Cannabinoid granule composition

Abstract

A pharmaceutical composition for oral administration comprising a plurality of granules provided. The granules comprise a cannabinoid active ingredient component such as THC and / or CBD, a saccharide carrier and an antioxidant, and are characterised by a large sieve diameter. In further aspects, capsules comprising the composition and tablets compressed from the composition are disclosed, as well as methods for preparing the granule composition.

Description

[0001]VXT23P01PC1 GRANULE^COMPOSITION Description BACKGROUND OF THE INVENTION The present disclosure is in the field of compositions for oral administration of cannabinoids. Cannabinoids include several structural classes of compounds found in cannabis plants such as Cannabis^sativa, Cannabis^indica and Cannabis^ruderalis, as well as structurally or functionally related synthetic compounds. A well-known example is the phytocannabinoid tetrahydrocannabinol (THC), which also represents the primary psychoactive compound in cannabis plant material. Cannabidiol (CBD) is another major constituent of cannabis. In total, more than 100 phytocannabinoids have been isolated from cannabis. In general, phytocannabinoids are multi-ring phenolic compounds structurally related to THC. Functionally related synthetic cannabinoids also include compounds based on other chemical structures such as quinolines, arylsulfonamides, eicosanoids and aminoalkylindoles. In recent years, cannabinoids have shown promise as potential therapeutic agents for various medical conditions, but their status in therapy is complex and varies depending on the specific cannabinoid and national legal and regulatory frameworks. In some jurisdictions, THC-based medications are available for treating symptoms associated with chemotherapy (e.g., nausea and vomiting) and appetite stimulation in certain conditions like HIV / AIDS- related wasting syndrome. CBD, a non-psychoactive phytocannabinoid, has also gained significant attention for its potential therapeutic effects. It is commonly used to alleviate pain, reduce inflammation, and treat certain forms of epilepsy, notably Dravet syndrome and Lennox-Gastaut syndrome. In some countries, CBD-based medications have been approved for these specific indications. There is ongoing research to explore the potential therapeutic applications of cannabinoids for a wide range of conditions, such as chronic pain, multiple sclerosis, anxiety disorders, and post-traumatic stress disorder (PTSD). Clinical trials are being conducted to gather evidence on the safety and efficacy of cannabinoid-based therapies. Cannabinoids may be used in various forms. Some authors suggest differentiating between medical cannabis, by which they mean the whole plant or its extracts used for medical purposes, and on the other hand pharmaceutical cannabinoids, by which they refer to isolated compounds or standardised extracts. Pharmaceutical cannabinoids offer more precise dosing and standardized formulations compared to medical cannabis. Cannabinoids formulated as water-soluble or water-dispersible powders or granules are desirable in that these compositions may be orally administered as such, but also be used as intermediate products which may be used for preparing small batches of single dosage units such as capsules, e.g. upon prescription for an individual patient. However, the technical requirements or target properties are challenging. Not only should the compositions be water-soluble or water-dispersible, they should also show a sufficient chemical and physical stability to enable a commercially viable shelf life. They should be easy to process and handle, and have good flowability. Moreover, their cannabinoid content should be highly uniform such that small batches of individual dosage units such as capsules prepared from such powder or granule compositions precisely contain the nominal cannabinoid dose and also show a high degree of content uniformity. An example of a cannabinoid powder is described in WO 2021 / 022065. The document proposes a water-soluble powder comprising a cannabis extract and a polysaccharide, and methods for making such powders. However, the document does not address certain technical problems and challenges such as that of content uniformity as described above. Further improvements are needed to address such challenges. The present disclosure relates to these problems. One of its objects is to overcome any one of the drawbacks or disadvantages of the state of the art and to provide improved cannabinoid compositions. Other problems and objects addressed by the present disclosure will become clear on the basis of the description and the patent claims. SUMMARY OF THE INVENTION In one aspect, the invention provides a pharmaceutical composition for oral administration comprising a plurality of granules comprising (i) 0.5 wt.% to 15 wt.% of a cannabinoid active ingredient component selected from THC, CBD and combinations thereof, (ii) at least 50 wt.% of a carrier composed of one or more sugars and / or sugar alcohols having a molecular weight of less than 400 g / mol, and (iii) from 0.02 wt.% to 0.3 wt.% of an antioxidant selected from ascorbic acid and ascorbyl palmitate; wherein at least 30 wt.% of the granules exhibit a sieve diameter above about 250 µm. The composition may be designed to be orally administered as such, or it may be filled into capsules for oral administration. In a further aspect, pharmaceutical tablets are provided which are prepared by compressing the composition comprising the granules. In a yet further aspect, the invention provides a method for the preparation of the composition comprising the granules. The method includes the steps of (a) providing a measured amount of the carrier in the form of a powder or granules; (b) providing a measured amount of a liquid comprising the cannabinoid active ingredient component and the antioxidant; (c) combining the carrier provided in step (a) and the liquid provided in step (b) such as to form a wetted powder or granulate; and (d) drying the wetted powder or granulate obtained in step (c) until reaching a residual moisture content in the range of 1 wt.% to 5 wt.%. Further aspects of the invention will become clear on the basis of the detailed description, the examples and the claims below. DETAILED DESCRIPTION OF THE INVENTION In a first aspect, the present invention relates to a pharmaceutical composition for oral administration comprising a plurality of granules. The granules are characterised in that they comprise, based on the total weight of the water-free granules, (i) from about 0.5 wt.% to about 15 wt.% of a cannabinoid active ingredient component selected from THC, CBD and combinations thereof; (ii) at least 50 wt.% of a carrier composed of one or more sugars and / or sugar alcohols having a molecular weight of less than about 400 g / mol; and (iii) from 0.02 wt.% to 0.3 wt.% of an antioxidant selected from ascorbic acid and ascorbyl palmitate. Moreover, at least 30 wt.% of the granules exhibit a sieve diameter above about 250 µm. The inventors have found that the pharmaceutical composition as disclosed herein not only shows good stability, but is also unexpectedly advantageous in terms of versatility and processability. For example, the high content uniformity of the active ingredient in the granules and their good flowability enables the accurate volumetric filling into hard capsules or sachets in small batches, even when using simple tools and techniques such as capsule filling trays as often used in pharmacies. Further unexpected effects and advantages will become clear on the basis of the detailed disclosure of the various features potentially associated with the composition. As used herein, a pharmaceutical composition for oral administration is understood as a composition formulated and processed in compliance with generally established practices and regulations for drug products for oral administration. In other words, the composition is not only potentially suitable for oral intake in the sense that it can be ingested, but it is actually adapted to conform with the general requirements for pharmaceutical compositions for oral administration. In this context, oral administration should be interpreted broadly such to include any type of administration by mouth, such as swallowing of the composition as such or with liquid, dissolving or suspending the composition in a liquid medium to prepare a liquid composition for drinking, sprinkling the composition on food such as semisolid food products, intraoral administration by placing the composition into the mouth and allowing it to disintegrate and potentially release the active ingredient into the saliva for buccal, sublingual or gastrointestinal absorption, or swallowing the composition after filling it into a capsule or another vehicle that is adapted for being orally ingested. A granule, in this context, is understood as a solid particle that typically comprises a plurality of agglomerated primary particles that adhere to one another by sufficiently strong bonds that allow the granules to be handled and further processed. The bonds between the small primary particles within a granule may, for example, include various adhesive, cohesive and interfacial forces, solid bridges, attractive forces, or mechanical interlocking of particles with different shapes. A plurality of granules of substantially the same type and composition, for example the granules resulting from a batch manufacture, are also often referred to as a granulate. As mentioned, the granules comprise a cannabinoid active ingredient component selected from THC, CBD and combinations of THC and CBD. As used herein, THC means tetrahydrocannabinol, one of the principal pharmacologically active constituents of cannabis plants. While the name of the compound, THC or tetrahydrocannabinol, strictly speaking, includes various isomers, it is commonly used to refer to the delta-9-THC isomer, also having the chemical name (−)-trans-Δ9-tetrahydrocannabinol or (6aR,10aR)-delta-9- tetrahydrocannabinol, and whose international nonproprietary name is dronabinol. In the context of the present invention, THC or tetrahydrocannabinol should be interpreted as the delta-9-THC isomer, even though other THC isomers may also be present, but at a smaller amount than the delta-9-THC isomer. Preferably, the THC, if present in the composition according to this aspect of the invention, comprises at least about 80 wt.