WO2023055648A1

WO2023055648A1 - Cannabidiol formulation with improved dissolution

Info

Publication number: WO2023055648A1
Application number: PCT/US2022/044420
Authority: WO
Inventors: Jianmin Xu; Ling-Chieh Chen; Andrew X. Chen
Original assignee: Latitude Pharmaceuticals Inc.
Priority date: 2021-09-28
Filing date: 2022-09-22
Publication date: 2023-04-06
Also published as: WO2023055648A9

Abstract

A solid dispersion matrix formulation, comprising CBD and a polymer selected from the group consisting of polyvinylpyrrolidone (PVP) and poly (vinylpyrrolidone-vinyl acetate) copolymer, and mixtures thereof, and wherein CBD is non-crystalline and uniformly dispersed in the matrix. Method of making the same are also disclosed.

Description

CANNABIDIOL FORMULATION WITH IMPROVED DISSOLUTION

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to US Provisional Application No. 63/249,429, filed September 28, 2021, the contents of which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND

[0002] More and more states within the United States and other countries across the world have legalized cannabidiol (“CBD”) for medicinal use since studies have shown that CBD has many benefits such as relieving pain, reducing anxiety and depression, and functioning as a sleep aid.

[0003] In the United States, the FDA has approved a prescription cannabidiol drug called “Epidiolex” for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex in people one year of age and older. In Europe, cannabidiol (Epidyolex) is indicated for use as adjunctive therapy of seizures associated with Lennox Gastaut syndrome (LGS) or Dravet syndrome (DS), in conjunction with clobazam, for people two years of age and older. Epidiolex/Epidyolex is the first prescription formulation of plant-derived cannabidiol approved by regulatory bodies in the US and Europe.

[0004] Nabiximols (brand name Sativex) - an oral mucosal spray made of a complex botanical mixture containing cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), and additional cannabinoid and non-cannabinoid constituents from cannabis sativa plants - was approved by Health Canada in 2005 to treat central neuropathic pain in multiple sclerosis and in 2007 for cancer-related pain. In New Zealand, Sativex is “approved for use as an add-on treatment for symptom improvement in people with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication.”

[0005] One of the biggest barriers for CBD research is having a convenient administration route while maintaining high bioavailability. Oral administration is the most convenient way, but it has the lowest bioavailability at about 3-5% compared to other routes of administration. The low bioavailability of CBD via oral administration is mainly due to its extremely high lipophilicity with a computed log P of 6.5.

[0006] This high lipophilicity results in poor water solubility and essentially no dissolution in water for CBD. Since drug dissolution is a prerequisite for absorption, enhancing dissolution is key for an improved CBD oral dosage form with a greater bioavailability. Most currently marketed CBD products are formulated in oil (“CBD oil”). For example, Epidyolex is a CBD oil containing CBD, alcohol, sesame seed oil, strawberry flavor, and sucralose as sweetener. In most cases, the CBD oil does not provide any dissolution enhancement for CBD.

[0007] Furthermore, CBD is extremely bitter, and the oil formulation does not help mask its bitterness compared to a solid formulation such as a capsule or tablet. In addition to an unpalatable taste, CBD oil is inconvenient to manufacture, costly to package, inaccurate to measure doses, and exposes the CBD to greater degradation stress, as compared to a solid dosage form such as capsules or tablets.

[0008] There is a need in the field for a new formulation for CBD that is

(1) Solid,

(2) With enhanced CDB dissolution compared to CBD or CBD oil,

(3) With better CBD stability compared to CBD oil,

(4) Can be incorporated into the conventional capsule or tablet form, and

(5) Can be provided in an immediate-release or sustained-release dosage form

The present disclosure satisfies this need and offers other advantages as well.

BRIEF SUMMARY

[0009] The present disclosure provides a solid dispersion matrix formulation with an enhanced dissolution for an increased oral bioavailability for CBD in a pharmaceutically acceptable dosage form.

[0010] As such, in one embodiment, the present disclosure provides a solid dispersion matrix formulation, comprising, consisting essentially of, or consisting of CBD and a polyvinylpyrrolidone (PVP, povidone) or a copolymer thereof and wherein a CBD molecule is non-crystalline and is uniformly dispersed within a polymer matrix.

[0011] In certain aspects, the solid dispersion matrix is an amorphous solid with a glass transition temperature between about 90°C and 180°C.

[0012] In certain aspects, the solid dispersion matrix is free of or has a reduced heat of fusion relating to the crystalline CBD melting as determined by thermal analysis such as DTA.

