WO2022122904A1

WO2022122904A1 - A delayed-release capsule of cannabidiol

Info

Publication number: WO2022122904A1
Application number: PCT/EP2021/084970
Authority: WO
Inventors: Caroline GLYNN
Original assignee: Chanelle Mccoy Cbd Limited
Priority date: 2020-12-09
Filing date: 2021-12-09
Publication date: 2022-06-16

Abstract

A delayed-release capsule comprising a capsule shell comprising a combination of microcrystalline cellulose, stearic acid, and silicon dioxide, wherein the capsule shell encapsulates or is filled cannabidiol and the delayed-release capsule is chosen from a soft capsule and a hard capsule.

Description

Title

A delayed-release capsule of cannabidiol

Field of the Invention

The present invention generally relates to the field of pharmaceutical science, and more particularly to delayed-release capsule of cannabidiol.

Background to the Invention

Cannabidiol (CBD), chemically 2-[1 R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5- pentyl-1 ,3-benzenediol or 2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5- pentylbenzene-1 ,3-diol, has the following structure (Formula (I)):

CBD is a non-psychoactive cannabinoid which preferentially binds to the type 2 cannabinoid receptor (CBR2) and has been shown to have analgesic, anticonvulsive, antiemetic, anxiolytic, anti-oxidant, anti-psychotic properties, as well as utility as a muscle relaxant.

An orally administered liquid containing Cannabidiol has received orphan drug status in the United States for the treatment of Dravet Syndrome (a form of epilepsy), under the brand name Epidolex®. Cannabidiol is also an active component of Sativex®, which is an aerosolized mist for an oral administration containing a near 1 :1 ratio of Cannabidiol and THC. Cannabidiol has been suggest as an agent for the treatment of epilepsy in U.S. Patent No. 9,125,859, for treating tumors associated with Tuberous Sclerosis Complex (TSC) in GB Patent No. 2564383, and for treating degenerative skeletal muscle disease in EU Patent No. 3206681. Cannabidiol is currently ongoing various clinical trials.

W02008/033024 broadly describes sublingual, buccal or oral administration of waterinsoluble active substances including Cannabidiol in Example 1.

WO2012/033478 describes an oral dosage form of cannabinoids, among which CBD, in a selfemulsifying system operable to avoid hepatic first pass metabolism. US Patent No. 10,245,237 describes a compressed tablet for peroral delivery of the cannabinoid CBD. delayed-release Oral bioavailability of CBD is widely known to be low, indicating that it is not absorbed to any notable extent following ingestion, with the bioavailability of CBD reported to be between 6% and 19%. In addition, when CBD is exposed to an acidic environment, CBD degrades to A9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids.

In one study (Martin Santos etal., Curr Pharm Des. 2012;18(32):4966-79), after healthy adults consumed a single oral dose of 600 mg CBD (99.9% purity), mean whole blood levels of CBD at 1-, 2- and 3-hours post-administration were 0.36, 1.62 and 3.4 ng/mL, respectively, demonstrating the low systemic availability of CBD. Following a systematic literature search to identify articles reporting on the pharmacokinetics of CBD in humans, Millar et al. (Front Pharmacol. 2018 Nov 26;9:1365, pp. 1-13)) concluded that peak plasma concentrations of CBD and area under the curve are dose-dependent and show minimal accumulation.

Poor bioavailability, which is dependent on these factors, generally leads to insufficient therapeutic efficacy and is more likely to produce high inter-individual variability in pharmacokinetic (PK) parameters.

It is an object of the subject application to overcome at least one of the above-mentioned problems.

Summary of the Invention

The invention provides a novel formulation that delays the immediate release of CBD in the stomach acids versus standard CBD capsules. By delaying the immediate release of CBD, the capsules of the claimed invention will protect CBD against the rapid breakdown of the CBD upon exposure of the gastrointestinal tract acid and will aid in reducing other psychoactive cannabinoids and or degradants to be formed in comparison to standard CBD capsules. The application formulation uses pH neutral excipients.

In one aspect, the delayed-release capsule of the present invention is composed of (a) a delayed-release capsule shell, and (b) a pharmaceutical composition comprising micronized cannabidiol, microcrystalline cellulose, stearic acid magnesium and/or a salt thereof, and silicon dioxide, encapsulated in the capsule shell. The weight of the delayed-release capsule preferably is within the range of 200-250mg.

The amount of cannabidiol contained in the delayed-release capsules preferably lies within the range 10-25mg.

The stearic acid salt is selected from magnesium stearate, sodium stearyl fumarate, and the like. Other suitable lubricants would be known to the person skilled in the art. It should be noted that the stearic acid and its salt can be used in combination in the delayed-release capsule of the claimed invention.