% delta-9-THC isomer, or at least about 90 wt.% delta-9-THC isomer, relative to the weight of the entire THC in the composition. In other embodiments, the THC comprises at least about 95 wt.%, 96 wt.%, 97 wt.%, 98 wt.%, or 99 wt.% delta-9-THC isomer, respectively. CBD, in the context of the present invention, means cannabidiol, and more specifically (-)trans-cannabidiol, chemically also referred to as 2-[(1R,6R)-3-methyl-6-prop-1-en-2-yl-1- cyclohex-2-enyl]-5-pentylbenzo-1,3-diol. CBD is another principal native cannabinoid compound known to have pharmacological activity. In some embodiments, the cannabinoid active ingredient component is THC. In other words, the composition comprises primarily THC as cannabinoid. As the skilled person would know, many if not most commercially available THC grades comprise small amounts of other cannabinoids, in particular if obtained by extraction from a plant material. Accordingly, if THC is selected as the cannabinoid active ingredient component, this does not exclude minor amounts of other cannabinoids, as long as THC is the major cannabinoid compound in the cannabinoid active ingredient component. In some of the preferred embodiments, the cannabinoid active ingredient component comprises not more than about 15 wt.% of other cannabinoids, or not more than about 10 wt.%, 5 wt.%, 4 wt.%, 3 wt.%, or 2 wt.% of other cannabinoids, based on the total weight of cannabinoids in the composition. As mentioned about, the THC may also have a specific isomeric purity. In some further preferred embodiments, accordingly, the cannabinoid active ingredient component comprises at least about 70 wt.% (−)-trans-Δ9-tetrahydrocannabinol, based on total weight of cannabinoids, or at least 80 wt.%, 85 wt.%, 90 wt.%, 95 wt.%, or 97 wt.% (−)-trans-Δ9- tetrahydrocannabinol. Moreover, according to some embodiments, the THC or THC component is the sole active ingredient present in the composition, i.e. the composition does not comprise another pharmacologically active ingredient, whether cannabinoid or not. In this context, THC component means a cannabinoid active ingredient component comprising at least about about 70 wt.% (−)-trans-Δ9-tetrahydrocannabinol, based on the total amount of cannabinoids by weight. In some other embodiments, the cannabinoid active ingredient component is CBD. In other words, the composition comprises primarily CBD as cannabinoid. Again, the commercially available CBD grades may comprise small amounts of other cannabinoids, even though CBD is the major cannabinoid constituent. CBD may be incorporated as an extract or in form of an isolate. Accordingly, if CBD is selected as the cannabinoid active ingredient component, this does not exclude the presence of minor amounts of other cannabinoids, as long as CBD is the major cannabinoid compound in the cannabinoid component. In some of the preferred embodiments, the cannabinoid active ingredient component comprises not more than about 20 wt.% of other cannabinoids, or not more than about 10 wt.%, 5 wt.%, 4 wt.%, 3 wt.%, or 2 wt.% of other cannabinoids, based on the total weight of cannabinoids in the composition. Again, other pharmacologically active ingredients, whether cannabinoid or not, may be absent. According to these embodiments, the CBD or CBD component is the sole active ingredient present in the composition. CBD component means a cannabinoid active ingredient component comprising at least about 80 wt.% of CBD relative to the total amount of cannabinoids by weight present in the composition. In some further embodiments, the cannabinoid active ingredient component comprises THC and CBD in combination. Various weight ratios of THC to CBD are potentially useful, as will be described in more detail below. In general, a combination of THC and CBD in the context of the present disclosure means that both THC and CBD are each present at an amount of at least 2 wt.% relative to the total weight of cannabinoids, and that THC and CBD are the major cannabinoid compounds in the composition and together make up at least about 75 wt.% of the cannabinoids in the composition. In some related embodiments, the combination of THC and CBD constitutes the only active ingredient(s) in the composition. According to some further preferred embodiments relating to compositions whose cannabinoid active ingredient component is a combination of THC and CBD, the weight ratio of THC to CBD is from about 2 : 1 to about 1 : 10. Also in the context of these embodiments, the guidance provided herein-above with respect to the purity of THC and CBD is applicable. In other words, the THC and / or the CBD, especially if obtained from native sources by extraction and / or purification, may be accompanied by small amounts of other cannabinoids or other terpenes. In some related embodiments, the weight ratio of THC to CBD is from about 5 : 1 to about 1 : 20, or from about 2 : 1 to about 1 : 5, or from about 2 : 1 to about 1 : 2, respectively. According to one of the further preferences, the weight ratio of THC to CBD is about 1 : 1. As mentioned, the amount of the cannabinoid active ingredient component in the granules is in the range from about 0.5 wt.% to about 15 wt.%, relative to the total weight of the water- free granules. As the skilled person would understand, the weight of the water-free granules may, for example, be determined by performing a conventional test for the loss on drying, as described in major pharmacopoeias (e.g. Ph. Eur. Section 2.2.32). For example, the loss on drying may be performed in an oven at a temperature of 105 °C. The granules are characterised in that they comprise at least about 50 wt.% of a carrier composed of one or more sugars and / or sugar alcohols having a molecular weight of less than about 400 g / mol. Again, the percentage is relative to the weight of the essentially water- free granules. In this context of pharmaceutical formulations, a carrier should be understood as an excipient or excipient mixture whose main function in the respective composition is that of a diluent, filler, bulking agent or the like. A carrier is different from excipients used in very small amount or for their highly specific functionality, such as surfactants, lubricants, flow regulating agents, colouring agents, artificial sweeteners etc. Sugars and sugar alcohols having a molecular weight of less than about 400 g / mol are typically members of the groups of mono- and disaccharides and the sugar alcohols derived from these. Oligo- and polysaccharides having a molecular weight above about 400 g / mol may of course be present as well, provided that the low molecular weight sugar or sugar alcohol as specified herein is a major component of the composition. Examples of potentially suitable monosaccharide sugars and related sugar alcohols include, without limitation, glucose, mannose, galactose, fructose, ribose, xylose, erythritol, xylitol, mannitol, sorbitol, galactitol, and inositol; potentially suitable disaccharide sugars and related sugar alcohols include, again without limitation, sucrose, lactose, trehalose, maltose, isomalt, maltitol, and lactitol. In some of the preferred embodiments, the carrier is selected from isomalt, maltitol, sucrose, trehalose, mannitol, sorbitol, xylitol, lactose, and any combinations thereof. In further preferred embodiments, the carrier is selected from isomalt, maltitol, sucrose, trehalose, mannitol, sorbitol, xylitol, and any combinations thereof, and in particular from the group of isomalt, sorbitol and mannitol. According to some related embodiments which are also preferred, the carrier comprises isomalt. Optionally, the carrier essentially consists of isomalt, which means that no other excipient whose primary function is that of a carrier is present, at least not in technically significant amounts. Isomalt is a mixture of two sugar alcohols, 1-O-α-D-glucopyranosido-D- mannitol (1,1-GPM, also referred to as GPM) and 6-O-α-D-glucopyranosido-D-sorbitol (1,6- GPS, also referred to as GPS), each of which is a disaccharide and has a molecular weight, or molar mass, of about 344 g / mole. Isomalt is made from sucrose which is first transformed into isomaltulose using the bacterial enzyme isomaltulose synthase. In a second step, the isomaltulose is hydrogenated using a Raney nickel catalyst, which results in the 1 : 1 mixture of 1,1-GPM and 1,6-GPS. While the 1,6-GPS is typically obtained in anhydrous form, the 1,1- GPM may also be obtained in its dihydrated form, or as a mixture of anhydrous and dihydrated 1,1-GPM. Isomalt is also available in grades in which the ratio of GPM to GPS is modified, for example grades with a GPM to GPS ratio of about 1 : 3. These grades may also be used for preparing the compositions disclosed herein. As a side note, the expression "GPM to GPS ratio" may be understood as either weight ratio or molecular ratio, or both, since the molar mass of GPM is the same as that of GPS. In some of the preferred embodiments, the carrier comprises, or essentially consists of, isomalt having a GPM to GPS ratio of about 1 : 3. Such grade of isomalt is particularly useful for some product application in which a fast disintegration of the granules upon administration is desired. It is noted that the aqueous solubility of isomalt having a GPM to GPS ratio of about 1 : 3 is even higher than the already good aqueous solubility of isomalt having a GPM to GPS ratio of about 1 : 1. According to some further embodiments, an isomalt grade is selected which exhibits an aqueous solubility of at least about 30 g / L. In this context, the aqueous solubility should be understood as the solubility in water at a temperature of 20 °C. In related embodiments, the isomalt has an aqueous solubility of at least about 35 g / l, or of at least about 40 g / l, respectively. Moreover, as mentioned, the granules provided according to this aspect of the invention comprise from about 0.02 wt.