[0013] In certain aspects, the solid dispersion matrix shows no peaks of the original CBD crystal X-ray diffraction spectra.

[0014] In certain aspects, the solid dispersion matrix is in a form of powder, granule, pellets or other pharmaceutically acceptable form such as rod, noodle, film, caplet, tablet, etc.

[0015] In certain aspects, the solid dispersion matrix is provided as dry powder and later mixed with water or another liquid to form an oral liquid before dosing.

[0016] In certain aspects, the solid dispersion matrix is mixed with other excipients and filled into capsules for immediate release or sustained release.

[0017] In certain aspects, the solid dispersion matrix is mixed with other excipients and compressed into tablets for immediate release or sustained release.

[0018] In certain aspects, a pharmaceutical dosage form comprising the solid dispersion matrix provides faster and more complete dissolution than CBD or a CBD oil.

[0019] In certain aspects, a pharmaceutical dosage form comprising the solid dispersion matrix provides better CBD stability than a CBD oil.

[0020] As such, in another embodiment, the present disclosure provides a method for making a solid dispersion matrix, the method comprising, consisting essentially of, or consisting of:

Blending CBD and a polyvinylpyrrolidone or a copolymer thereof;

Heating the blend to melt or liquify it;

Extruding molten liquid to generate a noodle-like extrudate or into a mold with a defined size and shape; Cooling down the extrudate to solidify; and

Pulverizing the solid extrudate to smaller size such as powder or granules.

[0021] In certain aspects, the present disclosure provides a method for making a pharmaceutical dosage form by blending the solid dispersion matrix powder or granule with other excipients for oral suspension/solution, such as a flavoring or sweetener, and filling the blend into a bottle.

[0022] In certain aspects, the present disclosure provides a method for making a pharmaceutical dosage form by blending the solid dispersion matrix powder or granule with capsule excipients and filling the blend into capsules.

[0023] In certain aspects, the present disclosure provides a method for making a pharmaceutical dosage form by blending the solid dispersion matrix powder or granule with tablet excipients and compressing the blend into tablets.

[0024] In certain aspects, the present disclosure provides a method for making a sustained- release pharmaceutical dosage form by blending the solid dispersion matrix powder or granule with sustained-released excipients and filling the blend into capsules.

[0025] In certain aspects, the present disclosure provides a method for making a sustained- release pharmaceutical dosage form by blending the solid dispersion matrix powder or granule with sustained-released excipients and compressing the blend into tablets.

[0026] These and other embodiments, aspects and advantages will become more apparent when read with the accompanying figures and detailed descriptions that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 shows a differential thermal analysis (DTA) of a crystalline CBD, which exhibits a melting point at about 70°C and a thermal decomposition event at about 305°C.

[0028] FIG. 2 shows a differential thermal analysis (DTA) of a physical blend (F-l).

[0029] FIG. 3 shows a differential thermal analysis (DTA) of a solid dispersion matrix formulation (F2). [0030] FIG. 4 shows powder X-ray diffraction spectra of a solid dispersion matrix formulation (F-89) and a physical blend of the same components (F-89DC).

[0031] FIG. 5 shows a rapid dissolution or immediate release of CBD from a solid dispersion matrix formulation (F-2) and from unformulated crystalline CBD.

[0032] FIG. 6 shows a slow dissolution or sustained release or 24 h release of CBD from tablets containing solid dispersion matrix formulation (F-89) and tablets containing a physical blend of the same components (F89-DC).

DETAILED DESCRIPTION

I. Definitions

[0033] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”

[0034] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

[0035] As used in this specification and claims, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0036] The term “active ingredient” is intended to mean, in the context of the present disclosure, one active molecule or a combination of active molecules. The active ingredient can be in liquid form, or in solid or viscous form, but made liquid by solubilization, heating, or any other known means, depending on its chemical nature. Examples of active molecules include cannabidiol (CBD) or a combination of CBD and delta-9-tetrahydrocannabinol (THC) in any proportion. The active ingredient may be from a natural origin or from a synthetic origin. The formulation of the disclosure may contain one or more active ingredients.

[0037] The term “amorphous” means that a solid is in a non-crystalline state. The solid state form of a solid, such as the drug substance in the amorphous dispersion, may be determined by Polarized Light Microscopy, X-Ray Powder Diffraction (XPRD), Differential Thermal Analysis (DTA), or other standard techniques known to those skilled in this field. For example, a typical amorphous solid would exhibit no melting event by DTA as compared to the crystalline form which would show an endothermic melting event with well-defined melting temperature and heat of fusion.