In a preferred embodiment, the particle size distribution of micronized cannabidiol is such that D50 is in range of about 40pm to about 48pm.

In another embodiment, the particle size distribution of micronized cannabidiol is such that D90 is in range of about 116pm to about 134pm.

The total amount of microcrystalline cellulose present in the delayed-release capsule may vary from about 62% to about 67% by weight of the total weight of the capsule.

In one aspect, the weight ratio of cannabidiol to MCC (microcrystalline cellulose) is within the range of 1 :15 - 1 :6, most preferably 1 :14.7-1 :6.5.

The total amount of stearic acid and/or a salt thereof present in the delayed-release capsule may vary from about 0.2% to about 1% by weight of the total weight of the capsule. The stearic acid salt is selected from magnesium stearate, sodium stearyl fumarate, and the like. Other suitable lubricants would be known to the person skilled in the art.

The total amount of silicon dioxide present in the delayed-release capsule may vary from about 0.1 % to about 0.5% by weight of the total weight of the capsule.

In one aspect, the present invention provides for a delayed-release capsule of cannabidiol that includes micronized cannabidiol having a particle size distribution D50 in a range of about 40pm to about 48pm and D90 in a range of about 116pm to about 134pm.

In one aspect, the present invention provides for a delayed-release capsule of cannabidiol that includes micronized cannabidiol, microcrystalline cellulose, stearic acid and/or a salt thereof, and silicon dioxide. The weight ratio of cannabidiol to microcrystalline cellulose is in a range of 1 :6.5 to 1 :14.7. The stearic acid salt is selected from magnesium stearate, sodium stearyl fumarate, and the like. Other suitable lubricants would be known to the person skilled in the art.

In one aspect, the present invention provides for a delayed-release capsule shell encapsulating a pharmaceutical composition comprising (i) about 10.3mg of micronized cannabidiol; (ii) about 146.7mg of microcrystalline cellulose, (iii) about 2mg of stearic acid and/or a salt thereof; and (iv) about 1 mg of silicon dioxide. The stearic acid salt is selected from magnesium stearate, sodium stearyl fumarate, and the like.

In one aspect, the present invention provides for a delayed-release capsule shell encapsulating a pharmaceutical composition comprising (i) about 20.6mg of micronized cannabidiol; (ii) about 138.631 mg of microcrystalline cellulose, (iii) about 0.5mg of stearic acid and/or a salt thereof; and (iv) about 0.25mg of silicon dioxide.

The stearic acid salt is selected from magnesium stearate, sodium stearyl fumarate, and the like. It should be noted that the stearic acid and its salt can be used in combination in the delayed-release capsule of the claimed invention.

In one aspect, the present invention provides for a method of delayed-release of cannabidiol, the method including: (a) providing a delayed-release capsule shell, and (b) encapsulating a pharmaceutical composition comprising micronized cannabidiol in the capsule shell.

In one aspect, the capsule is selected from a sustained release capsule, a controlled release capsule, and a g astro resista nt capsule.

In one aspect, the delayed-release capsule is chosen from a soft capsule and a hard capsule.

In one aspect, there is provided a method for manufacturing the delayed-release capsule of any one of the preceding claims, the method comprising the steps of: adding materials to a transfer hopper to form a mixture; sieving the mixture through a 30-mesh screen; blending the sieved mixture in a blender; and encapsulating the blended mixture in a capsule shell.

In one aspect, the materials are micronized cannabidiol, microcrystalline cellulose, stearic acid and/or a salt thereof, and silicon dioxide. Preferably, the silicon dioxide is sieved through a 60 mesh screen prior to adding to the blender. In one aspect, half the amount of microcrystalline cellulose is sieved through a 30 mesh screen and added to the blender.

In one aspect, the sieved mixture is blended for 20 minutes and the remaining amount of microcrystalline cellulose is added to the blended mixture.

In one aspect, the capsule shell comprises hypromellose, gellan gum, and a colourant.

Typically, the silicon dioxide is sieved through a 60 mesh screen and added to a blender. Stearic acid/ magnesium stearate is sieved through a 30 mesh screen and added in the blender. Half the amount of microcrystalline cellulose is sieved through a 30 mesh screen and added to the blender. Micronized cannabidiol is sieved through a 30 mesh screen and added to the blender. The mixture is blended for 20 minutes and the remaining amount of microcrystalline cellulose is added to the blended powder. The blended powder is filled in a delayed-release capsule shell through encapsulators, also referred to as capsule fillers, are machines used for industrial and pharmaceutical purposes to fill empty soft or hard gelatin capsules. This process of filling empty capsules with substances is referred to as encapsulation.

Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.

Definitions

The present invention may be understood more readily by reference to the following detailed description. It is to be understood that this invention is not limited to the specific products, methods, conditions, or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of any claimed invention. Similarly, unless otherwise stated, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the invention herein is not be constrained by the correctness or incorrectness of any such suggested mechanism or more of action or reason for improvement. Throughout this text, it is recognized that the descriptions refer both to the features and methods of making and using the compositions described herein.

In the present disclosure the singular forms “a”, “an” and “the” include the plural reference, and references to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to "a material" is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

When a value is expressed as an approximation by use of the descriptor “about” it will be understood that the particular value forms another embodiment. In general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extend of the word “about”. In other cases, the gradations used in a series of values may be used to determine the intended range available to the term "about" for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range. The term "about" as used herein means ± approximately 10% of the indicated value.

It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising cannabidiol, and inactive ingredients. Such pharmaceutical compositions are synonymous with “formulations” and “dosage form”. Pharmaceutical composition of the invention include, but is not limited to, pellets, granules, beads, minitabs, spherules, beadlets, microcapsules, millispheres, microspheres and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a therapeutic, and a pharmaceutically acceptable carrier. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.

In the specification, the term “therapeutically effective amount” should be understood to mean an amount of the active required to illicit a therapeutic response in the individual taking the active.

The term “delayed-release (DR)”, insofar as it relates to the capsules of the claimed invention, refers to any type of delayed-release of cannabidiol from a composition of the invention after its administration that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject. A person skilled in the art knows how delayed-release differs from the release of plain, regular, or non-delayed-release (for example, controlled release, immediate release) capsules. DR capsules are capsules that are designed to release the active ingredient(s) later after taking it, which can help control where it's released in the body (e.g., small intestines). This is usually done to prevent the active from being broken down too early or lessen potential side effects.

A "delayed-release dosage form" is a modified-release dosage form showing a release of the active substance(s) (i.e., at least one agent) which is delayed. In a delayed release dosage form, the place or time of the release is controlled. Delayed-release dosage forms include gastro-resistant preparations.

A "gastro-resistant capsule" is a delayed-release capsule that is intended to resist the gastric fluid and to release the at least one agent in the intestinal fluid.

A delayed release capsule releases the content at a later time (relative to a conventional or immediate release dosage form), while a prolonged release dosage form releases the content at a slower rate. However, combinations of both delayed release dosage forms and prolonged release dosage forms can exist. In one aspect, the delayed-release capsule disclosed herein is a microcapsule. In one aspect, the delayed-release capsule is a macrocapsule.

Detailed Description of the Invention

Disclosed herein are capsules for the delayed-release of cannabidiol contained therein. To achieve the delayed or slow release of cannabidiol, the present invention provides a pharmaceutical composition comprising cannabidiol encapsulated in a delayed-release capsule shell.

Materials and Methods

Comparative Dissolution Protocol of delayed-release capsule of claimed invention:

The dissolution protocol used is as described by Chapter 2.9.3 of the European Pharmacopoeia (European Pharmacopoeia 10.0, page 326-333, July 2019). The dissolution test is a key test parameter routinely used for assessing the performance of solid and semisolid dosage forms in both drug development and quality control. The dissolution is used to assure batch-to-batch quality as well as providing process control information as part of the approach to process validation. The test is used to measure the release of an API from its formulation under standardized conditions.

Chapter 2.9.3 of the European Pharmacopoeia describes different methods and apparatuses to determine compliance with the dissolution requirements for solid dosage forms administered orally.

The following apparatuses are described:

• Apparatus 1 (Basket apparatus)

• Apparatus 2 (Paddle apparatus)

• Apparatus 3 (Reciprocating cylinder)

• Apparatus 4 (Flow-through cell)

The dimensions and tolerances of the listed apparatus are specified precisely in each case. The determination of the suitability of the apparatus to perform dissolution testing must include conformance to these parameters. Critical test parameters that have to be monitored periodically during use include volume and temperature of the dissolution medium, rotation speed (Apparatus 1 and 2), dip rate (Apparatus 3), and flow rate of medium (Apparatus 4).

In the subchapters "Procedure" and "Interpretation", the use of the apparatuses for the various release-types for solid dosage forms are described, that is, conventional-release, prolonged- release, and delayed-released forms. In brief, the assembly consists of the following: a vessel, which may be covered, made of glass or other inert, transparent material; a motor; a drive shaft; and a cylindrical basket (stirring element). The vessel is partially immersed in a suitable water-bath of any convenient size or heated by a suitable device such as a heating jacket. The water-bath or heating device permits maintaining the temperature inside the vessel at 37 ± 0.5 °C during the test and keeping the dissolution medium in constant, smooth motion. The apparatus shall mean the use of four standardized apparatus: basket, paddle, reciprocating cylinder, and flow-through cell as described in Chapter 2.9.3 of the European Pharmacopoeia (v. 10.0, 2019). The dissolution evaluations are conducted at between about 25-150 rpm.