% to about 0.3 wt.% of an antioxidant selected from ascorbic acid and ascorbyl palmitate, again relative to the total weight of the water-free granules. Ascorbic acid, also known as (5R)-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxyfuran-2(5H)-one, should be understood broadly such as to include the anion ascorbate and the salts of ascorbic acid such as sodium, calcium and potassium ascorbate. Ascorbyl palmitate, also named L- threo-hex-2-enono-1,4-lactone 6-hexadecanoate, is an ester of palmitic acid (providing the acyl function of the ester group) and ascorbic acid (providing the hydroxyl group the forms the ester). Ascorbic acid and its derivatives have been found by the inventors to be very effective antioxidants capable of stabilising the oxidation-prone cannabinoid in the present composition. In some further embodiments, the amount of the antioxidant is from about 0.05 wt.% to about 0.2 wt.%, such as about 0.05±0.02 wt.%, 0.1±0.03 wt.%, 0.15±0.03 wt.%, or 0.2±0.03 wt.%, in particular if ascorbic acid is used. A further key feature of the composition disclosed herein is the particle size distribution of the granules. Specifically, at least about 30 wt.% of the granules have a sieve diameter above 250 µm. The percentage is again based on the total weight of the water-free granules. As is well known to those skilled in the art, the particle sizes and particle size distributions of granule compositions may be characterised by different techniques, instruments and measuring principles. The sieve diameter, as used herein, is obtained by a sieve analysis, i.e. by passing a powder or granule composition through one or more analytical sieves with a specified aperture. For example, if using a sieve with a mesh size or aperture of 250 µm, at least about 30 wt.% of the granules would be retained on the sieve and not more than about 70 wt.% of the granules would pass through the sieve according to this aspect of the present invention. Preferably, simple mechanical sieving is used for performing the sieve analysis, in which the particles pass through sieves based on gravity and preferably vibration, as opposed to air jet-driven sieving. In this context, it is noted that the basis of these weight percentages is the total weight of the granules, which may or may not represent the total weight of the composition. For example, granules prepared to have the features as defined herein may subsequently be diluted with an excipient compound in powder form, which could alter the particle size distribution of the resulting composition, but not that of the granules, such that the resulting composition would also be within the scope of the invention. The inventors have unexpectedly found that, contrary to the guidance provided in the state of the art, such relatively large particle size of the granules is particularly favourable and leads to excellent granule properties, especially flowability, Hausner ratio and content uniformity of the active ingredient(s), as will be described in more detail below. The particle size distribution of the granules may also be characterised by the fraction of granules having a sieve diameter above 125 µm. The inventors have found that, in general, at least half of the granules by weight, i.e. at least 50 wt.% of the granules should have a sieve diameter above 125 µm. Among some of the particularly advantageous embodiments are compositions with granules of which at least about 70 wt.% have a sieve diameter above 125 µm. In some related embodiments, the granules have a particle size distribution which is characterised in that at least 70 wt.% of the granules have a sieve diameter between 125 µm and 500 µm. According to these embodiments, the major part of the particles has rather large particle sizes, and the amount of small particles is rather low, such as below about 20 wt.%, or below about 10 wt.%. In further preferred embodiments, less than about 5 wt.% of the granules have a sieve diameter below 63 µm. It would be clear to a skilled person that these limitations are also combinable with one another, and may be regarded as potentially complementary. For example, the size distribution may be characterised in that at least 70 wt.% of the granules have a sieve diameter between 125 µm and 500 µm and that less than 5 wt.% of the granules have a sieve diameter below 63 µm. In some related embodiments, at least 75 wt.% of the granules have a sieve diameter between 125 µm and 500 µm and that less than 5 wt.% of the granules have a sieve diameter below 63 µm. As described above, one of the preferred carriers according to the present aspect of the invention is isomalt. It should be understood that the particle size distribution characteristics that have been found to be particularly useful are fully applicable to compositions in which the carrier comprises isomalt, or in which the carrier essentially consists of isomalt. For example, compositions are provided herein which contain granules comprising at least about 50 wt.% of a carrier comprising, or essentially consisting of, isomalt, and wherein the at least 70 wt.% of the granules have a sieve diameter between 125 µm and 500 µm and that less than 10 wt.% of the granules have a sieve diameter below 63 µm. Optionally, the grade of isomalt used for preparing such compositions may be selected with the target characteristics of the particle size distribution of the granules already in mind. For example, various grades of agglomerated isomalt which differ in their particle size characteristics are commercially available. In some embodiments, the composition comprises granules incorporating agglomerated isomalt. In some further preferred embodiments, the granules comprise agglomerated isomalt having a GPM to GPS ratio of about 1 : 3. Further preferred is the use of an agglomerated isomalt having a particle size distribution characterised in that at least about 70 wt.% of the agglomerated isomalt particles have a sieve diameter above 125 µm, and / or in that at least 70 wt.% of the agglomerated isomalt particles have a sieve diameter between 125 µm and 500 µm. According to some further preferences, the agglomerated isomalt particles have a median particle size d50 of about 180±50 µm, 180±40 µm, 180±30 µm, or 180±20 µm, respectively. As used herein, the median particle size d50 is the particle size which divides the particle size distribution in two equal groups of particles, the first group having a size below the d50 value and the second group having a size above that value. In this respect, 50% means a percentage by weight if the particle size distribution is obtained by sieve analysis or another method based on the determination of the weight of particle size fractions; whereas it may mean a percentage by number if the particle size distribution is obtained by an analytical method that is based on the determination of numbers of particles having a particular size. If laser diffraction is used for particle size analysis, the d50 value typically refers to a volume-based median value. In some further embodiments, the granules in the composition comprise at least about 75 wt.% of agglomerated isomalt. For example, the granules may comprise from about 75 wt.% to about 99 wt.% of the agglomerated isomalt, wherein the isomalt may have any one or more of the further optional or preferred features described above. In some related embodiments, the granules comprise from about 80 wt.% to about 98 wt.% of the agglomerated isomalt, such as about 80 wt.%, about 85 wt.%, about 90 wt.%, or about 95 wt.% agglomerated isomalt. In this specific context, the expression "about" means ±5 wt.%. In some embodiments, one or more further components, in particular one or more pharmaceutically acceptable excipients or auxiliary agents are incorporated in the granules of the composition. In some alternative embodiments, further components are absent such that the granules essentially consist of the respective cannabinoid active ingredient component, the respective carrier composed of one or more sugars and / or sugar alcohols such as agglomerated isomalt, and the respective antioxidant in amounts specified above. As mentioned, the advantageous properties of the granules and the granule-based composition according to the present disclosure rely at least partially on the physical characteristics, such as parameters relating to the particle size distribution, as already described. Further physical features that enhance the handling properties of the composition, e.g. in the context of dividing of the bulk composition into single dosage units at small-scale, using semi-manual and / or volumetric techniques as are commonly employed for dispensing cannabinoid products, include selected residual moistures and densities. In some embodiments, the residual moisture content of the granules, as measured by determining the loss on drying at a temperature of 105 °C, is selected in the range of below about 6 wt.%, relative to the total weight of the dry granules. In further preferred embodiments, the residual moisture content is not more than about 5 wt.%, such as in the range from about 1 wt.% to about 5 wt.%, such as about 1±0.5 wt.%, about 2±1 wt.%, about 3±1 wt.