[0038] As used herein, “bioavailability” is a term meaning the degree to which a drug becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing a drug that is not highly soluble. In certain embodiments such as formulations of active ingredients, the active ingredients may be water soluble, poorly soluble, not highly soluble, or insoluble.

[0039] “ Cannabidiol,” or CBD, is a phytocannabinoid derived from Cannabis species, which is devoid of psychoactive activity, with analgesic, anti-inflammatory, antineoplastic and chemopreventive activities. Upon administration, cannabidiol (CBD) exerts its antiproliferative, anti-angiogenic and pro-apoptotic activity through various mechanisms. The IUPAC name is 2-[(lR,6R)-3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]-5-pentylbenzene- 1 ,3-diol having the following structure:

[0040] As used herein, “CBD oil” means a common CBD formulation that contains CBD and carrier oil. The carrier oil is used to dissolve CBD and provide a liquid CBD formulation that can be measured by volume, e.g., 5 drops or 1 teaspoonful. The carrier oil may be grapeseed oil, MCT oil, olive oil, soybean oil, sesame oil, or hempseed oil. Since both CBD and the carrier oil are very lipophilic, a CBD oil does not help with the CBD dissolution into an aqueous medium such as gastric fluid. A CBD oil product can also be very bitter because of CBD, therefore most CBD oil products contain flavoring agents or sweeteners. Both CBD and oil are prone to oxidation and the use of the carrier oil does not help with CBD stability. Hence, most CBD oil products have a short product shelf life (e.g., 6 months)

[0041] As used herein, “dissolution” measures the rate and extent of a drug substance, e.g., CBD released from its formulation or dosage form into an aqueous medium (such as water). The drug dissolution is generally measured in vitro by the drug concentration in the medium over time under controlled conditions (temperature, mixing device, stir rate etc.) using an officially defined apparatus such as a USP dissolution apparatus. The word “dissolution” is sometimes used interchangeably with the word “release”. A rapid dissolution or immediate release generally refers to a no less than 80% of the drug released or dissolved within 30 minutes. A slow dissolution or sustained release generally refers to about 80% of the drug released or dissolved within 12-24 hours.

[0042] As used herein, “excipients” are substances that are included in a formulation or pharmaceutical dosage form not for their direct therapeutic action, but to aid the manufacturing process; to protect, support, or enhance stability; or for bioavailability or patient acceptability

[0040] As used herein, “extrusion” is a method of applying pressure to a melted composition until it flows through an orifice, die or a defined opening. The extrudable length varies with the physical characteristics of the material to be extruded, the method of extrusion, and the process of manipulation of the particles after extrusion. Various types of extrusion devices can be employed, such as screw, sieve and basket, roll, and ram extruders. Furthermore, the extrusion can be carried out through melt extrusion. The solid dispersion matrices of the present disclosure can be melted and extruded with a continuous, solvent-free extrusion process, with or without the inclusion of additives. Such processes are well-known to skilled practitioners in the field.

[0043] As used herein, “glass transition temperature or T_g” means the temperature range where the polymer substrate changes from a rigid glassy material to a soft material, and is usually measured in terms of the stiffness or modulus. The word “glass transition temperature” can be used interchangeably with “melting temperature” for a polymer.

[0044] As used herein, “hot melt” means the process of heating a polymeric material to above its glass transition temperature in order to melt or liquify the polymer to allow for extrusion. [0045] As used herein, “lipophilic” or “lipophilicity” refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents. A lipophilic chemical such as CBD is generally insoluble in water. The word “hydrophobic” can be used interchangeably with “lipophilic”.

[0046] As used herein, the phrase “pharmaceutically acceptable” refers to molecular entities, compositions, materials, excipients, carriers, and the like that do not produce an allergic or similar untoward reaction when administered to humans in general.

[0047] As used herein, “polyvinylpyrrolidone” (“PVP”) is a water-soluble polymer made from the monomer N-vinylpyrrolidone, having an IUPAC name of poly[l-ethenylpyrrolidin- 2-one] and the following chemical structure:

[0048] As used herein, “polyvinyl acetate” (“PVA”) is an aliphatic synthetic polymer having an formula of (C4H6O2)n, IUPAC name of poly[l-(acetyloxy)ethylene] and the following chemical structure:

[0049] As used herein, “PVP-PVA copolymer” means linear and random copolymers produced by polymerization of the vinyl acetate to vinylpyrrolidone monomers in ratios varying from 70/30 to 30/70. For example, a preferred copolymer used for this invention is Kollidon VA64 which as a copolymer made with 60% by wt PVP and 40% by wt PVA.

