CANNABINOID COMPOSITION AND MANUFACTURING METHOD

Technical Field

This disclosure relates to solid pharmaceutical compositions and oral dosage forms having a cannabinoid, to methods of making the compositions and dosage forms, kits useful for making the compositions and dosage forms, and to therapeutic methods involving the use of the compositions and dosage forms.

Background

The discussion of the background to the disclosure is intended to facilitate an understanding of the disclosure. However, it should be appreciated that the discussion is not an acknowledgement or admission that any of the material referred to was published, known or part of the common general knowledge as at the priority date of the application.

There is growing interest in the use of cannabis and cannabinoids for treatment of a wide range of medical conditions and disorders.

Currently, medicinal cannabis may be administered in several forms including capsules containing dried powdered cannabis plant material; edible ‘food’ products produced by infusing cannabis extract into a lipid phase (e.g. butter, cooking oil, edible fat) or a solvent phase (e.g. glycerol, glucose, alcohol); hard or soft-shell gelatin capsules containing cannabinoids dissolved in medium chain triglycerides or carrier oils; oil-based liquids containing cannabis extracts in various ratios and concentrations of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC); chewing gum, inhalers produced by vaporisation of dried plant material; liquid sprays or aerosols by delivery to the oral mucosa; and as nutraceuticals combined with vitamins, minerals and other nutrients within lipid nano spheres.

Drawbacks of many of the above formulations include wide variability in the composition of active ingredients, poor stability and low bioavailability. Generally, these drawbacks arise because of the physicochemical properties of cannabinoids which are lipophilic, water-insoluble and typically exist as tacky, resinous tar-like substances comprising a complex mixture of diverse chemical compounds.

Further, many of these compositions and dosage forms are problematic for administering a controlled and consistent dosage of the cannabinoid of interest. This may be associated with factors such as variability of the cannabinoid compounds in the cannabinoid extract utilised to produce the medicine, or such as the nature of the formulation itself. For example, conventional oil-based formulations can be difficult to administer with precision, leading to variability in the amount of cannabinoid dosed.

In addition, the optimum cannabinoid therapy to be dosed (e.g. the cannabinoid(s) administered and their amounts) can vary based on factors such as the condition to be treated, and the patient’s tolerance of cannabinoid therapy and their susceptibility to side effects.

An effective oral delivery vehicle for cannabis and cannabinoids, in particular THC and CBD, providing consistent and stable dosages of the active ingredients with predictable bioavailability, and having tailored dosages of cannabinoid active, would be desirable. Further, methods of making such an oral delivery vehicle would also be desirable.

Various embodiments as disclosed herein seek to address at least some of the aforementioned issues.

Summary

In a first aspect, there is provided method of making a solid pharmaceutical composition for use in an oral dosage form, the solid pharmaceutical composition comprising one or more cannabinoids, a lipophilic solvent and a porous particulate solid; the solid pharmaceutical composition having a target cannabinoid profile; and the method comprising: blending a first mixture comprising a lipophilic solvent and a first cannabinoid extract having a first cannabinoid profile, with a second mixture comprising a lipophilic solvent and a second cannabinoid extract having a second different cannabinoid profile, to produce a modified cannabinoid extract; and incorporating the modified cannabinoid extract to the porous particulate solid; such that, following incorporation of the modified cannabinoid extract to the porous particulate solid, the solid pharmaceutical composition has the target cannabinoid profile.

In another aspect, there is provided a solid pharmaceutical composition for use in an oral dosage form; the solid pharmaceutical composition having a target cannabinoid profile; and the solid pharmaceutical composition comprising: a first cannabinoid extract having a first cannabinoid profile; a second cannabinoid extract having a second different cannabinoid profile; a lipophilic solvent; and a particulate porous solid.

In another aspect there is provided a method of making a solid pharmaceutical composition for use in an oral dosage form, the solid pharmaceutical composition comprising one or more cannabinoids, a lipophilic solvent and a porous particulate solid; the solid pharmaceutical composition having a target cannabinoid profile; and the method comprising: incorporating a mixture of a lipophilic solvent and a first cannabinoid extract having a first cannabinoid profile to a porous particulate solid to produce a first solid cannabinoid-containing particulate composition; separately incorporating a mixture of a lipophilic solvent and a second cannabinoid extract having a second different cannabinoid profile to a porous particulate solid to produce a second solid cannabinoid-containing particulate composition; and blending the first solid cannabinoid-containing particulate composition and the second cannabinoid-containing solid particulate composition such that the solid pharmaceutical composition has the target cannabinoid profile. In some embodiments, the method comprises: incorporating a lipophilic solvent to a porous particulate solid to produce a solid cannabinoid-free particulate composition, and blending the first solid cannabinoid-containing particulate composition and the second cannabinoid-containing solid particulate composition with the solid cannabinoid-free particulate composition such that the solid pharmaceutical composition has the target cannabinoid profile.

In another aspect, there is provided a solid pharmaceutical composition for use in an oral dosage form; the solid pharmaceutical composition having a target cannabinoid profile; and the solid pharmaceutical composition comprising a blend of: a first solid cannabinoid-containing particulate composition comprising a first cannabinoid extract having a first cannabinoid profile, a lipophilic solvent and a particulate porous solid; and a second solid cannabinoid-containing particulate composition comprising a second cannabinoid extract having a second different cannabinoid profile, a lipophilic solvent and a particulate porous solid.

In some embodiments, the solid pharmaceutical composition comprises a solid cannabinoid-free particulate composition comprising a lipophilic solvent and a particulate porous solid.

In another aspect, there is provided a kit for use in making a solid pharmaceutical composition for use in an oral dosage form, the solid pharmaceutical composition having a target cannabinoid profile; and the kit comprising: a first solid cannabinoid-containing particulate composition comprising a first cannabinoid extract having a first cannabinoid profile, a lipophilic solvent and a particulate porous solid; a second solid cannabinoid-containing particulate composition comprising a second cannabinoid extract having a second different cannabinoid profile, a lipophilic solvent and a particulate porous solid; and one or more containers for separate containment of the first and second solid cannabinoid-containing pharmaceutical compositions.

In some embodiments, the kit comprises a solid cannabinoid-free particulate composition comprising a lipophilic solvent and a particulate porous solid.

In embodiments of any aspect described herein having a first and second cannabinoid-containing particulate composition, the cannabinoid profile of the first solid cannabinoid-containing particulate composition is different from the cannabinoid profile of the second solid cannabinoid-containing particulate composition in wt% terms by at least ±10 %, preferably at least ±20 %, more preferably by at least ±30 % still more preferably by at least ±40 %, yet still more preferably by at least ±50 %, even still more preferably by at least ±100 % or by at least ±200 % or even ±300 %.

In another aspect, there is provided a method of making a solid pharmaceutical composition for use in an oral dosage form, the solid pharmaceutical composition comprising one or more cannabinoids, a lipophilic solvent and a porous particulate solid; the solid pharmaceutical composition having a target cannabinoid profile; and the method comprising: diluting a cannabinoid extract with a lipophilic solvent and producing a modified cannabinoid extract; and incorporating the modified cannabinoid extract to the porous particulate solid; the cannabinoid extract having a concentration of cannabinoid such that, following dilution and incorporation, the solid pharmaceutical composition has the target cannabinoid profile.

In any embodiments described herein, the solid pharmaceutical composition may comprise an emulsifier/surfactant.

In embodiments, the solid pharmaceutical composition is self-emulsifying.

In preferred embodiments, the emulsifier/surfactant is admixed with cannabinoid extract in the presence of lipophilic solvent, prior to incorporation to the porous particulate solid.

In some embodiments, the emulsifier/surfactant is a polyethoxylated castor oil. In embodiments, the solid pharmaceutical composition comprises one or more of a filler, binder and an anti-caking agent.

In preferred embodiments, the filler, binder and/or anti-caking agent is admixed with the porous particulate solid following incorporation of the cannabinoid extract.

In preferred embodiments, the solid particulate composition comprises one or more of microcrystalline cellulose and tricalcium phosphate.

In preferred embodiments, microcrystalline cellulose and tricalcium phosphate are admixed with the porous particulate solid following incorporation of the cannabinoid extract.

In some embodiments, the cannabinoid is selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichormevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabielsoin (CBE), cannabicyclol (CBL), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabitriol (CBT), delta-8- tetrahydrocanninol, delta-8-tetrahydrocannabinolic acid, delta-9-tetrahydrocannabinol (THC), delta-9-tetrahydrocannabinolic acid (THCA), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabivarinic acid (THCVA), ll-nor-9-carboxy-delta-9- tetrahydrocannabinol (THCCOOCH), 1 l-nor-9-carboxy-delta-8-tetrahydrocannabinol,

1 l-hydroxy-delta-8-tetrahydro-cannabinol, and 11 -hydro xy-delta-9- tetrahydrocannabinol, dimethyl heptylpentyl cannabidiol (DMHP-CBD), 6,12-dihydro- 6-hydroxy-cannabidiol, (3S,4R)-7-hydroxy-.DELTA.6-tetrahydrocannabinol homo logs and derivatives, (+)-4-[4-DMH-2,6-diacetoxy-phenyl]-2-carboxy-6,6- dimethylbicyclo[3.1.1]he- pt-2-en, and other 4-phenylpinene derivatives, and cannabidiol (-)(CBD) analogues such as (-)CBD-monomethylether, (-)CBD dimethyl ether; (-)CBD diacetate; (-)3'-acetyl-CBD monoacetate, cannabinol propyl variant (CBNV), and nabilone, or mixtures thereof.

In some embodiments, the cannabinoid is cannabidiol (CBD).

In some embodiments, the cannabinoid is delta-9-tetrahydrocannabinol (THC). In some embodiments, the target cannabinoid profile is a concentration of CBD that is about 150 mg CBD per 270mg composition.

In some embodiments, the target cannabinoid profile is a concentration of CBD that is about 100 mg CBD per 270mg composition.

In some embodiments, the target cannabinoid profile is a concentration of CBD that is about 50 mg CBD per 270mg composition.

In some embodiments, the target cannabinoid profile is a concentration of CBD that is about 20 mg CBD per 270mg composition.

In some embodiments, the target cannabinoid profile is a concentration of THC that is about 40 mg THC per 270g composition.

In some embodiments, the target cannabinoid profile is a concentration of THC that is about 20 mg THC per 270g composition.

In some embodiments, the target cannabinoid profile is a weight ratio of CBD to THC that is about 1:1.

In some embodiments, the target cannabinoid profile is a weight ratio of CBD to THC that is at least 20:1.

In some embodiments, the target cannabinoid profile is a weight ratio of CBD to THC that is at least 1:20.