%, or about 4±1 wt.%. Determining the loss on drying may, for example, be performed by the respective method as described in the European Pharmacopoeia (section 2.2.32) or in another major pharmacopoeia, using an oven and a drying time of at least about 1 hour, such as about 2 hours, or until no further weight change occurs. As is known to the skilled person, alternative methods which are equivalent to the method prescribed by the pharmacopoeias may also be used. Moreover, the granules of the composition may be characterised by a selected density, such as a selected bulk or tap density (or tapped density). As used herein, the bulk density of a powder or granule composition is the ratio of the mass of an untapped sample to its volume, including the contribution of the interparticulate void volume. The bulk density of the granules may be determined, for example, by one of the methods described in the European Pharmacopoeia (section 2.9.34) or by an equivalent method. In some embodiments, the bulk density is in the range from about 0.35 g / ml to about 0.6 g / ml, or in the range from about 0.3 g / ml to about 0.55 g / ml. In some further preferred embodiments, bulk density of the granules is selected in the range from about 0.35 g / ml to about 0.5 g / ml, or in the range from about 0.38 g / ml to about 0.48 g / ml, or in the range from about 0.40 g / ml to about 0.55 g / ml, or in the range from about 0.4 g / ml to about 0.45 g / ml, or in the range from about 0.45 g / ml to about 0.50 g / ml respectively. These rather low bulk densities are also preferred when isomalt is selected as carrier. Accordingly, in some embodiments, the carrier comprises isomalt, and the granules exhibit a bulk density in the range of 0.35 to 0.55 g / ml, or in the range of 0.40 to 0.55 g / ml, such as in the range of 0.40 to 0.50 g / ml. The tap density of the granules may, according to some further preferred embodiments, be selected in the range from about 0.4 g / ml to about 0.8 g / ml. If isomalt is selected as carrier, the tap density of the granules may also, according to further preferred embodiments, be selected in the range from about 0.4 g / ml to about 0.6 g / ml, or in the range from about 0.5 g / ml to about 0.6 g / ml. The tapped (or tap) density, as used herein, is an increased density attained after mechanically tapping a receptacle containing the sample. For example, the tapped density may be determined by mechanically tapping a graduated measuring cylinder or vessel containing the sample. Appropriate methods are described in the major pharmacopoeias, such as the European Pharmacopoeia (section 2.9.34). Again, alternative methods may be used if substantially equivalent. In further preferred embodiments, the tap density of the granules incorporated in the composition may be selected in the range from about 0.44 g / ml to about 0.58 g / ml. In yet further embodiments, the tap density after at least about 500 taps is in the range from about 0.48 g / ml to about 0.58 g / ml, or from about 0.48 g / ml to about 0.56 g / ml, or from about 0.49 g / ml to about 0.55 g / ml, or from about 0.50 g / ml to about 0.54 g / ml, respectively. Also preferred are embodiments in which the granules exhibit a bulk density in the range of 0.35 to 0.6 g / ml and a tap density in the range of 0.40 to 0.80 g / ml. A further parameter that is useful for describing the advantageous behaviour of the granules if the ratio of the tap density to the bulk density, also referred to as the Hausner ratio. It indicates to what extent a powder or granule composition changes the spatial arrangement of its primary particles and may be used as an indicator of flowability. In some preferred embodiments, the granules exhibit a Hausner ratio in the range from about 1.1 to about 1.5. In other embodiments, the granules exhibit a Hausner ratio of not more than 1.4, or not more than 1.3, respectively. In further preferred embodiments, the Hausner ratio is selected in the range from about 1.1 to about 1.45, or from about 1.12 to about 1.4, or from about 1.15 to about 1.35, respectively. In other preferred embodiments, the Hausner ratio is in the range from about 1.15 to about 1.30. The inventors found that the good flowability of the granules is also confirmed when performing other flowability tests, such as methods equivalent to the flowability test described in section 2.9.16 of the European Pharmacopoeia, or to the "Angle of Repose" test or the test for "Flow through an Orifice" as described in United States Pharmacopoeia, section <1174> (Powder Flow). In some further embodiments, the composition comprises granules exhibiting a bulk density in the range of about 0.35 to about 0.5 g / ml, a tap density in the range of about 0.4 to about 0.6 g / ml, and a Hausner ratio in the range of 1.1 to 1.5. It should be understood that also other preferences of the bulk density, the tap density and the Hausner factor as described above are combinable with one another. For example, the granules may be characterised by a bulk density in the range of about 0.4 to about 0.45 g / ml, a tap density in the range of about 0.44 to about 0.58 g / ml, and a Hausner ratio in the range of 1.1 to 1.4. The advantageous properties of the composition in terms of its physical behaviour as reflected, for example, by a good flowability allow the preparation of composition with a high content uniformity with respect to the active ingredient. A high content uniformity with respect to a powder or granule composition is of key importance for achieving a high content uniformity of any single dosage units that may be prepared from the powder or granule composition and thus for providing the correct dose of the active ingredient to an individual user or patient. Again, useful methods for determining content uniformity are provided in pharmacopoeias such as the European Pharmacopoeia. In some of the preferred embodiments, the composition is in the form of a granular powder, and the cannabinoid active ingredient component is uniformly distributed in the granules as characterised by a relative standard deviation of not more than about 10 % for the assay. In this specific context, the assay is the assay of the sole cannabinoid active ingredient or, if more than one active ingredient is present, the assay of at least one cannabinoid active ingredient. In further preferred embodiments, the relative standard deviation of the assay is not more about 8 %, not more than about 6 %, not more than about 5 %, or not more than about 4 %. Also preferred are embodiments in which the relative standard deviation of the assay is not more about 2.5%, 2.0 %, 1.75 %, 1.5 %, 1.25 %, or even 1.0 %, respectively. In this context, the percentage is based on the mean active ingredient content in the composition as determined by the assay based on a plurality of samples from a single batch of the composition. In this context, it is noted that the content uniformity is an important quality parameter not only for the bulk granulate but also for products in single dosage form that comprise the granulate, such as hard capsules. The preferences provided above for the relative standard deviation of the assay apply to both the bulk granulate and the singe dosage units, but are independently selected. In some preferred embodiments, for example, the relative standard deviation of the assay is not more than about 5 % for the bulk granulate and not more than 10 % for the single units comprising the granulate, such as the capsules. In other embodiments, the relative standard deviation is not more than about 4 % for the bulk granulate and not more than about 8 % for single dosage units, or not more than about 2.5 % for the bulk granulate and not more than about 5 % for single dosage units, respectively. As discussed in the context of the carrier material and its particle size distribution parameters, it should be understood that the chemical and physical nature of the sugar or sugar alcohol may have substantial impact on the quality of the granules and of the composition in terms of its physical parameters. Therefore, the options and preferences expressed with respect to the carrier are fully applicable to, and combinable with, the options and preferences as provided for the bulk and tap density and the Hausner ratio of the granules of the composition, the residual moisture content and the uniform distribution of the cannabinoid active ingredient component in the granules. For example, the present disclosure should be understood as also providing a composition according to claim 1 in which the granules comprise at least about 75 wt.% of agglomerated isomalt, in particular of an agglomerated isomalt having a GPM to GPS ratio of about 1 : 3 and an aqueous solubility of at least about 30 g / L, wherein the granules exhibit a bulk density in the range of about 0.35 to about 0.5 g / ml, a tap density in the range of about 0.4 to about 0.6 g / ml, a Hausner ratio in the range of 1.1 to 1.5, a residual moisture content of about 1 wt.% to about 5 wt.