[0050] As used herein, “poorly soluble” or “insoluble” refers to a drug, such as CBD, that cannot be completely dissolved in water at its intended dose, or that cannot dissolve in water fast enough to allow for oral absorption during its transit thorough the gastrointestinal tract. In either case, a poorly soluble or insoluble drug usually has a low oral absorption or bioavailability.

[0051] As used herein, “solid dispersion or solid dispersion matrix” means a solid formulation comprising at least two components, usually a hydrophilic polymer and hydrophobic crystalline drug substance, wherein drug substance is uniformly or molecularly dispersed throughout the polymer matrix. A solid dispersion matrix is different from a physical blend or physical mixture, in which the drug crystals and the polymer powder are combined by simple mixing or blending (not hot melt), whereas in a solid dispersion matrix the drug is “dissolved” or molecularly dispersed in the polymer by hot melt. Only selected polymers can be used to form a solid dispersion for a given drug depending upon a strong intermolecular interaction between the drug and polymer. Surprisingly, CBD can form a solid dispersion with a PVP or a PVP copolymer but not with other polymers such as celluloses or polyethylene. For example, CBD cannot disperse uniformly in a cellulose polymer (e.g., hydroxypropyl cellulose) even by hot melt, it instead forms a separate layer or phase in the polymer matrix. The drug dispersion or molecularly dispersion in a polymer matrix can be demonstrated by disappearance of the original melting signal of the drug in the solid dispersion as indicated by DTA.

II. CBD Formulation

[0052] A new dosage form has now been surprisingly found which exhibits improved dissolution for CBD. The present disclosure provides a solid dispersion matrix, comprising CBD and a PVP or a copolymer of thereof, and wherein CBD is non-crystalline and is dispersed within the solid matrix.

[0053] In general, a PVP or a PVP/PVA copolymer can be melted by heat to form a molten liquid (“hot-melt”) without decomposition. Upon cooling, the molten liquid will resolidify to form a hard solid. The molten liquid can be extruded into an elongated, noodlelike extrudate (“hot-melt extrusion” or “HME”) or injected into a mold of certain geometry (“injection molding”). The solid thus obtained is friable and can be pulverized by milling or other machinal means into smaller particles (powder or granules). A PVP or PVP/PVA copolymer is a preferred polymer for the hot-melt, HME, or injection molding process for CBD because it has great affinity with CBD. This allows CBD to molecularly disperse or dissolve in the molten polymer liquid and subsequently form a uniform and hard solid matrix or a “solid dispersion matrix” upon cooling. Such a solid dispersion matrix can be pulverized to small particles by milling and the pulverized solid dispersion matrix, e.g., in a powder or granule form, can provide a greatly enhanced dissolution for CBD. The CBD integrity or purity is not compromised by this hot-melt or HME process.

[0054] The inventors of this application discovered that not all polymers can provide the same CBD dissolution enhancement by the HM or HME process. Among the commonly used pharmaceutical polymers, cellulose derived polymers (e.g. ethyl cellulose and hydroxypropylcellulose), polycarbonate, polyethylene, polypropylenes, polylactic-co-glycolic acid (PLGA), polymethacrylates, polyethylene glycol and polyethylene oxide cannot dissolve CBD or form a uniform and one phase liquid when it is melted; therefore, they cannot form a uniform solid dispersion matrix with CBD or to provide an enhanced dissolution for CBD. Some other polymers with very high or very low melting or glass transition temperatures are also not suitable to form the desired CBD solid dispersion matrix of this invention. For example, high MW polyvinyl acetate or polyvinyl alcohol have higher glass transition temperatures (e.g., >180 °C) at which CBD will decompose during the hot melt. On the other hand, polymers with low melting or glass transition temperatures (e.g., <90 °C) such as polyethylene glycol and polyethylene oxide are either liquids or are too soft to form a “solid” matrix at room temperature. A liquid or soft matrix is undesirable for a solid dosage form such as tablets.

[0055] Suitable PVP polymers useful in the solid dispersion matrix of the disclosure include, but are not limited to, polyvinylpyrrolidone and its copolymer with polyvinyl acetate (PVA). The polymer makes up the solid dispersion matrix and CBD is dispersed within the matrix.