In some embodiments, the target cannabinoid profile is that at least 70% by weight of all cannabinoids present in the solid pharmaceutical composition is CBD, and that no other cannabinoid is present in the solid pharmaceutical composition at more than 10% by weight, or preferably at no more than 5% by weight.

In some embodiments, the target cannabinoid profile is that at least 70% by weight of all cannabinoids present in the solid pharmaceutical composition is THC, and that no other cannabinoid is present in the solid pharmaceutical composition at more than 10% by weight, or preferably at no more than 5% by weight.

In embodiments, the particulate porous solid is a colloidal silicon dioxide.

In some embodiments, the particulate porous solid is amorphous silica.

In some embodiments, the particulate porous solid is mesoporous and has a mean mesopore volume in the range of from about 1.5 to about 2.0 mL/g. In some embodiments, the particulate porous solid has a mean surface area of from about 150 to about 350 m ² /g.

In some embodiments, the particulate porous solid has a particle size dso in the range of from about 20 to about 150 pm.

In embodiments, the particulate porous solid may have a lipophilic solvent: particulate porous solid loading ratio of between 10:1 to 1:1, between 9:1 to 1:1, between 8:1 to 1:1, between 7:1 to 1:1, between 6:1 to 1:1, between 5:1 to 1:1, between 4:1 to 1:1, between 3:1 to 1:1, or between 2:1 to 1:1.

In some embodiments, the lipophilic solvent is selected from group consisting of a vegetable oil, a medium chain triglyceride, a long chain triglyceride, an emulsifier/surfactant, and mixtures thereof.

In embodiments, the solid pharmaceutical composition is a free flowing powder.

In another aspect, there is provided a method of making a dosage form for oral administration, comprising carrying out a method of making a solid pharmaceutical composition as defined above, and converting the solid pharmaceutical composition into a dosage form for oral administration.

In another aspect, there is provided a dosage form for oral administration, comprising a solid pharmaceutical composition as defined herein.

In some embodiments, the dosage form is a unit dosage form.

In some embodiments, the unit dosage form is a capsule.

In some embodiments, the capsule has a shell which comprises gelatin, pullulan and/or hydro xypropyl methylcellulose.

In some embodiments, the capsule is enteric coated.

In some embodiments, the dosage form is a unit dosage form containing 1 mg of CBD, or 2.5 mg of CBD, or 5 mg of CBD, or 10 mg of CBD, or 20 mg of CBD, or 20 mg of CBD, or 50 mg of CBD, or 100 mg of CBD, or 150 mg of CBD, or 200 mg of CBD.

In some embodiments, the dosage form is a unit dosage form containing 1 mg of THC, 2.5 mg of THC, or 5 mg of THC, or 10 mg of THC, or 20 mg of THC, or 40 mg ofTHC. In some embodiments, the dosage form is a unit dosage form containing CBD and THC in a weight ratio of 1 : 1.

In some embodiments, the dosage form is a unit dosage form containing CBD and THC in a weight ratio of at least 20:1.

In some embodiments, the dosage form is a unit dosage form containing CBD and THC in a weight ratio of at least 1:20.

In some embodiments, the dosage form is a unit dosage form, and wherein at least 70% by weight of all cannabinoids present in the unit dosage form is CBD, and that no other cannabinoid is present in the unit dosage form at more than 10% by weight, or preferably at no more than 5% by weight.

In some embodiments, the dosage form is a unit dosage form, and wherein at least 70% by weight of all cannabinoids present in the unit dosage form is THC, and that no other cannabinoid is present in the unit dosage form at more than 10% by weight, or preferably at no more than 5% by weight.

In another aspect, there is provided a kit comprising: an immediate release dosage form for oral administration, comprising a solid pharmaceutical composition comprising a cannabinoid extract, a lipophilic solvent, and a particulate porous solid; a modified release dosage form for oral administration comprising a solid pharmaceutical composition comprising a cannabinoid extract, a lipophilic solvent, and a particulate porous solid; and one or more containers for separate containment of the immediate release and modified release dosage forms.

In some embodiments, the immediate release dosage form is an immediate release capsule, and the modified release dosage form is a modified release capsule.

In some embodiments, the container is a blister pack.

In another aspect, there is provided a kit comprising: a first dosage form for oral administration, comprising a solid pharmaceutical composition comprising a cannabinoid having a first cannabinoid profile, a lipophilic solvent, and a particulate porous solid; a second dosage form for oral administration comprising a solid pharmaceutical composition comprising a cannabinoid having a second different cannabinoid profile, a lipophilic solvent, and a particulate porous solid; and one or more containers for separate containment of the dosage forms.

In some embodiments, at least 70% by weight of all cannabinoids present in the first dosage form is CBD, and no other cannabinoid is present in the first dosage form at more than 10% by weight, or preferably at no more than 5% by weight, and at least 70% by weight of all cannabinoids present in the second dosage form is THC, and no other cannabinoid is present in the second dosage form at more than 10% by weight, or preferably at no more than 5% by weight.

In some embodiments, the unit dosage forms are capsules.

In some embodiments, the container is a blister pack.

In some embodiments, the solid pharmaceutical composition, dosage form or kit comprises CBD, and wherein following storage of the solid pharmaceutical composition, dosage form or kit for a period of 3 months at 25°C and 60% relative humidity, the amount of CBD in the solid pharmaceutical formulation, dosage form or kit decreases by no more than 10 wt% or 10 mol%.

In some embodiments, the solid pharmaceutical composition, dosage form or kit comprises THC, and wherein following storage of the solid pharmaceutical composition, dosage form or kit for a period of 3 months at 25°C and 60% relative humidity, the amount of THC in the solid pharmaceutical formulation, dosage form or kit decreases by no more than 10 wt% or 10 mol%.

In some embodiments, the aqueous environment is 0.5% aqueous hexadecyltrimethylammonium bromide comprising a phosphate buffer at pH 6.8, and wherein the contacting is carried out at 37°C ± 0.5°C with stirring at 100 rpm.

There is also provided a solid pharmaceutical composition or unit dosage form as defined herein wherein, following contacting of the solid pharmaceutical composition or dosage form with an aqueous environment, at least 50% by weight of cannabinoid is released within 1 hour.

In some embodiments, the cannabinoid is CBD. In other embodiments, the cannabinoid is THC. In another aspect, there is provided a method of preventing, treating and/or lessening the severity of a disease, disorder or condition in a subject, wherein the disease disorder or condition is selected from the group consisting of an inflammatory disorder, a neurological disorder, a psychiatric disorder, a malignancy, an immune disorder, a metabolic disorder, a nutritional deficiency, an infectious disease, a gastrointestinal disorder, a cardiovascular disorder, cancer, and pain, and wherein the method comprises administering to the subject in need thereof an effective amount of a solid pharmaceutical composition or unit dosage form as defined herein.

In another aspect, there is provided use of a solid pharmaceutical composition, kit or unit dosage form as defined herein, in the manufacture of a medicament for preventing, treating, and/or lessening the severity of a disease or disorder, wherein the disease or disorder is selected from the group consisting of an inflammatory disorder, a neurological disorder, a psychiatric disorder, a malignancy, an immune disorder, a metabolic disorder, an infectious disease, a gastrointestinal disorder, a cardiovascular disorder, cancer, and pain.

In another aspect, there is provided a solid pharmaceutical composition or a unit dosage form as defined herein for use in preventing, treating and/or lessening the severity of a disease or disorder in a subject, wherein the disease is selected from the group consisting of an inflammatory disorder, a neurological disorder, a psychiatric disorder, a malignancy, an immune disorder, a metabolic disorder, a nutritional deficiency, an infectious disease, a gastrointestinal disorder, a cardiovascular disorder, cancer, and pain.

Detailed Description

Definitions

Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. For example, reference to "a" includes a single as well as two or more; reference to "an" includes a single as well as two or more; reference to "the" includes a single as well as two or more and so forth.

Each embodiment of the present disclosure described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise. For example, any reference to the % variation between cannabinoid profiles within first and second and any further cannabinoid-containing solid compositions are applicable to all aspects and embodiments described herein. Similarly, all comments on the nature and relative amounts of the components of the solid pharmaceutical compositions described herein, such as the one or more cannabinoids, lipophilic solvent, emulsifier/surfactant and porous particulate solid, are to be taken as applicable to all aspects and embodiments. The present disclosure is not to be limited in scope by the specific examples or embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the disclosure as described herein.

The term "and/or", e.g., "X and/or Y" shall be understood to mean either "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. The term “about” as used herein means within 5%, and more preferably within 1%, of a given value or range. For example, “about 3.7%” means from 3.5 to 3.9%, preferably from 3.66 to 3.74%. When the term “about” is associated with a range of values, e.g., “about X% to Y%”, the term “about” is intended to modify both the lower (X) and upper (Y) values of the recited range. For example, “about 20% to 40%” is equivalent to “about 20% to about 40%”.

The term “pharmaceutically acceptable” with respect to a substance as used herein means that substance which is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for the intended use when the substance is used in a pharmaceutical composition

The term “therapeutically effective amount” as used herein refers to an amount of active ingredient needed to provide a desired level of active ingredient in the bloodstream or at a target organ of to provide an anticipated physiological response.

The precise amount will vary in response to several factors including, but not limited to, the type of active ingredient, bio availability of the active ingredient, patient characteristics (e.g. age, weight, gender), severity of symptoms, contraindications, and so forth. A therapeutically effective amount of an active ingredient may be administered in a single dosage, or through multiple dosages of an amount that cumulatively provides a therapeutic effect. The ‘therapeutic effect’ may reduce the severity of a disease, medical condition or one or more associated symptoms, and/or may be therapeutic in terms of a partial or complete cure of a disease or medical condition.

The present disclosure relates to methods of making solid cannabinoid- containing pharmaceutical compositions and unit dosage forms containing the compositions, as well as to the compositions and dosage forms themselves.

As discussed above, currently available compositions containing one or more cannabinoids are available in forms which may be unstable and/or difficult to use when delivering an accurate pre-defined dosage of cannabinoid.

For example, cannabinoids are currently available in forms such as a dried powdered form of cannabis plant material or as a resinous extract. In these particular forms, the active ingredient(s) of interest may be present in varying amounts and therefore it is difficult to administer a pre-defined therapeutically effective dosage. Consequently, the anticipated therapeutic effect of the active ingredient(s) may be considerably altered. Resinous extracts are also extremely difficult to handle and manufacture pharmaceutical- grade dosages therefrom.

