Compressible Cannabinoid Pharmaceutical Composition

Abstract

A compressible pharmaceutical composition is provided as a bulk product including a cannabinoid and at least one excipient for use as an intermediate in oral formulations of cannabinoid drugs. The composition may be used in the manufacture of compressible dosage forms of cannabinoids such as tablets. The cannabinoid may be CBD or THC. The compressible excipient may be a material such as microcrystalline cellulose or lactose, or a matrix forming polymer such as a polyvinylpyrrolidone-vinyl acetate copolymer; a polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000 copolymer; and an ethylene oxide and propylene oxide copolymer. Also disclosed are dry granulation processes for manufacturing the inventive composition, including slugging, roller compaction, and hot-melt extrusion.

Claims

1. A compressible bulk pharmaceutical composition for use as a pharmaceutical intermediate suitable for further processing into oral dosage forms comprising a substantially pure cannabinoid and at least one excipient wherein the composition is formed without the use of a solvent, wherein the cannabinoid loading comprises 25%-90% w/w of the composition, and wherein the excipient is a compressible pharmaceutical binder, wherein the composition is a dry powder of 20 mesh or smaller particle size.

2. The composition of claim 1 wherein the cannabinoid is selected from cannabidiol or Δ-9-tetrahydrocannabinol or a mixture thereof.

3. The composition of claim 1, wherein the compressible pharmaceutical binder is selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SiMCC), hydroxypropyl cellulose (HPC), lactose, mannitol, or a starch.

4. The composition of claim 1, wherein the compressible pharmaceutical binder is selected from a polyvinylpyrrolidone-vinyl acetate copolymer, a polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol copolymer, or an ethylene oxide and propylene oxide copolymer.

5. (canceled)

6. The composition of claim 1, wherein the cannabinoid loading is 25%-50% w/w.

7. The composition of claim 1, wherein the cannabinoid loading is 40%-60% w/w.

8. The composition of claim 1, wherein the cannabinoid loading is 50%-90% w/w.

9. The composition of claim 1, wherein the cannabinoid loading is 50% w/w.

10. The composition of claim 1, wherein the cannabinoid loading is 75% w/w.

11. The composition of claim 1, wherein the cannabinoid loading is CBD present in 75% w/w of the composition.

12-27. (canceled)

28. The compressible bulk pharmaceutical composition of claim 1, wherein the bulk intermediate is packaged and transported to another location.

Description

DETAILED DESCRIPTION

[0089] Disclosed herein is a compressible bulk pharmaceutical composition comprising a cannabinoid API and a compressible excipient formed by a dry granulation method, and suitable for compression into tablets or other oral formulations of cannabinoids. By the term “dry granulation” it is meant that no solvent is used in the granulation process, such as water, ethanol, or another solvent or solvent blend. The bulk pharmaceutical composition is also termed a “granulate.” Thus, in an embodiment, the composition is a bulk pharmaceutical intermediate suitable for further processing into oral dosage forms, such as immediate release, controlled release formulations or orally dissolving formulations. Cannabinoids include CBD, THC, or synthetic variants that have medical or recreational pharmaceutical value.

[0090] The terms “bulk pharmaceutical composition” or “bulk product” mean that the inventive composition is manufactured and supplied to others as a packaged material, not as a finished dosage form. This is distinguished from any of various manufacturing methods wherein a granulate of a cannabinoid is prepared and optionally blended with other excipients and used to prepare a finished dosage form or a food product.

[0091] Compressible excipients may be a compressible pharmaceutical binder such as microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SiMCC), hydroxypropyl cellulose (HPC), lactose, mannitol, or a starch. In an embodiment, a compressible excipient includes “Soluplus,” a co-polymer of polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000, in a ratio of 57/30/13, available from BASF (https://pharmaceutical.basf.com/en/Drug-Formulation/Hot-melt-extrusion.html, visited Jul. 17, 2019).

[0092] In an embodiment, additional ingredients may be included, such as magnesium stearate. In an embodiment, this material has a particle size of 20 mesh or less.

[0093] The inventive compositions are pharmaceutical intermediates meaning that the invention covers an intermediate product, where such intermediate product is not a final drug product for use as a finished dosage form for consumption by humans or animals. This is also termed herein a “bulk product” or “bulk pharmaceutical composition.” In an embodiment, the bulk products of this invention may be packaged and sold or transported to another location for manufacturing into finished dosage forms, such as tablets or capsules. In an embodiment, the bulk intermediate products of this invention are granulates that may be directly compressible, meaning that the granulate requires no pre-preprocessing before compression into tablets, i.e., it is directly compressible. In an embodiment, the inventive granulate is blended with additional excipients prior to compression into tablets.