[0056] In certain instances, the preferred PVP has MW between 2,000 and 54,000 AMU, more preferably between 2,000 and 11,000 AMU, and most preferably a MW of about 2,000 and 3,000 AMU.

[0057] In certain instances, the preferred PVP copolymer is a copolymer of polyvinylpyrrolidone-polyvinyl acetate (PVP -PVA) at a PVP/PVA ratio of between 30/70 and 70/30, preferably between 50/50 and 70/30, and most preferably at 60/40. The preferred PVA has MW of about 45,000-70,000.

[0058] In certain instances, the PVP or PVP copolymer has a glass transition point between 90 and 180°C, preferably between 120 and 180°C and most preferably between 150 and 170°C. A polymer with a lower melting point will produce a matrix that is too soft for pulverization and less physically stable. A polymer with a higher melting point requires a higher temperature for the hot melt or hot-melt extrusion and the higher temperature (e.g., > 200°C) can cause thermal degradation of CBD.

[0059] In certain instances, the polymer is a co-polymer of poly(vinylpyrrolidone-vinyl- acetate) or poly(l-vinylpyrrolidone-co-vinyl acetate). In certain instances, the polymer is Kollidon® VA 64, which is a copovidone (a co-polymer) useful for a matrix former for CBD amorphous solid dispersions. Copolyvidone (aka Copovidone or PVP/PVA) is a copolymer of l-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6:4 by mass. The average molecular weight ranges from 45,000-70,000 for Kollidon VA 64.

[0060] In certain instances, the CBD represents between about 5% and about 60% wt of the total weight of the solid dispersion matrix such as about 5% 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or about 60% wt/wt.

[0061] In certain instances, the CBD represents between about 10% and about 50% wt/wt of the total weight of the solid dispersion matrix.

[0062] In certain instances, the CBD represents between about 20% and 40% wt/wt of the total weight of the solid dispersion matrix.

[0063] In certain instances, the ratio of CBD to the polymer(s) is 1 :1 to 1 :8, such as 1 :8, 1 :7, 1 :6, 1 :5, 1 :4; 1 :3, 1 :2, or 1 : 1 in the solid dispersion matrix.

[0064] In certain instances, the PVP or PVP copolymer has a glass transition temperature between 90 and 180°C, preferable between 120 and 180°C, and most preferably a between 150 and 170 °C.

[0065] In certain instances, CBD used to make the solid dispersion matrix of this invention is provided as a solid crystalline material or as a CBD oil. The preferred CBD form for this invention is the solid crystalline material.

[0066] In certain instances, the solid dispersion matrix of this invention is a hard, transparent and glass-like solid. In other certain instances, the solid dispersion matrix of this invention is opaque.

[0067] In certain instances, the solid dispersion matrix of this invention is substantially free of the CBD melting event by thermal analysis (DTA). [0068] In certain instances, the solid dispersion matrix of this invention is substantially free of the characteristic x-ray diffraction pattern of CBD.

[0069] In certain instances, the solid dispersion matrix of this invention retains the CBD chemical integrity by maintaining no less than 98% of its initial HPLC chromatographic purity.

[0070] In certain instances, the solid dispersion matrix of this invention is provided as a noodle, filament, powder, granule, or a molded shape. The preferred form is powder.

[0071] In certain instances, a powder form of the solid dispersion matrix of this invention has a size between 1 micron to 2000 microns, preferably between 5 microns to 200 microns, and most preferably between 5 microns to 100 microns. In general, within a preferred range, the smaller the size, the faster dissolution for CBD; however, a smaller size, such as less than 1 micron, can be difficult to produce using dry milling technology.

[0072] In certain instances, the solid dispersion matrix of this invention provides a rapid CBD dissolution using small particles of the solid dispersion matrix.

[0073] In certain instances, the solid dispersion matrix of this invention provides a slow and prolonged CBD dissolution using large particles of the solid dispersion matrix.

[0074] In certain instances, the solid dispersion matrix of this invention provides both a rapid and slow and prolonged CBD dissolution using a combination of small and large particles of the solid dispersion matrix.

[0075] In certain instances, the solid dispersion matrix of this invention provides a near complete dissolution, i.e., no less than 80% of the CBD in the solid dispersion matrix is released.

[0076] In certain instances, the solid dispersion matrix of this invention provides a near complete dissolution, i.e., no less than 80% of the CBD in the solid dispersion matrix is released, within 1 hour. This rapid dissolution is preferred for a dosage form that is intended to provide a quick onset of action of CBD. Such as dosage form is preferred for an application where a quick action is desired, such as for sleep induction.

