain comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein.

[0053] All documents referenced herein are incorporated by reference, however, it should be appreciated that any patent, publication, or other disclosure material, in whole or in part, that is incorporated by reference herein is incorporated only to the extent that the incorporated material does not conflict with definitions, statements, or other disclosure material set forth in this disclosure. As such, and to the extent necessary, the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference.

[0054] It will be understood that numerous modifications thereto will appear to those skilled in the art. Accordingly, the above description and accompanying drawings should be taken as illustrative of the invention and not in a limiting sense. It will further be understood that it is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features herein before set forth, and as follows in the scope of the appended claims. [0055] The embodiments of the invention described above are intended to be exemplary only. The scope of the invention is therefore intended to be limited solely by the scope of the appended claims. EXAMPLE 1 - Preparation of HAMC gels and CBD-loaded PLGA particles Preparation of HAMC gel

[0056] 1.4:3 w/w HAMC with CBD-loaded particles was prepared as follows (per mL of gel made):

[0057] HAMC hydrogels were prepared through the physical blending of HA and MC in PBS. (Speed mixed at max speed for 30 seconds, centrifuged at 5000 RPM for 1 min.) MC and HA were allowed to dissolve overnight at 4°C.

Encapsulation of Cannabidiol in PLGA particles

[0058] Abnormal cannabidiol was loaded into PLGA microparticles by oil/water emulsion solvent evaporation technique. The organic phase consisting of 120 mg PLGA, 1 mg abnormal cannabidiol and 0.9 mL DCM was added to 18 mL of 1% PVA and homogenized for 1 minute at 4300 rpm. The emulsion was then added to a 150 mL solution of 0.1% PVA and stirred for 3 hours at room temperature. Particles were collected, washed by centrifugation, lyophilized and stored at -20 °C. CBD-loaded particles were then dispersed in 1.4:3 HAMC.

EXAMPLE 2 - Release Kinetics [0059] Abnormal CBD encapsulated in PLGA was loaded in HAMC and release profiles were measured in vitro in PBS. Samples for release studies were prepared by first recording the mass of 2 mL plastic microtubes and aliquoting 100 pL of CBD-loaded HAMC into a 2 mL microcentrifuge tube, and spinning the tubes for 10 seconds at 5000 RPM to ensure a planar geometry at the surface. Each sample was then allowed to gel at 37 °C for 30 minutes. At time zero, 0.9 mL of pre-warmed PBS was added to the gel and incubated on an orbital shaker rotating at 45 RPM at 37 °C for 1, 2, 4, 6, 24, 48, 72, 96, 120, 144 and 168 h, after which the PBS was completely removed, collected and replaced with 0.9 mL of fresh, pre-warmed PBS and returned to the orbital shaker rotating at 45 RPM at 37 °C. Samples were stored at 4°C until they were analyzed. Each release sample was analyzed for drug concentration by UV-Vis spectrophotometry. Following the final time point, the amount of drug remaining in HAMC was extracted by dissolving the HAMC in 2 ml_ of PBS, by vortexing the tubes for 10 seconds and storing them at 4 °C overnight in a shaker, after which they were vortexed for an additional 10 seconds. The extracted mass was then quantified through by UV-Vis spectrophotometry, diluting as necessary if the sample was too concentrated.

HAMC sustains release of CBD

[0060] Release of encapsulated CBD from HAMC was sustained up to 14 days (Figure 1).

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising: a hydrogel comprising a gel polymer matrix comprising between 0.5 wt% and 6 wt% hyaluronan or a derivative thereof and between 0.5 wt% and 10 wt% methylcellulose or a derivative thereof based on the total weight of the hydrogel; and an unencapsulated cannabinoid dispersed directly in the hydrogel.

2. A pharmaceutical composition comprising: a hydrogel comprising a gel polymer matrix comprising between 0.5 wt% and 6 wt% hyaluronan or a derivative thereof and between 0.5 wt% and 10 wt% methylcellulose or a derivative thereof based on the total weight of the hydrogel; and a cannabinoid encapsulated in a biocompatible polymer, wherein the encapsulated cannabinoid is dispersed in the hydrogel.

3. The pharmaceutical composition of claim 2, wherein the biocompatible polymer is poly(lactic-co-glycolic acid) PLGA.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition is formulated for oral administration.

5. The pharmaceutical composition of any one of claims 1 to 3 wherein the composition is formulated for administration by injection and comprises between 0.5 wt% and 2.8 wt% hyaluronan or derivative thereof and between 0.5 wt% and 4.0 wt% methylcellulose or derivative thereof based on the total weight of the hydrogel.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the hyaluronan or derivative thereof has a molecular weight between 100,000 g/mol and 3,000,000 g/mol and the methylcellulose or derivative thereof has a molecular weight between 2,000 g/mol and 500,000 g/mol.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the methylcellulose or derivative thereof has a viscosity above 400 cP.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the composition comprises between 0.1 and 40 percent by weight cannabinoid relative to the combined weight of the hydrogel, the biocompatible polymer if present and the cannabinoid.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the pharmaceutical composition is a sustained release composition.

10. A method of treating or preventing nausea comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 9 to a subject in need thereof.

11. The method of claim 10, wherein the nausea is caused by chemotherapy.

12. A method of treating or preventing anxiety comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 9 to a subject in need thereof.

13. A method of stimulating appetite comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 9 to a subject in need thereof.

14. The method of claim 13, wherein the subject has cancer and/or AIDS.

15. A method of treating multiple sclerosis and/or Parkinson’s disease comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 9 to a subject in need thereof.

16. A method of treating pain comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 9 to a subject in need thereof.