[0094] This invention addresses the need in the art to provide a pharmaceutical intermediate as a bulk product of cannabinoid active pharmaceutical ingredients (API's) that can be readily used in the manufacture of tablets, capsules, and other finished pharmaceutical products containing cannabinoid API's.

[0095] Particular advantages of the instant invention compared to conventional formulations are the dry granulation methods, and the high drug loadings that can be achieved relative to prior art methods. High drug loadings are particularly advantageous as intermediate products in order to minimize the quantity of the API needed for the manufacture of final products and to increase the flexibility in final products that can be produced, for example, by manufacturing tablets or capsules with high drug loadings in small sizes. Because of the excellent flow, and precision of dosing obtainable with the inventive bulk product, the bulk product can also be formulated into candies, baked goods, sugar cubes, or other food items either as confections or with another non-sweet flavoring.

[0096] In some embodiments, a matrix-forming agent for hot-melt extrusion may be used to form the inventive granulates. These matrix forming agents include various co-polymers, for example Kollidon® VA 64, a polyvinylpyrrolidone-vinyl acetate copolymer; Soluplus®, a co-polymer of polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000, available from BASF; and Kolliphor® P 188, a poloxamer (BASF). Other Kolliphor grades are available also and are within the scope of this invention. Poloxamers are copolymers of ethylene oxide and propylene oxide. All of these matrix forming agents are compressible and are supplied as free flowing powders.

[0097] The inventive intermediate product may be combinable with other materials that can be formed into tablets by a compression method. For example, the inventive intermediate can be blended with diluents, controlled release agents, fillers, disintegrants, and the like known in the art of tablet formulations. However, tablet manufacturing is known in the art and outside the scope of this invention.

[0098] In an embodiment, a very high concentration of cannabinoid is desirable in the inventive bulk granulates, such as 70% to 90% by weight. This is termed herein “cannabinoid loading.” This type of intermediate (composition) may give maximal flexibility to formulators to blend the inventive intermediate with other materials to achieve a desired effect, for example a controlled-release formulation or a quick-release formulation, such as a sublingual orally dissolving tablet. In an alternative embodiment, the cannabinoid concentration may be lower. A concentration as low as 5% is envisioned by this invention. Thus, an embodiment may have 5% to 30% by weight of cannabinoid, or 30% to 50% by weight of cannabinoid, or 50% to 90% by weight of cannabinoid, wherein any of the embodiments mentioned in this paragraph are made by the dry granulation of this invention.

[0099] In an embodiment, the cannabinoid loading of the bulk product of the instant invention is 25%-90% w/w, or 25%-50% w/w, or 40%-60% w/w, or 50%-90% w/w, or 50% w/w, or 75% w/w, or 85% w/w or 90% w/w.

[0100] In the utility of the inventive composition as a bulk pharmaceutical intermediate, low concentration compositions may also be desirable, allowing tablet manufacturers to minimize additional processing by directly using a low concentration material having e.g., 5-10% w/w of a cannabinoid. For example, it may be possible to compress the inventive composition into a tablet with no additional ingredients, or only 1-2% of additional ingredients, such as a coloring agent, fragrance, artificial sweetener or other flavoring agent. CBD doses are typically in the 1 mg to 10 mg per dose range, so a 100 mg tablet (total tablet weight) made from the inventive mixture having 10% w/w CBD would provide a tablet with a 10 mg dose.

[0101] The cannabinoid may be any pharmaceutically active agent extracted from cannabis plant material, or a chemically related synthetic variant thereof, termed herein a cannabinoid active pharmaceutical ingredient, or API. In an embodiment, the cannabinoid may be cannabidiol, also termed herein CBD, or (−)-trans-Δ.sup.9-tetrahydrocannabinol, referred to herein as THC. In an embodiment, the cannabinoid API is a pure product, not a cocrystal form, a salt, hydrate, or solvate. This is termed herein a “substantially pure cannabinoid.” Pharmacologically active cannabinoids do not have acidic or basic moieties, and generally do not form salts or solvates and typically are stable materials in the pure state and do not require salts, hydrates, solvates, or cocrystals to be storage stable.