[0077] In certain instances, the solid dispersion matrix of this invention provides a near complete dissolution, i.e., no less than 80% of the CBD in the solid dispersion matrix is released, within 24 hours. This slow and prolonged dissolution is preferred for a dosage form that is intended to provide a sustained action of CBD, i.e., a sustained release, extended release, timed release, or controlled release formulation for twice a day or once-a-day dosing. Such a dosage form is desired for chronic application, such as pain relief.

[0078] In certain instances, the solid dispersion matrix of this invention provides a greater dissolution rate than the unformulated CBD as measured by a USP dissolution apparatus (Example 4).

[0079] In certain instances, the solid dispersion matrix of this invention provides a greater dissolution completion than the unformulated CBD as measured by a USP dissolution apparatus (Example 4).

[0080] In certain instances, the solid dispersion matrix of this invention provides both greater dissolution rate and completion than the unformulated CBD as measured by a USP dissolution apparatus (Example 4).

[0081] In certain instances, a solid dispersion matrix of this invention provides a CBD dissolution profile with no less than 50% dissolved within 1 hr.

[0082] In certain instances, a solid dispersion matrix of this invention provides a CBD dissolution profile with no less than 70% dissolved within 24 hr.

[0083] In certain instances, a solid dispersion matrix of this invention provides a CBD dissolution profile with no less than 50% dissolved between 1 hr and 24 hr.

[0084] In certain instances, the solid dispersion matrix of this invention provides a greater oral bioavailability than the unformulated CBD.

[0085] In certain instances, the solid dispersion matrix of this invention provides less bitterness than the unformulated CBD.

[0086] In certain instances, the solid dispersion matrix of this invention provides better stability for CBD than the CBD oil.

[0087] In certain instances, a solid dispersion matrix of this invention is made by a hot- melt, HME, or injection molding process.

[0088] In certain instances, the CBD solid dispersion matrix of this invention tastes less bitter than a crystalline CBD or CBD oil. III. Methods of Making

[0089] In certain instances, a solid dispersion matrix of this invention is made by a general process with the following steps:

(1) Melt the polymer by heat

(2) Dissolve or disperse CBD in the molten polymer

(3) Cool to solidify

(4) Mill into powder or granules

(5) Optimally, extrude the molten polymer to an elongated shape (e.g., noodles), cast into a film/sheet, or inject into a mold of certain size and shape (e.g., tablet), before the molten polymer is cooled to solidify.

[0090] In certain instances, the solid dispersion matrix is milled to a smaller size by a dry mill including, but limited to, a mortar and pestle, ball mill, Comill, Fitzmill, and jetmill.

[0091] In certain instances, the solid dispersion matrix is milled to a smaller size by a wet mill including, but limited to, a mortar and pestle, or ball mill in a liquid vehicle in which the solid dispersion matrix is insoluble.

[0092] In certain instances, the solid dispersion matrix of this invention is further mixed with one or more excipients which is a member selected from the group consisting of fillers, disintegrants, adsorbents, lubricants, flowability agents, dyes, stabilizers, antioxidants, wetting agents, preservatives, release agents, flavorings, and/or sweeteners.

[0093] In certain instances, the solid dispersion matrix of this invention may be formulated into an oral dosage form, such as a tablet, a capsule, or a sachet. In certain instances, the oral dosage is a tablet produced by compression.

EXAMPLES

[0094] Example 1 illustrates a hot-melt extrusion (HME) process

[0095] Crystalline CBD, Kollidon VA64 powder (BASF, Lot 05762275L0), polysorbate 80 (Croda, Lot 0001533390), and silica (Fuji Chemical, 90100Z) were manually blended at a ratio of 10/82/7/1 wt% for 10 minutes. The mixture was then fed into a twin-screw hot melt extruder (Thermo Electron Corporation, Minilab CTW5) with a 0.4 mm rod die. The temperature of the extruder was set at 160°C, and the screw speed at 8 rpm. The extrudate was air cooled and solidified to obtain the solid dispersion matrix which is hard, semitransparent, and noodle-like. The noodles were cut into small pellets of about 1 to about 4 mm diameter and about 10 to 30 mm length. This pellet formulation is coded as F-2.

[0096] The CBD-Kollidon VA64 solid dispersion formed as in F-2 was confirmed by thermal analysis (DTA) based on the disappearance of the CBD melting point in the F-2 sample.