Methods of making cannabinoid-containing compositions have now been identified which provide for precise control in respect of the amount of cannabinoid that is delivered to a patient in a dosage form, and also in respect of the cannabinoid or blend of cannabinoids that is provided. The technology, which is based on incorporation (e.g. adsorption and/or absorption) of a mixture of cannabinoid and lipophilic solvent to a porous particulate solid producing solid cannabinoid-containing compositions, also enables facile blending of different cannabinoid extracts and/or dilution with carrier solvents so as to achieve the desired concentration and/or ratio of cannabinoid for optimum treatment of a given disorder, or to suit patients’ changing needs.

The solid compositions obtained are typically free-flowing powders, facilitating convenient and reproducible handling and measurement, which can readily be analysed for cannabinoid content. Thus, powders containing different cannabinoid distributions (e.g. predominantly CBD, or predominantly THC) and/or different concentrations of cannabinoids, can also be blended together so as to achieve a target amount or amounts of the cannabinoid(s) of interest, and/or a target ratio of two or more cannabinoids in the final dosage form which is to be administered to a patient.

Further, the compositions developed have good storage stability properties, such that they again facilitate consistent dosing of a desired dose of cannabinoid even after storage for extended periods of time.

Experiments have also been conducted showing that contacting oral dosage units such as capsules containing the cannabinoid compositions with an aqueous environment can lead to efficient release of cannabinoid from the solid compositions.

Solid Pharmaceutical Compositions The solid pharmaceutical compositions of the disclosure comprise at least one cannabinoid, a lipophilic solvent, and a porous particulate solid. Typically, the substances used in the preparation of the solid pharmaceutical compositions, and the dosage forms, are pharmaceutically acceptable.

Cannabinoid

The solid pharmaceutical composition comprises a cannabinoid. The term “cannabinoid” as used herein refers to a class of C21 terpenophenolic compounds that represent a group of compounds found in Cannabis sativa. The term encompasses synthetic analogues of such C21 terpenophenolic compounds.

An extract comprising a mixture of cannabinoids may be used. An extract which has undergone processing and/or purification to increase the proportion of one or more target cannabinoids may be utilised.

In some embodiments, solid pharmaceutical composition comprises one or more cannabinoids selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichormevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabielsoin (CBE), cannabicyclol (CBL), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabitriol (CBT), delta-8-tetrahydrocanninol, delta-8- tetrahydrocannabinolic acid, delta-9-tetrahydrocannabinol (THC), delta-9- tetrahydrocannabinolic acid (THCA), delta-9-tetrahydrocannabivarin (THCV), delta-9- tetrahydrocannabivarinic acid (THCV A), ll-nor-9-carboxy-delta-9- tetrahydrocannabinol (THCCOOCH), 1 l-nor-9-carboxy-delta-8-tetrahydrocannabinol,

1 l-hydroxy-delta-8-tetrahydro-cannabinol, and 11 -hydro xy-delta-9- tetrahydrocannabinol, dimethyl heptylpentyl cannabidiol (DMHP-CBD), 6,12-dihydro- 6-hydroxy-cannabidiol, (3S,4R)-7-hydroxy-.DELTA.6-tetrahydrocannabinol homo logs and derivatives, (+)-4-[4-DMH-2,6-diacetoxy-phenyl]-2-carboxy-6,6- dimethylbicyclo[3.El]he- pt-2-en, and other 4-phenylpinene derivatives, and cannabidiol (-)(CBD) analogues such as (-)CBD-monomethylether, (-)CBD dimethyl ether; (-)CBD diacetate; (-)3'-acetyl-CBD monoacetate, cannabinol propyl variant (CBNV), and nabilone.

In some embodiments, the solid pharmaceutical composition comprises cannabidiol (CBD). In some embodiments, cannabidiol (CBD) is the main cannabinoid present in the solid pharmaceutical composition. In embodiments comprising cannabidiol (CBD), at least 35%, at least 50%, at least 60%, at least 70%, at least 80% at least 90%, or at least 95% by weight of the cannabinoid present in the solid pharmaceutical composition is cannabidiol (CBD). In some embodiments, no cannabinoid is present in the cannabinoid extract in an amount of greater than 10% by weight, or, preferably, in an amount of greater than 5% by weight other than cannabidiol (CBD). In some embodiments substantially all of the cannabinoid present in the solid pharmaceutical composition is cannabidiol (CBD).

In some embodiments, the solid pharmaceutical composition comprises delta- 9-tetrahydrocannabinol (THC). In some embodiments, delta-9-tetrahydrocannabinol (THC) is the main cannabinoid present in the solid pharmaceutical composition. In some embodiments, at least 35%, at least 50%, at least 60%, at least 70%, at least 80% at least 90%, or at least 95% by weight of the cannabinoid present in the solid pharmaceutical composition is delta-9-tetrahydrocannabinol (THC). In some embodiments, no cannabinoid is present in the cannabinoid extract in an amount of greater than 10% by weight, or, preferably, in an amount of greater than 5% by weight other than delta-9-tetrahydrocannabinol (THC). In some embodiments substantially all of the cannabinoid present in the solid pharmaceutical composition is delta-9- tetrahydrocannabinol (THC).

The present disclosure enables the provision of compositions and dosage forms with control over the amounts and types of cannabinoid administered, allowing tailoring of dosage forms for a given indication and/or for a particular patient or group of patients.

For example, the weight ratio of different cannabinoids may be adjusted in order to deliver a desired blend, e.g. by blending cannabinoid extracts and/or by blending different solid cannabinoid-containing pharmaceutical compositions. Where the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), the weight ratio may for example be a ratio within the range of from 1:100 to 100:1, or from 1:20 to 20:1, or from 1:10 to 10:1, or from 1:5 to 5:1, or from 1:3 to 3:1, or from 1:2 to 2:1, or about 1:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is at least 20:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 20:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 15:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 10:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 8:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 6:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 5:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 4:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 3:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 2:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:2. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:3. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:4. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:5. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:6. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:8. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 10:1. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:15. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is 1:20. In some embodiments, the cannabinoid comprises a mixture of cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), and the weight ratio is at least 1:20.

The concentration of one or more cannabinoids which may be present in the solid pharmaceutical composition may similarly be tailored for a given indication, patient or patient group, for example by diluting a cannabinoid extract with a lipophilic solvent prior to forming a solid pharmaceutical composition, by blending solid cannabinoid-containing pharmaceutical compositions, or diluting a solid cannabinoid- containing pharmaceutical composition with a solid pharmaceutical composition which does not contain cannabinoid.

In some embodiments, the solid pharmaceutical composition comprises cannabidiol (CBD) and has a concentration of CBD which is a concentration within the range of from 1 to about 150 mg CBD per 270 mg composition.

In some embodiments, the solid pharmaceutical composition comprises cannabidiol (CBD) and has a concentration of CBD which is about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50mg, lOOmg, or 150 mg CBD per 270 mg composition.

In some embodiments, the solid pharmaceutical composition comprises delta- 9-tetrahydrocannabinol (THC) and has a concentration of THC which is a concentration within the range of from 1 to 50 mg THC per 270 mg composition. In some embodiments, the solid pharmaceutical composition comprises delta- 9-tetrahydrocannabinol (THC) and has a concentration of THC which is about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg THC per 270 mg composition.

In some embodiments, the solid pharmaceutical composition comprises up to about 60% wt% cannabinoid, up to about 50 wt% cannabinoid, up to about 40 wt% cannabinoid, up to about 35 wt% cannabinoid, up to about 30 wt% cannabinoid, up to about 25 wt% cannabinoid, up to about 20 wt% cannabinoid, up to about 15 wt% cannabinoid, up to about 10 wt% cannabinoid, up to about 5 wt% cannabinoid, up to about 1 wt% cannabinoid or up to about 0.5 wt% cannabinoid. In some embodiments, the amount of cannabinoid present in the solid pharmaceutical composition is in the range of from about 0.25 wt% to about 60 wt%, 0.25 wt% to about 50 wt%, 0.25 wt% to about 40 wt%, from about 0.25 wt% to about 10 wt%, from about 0.25 wt% to about 5 wt%, from about 0.25 wt% to about 4 wt%, from about 0.25 wt% to about 3 wt%, from about 0.25 wt% to about 2 wt%, from about 0.25 wt% to about 1 wt%, or about 0.25 wt%, about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.5 wt%, about 2 wt% about 2.5 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt%.

Lipophilic Solvent

The solid pharmaceutical composition is produced by incorporation of a mixture comprising cannabinoid and a lipophilic solvent to the porous particulate solid (e.g. adsorption and/or absorption onto and/or into the porous particulate solid).

The lipophilic solvent may be a solvent having suitable properties for dissolution of and/or admixing with cannabinoid.

In some embodiments, the lipophilic solvent is a vegetable oil, medium chain triglyceride, long chain triglyceride, an emulsifier/surfactant or a mixture thereof.

In embodiments wherein the lipophilic solvent is an emulsifier/surfactant then this one component of the composition may address both of these functional roles, i.e. a separate further lipophilic solvent is not required if the emulsifier/surfactant is appropriate to solvate the cannabinoid. In some embodiments, the lipophilic solvent is a vegetable oil. Suitable examples of vegetable oils include, but are not limited to, cotton seed oil, safflower oil, sunflower oil, peanut oil, linseed oil, corn oil, olive oil, coconut oil, soybean oil, sesame oil, chia ( Salvia Hispanica L.) seed oil, wheat germ oil, canola oil, castor oil, hydrogenated castor oil and any mixtures thereof.

In some embodiments, the lipophilic solvent is a medium chain triglyceride. The term “medium-chain triglycerides (MCTs) as used herein refers to triglycerides whose fatty acids have an aliphatic tail of 6-12 carbon atoms. Examples of medium chain triglycerides that may be suitable for use in embodiments of the present disclosure include tricaproin, tricaprylin, tricaprin, trilaurin, and mixtures thereof.

In some embodiments, the medium chain triglyceride is a triglyceride of a fatty acid having from 8 to 10 carbon atoms, e.g. mixtures of tricaprylin and tricaprin may be used for example.

Medium chain triglycerides may, for example, be produced by processing of coconut oil or palm kernel oil.

In some embodiments, the lipophilic solvent is a long chain triglyceride. The term “long-chain triglycerides (LCTs) as used herein refers to triglycerides whose fatty acids have an aliphatic tail of 16-20 carbon atoms. Examples of long chain fatty acids that may form triglycerides that may be suitable for use in embodiments of the present disclosure include palmitic acid, oleic acid, linoleic acid, and mixtures thereof.

In some embodiments, the long chain triglyceride is a triglyceride of a fatty acid having from 16 to 20 carbon atom.

Long chain triglycerides may, for example, be produced by processing of corn oil.