[0102] Any of various cannabinoids can be used to manufacture the intermediate product of this inventions. Exemplary cannabinoid API's that may be of value in this invention include: [0103] Δ-9-Tetrahydrocannabinol (also called THC or dronabinol), Chemspider ID 15266 [0104] Δ-9-tetrahydrocannabinolic acid A, Chemspider ID 88974 [0105] Δ-9-tetrahydrocannabinolic acid B [0106] Δ8-Tetrahydrocannabinol, Chemspider ID 553592 [0107] Cannabidiol (CBD), Chemspider ID 454786 [0108] Cannabinol, ChemSpider ID2447 [0109] Cannabichromene, ChemSpider ID 28064 [0110] Cannabigerol, ChemSpider ID 4474921 [0111] Cannabigerol Monomethyl Ether [0112] Cannabicyclol, ChemSpider ID 58828783 [0113] Cannabidivarin, ChemSPider ID 9776426 [0114] Cannabivarin, ChemSpider ID 540898 [0115] Tetrahydrocannabivarin, ChemSpider 84092 [0116] Cannabichromevarin, ChmeSpider ID 4954183 [0117] Cannabigerovarin, ChemSpider ID 32702027 [0118] HU-210, ChemSpider ID 7997318 [0119] JWH-133, ChemSpider ID 5293702 [0120] HU-320, ChemSpider ID 9398378 [0121] Levonantradol, ChemSpider ID 4514867 [0122] Nabilone ChemSpider 36449

[0123] Generally, any of the above API's or other cannabinoid compounds may be used in a pure form in the bulk intermediate compositions of this invention. Thus, the substantially pure cannabinoids of this invention may be, for example, greater than 95% pure, greater than 98% pure, greater than 99.0% pure, greater than 99.7% pure, or greater than 99.9% pure. Several suppliers provide pure cannabinoid API's, including Echo Pharmaceuticals (https://www.echo-pharma.com/), Aphios Corp. (https://aphios.com/products/research-chemicals-apis), and Rhizo Sciences (https://rhizosciences.com/gxp-good-cannabis-practices-2/gmp-good-manufacturing-practice/api-manufacture/).

[0124] Some of these API's are naturally occurring, meaning they are isolated in pure form from plant materials, in particular Cannabis sativa or Cannabis indica plants or related species. Some of the API's on this may be semi-synthetic, meaning they are made with chemical modifications of a naturally occurring cannabinoid. Other cannabinoids on this list may be entirely synthetic, meaning they are made artificially from non-cannabinoid starting materials.

Manufacturing Processes

[0125] In an embodiment, this invention provides a process for manufacturing the compressible intermediate pharmaceutical composition as a bulk dry granulate. By the term “bulk dry granulate” (or bulk product) it is meant that the inventive composition is not a finished dosage form but rather a granulate, i.e., free flowing powdered material, that is packaged for use in another location or sold.

[0126] In an embodiment, the inventive intermediate is formed by a dry granulation method. Several dry granulation methods are known in the art, for example slugging, roller compaction, and hot-melt extrusion. In the slugging and roller compaction methods, two or more ingredients are subjected to a compression force (also termed “compaction”), so the ingredients form an intimate uniformly distributed mixture of the ingredients without the use of a solvent. In the hot-melt extrusion method, ingredients with a meltable polymer are mixed in a hot zone in a machine with an Archimedes screw and extruded and milled to a desired particle size. Thus, hot-melt extrusion does not involve the use of a solvent and can be termed a dry-granulation method. Dry granulation methods do not use a solvent such as water, alcohol, or some other solvent to assist in the uniform blending of ingredients. For this reason, dry granulation may have the advantage of lower costs of not requiring a solvent that must be safely disposed of.

Slugging Dry Granulation

[0127] The slugging dry granulation method employs a tablet press to compact a mixture into crude tablets called “slugs” that are then broken apart to a desired size by milling.

[0128] In a slugging process, a mixture of a cannabinoid such as pure CBD in a solid powdered form is blended in a V-blender with a compressible excipient and any other ingredients, such as a disintegrant or lubricant such as magnesium stearate. The blend is then compressed into tablets on a tablet press. These tablets are not intended for consumption. The tablet press may use any of several available punches, such as a flat face punch, and be anywhere from 7-20 mm along the longest dimension. The compression force is not highly critical at this stage, and may be from about 5-30 KN. The resulting tablets are termed “slugs.” The slugs are then milled and sieved. In an embodiment, there may be sequential milling and sieving steps. The resultant product is a granulate, which may be packaged as a bulk product for further processing into finished dosage forms.

Roller Compaction Dry Granulation

[0129] In an embodiment of this invention, roller compaction may be used to form the granulate of this invention. Roller compaction processes employ a roller compaction machine. Leading manufacturers are Gerteis, Komareck, and others. These devices typically have settings for the gap and roller speed, which determine the compaction force. The method is usually used to produce a ribbon or briquets of the compressed material. Either product may be milled to a desired particle size.