%, and wherein the cannabinoid active ingredient component is uniformly distributed in the granules as characterised by a relative standard deviation of 2.5 % or less. Similarly, other preferred features may be combined to further potentially advantageous combinations and embodiments. As already described above, the composition is adapted for any type of oral administration. This includes direct administration of the composition as such, optionally after dispersing the composition in a liquid. It also includes the oral administration of e.g. a single dosage unit comprising, or prepared from, the composition disclosed herein. Non-limiting examples of such dosage units are pharmaceutical tablets prepared by compressing the composition or (two-piece) hard capsules comprising the composition as disclosed above. Such tablets and capsules represent further aspects and embodiments of the invention. It is generally known to a skilled person how tablets or capsules may be obtained from a flowable and / or compressible pharmaceutical powder or granule composition. It is noted that, for this purpose, the composition may incorporate one or more further excipients useful for capsule or tablet manufacture, such as glidants, lubricants, disintegrants, anticaking agents, diluents or the like. Accordingly, the present disclosure provides a hard capsule or a plurality of hard capsules comprising the granulate composition as described above, as well as a pharmaceutical tablet or a plurality of pharmaceutical tablets prepared by compressing such granulate composition. Accordingly, in a further aspect, the invention relates to a method of treating a subject affected with a disease or condition which may be treated or modulated by a cannabinoid active ingredient selected from THC and / or CBD, the method comprising a step of orally administering an amount of a composition as defined herein-above, wherein the amount comprises a single effective dose of the THC and / or CBD. In some related embodiments, the invention relates to the use of the composition as defined herein-above for the manufacture of a medicament for the treatment of a disease or condition may be treated or modulated by a cannabinoid active ingredient selected from THC and / or CBD, wherein the medicament is adapted for oral administration. In this context, the disease or condition which may be treated or modulated by a cannabinoid active ingredient selected from THC and / or CBD according to aspects of the present invention includes, without limitation: - Behavioral disorders, such as social anxiety, generalized anxiety disorder, social phobia, post-traumatic stress disorder (PTSD), autism spectrum disorder, hoarding disorder, anorexia nervosa, obsessive-compulsive disorder; - Sleep related disorders, such as insomnia, sleep disturbance, rapid eye movement sleep behaviour disorder or REM behaviour disorder (RBD), obstructive sleep apneas; - Psychiatric disorders, such as bipolar disorder, attention-deficit / hyperactivity disorder, depressive symptoms, schizophrenia, obsessive-compulsive disorder, trichotillomania (hair-pulling disorder); - Neurological disorders, such as dementia, multiple sclerosis, Tourette syndrome, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, major neurocognitive disorder with aggressive behavior; - Substance related disorders, such as alcohol, opioid, heroin, or tobacco dependency; - Cancer, such as breast cancer, glioblastoma, prostate cancer, prostate adenocarcinoma, colorectal cancer, ovarian cancer, uterine cancer, pancreatic cancer; - Infectious diseases, such as HIV / AIDS, chronic periodontitis; - Inflammatory and immunological disorders, such as neuroinflammatory disease, transplant complication, arthralgia, chronic inflammation, rheumatoid arthritis; - Gynecological disorders, such as menstrual discomfort, endometriosis, pelvic pain, menopausal syndrome; - Pain, such as chronic pain, post surgery pain, diabetic neuropathic pain, back pain, lower back pain, neck pain, hyperalgesia, acute pain, myofascial pain, cancer related pain, temporomandibular disorder, orofacial pain, musculoskeletal pain, migraine, neuropathic pain including corneal neuropathic pain, chemotherapy-induced peripheral neuropathy, diabetic neuropathic pain; - Metabolic disorders, such as glucose metabolism disorders including diabetes mellitus, lipid metabolism disorders, metabolic syndrome, morbid obesity, hypercholesterolemia, hyperglycemia; - Congenital disorders, such as Rett syndrome, sickle cell disease, fragile X syndrome, Prader-Willi syndrome, 22q deletion syndrome; - Epilepsy and epilepsy syndromes such as Lennox Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex; - other diseases such as chronic kidney disease, knee arthritis, temporomandibular disorder, bruxism, spinal cord injury. According to some of the preferred embodiments, the disease or condition is breast cancer, nausea and vomiting, in particular cancer-related nausea and vomiting, sleep disturbance, rem behaviour disorder, attention-deficit / hyperactivity disorder, Alzheimer disease, amyotrophic lateral sclerosis, endometriosis, neuropathic pain, chronic pain, cancer-related pain, fibromyalgia, chemotherapy-induced neuropathic pain, lipid metabolism disorders, morbid obesity, early palliative care including early palliative care in oncology patients, and late palliative care. In a yet further aspect, the present disclosure relates to a method for the preparation of the composition described herein. The method comprises the steps of (a) providing a measured amount of the carrier in the form of a powder or granules; (b) providing a measured amount of a liquid comprising the cannabinoid active ingredient component and the antioxidant; (c) combining the carrier provided in step (a) and the liquid provided in step (b) such as to form a wetted powder or granulate; and (d) drying the wetted powder or granulate obtained in step (c) until reaching a residual moisture content in the range of about 1 wt.% to about 5 wt.%. In this context, and for the avoidance of repetition, it should be understood that all optional and preferred features relating to the composition itself and to its components, including their amounts and their physical properties, are also applicable as optional or preferred features of the method according to this aspect of the invention. Reference is made to the respective disclosure of these features in the context of the description of the composition. Specifically relating to the method steps, the following should be noted. Regarding step (a) which requires providing a measured amount of the carrier in the form of a powder or granules, it should be understood that the powder or granules comprising the carrier may also comprise one or more further constituents, such as an amount of a further pharmaceutical excipient or auxiliary material, such as a taste modifier, a surfactant, a colouring agent or the like. In some alternative embodiments, the powder or granules provided in this step only comprise the carrier, i.e. essentially consist of the carrier. Similarly, with respect to step (b), it should be understood that the liquid may also comprise one or more further constituents beyond the cannabinoid active ingredient component, the antioxidant and a liquid carrier. It should also be understood that providing a liquid comprising the cannabinoid active ingredient component and providing a liquid comprising the antioxidant is also considered fulfilling the requirements of step (b). After all, the liquids even if initially provided in separate form, will subsequently be combined and form a liquid that comprises the cannabinoid active ingredient component and the antioxidant. The liquid may be provided as any type of liquid, for example as a liquid solution, an emulsion, a liquid foam, or a suspension. In some of the preferred embodiments, the liquid represents a liquid solution that comprises the cannabinoid active ingredient component and / or the antioxidant in dissolved form. The liquid further incorporates at least one liquid carrier. The liquid carrier may be understood as a process material which is subsequently removed and does not become a constituent of the final product. Examples of potentially useful liquid carriers include, without limitation, organic solvents such as acetone, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, or any combinations thereof. Some amounts of water may also be present. In order to be able to dissolve the cannabinoid active ingredient component and the antioxidant, the amount of water should preferably be limited. Also preferred are substantially water-free liquids. In some further preferred embodiments, the liquid comprises ethanol, the cannabinoid active ingredient component and the antioxidant. In yet further preferred embodiments, the liquid essentially consists of the cannabinoid active ingredient component and ascorbic acid. Regarding step (c) which requires that the carrier provided in step (a) and the liquid provided in step (b) are combined such as to form a wetted powder or granulate, any commonly known method for preparing a wetted powder from combining a dry powder or granules with a liquid may in principle be used. Optionally, the liquid may be slowly poured over the carrier powder or granules, and the powder or granules may be agitated during and / or after this step. Various types of equipment may be used to perform the step, such as pharmaceutical granulation equipment, which may include a vessel for holding the powder or granules and a stirrer (or kneader, or impeller) for agitation, or granulation equipment based on fluid-bed technology. Either type may be equipped with means for dripping or spraying the liquid onto the powder or granules. In this context, a wetted powder or granulate should be understood as a moist powder or granule mass in which the flowability of the material is substantially reduced due to the presence of the moisture, but in which the amount of liquid is insufficient to generate a dough or to dissolve a substantial fraction of the powder or granulate particles. In some embodiments, the wetted powder or granulate has a liquid content of not more than about 25 wt.%, relative to the total mass of the wetted powder. Also preferred are embodiments according to which the liquid content is not more than about 23 wt.%, such as about 15 to about 23 wt.%, or about 15±3 wt.%, 18±3 wt.%, or 20±3 wt.