In some embodiments, the lipophilic solvent is present in the solid pharmaceutical composition in an amount within the range of from about 2 wt% to about 35 wt%, or from about 5 wt% to about 35 wt%, or from about 6 wt% to about 35 wt%, or from about 8 wt% to about 35 wt%, or from about 10 wt% to about 35 wt%, or from about 12 wt% to about 35 wt%, or from about 5 wt% to about 30 wt%, or from about 6 wt% to about 30 wt%, or from about 8 wt% to about 30 wt%, or from about 10 wt% to about 30 wt%, or from about 12 wt% to about 30 wt%, or from about 5 wt% to about 25 wt%, or from about 6 wt% to about 25 wt%, or from about 8 wt% to about 25 wt%, or from about 10 wt% to about 25 wt%, or from about 12 wt% to about 25 wt%, or from about 13 wt% to about 23 wt%, or about 14 wt%, or about 15 wt%, or about 16 wt%, or about 17 wt%, or about 18 wt%, or about 19 wt%, or about 20 wt%, or about 21 wt%, or about 22 wt%.

The cannabinoid is typically present in the lipophilic solvent for loading at a dilution factor of from about 1:1 w/w to about 1:90 w/w, and may for example depend on the concentration of cannabinoid desired in the solid pharmaceutical composition.

Porous Particulate Solid

The solid pharmaceutical composition comprises a porous particulate solid. Any porous particulate solid which can incorporate (e.g. adsorb and/or absorb) a mixture of cannabinoid and lipophilic solvent, which is suitable for oral administration, and which can release cannabinoid following oral administration may be utilised. The porous particulate solid is typically inert.

In some embodiments, the porous particulate solid is a silica. In preferred embodiments, the silica is a colloidal silica (silicon dioxide). In embodiments, the silica is an amorphous silica. The term “amorphous” as used herein refers to a non crystalline state. Suitable examples of amorphous silica include, but are not limited to, colloidal amorphous silica sold under the trade names Aeroperl 300 Pharma grade, Syloid 244 FP Silica, Syloid XDP Silica, the Supemat range of silica, or the Aerosil range of colloidal silicon dioxide.

In embodiments in which the porous particulate solid is a silica, the silica is present as a carrier for the cannabinoid and is not fulfilling a significant role as a glidant or other excipient, diluent or filler even though, to an extent and due to its inherent properties, it may naturally provide some benefits in one or more of these manners.

Put another way, in embodiments of the solid pharmaceutical composition or unit dosage form described herein wherein the porous particulate solid is a silica then the majority of the cannabinoid in the composition is loaded, adsorbed, absorbed, adhered or otherwise accommodated on or within this silica. Preferably, at least 70%, 80%, 90%, 95% or substantially all cannabinoid not free in any liquid component will be loaded, adsorbed, absorbed, adhered or otherwise accommodated on or within the silica of the composition.

In some embodiments, the porous particulate solid is a zinc oxide, titanium dioxide, cerium oxide or iron oxide.

In some embodiments, the porous particulate solid is mesoporous. The term “mesoporous” as used herein refers to pores ranging in size from about 2 nm to about 100 nm.

In embodiments, the porous particulate solid is a mesoporous silica, preferably a colloidal mesoporous silica.

Pores may be categorized as “open pores” that connect through and open onto a surface of a particle, or as “closed pores” that are sealed from fluid ingress from the surface of the particle. The distribution of pore sizes and total pore volume of the particle may be measured using gas adsorption and pycnometry or other techniques which are known to those of skill in the art. The cannabinoid(s) may be accommodated with the pores.

In some embodiments the porous particulate solid has a mean mesopore volume within the range of from about 1.5 to about 2.0 mL/g.

In some embodiments, the porous particulate solid has a mean particle diameter in the range of from about 5pm to about 200pm.

In some embodiments, the porous particulate solid has a mean particle diameter in the range of from about 5pm to about 175pm.

In some embodiments, the porous particulate solid has a mean particle diameter in the range of from about 5pm to about 150pm.

In some embodiments, the porous particulate solid has a mean particle diameter in the range of from about 10pm to about 175pm.

In some embodiments, the porous particulate solid has a mean particle diameter in the range of from about 10pm to about 150pm.

In some embodiments, the porous particulate solid has a mean particle diameter in the range of from about 10pm to about 100pm.

In some embodiments, the porous particulate solid has a mean particle diameter in the range of from about 20pm to about 200pm. In some embodiments, the porous particulate solid has a mean particle diameter in the range of from about 20pm to about 175pm.

In some embodiments, at least 50% of the particles of the porous particulate solid have a diameter in the range of from about 20pm to about 175pm.

In some embodiments, at least 90% of the particles of the porous particulate solid have a diameter in the range of from about 20pm to about 175pm.

The distribution of particle size may be measured using optical microscopy, laser diffraction particle size analysis, dynamic light scattering, imaging particle analysis or other techniques which are known to those of skill in the art.

In some embodiments, the porous particulate solid has a surface area in the range of from about 100 to about 500 m ² /g, or from about 200 to about 400m ² /g, or from about 260 to about 320 m ² /g.

In some embodiments, the porous particulate solid has a mean mesopore volume within the range of from about 1.5 to about 2.0 mL/g, a mean particle diameter in the range of from about 20pm to about 200pm (preferably from about 20pm to about 150pm) , and a surface area in the range of from about 260 to about 320 m ² /g.

The porous particulate solid is typically capable of incorporating (e.g. adsorbing and/or absorbing) significant quantities of cannabinoid-containing liquid. In some embodiments, the weight ratio of porous particulate composition to liquid mixture comprising lipophilic solvent and cannabinoid is in the range of from about 1:1.0 to about 1:2, from about 1:1.5 to about 1:2.

In embodiments, the particulate porous solid may have a lipophilic solvent: particulate porous solid loading ratio of between 10:1 to 1:1, between 9:1 to 1:1, between 8:1 to 1:1, between 7:1 to 1:1, between 6:1 to 1:1, between 5:1 to 1:1, between 4:1 to 1:1, between 3:1 to 1:1, or between 2:1 to 1:1.

In embodiments, the ratio of liquid self-emulsifying composition (being the lipophilic solvent plus cannabinoid plus emulsifier/surfactant and recognising the lipophilic solvent may act as emulsifier/surfactant) to the porous particulate solid may be between 1:4 to 4:1, between 1:3 to 3:1 or between 1:2 to 2:1.

The porous particulate solid may be present in an amount of at least 2 wt% of the solid pharmaceutical composition, or at least 3 wt%, or at least 4 wt%, or at least 5 wt%, or at least 6 wt%, or at least 8 wt%, or at least 10 wt%, or at least 12 wt%, or at least 15 wt%, or at least 18 wt%, each of which lower values may be combined with an upper value of less than 80 wt%, less than 70 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt% or less than 30 wt%.

Preferably, the porous particulate solid may be present in the solid pharmaceutical composition in an amount of between about 10 wt% to 40 wt%, about 10 wt% to 35 wt%, about 10 wt% to 30 wt%, about 15 wt% to 40 wt%, about 15 wt% to 35 wt%, about 15 wt% to 30 wt%.

In embodiments, the solid pharmaceutical composition is a free flowing powder. In embodiments, the solid pharmaceutical composition is a solid self- emulsifying composition. Such powders facilitate convenient, accurate and reproducible dosing of cannabinoid, since the desired amount of powder to provide a required dose of cannabinoid can readily be measured out and the loading is predictable.

Surfactant/Emulsifier

In some preferred embodiments, the solid pharmaceutical composition contains an emulsifier and/or surfactant. Inclusion of an emulsifier in the composition is understood to facilitate formation of a liquid self-emulsifying composition. The liquid self-emulsifying composition is typically prepared by dissolving at least one cannabinoid, as previously described, in the lipophilic solvent and mixing or blending the solution with the emulsifier. In alternative embodiments, and as previously described, the selected lipophilic solvent may also act as or have a role as an emulsifier/surfactant.

Such a liquid self-emulsifying composition can be incorporated into/onto the porous particulate solid, thereby producing a solid self-emulsifying composition.

It is believed that such solid self-emulsifying compositions have good cannabinoid release properties, in that they can assist in forming an emulsion and in releasing high levels of cannabinoid from the solid pharmaceutical composition when contacted with an aqueous environment. It is also considered that addition of emulsifier facilitates the dispersion and incorporation of the lipophilic mixture of cannabinoid and lipophilic solvent into/onto the porous particular solid.

The term “solid self-emulsifying composition” as used herein refers to a solid phase of a liquid self-emulsifying composition in the form of powders or nanoparticles suitable for use in oral solid dosage formulations. As discussed herein, the compositions typically have flowability characteristics which allow them to be accurately measured, characterised and formulated into oral solid dosage formulations.

In some embodiments, the solid pharmaceutical composition comprises an emulsifier, and the emulsifier is admixed with cannabinoid extract which may or may not be in the presence of an additional lipophilic solvent (depending on whether the lipophilic solvent and emulsifier/surfactant are one and the same), prior to incorporation to the porous particulate solid.

The solid pharmaceutical composition may comprise a surfactant. Surfactants may for example be used to increase the rate of dissolution and dispersion in an aqueous environment of the cannabinoid, by facilitating wetting thereof. Where an emulsifier is used, in some embodiments the emulsifier is a surfactant.

Suitable examples of surfactants include fatty acid and alkyl sulfonates, benzalkonium chloride, dioctyl sodium sulfo succinate, polyoxyethylene sorbitan fatty acid esters, natural surfactants such as sodium taurocho lie acid, l-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine, lecithin, and other phospholipids and mono- and diglycerides, and any combination thereof.

In some embodiments, the surfactant is a non-ionic surfactant. The term “non ionic surfactant” as used herein refers to an organic compound having covalently bonded heteroatom-containing (e.g. oxygen-containing) hydrophilic groups which are bonded to hydrophobic parent structures, and which are capable of lowering the surface tension between two non-miscible liquids, in particular a hydrophilic liquid and a hydrophobic liquid.

Examples of non-ionic surfactants include ethoxylated linear alcohols, ethoxylated alkyl-phenols, acid ethoxylated fatty acids, glycerol esters, esters of hexitols and cyclic anhydrohexitols. In some embodiments, the surfactant is a polyethoxylated non- ionic surfactant.

In some preferred embodiments, the surfactant is a polyethoxylated castor oil (also known as polyoxyl castor oil), such as that sold under the trade name Kolliphor EL®.

In some preferred embodiments the lipophilic solvent is medium chain triglycerides and the solid pharmaceutical composition comprises an emulsifier/surfactant which is a polyethoxylated castor oil.