[0130] Roller compaction is a dry-granulation method employing two counter-rotating rollers that compact a mixture forcing a feed between the rollers. Typically, roller compaction employs the following steps: powdered material is conveyed to the compaction area, e.g. with a screw feeder. The powder is compacted between two counter-rotating rollers with applied forces and milling the resulting compact to a desired particle size distribution. Preferably, during roller compaction the powdered material is transported by gravity forces or screws into a gap between two counter rotating rolls. Within the gap the material is densified to a compact by the force transmitted from the rolls. Depending on the surface of the used rolls different types of compacts may be generated (e.g., ribbons, briquettes). Using knurled or smooth surfaces of the rolls a compact band is produced, which is called ribbon. In a second step, the grinding step, the produced compacts may be grinded through a sieve to produce granules. The resultant granulate is a bulk product suitable as a pharmaceutical intermediate in accordance with this invention.

Hot-Melt Extrusion

[0131] In an embodiment, hot-melt extrusion may be used to manufacture the inventive compositions (Rina Chokshi et al., “Hot-Melt Extrusion Technique: A Review,” Iranian J. Pharm, 2004, 3, 3-16). In a hot-melt process (also referred to in the literature as a “melt process”), the active agent is mixed with a matrix-forming polymer that melts at elevated temperature, which typically ranges from about 60° C. to 160° C. The active agent and polymer are fed into a hot-melt extruder which comprises one or two Archimedes screws in a hot zone that mixes the materials and melts the matrix-forming polymer to form a plastic mixture. A barrel section in the extruder houses the screw and is heated to the desired temperature as the screw conveys and mixes the material. A variety of screws with different pitches may be selected to achieve the desired mixing and conveyance. Some extruders have twin screws in the mixing process. At the end of the barrel, the melt is forced by the screw(s) through an orifice that may make a ribbon, rod, or other extruded shape. The extrudate is then cooled and milled to a desired mesh size to provide a granulate according to this invention. The resultant granulate is a bulk product suitable as a pharmaceutical intermediate in accordance with this invention.

[0132] A particular advantage to hot-melt extrusion is that the percentage of active agent (active pharmaceutical ingredient, or API) may be fairly high, with 40-60% of active agent can be used, with about 60-40%% of matrix forming polymer. This gives the kind of concentrated product that is desirable in many embodiments of this invention, that can be used in blends for tableting and other formulations as discussed in this disclosure. Moreover, CBD and THC can easily withstand the elevated temperatures in hot-melt extrusion without degradation. Appropriate temperatures and matrix-forming polymers should be selected to prevent thermal degradation in the hot-melt apparatus.

[0133] Some common matrix-forming polymers that may be useful in this invention include Kollidon® VA 64, a polyvinylpyrrolidone-vinyl acetate copolymer (BASF); Soluplus®, a co-polymer of polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000, available from BASF; and Kolliphor® P 188, a poloxamer (BASF). Other Kolliphor grades are available also and are within the scope of this invention. These materials all act as matrix forming agents and binders and are compressible.

Melt Granulation

[0134] Another process that may be used is melt granulation. See Desai, et al., “Melt granulation: An alternative to traditional granulation techniques,” Indian Drugs. 2013. 50. 5-13; see also T. Listro, https://www.pharmasalmanac.com/articles/twin-screw-melt-granulation-as-a-platform-technology-for-continuous-manufacturing. Melt granulation is a size enlargement process in which the addition of a binder that melts or softens at relatively low temperatures (about 60° C.) is used to achieve agglomeration of solid particles in the formulation. These are lower temperatures than HME, but the equipment (single or twin screw extruders) may be the same. The process utilizes materials that are effective as granulating agents when they are in the softened or molten state. This process is particularly useful for formulations of lipophilic drug products. This technique can produce cannabinoid drug loadings as high as 80-90%.

[0135] In this method, a combination of a dry powdered cannabinoid and a matrix-forming polymer and optionally additional excipients into a hot-melt extrusion machine, wherein the hot zone of the extruder is kept at a temperature of 60-120° C., which is sufficient to soften but not melt the polymer. Under the action of the screw, a granulate is formed that is forced through the orifice of the extruder. The granulate can then be milled to a desired particle size, for example 20 mesh. The resultant granulate is a bulk product suitable as a pharmaceutical intermediate in accordance with this invention. The approximately 20 mesh particles of any of these methods may be used in a tablet formulation to produce cannabinoid tablets.