%, respectively. Moreover, it should be kept in mind that, especially in case a carrier has the preferred particle size distribution characteristics as described above, the primary purpose of step (c) is to load the carrier particles or granules with the active ingredient component and the antioxidant, rather than to agglomerate small primary particles into substantially larger granules as in conventional wet granulation. As used in this context, the expressions "wetted", "moist" and "moisture" should be interpreted broadly such as to include the modulation of the properties of powders and granules by small amounts of any type of liquid, not just water. The drying step (d) provides that the wetted powder or granulate obtained in step (c) is dried until reaching a residual moisture content of not more than about 5 wt.%, or a residual moisture content within the range of 1 wt.% to 5 wt.%. In other words, the drying step removes most or substantially all of the liquid constituent(s) applied to the powder or granules in step (c). Any type of pharmaceutically acceptable drying method or drying equipment may be used for carrying out the drying step. For example, the wetted powder or granulate may be spread on a tray and dried in an oven. If accelerated drying by heat is performed, the drying temperature should be selected with an eye on the solvent used in the granulation liquid. Generally speaking, the initial drying temperature should be above the ambient temperature and below the boiling point of the respective solvent. For example, if ethanol is used, the wetted powder or granulate may be dried at ambient conditions, or at an elevated temperature of e.g. about 40 °C to about 75 °C, or from about 45 °C to about 70 °C. Alternatively, or in addition to the initial drying at elevated temperature, drying may simply be performed at ambient conditions over an extended period of time. In the case that fluid-bed equipment and techniques are used for performing step (c), it is convenient to perform step (d) at least partially simultaneously to step (c). The drying process would then be controlled by the temperature of the air stream used for fluidising the substrate powder or granules in the equipment. While the liquid is sprayed onto the powder or granules, the air stream would already start to cause the evaporation of the liquid carrier or solvent. These and other process variants are generally known to those skilled in the art. Moreover, a method for the preparation of the plurality of hard capsules comprising a granulate as described above is provided. The method comprises steps (a) to (d) as already described, followed by a step (e) of filling the dried granulate obtained in step (d) into two- piece capsules (i.e. capsule shells). The hard capsules may be filled using any appropriate capsule filling device or apparatus. In some preferred embodiments, the capsules are filled volumetrically. Also preferred are embodiments in which the hard capsules are filled in small batches, such as not more than about 100 capsules per batch, using a manual or semi-manual capsule filling device as commonly available in a pharmacy laboratory. It is noted that the use of such devices and methods benefits significantly from the advantageous granulate properties as described above, in particular its highly reproducible and consistent density. EXAMPLES Example 1: Preparation of granulates Various liquid solutions of THC, CBD, and ascorbic acid or ascorbyl palmitate in ethanol (96 % V / V) were prepared. The THC component was incorporated as a dried cannabis extract whose THC content was determined as delta-9-THC, whereas CBD was used as purified CBD isolate. The compositions of the liquid solutions are provided in Table 1. In addition, two control formulations composed like batches 1.2.1 and 2.2.1 but without ascorbic acid or ascorbyl palmitate were prepared. The weight percentages provided in Table 1 are based on the total weight of the constituents listed in the table, without considering the small amounts of cannabis extract constituents that were also present as THC was incorporated in the form of such extract. Table 1 Amounts [wt.%] 1.2.1 1.2.2 1.3.1 1.3.2 2.2.1 2.2.2 2.3.1 2.3.2 THC 9.53 9.46 9.55 9.48 18.29 18.23 18.27 18.23 CBD 9.51 9.42 9.53 9.54 18.28 18.26 18.30 18.30 Ascorbic acid 0.20 0.37 - - 0.19 0.37 - - Ascorbyl palmitate - - 0.17 0.39 - - 0.17 0.39 Ethanol 96% V / V 80.76 80.74 80.74 80.59 63.24 63.14 63.25 63.09 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Aliquots of each of the liquid solutions were subsequently combined with measured amounts of an agglomerated isomalt having a GPM to GPS ratio of about 1 : 3, an aqueous solubility of about 42 g / L and a particle size distribution determined by sieve analysis as provided in Table 2. The amounts of the isomalt and of the aliquots of the liquid solutions were measured to result in granulates having the compositions as provided in Table 3. The weight percentages provided in Table 3 are based on the total weight of the respective granulates. In detail, the isomalt was placed in the mixing vessel (capacity 7 L) of a small-scale electric mixing machine (Kenwood Chef Excel), equipped with a stainless steel mixer tool (K Beater). At very low mixing speed, the liquid solution was slowly added. Mixing was continued for another 10 min. The wetted granulate was spread out on a drying tray and dried at ambient conditions for about 2 hours. Coarse agglomerates were then deagglomerated by passing the granules through a sieve with a 500 µm aperture. Subsequently, the granules were filled into glass bottles with air-tight closures and stored at 25 °C and 65% RH, or at 40 °C and 75% RH, respectively. Table 2 Particle size fraction [µm] [wt.%] <45 2.2 45-63 4.9 63-125 17.1 125-250 39.2 250-500 35.5 500-1000 0.0 1000-2000 0.71 >2000 0.61 Table 3 Amounts 1.2.1 1.2.2 1.3.1 1.3.2 2.2.1 2.2.2 2.3.1 2.3.2 [wt.%] THC 2.50 2.50 2.52 2.48 5.00 5.00 5.00 5.00 CBD 2.49 2.49 2.51 2.50 4.99 5.00 5.01 5.02 Ascorbic acid 0.05 0.10 - - 0.05 0.10 - - Ascorbyl - - 0.05 0.10 - - 0.05 0.11 palmitate Isomalt 93.61 93.56 93.57 93.57 87.26 87.20 87.24 87.18 Example 2: Characterisation of the granulates of Example 1 The particle size distributions of the batches were obtained by sieve analysis. Moreover, the loss on drying, the bulk densities and the tap densities were obtained by methods equivalent to the pharmacopoeial method, and the Hausner ratios were calculated from the densities. Table 4 shows the values that were obtained by the sieve analyses, and Table 5 shows the loss on drying, the bulk densities, the tap densities, and the Hausner ratios. Table 4 [µm] / [wt.%] 1.2.1 1.2.2 1.3.1 1.3.2 2.2.1 2.2.2 2.3.1 2.3.2 <45 0.10 0.17 0.48 0.28 0.10 0.00 1.09 0.28 45-63 2.76 2.24 1.94 1.14 0.00 0.00 0.00 0.00 63-125 15.26 23.13 13.37 16.58 7.93 4.17 8.48 7.25 125-250 39.37 42.39 37.31 41.90 52.03 39.62 44.94 37.85 250-500 41.14 30.87 45.25 38.48 38.78 49.26 43.76 46.05 500-1000 0.79 0.52 0.78 0.76 0.39 4.00 1.28 6.50 1000-2000 0.59 0.52 0.58 0.38 0.48 2.17 0.18 2.07 >2000 0.00 0.17 0.29 0.38 0.87 0.96 0.64 0.38 Table 5 Parameter 1.2.1 1.2.2 1.3.1 1.3.2 2.2.1 2.2.2 2.3.1 2.3.2 Bulk density [g / ml] 0.432 0.414 0.432 0.425 0.413 0.427 0.429 0.441 Tap density [g / ml] 0.526 0.506 0.518 0.505 0.524 0.531 0.513 0.530 Hausner ratio 1.22 1.22 1.19 1.19 1.27 1.24 1.20 1.20 Loss on drying 2.50 2.53 2.52 2.68 2.54 2.45 2.62 2.60 [wt.%] The stability of the granulates packed into glass bottles of about 30 ml closed by a PP screw cap was determined by taking samples and analysing them by HPLC for their THC (delta-9- THC) and CBD content at the beginning of storage (t0), and after 1, 2 and 3 months of storage at 25 °C / 65% RH and 40 °C / 75% RH, respectively. The initial THC and CBD content at t0 was set as 100%. The main parameters of the analytical method are provided in Table 9. The results are presented in Table 6 (for THC) and Table 7 (for CBD). The results indicate the feasibility of a shelf life of at least 6 months under storage conditions of 25 °C and 65% RH for all granule compositions, as may be concluded from the trend of data at 25°C. They also show a trend indicating a superiority of the compositions comprising ascorbic acid over those that contain ascorbyl palmitate, which was surprising in view of the fact that ascorbyl palmitate is more prominently recommended and typically used or preferred as antioxidant especially for THC in the prior art. Moreover, the results indicate a superiority of compositions comprising 0.1 wt.% of the antioxidant over those that contain 0.05 wt.% antioxidant. At the same time, both antioxidant levels were substantially superior to the two control batches without antioxidant, whose THC content was below 80% after 3 months of storage at 40° C. Table 6 THC Assay [%] 1.2.1 1.2.2 1.3.1 1.3.2 2.2.1 2.2.2 2.3.1 2.3.2 Storage at 25 °C 1 mo 98.11 100.04 100.25 99.75 99.87 101.57 100.09 101.82 2 mo 98.37 100.31 97.83 99.49 99.85 101.76 99.98 101.15 3 mo 100.55 99.33 98.75 98.67 97.44 99.53 97.75 98.26 Storage at 40 °C 1 mo 98.87 100.14 97.93 99.15 99.19 99.52 99.02 98.71 2 mo 93.42 97.55 92.11 94.22 90.29 93.65 90.77 93.98 3 mo 84.36 91.38 82.18 87.04 83.24 85.47 81.62 87.23 Table 7 CBD Assay [%] 1.2.1 1.2.2 1.3.1 1.3.2 2.2.1 2.2.2 2.3.1 2.3.2 Storage at 25 °C 1 mo 96.31 98.32 100.25 98.25 97.71 99.08 97.80 99.47 2 mo 97.10 98.89 97.83 98.55 98.91 99.29 98.00 98.89 3 mo 99.43 98.14 98.75 98.14 97.51 98.36 97.33 97.43 Storage at 40 °C 1 mo 98.90 99.00 97.30 99.37 99.48 98.18 98.81 98.24 2 mo 98.26 99.28 98.92 98.87 98.28 98.84 98.40 99.20 3 mo 96.76 97.97 97.27 98.09 97.99 97.48 96.91 97.99 The content uniformity was evaluated by taking, from each batch, 6 samples of granulate from different locations within the bulk product at t0. The relative standard deviation (SDrel) was calculated from the THC and CBD content found for each sample. The results are provided in Table 8. They indicate excellent content uniformity for all batches. The somewhat higher values for batch 2.3.2 are likely analytical artefacts as subsequent testing after storage with 3 samples taken at each point of time