In some embodiments, the emulsifier/surfactant is present in the solid pharmaceutical composition in an amount of from about 1 wt% to about 30 wt%, or from about 1 wt% to about 25 wt%, or from about 1 wt% to about 20 wt%, or from about 1 wt% to about 15 wt%, or from about 1 wt% to about 10 wt %, or from about 2 wt% to about 15 wt%, or from about 2 wt% to about 10 wt%, or from about 2 wt% to about 8 wt%, or from about 2 wt% to about 6 wt%, or about 2 wt%, or about 3 wt%, or about 4 wt%, or about 5 wt%, or about 6 wt%.

Additional Excipients

The solid pharmaceutical composition may comprise one or more further pharmaceutical excipients. For example, following adsorption of the mixture of lipophilic solvent and cannabinoid (and, if desired, emulsifier/surfactant), additional excipients may be blended with the resulting solid cannabinoid-containing composition.

Examples of excipients include fillers, binders, anti-caking agents, disintegrants, lubricants, glidants, preservatives, antioxidants, surfactants, effervescent excipients, colouring agents, coating agents, and sweetening agents. Such excipients are typically used for their customary purposes and in typical amounts without adversely affecting the properties of the compositions. They are not used as a carrier for a cannabinoid to any significant extent.

In some embodiments, the solid pharmaceutical composition comprises a filler and/or a binder. Suitable examples of fillers and binders include, but are not limited to, lactose, mannitol, xylitol, microcrystalline cellulose, methyl cellulose, dibasic calcium phosphate (anhydrous and dihydrate), starch, and any combinations thereof. In some embodiments, the solid pharmaceutical composition comprises microcrystalline cellulose.

An anti-caking agent may be included to prevent the formation of lumps (caking) and to assist flowability properties of the solid pharmaceutical composition.

In some embodiments, the solid pharmaceutical composition comprises an anti-caking agent. Suitable examples of anti-caking agents include, but are not limited to, silicon dioxide, lactose, tricalcium phosphate, and any combination thereof. In some embodiments the solid pharmaceutical composition comprises tricalcium phosphate.

In some embodiments, the solid pharmaceutical composition comprises one or more of a filler, binder and an anti-caking agent. In some embodiments, the filler, binder and/or anti-caking agent is admixed with the porous particulate solid following adsorption of the cannabinoid extract.

In some embodiments, the solid pharmaceutical composition comprises microcrystalline cellulose and/or tricalcium phosphate. In some embodiments that microcrystalline cellulose and/or tricalcium phosphate are admixed with the porous particulate solid following adsorption of the cannabinoid extract.

The filler/binder, such as microcrystalline cellulose, may be present in the solid pharmaceutical composition at between about 15 wt% to 60 wt%, about 20 wt% to 50 wt%, about 25 wt% to 40 wt%.

The anti-caking agent, such as tricalcium phosphate, may be present in the solid pharmaceutical composition at between about 5 wt% to 30 wt%, about 8 wt% to 25 wt%, about 10 wt% to 20 wt%.

In some embodiments, the solid pharmaceutical composition comprises an emulsifier/surfactant, a filler and/or binder, and an anti-caking agent. In some embodiments, the solid pharmaceutical composition comprises polyethoxylated castor oil, microcrystalline cellulose and tricalcium phosphate.

In some embodiments, the lipophilic solvent is medium chain triglycerides, and the solid pharmaceutical composition comprises polyethoxylated castor oil, microcrystalline cellulose and tricalcium phosphate.

Disintegrants may be added to oral solid pharmaceutical formulations, for example to aid in their de-aggregation and to cause rapid break-up of the solids when they come into contact with moisture. In some embodiments, the solid pharmaceutical composition comprises a disintegrant. Suitable examples of disintegrants include, but are not limited to, corn starch, potato starch, sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methyl cellulose, and croscarmellose sodium, crospovidone, and crosslinked forms of polyvinyl pyrrolidone, and any combinations thereof.

Lubricants and glidants may be added to solid pharmaceutical formulations to enhance powder flow by reducing inter-particle friction. In some embodiments, the solid pharmaceutical composition comprises a lubricant and/or glidant. Suitable examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and any combination thereof. Suitable examples of glidants include, but are not limited to, metal silicates, silicon dioxides such as colloidal anhydrous silica, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, and any combination thereof.

A lubricant, such as magnesium stearate or sodium stearyl fumarate, may be present in the solid pharmaceutical composition at between about 0.3 wt% to 2 wt%, about 0.4 wt% to 1.5 wt%, about 0.5 wt% to 1.0 wt%.

Preservatives may be added to solid pharmaceutical compositions to prolong the storage life of the composition, for example by reducing degradation and alteration of the active ingredient over time. In some embodiments, the solid pharmaceutical composition comprises a preservative. Suitable examples of preservatives include, but are not limited to, sulphites, benzalkonium chloride, methyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, and any combination thereof.

Antioxidants are a class of preservatives which inhibit or reduce oxidation of other molecules when added to compositions, such as active ingredient. In some embodiments, the solid pharmaceutical composition comprises one or more antioxidants. Suitable examples of antioxidants include, but are not limited to, phenolic-based antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butyl-hydroquinone (TBHQ), 4-hydroxymethyl-2,6-di-tert- butylphenol (HMBP), 2,4,5-trihydroxy-butyrophenone (THBP), propyl gallate (PG), triamyl gallate, gallic acid (GA), vitamin E (alpha-tocopherol), tocopherol acetate, reducing agents such as L-ascorbic acid (vitamin C), L-ascorbyl palmitate, L-ascorbyl stearate, thioglycolic acid (TGA) ascorbyl palmitate (ASP), sulphite-based antioxidants such as sodium sulphite, sodium metabisulphite, sodium bisulphite and thioglycerol and other agents such as disodium ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, sodium metaphosphate, methionine, erythorbic acid and lecithin and any combination thereof. In some embodiments, a lipophilic antioxidant, such as vitamin E (alpha-tocopherol) is used.

Effervescent excipients may be used in powders and tablets in combination with acidic agents to cause a reaction that produces carbon dioxide. In some embodiments the solid pharmaceutical composition comprises an effervescent excipient. Suitable examples of effervescent excipients include sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, ammonium bicarbonate. The effervescent excipients may be combined with acidic agents, typically weak organic acids such as citric acid and/or ascorbic acid. In some embodiments, the solid pharmaceutical composition comprises an acidic agent. In some embodiments, the solid pharmaceutical composition comprises and effervescent excipient and an acidic agent.

If desired, the solid pharmaceutical composition may additionally include inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate and organic salts such as sodium citrate, potassium citrate, sodium acetate and so forth.

Blending of Cannabinoid Extracts

It has been recognised that solid pharmaceutical compositions having a target cannabinoid profile may be achieved by blending of cannabinoid extracts and/or diluting of cannabinoid extract. Thus, in one aspect there is provided a method of making a solid pharmaceutical composition for use in an oral dosage form, the solid pharmaceutical composition comprising one or more cannabinoids, a lipophilic solvent and a porous particulate solid; the solid pharmaceutical composition having a target cannabinoid profile; and the method comprising: blending a first mixture comprising lipophilic solvent and a first cannabinoid extract having a first cannabinoid profile, with a second mixture comprising a lipophilic solvent and a second cannabinoid extract having a second different cannabinoid profile, in the presence of a lipophilic solvent, to produce a modified cannabinoid extract; and incorporating the modified cannabinoid extract to the porous particulate solid; such that, following incorporation of the modified cannabinoid extract to the porous particulate solid, the solid pharmaceutical composition has the target cannabinoid profile.

The solid pharmaceutical composition produced by the method comprises a cannabinoid, a lipophilic solvent and a porous particulate solid. The cannabinoid, lipophilic solvent and porous particulate solid may for example be as discussed above for the solid pharmaceutical compositions of the disclosure.

The solid pharmaceutical composition has a target cannabinoid profile. For treatment of different patients, and/or of different conditions, it may be desirable to dose different amounts of a cannabinoid such as CBD, or to dose a mixture of cannabinoids (such as CBD and THC) in particular amounts and ratios. It may also be desirable to dose a cannabinoid therapy which contains low amounts or substantially none of a particular cannabinoid or cannabinoids. Accordingly, the target cannabinoid profile is the desired cannabinoid profile which the solid pharmaceutical composition contains.

In some embodiments, the target cannabinoid profile may be or include a requirement for the presence of one or more cannabinoids in the composition, e.g. CBD and/or THC.

In some embodiments, the target cannabinoid profile may be or include a requirement for a concentration of one or more cannabinoids in the composition, e.g. about 150mg CBD/g of composition, about lOOmg CBD/g of composition, 75mg CBD/g of composition, 74mg CBD/g of composition, 50mg CBD/g of composition, 25 mg CBD/g of composition, 75mg THC/g of composition, 74mg THC/g of composition, 50 mg THC/g of composition, or 25 mg THC/g of composition, or 75mg CBD and 75 mg THC/g of composition, 74mg CBD and 74 mg THC/g of composition, 50mg CBD and 50 mg THC/g of composition, or 25 mg CBD and 25 mg THC/g of composition. In some embodiments, the target cannabinoid profile may be or include a requirement for a ratio of two or more cannabinoids in the composition, e.g. 1:1 weight ratio of CBD:THC, or at least a 20:1 weight ratio of CBD:THC.

In some embodiments, the target cannabinoid profile may be or include a requirement that a minimum percentage by weight of the cannabinoid substances present in the composition is a specific cannabinoid, e.g. at least 70% by weight of all cannabinoids present in the composition is CBD, or at least 70% by weight of all cannabinoids present in the composition is THC.

In some embodiments, the target cannabinoid profile may be or include a requirement that the composition contains CBD and THC, that at least 35% by weight of all cannabinoids present in the composition is CBD, and at least 35% by weight of all cannabinoids present in the composition is THC.

In some embodiments, the target cannabinoid profile may be or include a requirement that cannabinoids other than the cannabinoid or cannabinoids of therapeutic interest do not form more than a specified weight % of the cannabinoids in the composition, e.g. that no cannabinoid other than CBD is present in the solid pharmaceutical composition at more than 10% by weight or at more than 5% by weight of all the cannabinoid present, or that no cannabinoid other than THC is present in the solid pharmaceutical composition at more than 10% by weight or at more than 5% by weight of all the cannabinoid present, or that no cannabinoid other than CBD and THC is present in the solid pharmaceutical composition at more than 10% by weight or at more than 5% by weight of all the cannabinoid present.

Typically, the target cannabinoid profile is the cannabinoid profile (e.g. the concentration of the desired cannabinoid or cannabinoids) to be achieved in the solid pharmaceutical compositions, such that oral dosage forms (e.g. capsules) containing the solid pharmaceutical composition will contain the appropriate dose of the appropriate cannabinoid(s).