EXAMPLE 1

[0136] This is an example of the slugging method so produce a suitable compressible granulate.

TABLE-US-00001 Ingredient % w/w g/batch CBD (>98% pure) 75.00 22.50 SiMCC 24.50 7.35 Mg Stearate 0.50 0.15 Total 100.00 30.00
1. CBD, Cellulose and Mg Stearate were blended in a twin shell mixer for 5 minutes.
2. The blend was slugged blend using 10 mm flat face punches with 20 kN pressure.
3. The slugs were milled with an oscillating mill equipped with a 12-mesh screen
4.The granulate was milled further with an oscillating mill and passed through a 20-mesh screen to give a 20-mesh granulate.

[0137] This experiment yielded a satisfactory granulate that was a bulk product suitable for compression into tablets.

EXAMPLE 2

[0138] This example employs a roller-compactor method to make the inventive dry granulate. The following ingredients are used.

TABLE-US-00002 Ingredient % w/w g/batch CBD 75.00 22.50 SiMCC 24.50 7.35 Mg Stearate 0.50 0.15 Total 100.00 30.00
1. Blend CBD, Cellulose and Mg Stearate in Twin shell mixer for 5 minutes.
2. The blend is compressed on a Gerteis Mini-Pactor® pilot scale roller compactor to form a ribbon, using the following parameters:
Press Force 1-20 kN/cm

Roller Speed 1-30 rpm

Gap 1-6 mm

[0139] 3. The ribbon is broken up with an oscillating mill equipped with a 20-mesh screen, to give the granulate.

[0140] This experiment yields a 20 mesh or less granulate that is a bulk product suitable for compression into tablets or other oral dosage forms.

EXAMPLE 3

[0141] This example employs hot-melt extrusion to form a dry granulate.

TABLE-US-00003 Ingredient % w/w g/batch CBD 39.50 11.85 Soluplus ® 60.00 18.00 Mg Stearate 0.50 0.15 Total 100.00 30.00

[0142] Soluplus® is a co-polymer of polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000, in a ratio of 57/30/13, available from BASF (https://pharmaceutical.basf.com/en/Drug-Formulation/Hot-melt-extrusion.html, visited Jul. 17, 2019). Soluplus exhibits both matrix-forming and solubilization properties. This material may be blended with active ingredient (e.g., CBD) and any other excipient such as magnesium stearate. The blended powder is fed through a hot-melt extrusion apparatus at 120° C., at a rate of 1 kg/h, with a 1 kneading block with 5×0.25 D kneading elements at 90°, screw speed 200 rpm, and torque 0.5 Nm. The method produces an extrudate that can be milled to a desired size such as 20 mesh with an oscillating sieve. The resulting granulate is a bulk product suitable for compression into tablets or other oral dosage forms.

EXAMPLE 4

[0143] This example employs hot-melt extrusion to form a dry granulate of THC.

TABLE-US-00004 Ingredient % w/w g/batch THC 60.00 18.00 Soluplus ® 39.50 11.85 Mg Stearate 0.50 0.15 Total 100.00 30.00

[0144] Soluplus may be blended with THC ((−)-trans-Δ.sup.9-tetrahydrocannabinol) as the active ingredient and any other excipient such as magnesium stearate. The blended powder is fed through a hot-melt extrusion apparatus at 120° C., at a rate of 1 kg/h, with a 1 kneading block with 5×0.25 D kneading elements at 90°, screw speed 200 rpm, and torque 0.5 Nm. The method produces an extrudate that can be milled to a desired size such as 20 mesh with an oscillating sieve. The resulting granulate is a bulk product suitable for compression into tablets or other oral dosage forms with recreational or medical value.

EXAMPLE 5

[0145] This example employs the hot-melt granulation technique to form a dry granulate of THC.

TABLE-US-00005 Ingredient % w/w g/batch THC or CBD 89.50 26.85 Soluplus ® 10.00 3.00 Mg Stearate 0.50 0.15 Total 100.00 30.00

[0146] Soluplus may be blended with THC or CBD, or a combination thereof, as the active ingredient and any other excipient such as magnesium stearate. The blended powder is fed through a hot-melt extrusion apparatus at 80° C., at a rate of 1 kg/h, screw speed 100 rpm, and torque 0.5 Nm. The method produces a granulate that can be milled to a desired size such as 20 mesh with an oscillating sieve. The resulting granulate is a bulk product suitable for compression into tablets or other oral dosage forms with recreational or medical value.