Compressible Cannabinoid Pharmaceutical Composition

Abstract

A compressible pharmaceutical composition comprising a cannabinoid and at least one excipient is disclosed. The composition may be an intermediate 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, hot-melt extrusion, and melt granulation.

Claims

1. A compressible pharmaceutical composition comprising a 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, and 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 CBD or THC 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, and a ethylene oxide and propylene oxide copolymer.

5. (canceled)

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

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

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

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

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

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

12. (canceled)

13. A process for the preparation of a compressible pharmaceutical composition, comprising the steps of: a. Mixing a dry powdered cannabinoid with magnesium stearate and a binding excipient in a blender for 5-30 minutes to form a uniform mixed blend; b. Slugging the uniformly mixed blend in a tablet press using 7-20 mm punches with 5-30 kN compression pressure to form slugs; c. Breaking the slugs with an oscillating mill equipped with 12-mesh screen; d. Passing the granulation through a 20-mesh screen using an oscillating mill to obtain a 20-mesh granulate; and e. wherein the total weight percent of the cannabinoid is 25-90% w/w of the granulate.

14. The process of claim 13, wherein the cannabinoid is selected from CBD or THC or both.

15. The process of claim 13, wherein the binding excipient selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SiMCC), hydroxypropyl cellulose (HPC), lactose, mannitol, or a starch.

16. (canceled)

17. The process of claim 13, wherein the weight percent of the binder is 19.5% to 50%.

18. The process of claim 13, wherein the amount of magnesium stearate is 0.25% to 2.0% w/w of the composition.

19. The process of claim 13, wherein the amount of magnesium stearate is about 0.5% w/w of the composition.

20. A process for the preparation of a compressible pharmaceutical composition, the process comprising the steps of: a. Mixing 75.00% by weight of dry powdered cannabidiol with 0.50% by weight of Magnesium Stearate and 24.500% by weight of a binding excipient in a twin shell blender for at least 5 minutes; b. Slugging the uniformly mixed blend in a tablet press using 10 mm flat face punches with 20 kN compression pressure; c. Breaking the slugs with an oscillating mill equipped with 12-mesh screen; d. Passing the granulation through a 20-mesh screen using an oscillating mill to obtain a 20-mesh granulate.

21. (canceled)

22. A process for the preparation of a compressible pharmaceutical composition, comprising the steps of: a. Mixing a dry powdered cannabinoid with magnesium stearate and a binding excipient in a blender for 5-30 minutes to form a uniform mixed blend; b. compacting the uniform mixed blend in a roller compacter with 5-30 kN pressure to form a ribbon; c. Breaking the ribbon with an oscillating mill equipped with 20-mesh screen to obtain a 20-mesh granulate; and d. wherein the total weight percent of the cannabinoid is 25-90% w/w of the granulate.

23-27. (canceled)

Description

DETAILED DESCRIPTION

[0098] Disclosed herein is a compressible pharmaceutical composition comprising a cannabinoid and a compressible excipient formed by a dry granulation method, and suitable for compression into tablets. 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. Thus, in an embodiment, the composition is a 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. Compressible excipients include microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SiMCC), hydroxypropyl cellulose (HPC), lactose, mannitol, or a starch. In an embodiment, the composition is 70%-90% by weight of the cannabinoid. 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.

[0099] 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.

[0100] In some embodiments, a matrix-forming agent for hot-melt extrusion may be used. 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.

[0101] In an embodiment, this material is intended to be mixed 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.

[0102] In an embodiment, a very high concentration of cannabinoid is desirable, such as 70% to 90% by weight. 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.

[0103] In the utility of the inventive composition as a 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.

[0104] The cannabinoid may be any pharmaceutically active agent extracted from cannabis plant material, or a chemically related synthetic variant thereof. In an embodiment, the cannabinoid may be cannabidiol, also termed herein CBD, or (−)-trans-Δ.sup.9-tetrahydrocannabinol, referred to herein as THC.

Manufacturing Processes

[0105] In an embodiment, this invention provides a process for manufacturing the compressible pharmaceutical composition.

[0106] 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.

[0107] Slugging Dry Granulation

[0108] 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.

[0109] 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.

[0110] Roller Compaction Dry Granulation

[0111] 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.

[0112] 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.

[0113] Hot-melt Extrusion

[0114] 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.

[0115] 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.

[0116] 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.

[0117] Melt Granulation

[0118] 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%.

[0119] 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.

[0120] The approximately 20 mesh particles of any of these methods may be used in a tablet formulation to produce cannabinoid tablets.

EXAMPLE 1

[0121] This is an example of the slugging method so produce a suitable compressible granulate.

TABLE-US-00001 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. 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.

[0122] This experiment yielded a satisfactory granulate that can be compressed into tablets.

EXAMPLE 2

[0123] 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:

TABLE-US-00003 Press Force 1-20 kN/cm Roller Speed 1-30 rpm Gap 1-6 mm
3. The ribbon is broken up with an oscillating mill equipped with a 20-mesh screen, to give the granulate. This experiment yields a 20 mesh or less granulate that can be compressed into tablets.

EXAMPLE 3

[0124] This example employs hot-melt extrusion to form a dry granulate.

TABLE-US-00004 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  

[0125] 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.

EXAMPLE 4

[0126] This example employs hot-melt extrusion to form a dry granulate of THC.

TABLE-US-00005 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  

[0127] 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. This material can be formulated into pharmaceutical compositions with recreational or medical value.

EXAMPLE 5

[0128] This example employs the melt granulation technique to form a dry granulate of a cannabinoid. This example can be used with THC or CBD, or a combination of the two, or include another cannabinoid.

TABLE-US-00006 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  

[0129] 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. This material can be formulated into compressible pharmaceutical compositions with recreational or medical value.