The prescribed volume of dissolution medium as described in Chapter 2.9.3 of the European Pharmacopoeia (v. 10.0, 2019) is placed in the vessel, the apparatus is assembled, and the dissolution medium is heated to about 37°C. The thermometer can be removed from the apparatus (if required). One delayed-release capsule of the claimed invention is placed in the apparatus.

For a paddle apparatus, the preparation is placed at the bottom of the vessel before rotation of the blade begins; dosage forms that would otherwise float are kept horizontal at the bottom of the vessel using a suitable device, such as a wire or glass helix, as described in Chapter 2.9.3 of the European Pharmacopoeia (v. 10.0, 2019).

Overall comparative dissolution profiles are conducted for the delayed-release capsules of the claimed invention versus standard CBD capsules, that is CBD enclosed in a conventional capsule and also CBD, which are delayed release capsules, in three media across the physiological pH range; 0.1 N HCI (proposed media), pH 4.5 buffer, and pH 6.8 buffer using about 24 capsules of each. The media shall be prepared in Chapter 2.9.3 of the European Pharmacopoeia (v. 10.0, 2019). Readings are made over a series of time points such as 15 minutes, 30 minutes, 45 minutes and 60 minutes.

The following non-limiting examples are intended to further illustrate certain preferred embodiments of the invention. They are, however not intended to be limiting the scope of the present invention in any way.

Example 1

Preparation of Cannabidiol capsule Table 1 : Components used for the preparation of cannabidiol capsule.

Silicon dioxide is sieved through a 60 mesh screen and added to a blender suitable for use the pharmaceutical industry (such as but not limited to double cone blender, vertical blender etc,). Stearic acid or salt thereof (for example, magnesium stearate) is sieved through a 30 mesh screen and added to the blender. Half of the amount of microcrystalline cellulose is sieved through a 30 mesh screen and added to the blender. Micronized cannabidiol is sieved through a 30 mesh screen and added to the blender. The mixture is blended at speed ranging between 4-18 rpm for 20 minutes and the remaining amount of microcrystalline cellulose is added to the blended powder. The blended powder is filled in a delayed-release capsule shell by encapsulation. This is performed using capsule fillers, which are machines used for industrial and pharmaceutical purposes to fill empty soft or hard gelatin capsules.

Example 2 Preparation of Cannabidiol capsule

Table 2: Components used for the preparation of cannabidiol capsule.

Silicon dioxide is sieved through a 60 mesh screen and added to a blender. Stearic acid and/or a salt thereof (for example, magnesium stearate) is sieved through a 30 mesh screen and added in the blender. Half the amount of microcrystalline cellulose is sieved through a 30 mesh screen and added to the blender. Micronized cannabidiol is sieved through a 30 mesh screen and added to the blender. The mixture is blended for 20 minutes at between about 4- 18 rpm, and the remaining amount of microcrystalline cellulose is added to the blended powder. The blended powder is filled in a delayed-release capsule shell encapsulation. This is performed by capsule fillers, which are machines used for industrial and pharmaceutical purposes to fill empty soft or hard gelatin capsules.

Results and Discussion

The dissolution studies have shown that the formulation of the delayed-release capsules will delay the immediate release of CBD in the stomach acids versus standard CBD capsules. By delaying the immediate release of CBD in the stomach, the delayed-release capsules of the claimed invention will protect the CBD contained therein against exposure of the CBD to the acidic environment of the gastrointestinal tract and stomach acid and will aid in reducing other psychoactive cannabinoids and/or degradants to be formed, such as what happens when a standard CBD capsule are exposed to the same environment.

The efficacy of the delayed-release CBD capsule of the claimed invention is increased when compared to the efficacy of the CBD released from a standard capsule and/or a delayed- release capsule of the art. Moreover, the delayed-release CBD capsule of the claimed invention also limits other psychoactive cannabinoids and/or degradants, principally tetrahydrocannabinol (THC), that may be formed over the physiological pH range when ingested by the user.

In the specification the terms "comprise, comprises, comprised and comprising" or any variation thereof and the terms “include, includes, included and including" or any variation thereof are considered to be totally interchangeable, and they should all be afforded the widest possible interpretation and vice versa.