showed much lower standard deviations, most of which were below 1%. Table 8 1.2.1 1.2.2 1.3.1 1.3.2 2.2.1 2.2.2 2.3.1 2.3.2 SDrel for THC [%] 1.20 0.59 1.23 0.24 0.64 0.19 0.56 2.92 SDrel for CBD [%] 1.21 0.64 2.26 0.22 0.63 0.21 0.59 2.92 Table 9 HPLC parameters Instrument Agilent Column Agilent InfinityLab Poroshell 120 EC-C18, 3.0 x 50 mm, 2.7 µm Mobile phase A Formic acid 0.1% (V / V) in water Mobile phase B Formic acid 0.05% (V / V) in methanol Flow rate 1.0 mL / min Stop time 9.5 min Column temperature 50 °C isothermal Injection volume 5.0 µL Autosampler temperature Room temperature Data rate / peak width >0.0063 min (0.13 sec response time) (80 Hz) Detector wavelength 230 nm Gradient: t = 0 min 60% mobile phase B t = 1 min 60% mobile phase B t = 7 min 77% mobile phase B t = 8.2 min 95% mobile phase B Example 3: Preparation and characterisation of further granulates Using essentially the same preparation method as described in Example 1 but with modified compositions of solutions of THC, CBD and ascorbic acid in ethanol (96% V / V), further granulates were prepared, including a control batch without ascorbic acid. The compositions of the granulates are provided in Table 10, their bulk and tap densities and Hausner ratios in Table 11. The weight percentages provided in Table 10 are based on the total weight of the listed constituents, ignoring the minor amounts of cannabis extract constituents other than THC that were also present. As in Example 1, an agglomerated isomalt grade having a GPM to GPS ratio of about 1 : 3, an aqueous solubility of about 42 g / L and a similar particle size distribution as shown in Table 2 was used. Sieve analysis showed that in all batches substantially more than 30 wt.% of the granules had a sieve diameter of more than 250 µm (38.6 wt.%, 39.8 wt.%, 40.2 wt.% and 40.4 wt.% for batches 3.0, 3.1, 3.2 and 3.3, respectively). Table 10 Amounts 3.0 3.1 3.2 3.3 [wt.%] THC 2.50 2.50 2.50 2.50 CBD 2.50 2.50 2.50 2.50 Ascorbic acid 0.00 0.15 0.20 0.25 Isomalt 95.00 94.85 94.80 94.75 Table 11 Parameter 3.0 3.1 3.2 3.3 Bulk density 0.48 0.49 0.50 0.49 [g / mL] Tap density 0.57 0.57 0.57 0.57 [g / mL] Hausner ratio 1.19 1.18 1.15 1.16 The stability of the granulates was tested as described in Example 2, except that 30 °C / 65% RH was used as an additional level of storage conditions. The results are provided in Table 12 and Table 13. Table 12 THC assay [%] 3.0 3.1 3.2 3.3 Storage at 25 °C 1 mo 96.4 99.6 98.1 99.2 2 mo 95.8 101.6 99.9 101.7 3 mo 92.0 103.2 101.7 103.3 Storage at 30 °C 1 mo 96.9 98.7 97.8 98.7 2 mo 93.9 100.5 99.6 101.0 3 mo 88.1 100.4 99.5 102.2 Storage at 40 °C 1 mo 88.5 97.2 96.2 98.2 2 mo 74.2 93.3 92.1 97.7 3 mo 53.1 80.0 79.5 89.9 Table 13 CBD assay [%] 3.0 3.1 3.2 3.3 Storage at 25 °C 1 mo 100.2 100.7 99.0 100.2 2 mo 101.1 101.6 100.0 101.6 3 mo 105.9 107.0 105.4 106.5 Storage at 30 °C 1 mo 101.0 100.0 99.0 99.9 2 mo 102.1 101.0 100.0 101.1 3 mo 106.1 106.8 104.3 105.9 Storage at 40 °C 1 mo 98.9 99.6 99.2 99.2 2 mo 98.6 99.4 99.6 99.8 3 mo 103.9 103.3 103.2 102.7 Example 4: Preparation and characterisation of hard gelatin capsules Portions of the granulate batches 3.0 to 3.3 of Example 3 were filled into two-piece gelatin capsules of size 1, using a capsule filling device as commonly available in public pharmacies (aponorm®), resulting in capsule batches 4.0 to 4.3, respectively. These capsule batches were then tested for the uniformity of mass according to method 2.9.5 of Ph. Eur. The results as given in Table 14 indicate that the batches not only complied with the requirements of the pharmacopoeia, according to which not more than 2 capsule fills out of a randomly selected sample of 20 capsules should have individual masses deviate from the average mass by more than 10%, and no capsule fill should deviate from the mean mass by more than 20%; but also exceeded the requirements by far. In other words, the highly uniform capsule fill weights indicate a very high pharmaceutical quality of the granulates as provided herein. Table 14 Parameter 4.0 4.1 4.2 4.3 Mean fill weight [mg] 209.61 202.37 197.41 207.33 SDrel [%] 2.01 1.55 1.59 1.91 Min. fill weight [mg] 203.88 195.18 192.72 197.97 Deviation from mean [%] 2.73 3.55 2.38 4.52 Max. fill weight [mg] 219.58 206.95 204.65 214.67 Deviation from mean [%] 4.76 2.26 3.67 3.54 Moreover, the capsules were subjected to a stability test in analogy to Example 3, the results of which are listed in Tables 15 and 16. The stability results of the capsule batches closely match and confirm the results of the stability tests of the non-encapsulated granulates as shown in Table 13. Again, it is evident that ascorbic acid increases the product stability. Table 15 THC assay [%] 4.0 4.1 4.2 4.3 Storage at 25 °C 1 mo 97.0 98.8 98.9 99.7 2 mo 97.4 101.1 100.8 100.9 3 mo 96.0 102.2 103.3 102.5 Storage at 30 °C 1 mo 96.0 98.9 98.5 98.5 2 mo 96.0 100.5 100.1 100.8 3 mo 94.9 98.9 98.0 100.8 Storage at 40 °C 1 mo 91.8 95.3 95.6 95.5 2 mo 84.4 88.8 88.8 88.4 3 mo 72.7 76.7 75.5 74.8 Table 16 CBD assay [%] 4.0 4.1 4.2 4.3 Storage at 25 °C 1 mo 99.3 99.6 99.7 100.5 2 mo 99.4 100.6 100.4 100.4 3 mo 104.9 105.0 106.1 105.4 Storage at 30 °C 1 mo 99.5 99.8 99.4 99.7 2 mo 101.0 99.8 101.1 100.7 3 mo 104.7 105.0 104.6 105.0 Storage at 40 °C 1 mo 98.9 99.6 99.2 99.2 2 mo 98.6 99.4 99.6 99.8 3 mo 103.9 103.3 103.2 102.7 Example 5: Filling of granulates into containers under inert gas atmosphere Granulate batches were prepared as previously described, having the compositions as shown in Table 17. Aliquots of 30 g of these granules were subsequently filled into 40 mL HDPE bottles (Duma® MG, Gerresheimer) under argon gas atmosphere and closed with screw caps. Table 17 Amounts 5.0 5.1 5.2 [wt.%] THC 2.50 2.50 2.50 CBD 2.50 2.50 2.50 Ascorbic acid 0.00 0.10 0.20 Isomalt 95.00 94.90 94.80 The stability of batches 5.0 to 5.2 was tested as described in previous Examples. The results are provided in Tables 18 and 19. It is believed that the filling method involving an inert gas atmosphere may potentially further enhance the stability of the granules. Table 18 THC assay [%] 5.0 5.1 5.2 Storage at 25 °C 3 mo 95.7 103.8 111.3 Storage at 30 °C 3 mo 93.7 98.0 108.7 Storage at 40 °C 1 mo 91.7 104.1 103.0 3 mo 54.2 76.1 90.1 Table 19 CBD assay [%] 4.0 4.1 4.2 Storage at 25 °C 3 mo 103.0 106.8 113.3 Storage at 30 °C 3 mo 105.0 100.8 110.7 Storage at 40 °C 1 mo 101.7 103.5 101.1 3 mo 98.6 96.9 105.4 Example 6: Preparation and characterisation of CBD granules with alternative carriers Using essentially the same preparation method as described in the previous Examples, further granulates were prepared, except that a solution of CBD in ethanol (96% V / V) was used as a granulation liquid. Various carriers composed of lactose monohydrate (referred to as lactose A, B and C, respectively), sorbitol or mannitol were used. The carrier materials were characterised by sieve analysis; Table 20 shows their particle size fractions. Table 20 6.1 6.2 6.3 6.4 6.5 [µm] / [wt.%] Lactose A Lactose B Lactose C Sorbitol Mannitol <45 1.4 1.3 1.5 1.5 2.4 45-63 3.4 8.3 1.7 0.2 3.0 63-125 10.3 55.0 21.9 9.5 14.3 125-250 65.5 25.7 31.1 55.0 41.0 250-500 21.2 10.2 42.5 33.5 32.7 500-1000 0.2 0.8 2.8 2.4 8.2 1000-2000 0.1 0.7 1.3 0.3 0.1 >2000 0.0 0.4 1.0 0.1 0.1 The resulting granulates essentially consisted of CBD and the respective carrier, wherein the CBD content in all batches was 2.40±0.01 wt.%. These simplified granule compositions were used as the focus of these experiments was on characterising the physical granulate properties that are important for mass and content uniformity such as to allow precise volumetric dosing (e.g. hard capsule filling). Upon preparation of the granulates, their particle size distributions (Table 21), bulk densities, tap densities, and the loss on drying were determined. Hausner ratios were calculated from the bulk and tap densities (Table 22). Table 21 6.1 6.2 6.3 6.4 6.5 [µm] / [wt.%] Lactose A Lactose B Lactose C Sorbitol Mannitol <45 1.4 1.4 1.4 1.4 1.5 45-63 0.1 0.7 0.3 0.1 0.5 63-125 0.4 14.8 14.0 1.9 14.4 125-250 16.5 45.9 32.8 44.0 50.3 250-500 82.1 32.9 42.4 54.1 34.1 500-1000 0.7 3.6 10.6 0.6 1.2 1000-2000 0.0 1.8 2.9 0.1 0.4 >2000 0.0 1.4 1.4 0.1 0.3 Table 22 6.1 6.2 6.3 6.4 6.5 Parameter Lactose A Lactose B Lactose C Sorbitol Mannitol Bulk density [g / ml] 0.67 0.53 0.53 0.53 0.59 Tap density [g / ml] 0.78 0.77 0.75 0.63 0.71 Hausner ratio 1.17 1.44 1.42 1.19 1.20 Loss on drying [wt.%] 2.3 2.7 2.6 2.2 2.1 Portions of the granulate batches 6.1 to 6.5 were filled into two-piece gelatine capsules of size 1 as described in Example 4, resulting in capsule batches 7.1 to 7.5, respectively. These capsule batches were then tested for the uniformity of mass according to method 2.9.5 of Ph. Eur. The results as given in Table 23 below. As the granulate densities differ between the batches, volumetric capsule filling necessarily results in differences in the mean fill weights. In the context of the experiments, however, the mass uniformity rather than the fill weights is important. Also shown in Table 23 is the mean CBD dose per capsule and its relative standard deviation, as determined from 10 capsules of each batch as an indicator of the content uniformity. Table 23 Parameter 7.1 7.2 7.3 7.4 7.5 Lactose A Lactose B Lactose C Sorbitol Mannitol Mean fill weight [mg] 330.13 246.54 258.20 257.58 279.60 SDrel [%] 2.05 10.71 6.80 2.36 2.43 Mean CBD content [mg] 7.91 5.77 5.88 5.76 6.48 SDrel [%] 3.50 10.05 6.62 2.78 2.80 In result, it appears that the sorbitol- and mannitol-based batches have suitable physical properties allowing consistent and uniform dosing, e.g. of two-piece gelatine capsules. This is also true for the lactose-based batches even though there is a clear preference for lactose grades with larger overall particle sizes which also lead to CBD granulates with larger overall particle sizes.