[0097] Example 2 illustrates a 24 h release tablet process

[0098] A slow dissolution or 24 h release tablet was formulated in this example. Crystalline CBD, Kollidon VA64 (BASF, Lot 05762275L0), polysorbate 80 (Croda, Lot 0001533390), silica (Fuji Chemical, 90100Z), glyceryl dibehenate (ABITEC, Lot 36798 ) and Carnauba Wax (Strahl & Pitsch, Lot 22470119) were mixed at a weight ratio of

4.2/34.5/2.9/19.1/10.9/7.8. The mixture was hot-melt extruded at 145°C, and the extrudate (a solid dispersion matrix) was co-milled to fine powder. The solid dispersion matrix powder was mixed with microcrystalline cellulose (DFE pharma, Lot 733326), starch (Rain Processing Corp., Lot S0104676) and magnesium stearate (Spectrum chemicals, Lot

2FH0319) at a weight ratio of 88.7/7.8/3/0.5. The mixed powder was compressed into tablets and tablets were sintered at 100°C for 10 minutes to obtain 24 h release tablets (coded as F- 89). For dissolution comparison, a mixture of the same components in the same quantitative composition was directly tableted (without the hot-melt extrusion treatment) and named as F- 89DC.

[0097] Example 3 illustrates the heat stability of CBD

[0099] Crystalline CBD and Kollidon VA64 were mixed at a weight ratio of 10/90. The mixture was placed in a 160°C pre-heated oven to melt for 5 min and air-cooled to form a solid dispersion matrix. The solid dispersion matrix was dissolved and diluted with methanol for HPLC analysis. No new impurity of CBD was observed in the solid dispersion matrix and the CBD assay recovery was 99.1%. The results suggested that the CBD molecule maintains its integrity in the solid dispersion matrix.

[0100] Example 4 illustrates differential thermal analysis (DTA) of a CBD polymer solid dispersion matrix [0101] A physical mixture (coded as F-l) was prepared by simply mixing crystalline CBD powder, Kollidon VA64 powder, polysorbate 80 and silica at a weight ratio of 10/82/7/1 or in the same composition as F-2 in the Example 1. A DTA study was carried out by running crystalline CBD, F-l, and F-2. For each sample, about 10 mg of the sample was placed in an aluminum pan, then heated at 10°C/min from 25°C to 380°C under a dry nitrogen atmosphere.

[0102] DTA was used to determine the presence of CBD in the crystalline state, which has a melting event at about 70°C in the crystalline CBD, F-l, and F-2. The DTA thermogram of crystalline CBD shows a sharp melting endothermic event with a peak temperature at 70.7°C, enthalpy change at -19.5 uV and heat of fusion at about 65.2 uV.s/mg, followed by another endothermic peak at above 300°C which was due to decomposition of CBD (FIG. 1). DTA is able to detect the presence of crystalline CBD by the melting of a crystalline CBD.

[0103] F-l (a physical mixture) exhibited a similar endothermic melting event as the crystalline CBD with a peak temperature at 69.5°C and heat of fusion at about 78.2 uV.s/mg (FIG. 2). In contrast, F-2 showed no melting peak that corresponds to crystalline CBD (FIG. 3). Both F-l and F-2 showed a thermal decomposition event at temperature above 300°C.

[0104] The absence of sharp melting endotherms in the solid dispersion matrix in F-2 suggests that CBD was molecularly dispersed in the polymer matrix and has lost its crystallinity. The DTA analysis also confirmed that the solid dispersion matrix formed in F-2 is amorphous.

[0104] Example 5 illustrates X-ray powder diffraction (XRPD) of CBD polymer formulations

[0105] XRPD was used to determine the crystalline state of F-89 and F-89DC as prepared in Example 2. An X-ray powder diffraction (Rigaku Smartlab) was used for this study, with a copper anode at 40 kV and 44 mA, parallel beam Goebel mirror, 0.2 mm exit slit, LynxEye Position Sensitive Detector with 3° opening (Lynxiris at 6.5 mm) and sample rotation at 15 rpm . Each sample was scanned from 5 to 40° 29 with a step size of 0.02° 29 and a counting time of 0.2 s per step.

[0106] As shown in FIG. 4, the diffractogram of F-89DC showed distinct peaks at 9.8, 12.3, 17.02, 16.6, 17.4 29, suggesting that crystalline CBD retains its crystallinity in the physical mixture of F-89DC. In contrast, no distinct intensity peaks were observed in the diffractograms of F-89 formulation. The absence of CBD intensity peaks indicates F-89 is amorphous and does not contain crystalline CBD.