For example, in the case of a capsule which is intended to contain a 20mg dose of cannabidiol, and which contains 270mg of powder containing the cannabinoid and other excipients, the target cannabinoid profile for the solid pharmaceutical composition is 20mg CBD/270mg solid pharmaceutical composition, or 74mg CBD/lg of solid pharmaceutical composition. In the case of a capsule which is intended to contain a 20mg dose containing a 3:1 weight ratio of CBD to THC, and which contains 270mg of powder containing the cannabinoid and other excipients, the target cannabinoid profile for the solid pharmaceutical composition is 20mg of a 3:1 mixture of CBD:THC per 270mg solid pharmaceutical composition (e.g. 74 mg of 3:1 ratio of CBD:THC per lg of solid pharmaceutical composition).

In some embodiments, the target cannabinoid profile is or includes a requirement for a concentration of CBD in the solid pharmaceutical composition within the range of from 0.1 to 0.2 mg CBD/g of composition, from 0.2 to 0.4 mg CBD/g of composition, from 0.4 to 0.6 mg CBD/g of composition, from 0.6 to 0.8 CBD/g of composition, from 0.8 to 1 mg CBD/g of composition, from 1 to 2 mg CBD/g of composition, from 2 to 4 mg CBD/g of composition, from 4 to 6 mg CBD/g of composition, from 6 to 8 mg CBD/g of composition, from 8 to 10 mg CBD/g of composition, from 10 to 15 mg CBD/g of composition, from 15 to 20 mg CBD/g of composition, from 20 to 25 mg CBD/g of composition, from 25 to 30 mg CBD/g of composition, from 30 to 40 mg CBD/g of composition, from 40 to 50 mg CBD/g of composition, from 50 to 60 mg CBD/g of composition, from 60 to 80 mg CBD/g of composition, from 80 to 100 mg CBD/g of composition, about 0.1, about 0.2, about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.5, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 14, about 15, about 16, about 18, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 60, about 70, about 80, about 90, or about 100 mg CBD/g of composition.

In some embodiments, the target cannabinoid profile is or includes a requirement for a concentration of THC in the solid pharmaceutical composition within the range of from 0.1 to 0.2 mg THC/g of composition, from 0.2 to 0.4 mg THC/g of composition, from 0.4 to 0.6 mg THC/g of composition, from 0.6 to 0.8 THC/g of composition, from 0.8 to 1 mg THC/g of composition, from 1 to 2 mg THC/g of composition, from 2 to 4 mg THC/g of composition, from 4 to 6 mg THC/g of composition, from 6 to 8 mg THC/g of composition, from 8 to 10 mg THC/g of composition, from 10 to 15 mg THC/g of composition, from 15 to 20 mg THC/g of composition, from 20 to 25 mg THC/g of composition, from 25 to 30 mg THC/g of composition, from 30 to 40 mg THC/g of composition, from 40 to 50 mg THC/g of composition, from 50 to 60 mg THC/g of composition, from 60 to 80 mg THC/g of composition, from 80 to 100 mg THC/g of composition, about 0.1, about 0.2, about

0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.5, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 14, about 15, about 16, about 18, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 60, about 70, about 80, about 90, or about 100 mg THC/g of composition.

In some embodiments, the target cannabinoid profile may be or include a requirement for a weight ratio of CBD to THC in the solid pharmaceutical composition which is at least 20:1, in the range of from 20:1 to 15:1, in the range of from 15:1 to 10:1, in the range of from 10:1 to 5:1, in the range of from 5:1 to 2:1, in the range of from 2:1 to 1:1, in the range of from 1:1 to 1:2, in the range of from 1:2 to 1:5, in the range of from 1:5 to 1:10, in the range of from 1:10 to 1:15, in the range of from 1:15 to 1:20, at least 1:20, about 20:1, about 18:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:18, or about 1:20.

In some embodiments the target cannabinoid profile may be or include a requirement that at least 35%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% by weight of all cannabinoid present in the solid pharmaceutical composition, or substantially all of the cannabinoid present in the solid pharmaceutical composition, is CBD.

In embodiments the target cannabinoid profile may be or include a requirement that at least 35%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% by weight of all cannabinoid present in the solid pharmaceutical composition, or substantially all of the cannabinoid present in the solid pharmaceutical composition, is THC. In embodiments, no cannabinoid other than CBD is present in the solid pharmaceutical composition at more than 20%, more than 15%, more than 10%, more than 5%, more than 3%, more than 2% or more than 1% by weight of all the cannabinoid present. In some embodiments, no cannabinoid other than THC is present in the solid pharmaceutical composition at more than 20%, more than 15%, more than 10%, more than 5%, more than 3%, more than 2% or more than 1% by weight of all the cannabinoid present. In some embodiments, no cannabinoid other than CBD or THC is present in the solid pharmaceutical composition at more than 20%, more than 15%, more than 10%, more than 5%, more than 3%, more than 2% or more than 1% by weight of all the cannabinoid present.

The distribution and concentration of cannabinoids present in a cannabinoid extract can vary significantly depending on the extract utilised. In many cases where a cannabinoid therapy is required, a given cannabinoid extract may not have the desired concentration and/or ratio of cannabinoids suitable for incorporation into a final dosage form, such that it is optimal for treating the condition of interest, or the patient of interest. Accordingly, the present disclosure involves methods which provide for blending of different extracts and/or dilution with lipophilic solvent to achieve a desired concentration and/or ratio of cannabinoid(s). For example, cannabinoid extracts are frequently obtained as resins and/or as mixture of cannabinoids in a lipophilic solvent/oil.

Prior to blending, cannabinoid extracts and/or mixtures of cannabinoid extract and lipophilic solvent may be analysed to understand the cannabinoid profile, e.g. whether one or more cannabinoids are present and/or how much of a cannabinoid is present and/or the weight ratio of or more cannabinoids. Based on that analysis, cannabinoid extracts and mixtures of cannabinoid extract and lipophilic solvent may be selected for blending to achieve the target cannabinoid profile in the solid pharmaceutical composition. In some embodiments, that analysis may be carried out as part of the production method. In some embodiments, the analysis may be carried out separately from the method of producing the solid pharmaceutical composition, for example a cannabinoid producer may conduct analysis on extracts at the site where cannabis plants are harvested and processed to produce cannabinoid extracts. Any suitable analysis technique may be utilised for analysing the cannabinoid extracts. One such example of a suitable technique is high pressure liquid chromatography (HPLC). Other analytical techniques include gas chromatography (GC), gas chromatography-mass spectrometry, high pressure liquid chromatography- mass spectrometry, liquid chromatography-NMR spectroscopy and so forth.

In some embodiments, the first cannabinoid extract is mixed with a quantity of lipophilic solvent and analysed to determine its cannabinoid profile, the second cannabinoid extract is mixed with a quantity of lipophilic solvent and analysed to determine its cannabinoid profile, the respective first and second mixtures are then each diluted with further lipophilic solvent if required, and amounts of each resulting mixture are then combined as needed and then incorporated onto/into the required amount of particulate porous solid to produce the solid pharmaceutical composition having the target cannabinoid profile. Such an approach is advantageous since the mixtures containing lipophilic solvent and cannabinoid extract are typically less viscous than, for example, cannabinoid resins, and facilitate accurate provision of the composition having the desired cannabinoid profile. Density measurements for cannabinoid in medium chain triglycerides have been found to be approximately 0.95g per mL, for concentrations of cannabinoid at about 20 mg/mL and at about 260 mg/mL.

In some embodiments, the first and second cannabinoid profiles may be or include the presence of one or more cannabinoids in the cannabinoid extract, e.g. CBD and/or THC. In some embodiments, the cannabinoid profiles may be or include the concentration of one or more cannabinoids in the cannabinoid extract. In some embodiments, the cannabinoid profiles may be or include the weight ratio of two or more cannabinoids in the composition. In some embodiments, the cannabinoid profiles may be or include the percentage by weight of cannabinoids present in the composition.

Two or more cannabinoid extracts may be blended in the presence of a lipophilic solvent to produce the modified cannabinoid extract. For example, in some embodiments, the first and second cannabinoid extracts each contain cannabinoids and lipophilic solvent, and appropriate amounts of each extract are blended together to provide the modified cannabinoid extract. In some embodiments, first and second cannabinoid extracts are added to lipophilic solvent. Whilst in some embodiments two cannabinoid extracts are blended, in some embodiments more than two cannabinoid extracts are blended to provide the modified cannabinoid extract. For example, in some embodiments three different cannabinoid extracts are blended. In some embodiments four different cannabinoid extracts are blended. In some embodiments, five different cannabinoid extracts are blended.

The modified cannabinoid extract contains lipophilic solvent, and is typically in liquid form, e.g. a solution containing cannabinoid (and optionally excipients) in lipophilic solvent.

The first and second mixtures may be blended using conventional equipment. For example, a mixer equipped with a suitable stirrer may be used. A stirring rate in the range of from, e.g. 50rpm to 400rpm may for example be utilised. The rate of addition of components may for example be controlled, for example lipophilic solvent and/or cannabinoid extract may be added portion-wise or at a constant rate over a set period of time. The temperature of the mixer and/or its contents may for example be controlled during blending by use of a heating/cooling jacket. The blending step is typically carried out over a period of time sufficient to ensure that a homogeneous blend of the components is achieved. For example, the blending step may be carried out for a period of time in the range of from 2 minutes to 3 hours, from 5 minutes to 2 hours, from 5 minutes to 1 hour, from 5 minutes to 30 minutes, from 10 minutes to 20 minutes, or about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours or about 3 hours.

Following blending of the cannabinoid extracts to produce the modified cannabinoid extract, the modified cannabinoid extract is incorporated (e.g. adsorbed and/or absorbed and/or otherwise accommodated by) onto and/or into the porous particulate solid.

As discussed above, the modified cannabinoid extract is typically a liquid, e.g. a solution containing cannabinoid and lipophilic solvent. In some embodiments, the modified cannabinoid extract comprises cannabinoid and lipophilic solvent in a weight ratio in the range of from about 1:1 to about 1:90, or from about 1:1 to about 1:50, or from about 1:3 to about 1:30. Any suitable means of contacting the modified cannabinoid extract with the porous particulate solid may be used which enables cannabinoid to be incorporated into and/or onto the porous particulate solid in a controlled manner.

For example a mixer equipped with a suitable stirrer or impellor may be used. A high shear mixer blender or high shear mixer granulator may be used, for example.

In some embodiments, a high shear mixer granulator is used, such as a high shear mixer granulator produced by GMA and sold under the PMA™ brand name.