Claims

Claims 1. A pharmaceutical composition for oral administration comprising a plurality of granules, wherein the granules comprise, based on the total weight of the water-free granules: - from 0.5 wt.% to 15 wt.% of a cannabinoid active ingredient component selected from THC, CBD and combinations thereof; - at least 50 wt.% of a carrier composed of one or more sugars and / or sugar alcohols having a molecular weight of less than about 400 g / mol; and - from 0.02 wt.% to 0.3 wt.% of an antioxidant selected from ascorbic acid and ascorbyl palmitate; and wherein at least 30 wt.% of the granules have a sieve diameter above 250 µm.

2. The composition of claim 1, wherein the cannabinoid active ingredient component is a combination of THC and CBD, and wherein the combination exhibits a weight ratio of THC to CBD in the range from about 2 : 1 to about 1 : 10, such as about 1 :

1.

3. The composition of claim 1 or 2, wherein the carrier is selected from isomalt, maltitol, sucrose, trehalose, mannitol, sorbitol, xylitol, lactose, and any combinations thereof.

4. The composition of claim 3, wherein the carrier is selected from isomalt, maltitol, sucrose, trehalose, mannitol, sorbitol, xylitol, and any combinations thereof; or wherein the carrier is selected from isomalt, mannitol, and sorbitol.

5. The composition of claim 4, wherein the carrier comprises isomalt.

6. The composition of claim 5, wherein the isomalt has a GPM to GPS ratio of 1 : 3 and / or a water solubility of at least 30 g / L at a temperature of 20 °C.

7. The composition of claim 5 or 6, wherein the granules comprise at least 75 wt.% of agglomerated isomalt.

8. The composition of any one of the preceding claims, wherein at least 70 wt.% of the granules have a sieve diameter above 125 µm.

9. The composition of claim 8, wherein at least 70 wt.% of the granules have a sieve diameter between 125 µm and 500 µm, and wherein less than 5 wt.% of the granules have a sieve diameter below 63 µm.

10. The composition of any one of the preceding claims wherein the granules have a residual moisture content of not more than 5 wt.%, or in the range of 1 wt.% to 5 wt.%, as measured by determining the loss on drying at a temperature of 105 °C.

11. The composition of any one of the preceding claims, wherein the granules exhibit a bulk density in the range of 0.35 to 0.6 g / ml and a tap density in the range of 0.40 to 0.80 g / ml.

12. The composition of any one of the preceding claims, wherein the carrier comprises isomalt, and wherein the granules exhibit a bulk density in the range of 0.35 to 0.5 g / ml, or in the range of 0.40 to 0.45 g / ml.

13. The composition of any one of the preceding claims, wherein the granules exhibit a Hausner ratio of not more than 1.4, or not more than 1.

3.

14. The composition of any one of the preceding claims, wherein the granules exhibit - a bulk density in the range of 0.35 to 0.5 g / ml; and / or - a tap density in the range of 0.4 to 0.6 g / ml; and / or - a Hausner ratio in the range of 1.1 to 1.

5.

15. The composition of claim 14, wherein the granules exhibit - a bulk density in the range of 0.35 to 0.5 g / ml; - a tap density in the range of 0.4 to 0.6 g / ml; and - a Hausner ratio in the range of 1.1 to 1.

5.

16. The composition of any one of the preceding claims, being in the form of a granular powder, wherein the cannabinoid active ingredient component is uniformly distributed in the granules as characterised by a relative standard deviation of ≤5 % for the assay.

17. The composition of claim 16, wherein the relative standard deviation is ≤2.5 %, such as ≤2.0%, ≤1.75%, ≤1.5%, ≤1.25%, or ≤1.0%.

18. A pharmaceutical tablet or a plurality of pharmaceutical tablets prepared by compressing the composition of any one of the preceding claims.

19. A hard capsule or a plurality of hard capsules comprising the composition of any one of claims 1 to 17.

20. A method for the preparation of the composition of any one of claims 1 to 17, the method comprising the steps of: (a) providing a measured amount of the carrier in the form of a powder or granules; (b) providing a measured amount of a liquid comprising the cannabinoid active ingredient component and the antioxidant; (c) combining the carrier provided in step (a) and the liquid provided in step (b) such as to form a wetted powder or granulate; and (d) drying the wetted powder or granulate obtained in step (c) until reaching a residual moisture content of not more than 5 wt.%, or in the range of 1 wt.% to 5 wt.%.

21. A method for the preparation of the plurality of hard capsules according to claim 19, the method comprising the steps (a) to (d) as defined in claim 20, followed by a step (e) of filling the dried granulate obtained in step (d) into two-piece capsules.