[0107] Example 6 illustrates In Vitro Dissolution of CBD polymer formulations

[0108] CBD dissolution was measured by USP apparatus 1 (Vankel, VK7000), 5 mg of crystalline CBD powder and F-l formulation (comprised 5 mg of CBD) into 1 liter of DI water at 37 ± 0.5°C with 100 rpm basket rotation rate. At 1, 2, 8, 18 and 24 hours predetermined time intervals, 1 mL of sample was withdrawn through a 35 pm filter (LabECX, product # SF-17-4010) for HPLC assay analysis.

[0109] The dissolution profiles of crystalline CDB and F-2 are shown in FIG. 5.

Crystalline CBD powder showed essentially no dissolution in water within 2 hours whereas F-2 provided nearly 100% dissolution within 60 minutes. This result is in agreement with what was observed visually. When a small amount of F-l powder was dropped into water, it rapidly dissolved and formed a clear solution. The dissolution tests confirmed that CBD in the F-2 solid dispersion matrix formulation can provide a rapid (or immediate release) and complete CBD dissolution in water.

[0109] In vitro dissolution of F-89 and F89DC tablets was carried out in 1 L water containing 0.5% sodium lauryl sulfate for 24 h at 37 ± 0.5°C using USP apparatus 1 with 100 rpm basket rotation rate. At each set time point of 0.5, 2, 8, 18 and 24 hours, 1 mL of sample was collected into a HPLC vial through a 35 pm filter (LabECX, product # SF-17-4010) for HPLC assay analysis. The dissolution profiles in FIG. 6 depicted a slow and complete CBD dissolution within 24 hours from F-89, whereas F-89DC had only about 20% dissolution within 24 hours. This example demonstrates that a solid formulation containing a CBD solid dispersion matrix can provide slow and complete dissolution or sustained release of CBD in water.

[0110] It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those knowledgeable in the field upon reading the above description. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references cited in this application, including patent applications, patents, and PCT publications, are incorporated herein by reference for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A solid dispersion matrix formulation, comprising CBD and a polymer selected from the group consisting of polyvinylpyrrolidone (PVP) and poly (vinylpyrrolidone-vinyl acetate) copolymer, and mixtures thereof, and wherein CBD is noncrystalline and uniformly dispersed in the matrix.

2. The formulation of claim 1, wherein the CBD represents between about 1% and about 50% wt of the total weight of the formulation.

3. The formulation of claim 1, wherein the weight ratio of CBD to the polymer is 0.1 :10 to 1 : 1.

4. The formulation of claim 1, the solid dispersion matrix provides faster and more complete dissolution of CBD than an unformulated crystalline CBD in water.

5. The formulation of claim 1, the solid dispersion matrix provides no less than 80% CBD release within 1 to 24 hr in water.

6. The formulation of claim 1, the solid dispersion matrix is in a form of powder, granule, noodle, film, capsule, or tablet.

7. The formulation of claim 1, the solid dispersion matrix is in a powder form with particle size between 1 to about 3000 or 1 to about 2000 micron.

8. The formulation of claim 1, the solid dispersion matrix is blended with other excipients for an oral dosage form.

9. The formulation of claim 1, the solid dispersion matrix tastes less bitter than unformulated CBD.

10. The formulation of claim 1, the solid dispersion matrix provides greater oral bioavailability than unformulated CBD.

11. The formulation of any one of claims 1-10, wherein the solid dispersion matrix is made by a hot-melt, hot-melt extrusion, hot-melt casting or hot-melt injection molding process.

12. The formulation of any one of claims 1-10, wherein the solid dispersion matrix CBD is more bioavailable than a simple physical blend consisting of the same amounts of CBD and polymer.

13. The formulation of any one of claims 1-12, wherein the formulation further comprises one or more excipients which is a member selected from the group consisting of fillers, disintegrants, adsorbents, lubricants, flowability agents, dyes, stabilizers, antioxidants, wetting agents, preservatives, release agents, flavorings and sweeteners.

14. An oral dosage form as claimed in any one of claims 1-13, wherein the oral dosage is a tablet produced by compression.

15. A method for making a solid dispersion matrix formulation, the method comprising:

(1) Melt the polymer by heat;

(2) Dissolve or disperse CBD in the molten polymer;

(3) Cool to solidify;

(4) Mill into powder or granules; and

(5) Optimally, extrude the molten polymer to an elongated shape (e.g., noodles), cast into a film/sheet or inject into a mold of certain size and shape (e.g., tablet), before the molten polymer is cooled to solidify.