The invention is not limited to the embodiments hereinbefore described but may be varied in both construction and detail. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present invention contemplates and claims those inventions resulting from the combination of features of the invention cited herein and those of the cited prior art references which complement the features of the present invention. Similarly, it will be appreciated that any described material, feature, or article may be used in combination with any other material, feature, or article, and such combinations are considered within the scope of this invention.

Claims

1. A delayed-release capsule comprising a capsule shell comprising a combination of microcrystalline cellulose, stearic acid or a salt thereof, and silicon dioxide, wherein the capsule shell encapsulates or is filled with cannabidiol.

2. The delayed-release capsule of Claim 1 , wherein the cannabidiol is micronized cannabidiol.

3. The delayed-release capsule of Claim 1 or Claim 2, wherein the weight of the delayed- release capsule preferably is within the range of about 200mg to about 250mg.

4. The delayed-release capsule of any one of Claims 1 to 3, wherein the amount of cannabidiol contained therein is between about 10mg to about 25mg.

5. The delayed-release capsule of any one of the preceding claims, wherein the stearic acid salt is selected from magnesium stearate, sodium stearyl fumarate, and the like.

6. The delayed-release capsule of any one of the preceding claims, wherein the particle size distribution of the micronized cannabidiol has a D50 value in range of about 40pm to about 48pm.

7. The delayed-release capsule of any one of the preceding claims, wherein the particle size distribution of micronized cannabidiol has a D90 value in the range of about 116pm to about 134pm.

8. The delayed-release capsule of any one of the preceding claims, wherein the total amount of microcrystalline cellulose present in the delayed-release capsule is between about 62% to about 67% by weight of the total weight of the capsule.

9. The delayed-release capsule of any one of the preceding claims, wherein the weight ratio of cannabidiol to microcrystalline cellulose is between 1 :15 to 1 :6.

10. The delayed-release capsule of any one of Claim 8 or Claim 9, wherein the weight ratio of cannabidiol to microcrystalline cellulose is between 1 :14.7 to 1 :6.5. The delayed-release capsule of any one of the preceding claims, wherein the total amount of stearic acid and/or a salt thereof present in the delayed-release capsule is between about 0.2% to about 1 % by weight of the total weight of the capsule. The delayed-release capsule of any one of the preceding claims, wherein the total amount of silicon dioxide present in the delayed-release capsule is between about 0.1% to about 0.5% by weight of the total weight of the capsule. A delayed-release capsule comprising a capsule shell comprising a combination of microcrystalline cellulose, stearic acid and/or a salt thereof, and silicon dioxide, and micronized cannabidiol having a particle size distribution D50 in a range of about 40pm to about 48pm and a D90 in a range of about 116pm to about 134pm. The delayed-release capsule of Claim 12, wherein the weight ratio of cannabidiol to microcrystalline cellulose is in a range of 1 :6.5 to 1 :14.7. A delayed-release capsule comprising a capsule shell comprising a combination of about 146.7mg of microcrystalline cellulose, about 2 mg of stearic acid or a salt thereof; and about 1 mg of silicon dioxide, wherein the delayed-release capsule about 10.3 mg of micronized cannabidiol. A delayed-release capsule shell comprising a combination of about 138.631 mg of microcrystalline cellulose, about 0.5mg of stearic acid or a salt thereof; and about 0.25 mg of silicon dioxide, wherein the delayed-release capsule shell encapsulates about 20.6 mg of micronized cannabidiol. The delayed-release capsule of any one of the preceding claims, wherein the capsule is selected from a sustained release capsule, a controlled release capsule, and a g astro resista nt capsule. The delayed-release capsule of any one of the preceding claims, wherein the delayed- release capsule is chosen from a soft capsule and a hard capsule. A method for manufacturing the delayed-release capsule of any one of the preceding claims, the method comprising the steps of: adding materials to a transfer hopper to form a mixture; sieving the mixture through a 30-mesh screen; blending the sieved mixture in a blender; and encapsulating the blended mixture in a capsule shell. The method according to Claim 19, wherein the materials are micronized cannabidiol, microcrystalline cellulose, stearic acid and/or a salt thereof, and silicon dioxide. The method to Claim 20, wherein the silicon dioxide is sieved through a 60 mesh screen prior to adding to the blender. The method of Claim 20 or Claim 21, wherein half the amount of microcrystalline cellulose is sieved through a 30 mesh screen and added to the blender. The method of any one of Claims 20 to 22, wherein the sieved mixture is blended for 20 minutes and the remaining amount of microcrystalline cellulose is added to the blended mixture. The method of any one of Claims 19 to 23, wherein the capsule shell comprises hypromellose, gellan gum, and a colourant.