The rate of addition of modified cannabinoid extract to porous particulate solid may be controlled. In some embodiments, the adsorption step comprises adding the modified cannabinoid extract dropwise to the porous particulate solid, e.g. with continuous gentle mixing, followed by blending of the resulting mixture for a period sufficient to obtain the solid pharmaceutical composition. The modified cannabinoid extract may for example be added dropwise with a dripper, e.g. provided with an orifice size of between 0.1 mm to 10 mm, for example in the range of from 0.3 mm to 2 mm, or from 2 mm to 6 mm, or from 3 mm to 5 mm, or about 3.0mm, about 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9 mm, about 4.0 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, about 4.9 mm, or about 5.0 mm. A pump which provides for controlled addition may be used, for example a peristaltic pump, such as those produced by Watson Marlow. In some embodiments, a peristaltic pump is used on conjunction with a nozzle having a small orifice size, e.g. in the range of from 3 mm to 5 mm. Such an arrangement facilitates consistent creation of droplets of modified cannabinoid extract for addition to the particulate porous solid.

The rate of addition of modified cannabinoid extract to the porous particulate solid may for example be in the range of from 50 to 2000 drops per minute, e.g. in the range of from 1000 to 2000 drops per minutes, or 500 to 1000 drops per minute, or 60 to 600 drops per minute, or 60 to 360 drops per minute, or 1250 to 1750 drops per minute, or about 1500 drops per minute.

During the dropwise addition, the mixture may be gently mixed, e.g. at an impeller speed in the range of from 50 to 400 rpm. Following addition, the components (e.g. modified cannabinoid extract and porous particulate solid) may in some embodiments be mixed, and then held without further active mixing for a further period. Such an approach may facilitate contacting of the surfaces of the porous particulate solid with the modified cannabinoid extract, and also allow time for droplets of the modified cannabinoid extract to settle within pores of the porous particulate solid. In some embodiments, the modified cannabinoid extract is mixed with the porous particulate solid for a period in the range of from 2 minutes to 2 hours, or from 5 minutes to 60 minutes. The mixture may for example be blended following addition of modified cannabinoid extract at a speed in the range of from 100 to 1000 rpm.

In some embodiments, following mixing, the mixture containing porous particulate solid and modified cannabinoid extract is held for a period in the range of from 10 minutes to 24 hours, or from 30 minutes to 12 hours, prior to carrying out further processing.

In some embodiments, the step of incorporating the modified cannabinoid extract into/onto the porous particulate solid comprises spraying the modified cannabinoid extract onto the porous particulate solid. In some embodiment, the porous particulate solid is continuously stirred whilst the modified cannabinoid extract is sprayed. In some embodiments, the resulting mixture is blended for a period following addition of the modified cannabinoid extract (e.g. for a period in the range of from 5 minutes to 60 minutes). The mixture may for example be blended following addition of modified cannabinoid extract at a speed in the range of from 100 to 1000 rpm.

In some embodiments, following spraying and blending, the resulting mixture is held for a period (e.g. in the range of from 30 minutes to 12 hours) before carrying out further processing.

The resulting composition may for example then be sieved through a classifying sieve, typically from 200 micron to 1000 micron, in particular 425 micron.

As discussed above, the solid pharmaceutical composition may contain additional excipients, such as an emulsifier/surfactant (e.g. polyethoxylated castor oil), a filler/binder (e.g. microcrystalline cellulose) and/or an anti-caking agent (e.g. tricalcium phosphate). Excipients may be incorporated at any suitable stage of the method.

In the case where an emulsifier/surfactant (e.g. polyethoxylated castor oil) forms part of the solid pharmaceutical composition, it is typically added to the modified cannabinoid extract prior to incorporation to the porous particulate solid. Thus, in embodiments, the method comprises steps of blending a first cannabinoid extract having a first cannabinoid profile, and a second cannabinoid extract having a second different cannabinoid profile, and an emulsifier, in the presence of a lipophilic solvent, to produce a modified cannabinoid extract; and incorporating (e.g. adsorbing and/or absorbing) the modified cannabinoid extract into/onto the porous particulate solid. As discussed above, it is considered that such solid self-emulsifying compositions have excellent cannabinoid release properties, in that they can assist in forming an emulsion and in releasing high levels of cannabinoid from the solid pharmaceutical composition when contacted with an aqueous environment, and that addition of emulsifier facilitates the dispersion and adsorption/absorption of the lipophilic mixture of cannabinoid and lipophilic solvent to the porous particular solid.

In embodiments where an antioxidant, e.g. a lipophilic antioxidant such as vitamin E (a- tocopherol), is added, the antioxidant is typically also added to the modified cannabinoid extract prior to incorporation of the modified cannabinoid extract to the porous particulate solid.

In embodiments where a filler, binder and/or anti-caking agent forms part of the solid pharmaceutical composition, those excipients may for example be blended with the cannabinoid-containing porous particulate solid following the incorporation step. Accordingly, in embodiments, one or more excipients selected from a filler, binding agent and anti-caking agent is blended with the cannabinoid-containing porous particulate solid following the incorporation step. In some embodiments, microcrystalline cellulose and/or tricalcium phosphate is blended with the cannabinoid- containing porous particulate solid following the incorporation step.

Other excipients may, if desired, be incorporated in a blending step following incorporation of the modified cannabinoid extract to the porous particulate solid. For example a lubricant and/or glidant may be added in such a blending step. In some embodiments, a lubricant is added following the incorporation step. In some embodiments, the lubricant is magnesium stearate or sodium stearyl fumarate.

Solid excipients added during the blending step may, for example, be sieved prior to mixing with other components of the solid pharmaceutical formulation. For example, any solid excipients may be sieved through a classifying sieve, typically from 200 micron to 1000 micron, in particular 425 micron.

The blending step may be carried out using any suitable equipment, for example in some embodiments a blender may be used, e.g. operated at a chopper speed in the range of from 100 rpm to 500 rpm. The blending step is carried out for a sufficient period of time to ensure that the components are well mixed. In some embodiments, the components are blended for a period of time in the range of up to 1 hour, up to 30 minutes, up to 15 minutes, from 5 minutes up to 1 hour, from 5 minutes up to 30 minutes or from 5 minutes up to 15 minutes.

The method as described above produces a solid cannabinoid-containing pharmaceutical composition having blended cannabinoid extracts. Accordingly, in another aspect, there is provided a solid pharmaceutical composition for use in an oral dosage form; the solid pharmaceutical composition having a target cannabinoid profile; and the solid pharmaceutical composition comprising: a first cannabinoid extract having a first cannabinoid profile; a second cannabinoid extract having a second different cannabinoid profile; a lipophilic solvent; and a particulate porous solid.

The components of the solid pharmaceutical composition (e.g. the first cannabinoid extract, the second cannabinoid extract, the lipophilic solvent and the particulate porous solid) are as described above for the method of making the solid pharmaceutical composition. The solid pharmaceutical composition may also contain optional components, such as an emulsifier/surfactant, filler/binder, anti-caking agent, lubricant, and/or the like. The optional components of the solid pharmaceutical composition (for example further cannabinoid extracts, excipients such as emulsifier/surfactant (e.g. polyethoxylated castor oil), filler/binder (e.g. microcrystalline cellulose), anti-caking agent (e.g. tricalcium phosphate), lubricant (e.g. magnesium stearate or sodium stearyl fumarate), and other excipients such as antioxidants, preservatives, glidants and the like) are also as described above.

Blending Solid Pharmaceutical Compositions Containing Cannabinoid Extracts

It has been recognised that solid pharmaceutical compositions containing a target cannabinoid profile may also conveniently be produced by blending of solid pharmaceutical compositions (e.g. free-flowing powders) which contain different cannabinoid extracts. Different cannabinoid extracts having different profiles (e.g. different ratios of cannabinoids and/or different concentrations of a cannabinoid) may each be separately incorporated onto/into a porous particulate solid. The resulting solid cannabinoid-containing compositions, which are typically free-flowing powders, can then be easily combined in the correct proportions to provide a blended composition having the target cannabinoid profile, and allowing provision of tailored dosage forms suitable for a particular indication or patient.

Thus, in another aspect, there is provided a method of making a solid pharmaceutical composition for use in an oral dosage form, the solid pharmaceutical composition comprising one or more cannabinoids, a lipophilic solvent and a porous particulate solid; the solid pharmaceutical composition having a target cannabinoid profile; and the method comprising: incorporating a mixture of a lipophilic solvent and a first cannabinoid extract having a first cannabinoid profile to a porous particulate solid to produce a first solid cannabinoid-containing particulate composition; separately incorporating a mixture of a lipophilic solvent and a second cannabinoid extract having a second different cannabinoid profile to a porous particulate solid to produce a second solid cannabinoid-containing particulate composition; and blending the first solid cannabinoid-containing particulate composition and the second cannabinoid-containing solid particulate composition such that the solid pharmaceutical composition has the target cannabinoid profile.

Steps and features of the method of this aspect which are shared with the methods described above (e.g. the first and second cannabinoid extracts, first and second cannabinoid profiles, the cannabinoid, the target cannabinoid profile, the lipophilic solvent, the porous particulate solid) are as described for the methods described above.

The method of this aspect comprises incorporating (e.g. adsorbing and/or absorbing) a mixture of a lipophilic solvent and a first cannabinoid extract having a first cannabinoid profile to a porous particulate solid to produce a first solid cannabinoid-containing particulate composition, and separately incorporating (e.g. adsorbing and/or absorbing) a mixture of a lipophilic solvent and a second cannabinoid extract having a second different cannabinoid profile to a porous particulate solid to produce a second solid cannabinoid-containing particulate composition.

The mixtures of lipophilic solvent and first or second cannabinoid extract are typically in liquid form, e.g. solutions containing cannabinoid (and optionally excipients) in lipophilic solvent are used.

As discussed above, cannabinoid extracts may be analysed to understand whether one or more target cannabinoids are present and/or how much of a target cannabinoid is present and/or the weight ratio of or more target cannabinoids. Based on that analysis, cannabinoid extracts may be selected for production of solid cannabinoid-containing particulate compositions, which can then be blended to achieve the desired cannabinoid profile. By way of example, a solid pharmaceutical composition may have a target cannabinoid profile which is 20mg CBD/270 mg of composition and 20mg THC/270mg of composition. In order to produce such a composition, a first cannabinoid extract containing 500mg/g CBD and a second cannabinoid extract containing lOOmg/g CBD and 400mg/g THC may respectively be incorporated into a solid cannabinoid-containing particulate compositions at concentrations of 30mg CBD/270mg composition for the first solid cannabinoid- containing pharmaceutical composition, and lOmg CBD/270mg composition and 40mg THC/270mg composition for the second solid cannabinoid-containing pharmaceutical composition, and blending equal quantities of the two compositions to achieve a solid pharmaceutical composition containing 20mg CB D/270 mg composition and 20mg THC/270 mg composition. As a further example, a solid pharmaceutical composition containing 20mg CBD / 270mg composition, and a solid pharmaceutical composition containing 20mg THC / 270mg composition, may be mixed in 1:1 ratios to provide a composition having lOmg of CBD and lOmg of THC per 270 mg of composition.

The steps of incorporating a mixture of first cannabinoid extract and lipophilic solvent to a porous particulate solid, and of separately incorporating a mixture of second cannabinoid extract and lipophilic solvent to a porous particulate solid, may each be carried out in an analogous manner to the incorporation step described for the methods above. For example, any suitable means of contacting the mixture containing lipophilic solvent and first or second cannabinoid extract with a porous particulate solid may be used which enables cannabinoid to be incorporated into and/or onto the porous particulate solid in a controlled manner. For example a mixer equipped with a suitable stirrer or impellor may be used. A high shear mixer blender or high shear mixer granulator may be used, for example. In some embodiments, a high shear mixer granulator is used, such as a high shear mixer granulator produced by GMA and sold under the PM A™ brand name.

The rate of addition of the mixture containing lipophilic solvent and cannabinoid extract, to the porous particulate solid, may be controlled. In some embodiments, the incorporation step comprises adding the cannabinoid extract dropwise to the porous particulate solid, e.g. with continuous gentle mixing, followed by blending the resulting mixture for a period sufficient to obtain the solid cannabinoid- containing particulate composition. The mixture containing lipophilic solvent and cannabinoid extract may for example be added dropwise with a dripper, e.g. provided with an orifice size of between 0.1 mm to 10 mm, for example in the range of from 0.3 mm to 2 mm, or from 2 mm to 6 mm, or from 3 mm to 5 mm, or about 3.0mm, about 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9 mm, about 4.0 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, about 4.9 mm, or about 5.0 mm. A pump which provides for controlled addition may be used, for example a peristaltic pump, such as those produced by Watson Marlow. In some embodiments, a peristaltic pump is used on conjunction with a nozzle having a small orifice size, e.g. in the range of from 3mm to 5 mm. The rate of addition of the mixture containing lipophilic solvent and cannabinoid extract to the porous particulate solid may for example be in the range of from 50 to 2000 drops per minute, e.g. in the range of from 1000 to 2000 drops per minutes, or 500 to 1000 drops per minute, or 60 to 600 drops per minute, or 60 to 360 drops per minute, or 1250 to 1750 drops per minute, or about 1500 drops per minute. During the dropwise addition, the mixture may be gently mixed, e.g. at an impeller speed in the range of from 50 to 400 rpm.

Following addition, the components (e.g. mixture containing lipophilic solvent and cannabinoid extract, and porous particulate solid) may in some embodiments be mixed, and then held without further active mixing for a further period. Such an approach may facilitate contacting of the surfaces of the porous particulate solid with the mixture containing lipophilic solvent and cannabinoid extract, and also allow time for droplets to settle within pores of the porous particulate solid. In some embodiments, the mixture containing lipophilic solvent and cannabinoid extract is mixed with the porous particulate solid for a period in the range of from 2 minutes to 2 hours, or from 5 minutes to 60 minutes. The mixture may for example be blended by mixing at a mixing rate within the range of from lOOrpm to lOOOrpm.

In some embodiments, following mixing, the mixture containing porous particulate solid, lipophilic solvent and cannabinoid extract is held for a period in the range of from 10 minutes to 24 hours, or from 30 minutes to 12 hours, prior to carrying out further processing.

In some embodiments, the steps of incorporating the mixture containing lipophilic solvent and cannabinoid extract into and/or onto the porous particulate solid comprises spraying the mixture containing lipophilic solvent and cannabinoid extract onto the porous particulate solid. In some embodiments, the porous particulate solid is continuously stirred whilst the mixture containing lipophilic solvent and cannabinoid extract is sprayed. In some embodiments, the resulting mixture is blended for a period following addition of the cannabinoid extract (e.g. for a period in the range of from 5 minutes to 60 minutes). The mixture may for example be blended following addition of modified cannabinoid extract at a speed in the range of from 100 to 1000 rpm. In some embodiments, following spraying and blending, the resulting mixture is held for a period (e.g. in the range of from 30 minutes to 12 hours) before carrying out further processing.

The resulting compositions may for example then be sieved through a classifying sieve, typically from 200 micron to 1000 micron, in particular 425 micron.

The method also comprises blending the first solid cannabinoid-containing particulate composition and the second cannabinoid-containing solid particulate composition such that the solid pharmaceutical composition has the target cannabinoid profile. The appropriate quantities of solid cannabinoid-containing particulate compositions are blended together to produce a solid pharmaceutical composition having e.g. the desired concentration of a cannabinoid such as CBD, or the desired ratio and concentrations of CBD and THC. The blending step may be carried out using any suitable equipment, for example in some embodiments a blender may be used, e.g. operated at a chopper speed in the range of from 100 rpm to 500 rpm. The blending step is carried out for a sufficient period of time to ensure that the components are well mixed. In some embodiments, the components are blended for a period of time in the range of up to 1 hour, up to 30 minutes, up to 15 minutes, from 5 minutes up to 1 hour, from 5 minutes up to 30 minutes or from 5 minutes up to 15 minutes.

As discussed above, the solid pharmaceutical composition may contain additional excipients, such as an emulsifier/surfactant (e.g. polyethoxylated castor oil), a filler/binder (e.g. microcrystalline cellulose) and/or an anti-caking agent (e.g. tricalcium phosphate). Excipients may be incorporated at any suitable stage of the method.

In the case where an emulsifier/surfactant (e.g. polyethoxylated castor oil) forms part of the solid pharmaceutical composition, it is typically added to the mixture of first cannabinoid extract and lipophilic solvent, and added to the mixture of second cannabinoid/extract and lipophilic solvent, prior to incorporation into/onto the porous particulate solid. Thus, in some embodiments, the method comprises steps of incorporating (e.g. adsorbing and/or absorbing) a mixture of a lipophilic solvent, an emulsifier/surfactant (e.g. polyethoxylated castor oil) and a first cannabinoid extract having a first cannabinoid profile to a porous particulate solid to produce a first solid cannabinoid-containing particulate composition; and separately incorporating (e.g. adsorbing and/or absorbing) a mixture of a lipophilic solvent, an emulsifier/surfactant (e.g. polyethoxylated castor oil) and a second cannabinoid extract having a second different cannabinoid profile to a porous particulate solid to produce a second solid cannabinoid-containing particulate composition. As discussed above, it is considered that such solid self-emulsifying compositions have good cannabinoid release properties, in that they can assist in forming an emulsion and in releasing high levels of cannabinoid from the solid pharmaceutical composition when contacted with an aqueous environment, and that addition of emulsifier facilitates the dispersion and incorporation of the lipophilic mixture of cannabinoid and lipophilic solvent to the porous particular solid.

In embodiments where one or more antioxidants, e.g. a lipophilic antioxidant such as vitamin E (a-tocopherol), is added, the antioxidant(s) is typically also added to the mixtures containing lipophilic solvent and cannabinoid extract prior to incorporation onto/into porous particulate sohd.

In embodiments where a filler, binder and/or anti-caking agent forms part of the solid pharmaceutical composition, those excipients may, for example, be blended with the solid cannabinoid-containing particulate compositions following the incorporation steps. Accordingly, in some embodiments, one or more excipients selected from a filler, binding agent and anti-caking agent is blended with the solid cannabinoid-containing particulate compositions following the adsorption steps. In some embodiments, microcrystalline cellulose and/or tricalcium phosphate is blended with the solid cannabinoid-containing particulate compositions following the incorporation steps.

Other excipients may if desired be incorporated in a blending step. For example a lubricant and/or glidants may be added in such a blending step. In some embodiments, a lubricant is added following the incorporation step. In some embodiments, the lubricant is magnesium stearate or sodium stearyl fumarate.

Solid excipients added during the blending step may, for example, be sieved prior to mixing with other components of the solid pharmaceutical formulation. For example, any solid excipients may be sieved through a classifying sieve, typically from 200 micron to 1000 micron, in particular 425 micron.

Whilst in some embodiments two solid cannabinoid-containing pharmaceutical compositions are blended, in other embodiments, more than two different solid cannabinoid-containing pharmaceutical compositions are blended to provide the solid pharmaceutical composition with the target cannabinoid profile. For example, in some embodiments, three different solid cannabinoid-containing particulate compositions are blended. In some embodiments, four different solid cannabinoid-containing particulate compositions are blended. In some embodiments, five different solid cannabinoid-containing particulate compositions are blended.

In some embodiments, in order to achieve a desired target cannabinoid profile, where the concentration of cannabinoids in the first and second solid cannabinoid- containing pharmaceutical compositions is high, it may be necessary to prepare a diluted mixture of solid cannabinoid-containing pharmaceutical compositions. In some embodiments this may be achieved, for example, by incorporating an inert filler. In some embodiments, a solid cannabinoid-free particulate composition may be prepared and blended with the other components. Such a composition may for example be prepared by incorporating a lipophilic solvent onto/into a porous particulate solid to produce a solid cannabinoid-free particulate composition. Accordingly, in some embodiments, the method comprises: incorporating a lipophilic solvent to a porous particulate solid to produce a solid cannabinoid-free particulate composition, and blending the first solid cannabinoid-containing particulate composition and the second cannabinoid-containing solid particulate composition with the solid cannabinoid-free particulate composition such that the solid pharmaceutical composition has the target cannabinoid profile.

By way of example, using three solid particulate compositions, one containing 20mg CBD /270mg composition, the second containing 20 mg THC / 270 mg composition, and the third containing no cannabinoid (e.g. only a lipophilic solvent such as MCT taken up into the porous particulate solid), it would be possible to achieve combinations of CBD to THC in amounts/ratios in the range of from 20 mg CBD / 270 mg composition : 0 mg THC / 270 g composition to 0 mg CBD / 270 mg composition : 20 mg THC / 270 g composition.

The method as described above produces a solid cannabinoid-containing pharmaceutical composition having blended first and second cannabinoid-containing particulate compositions. Accordingly, in another aspect, there is provided a solid pharmaceutical composition for use in an oral dosage form; the solid pharmaceutical composition having a target cannabinoid profile; and the solid pharmaceutical composition comprising a blend of: a first solid cannabinoid-containing particulate composition comprising a first cannabinoid extract having a first cannabinoid profile, a lipophilic solvent and a particulate porous solid; and a second solid cannabinoid-containing particulate composition comprising a second cannabinoid extract having a second different cannabinoid profile, a lipophilic solvent and a particulate porous solid.

The first solid cannabinoid-containing particulate composition and second solid cannabinoid-containing particulate composition may be blended in any ratio required to achieve the desired end target profile.

The features of the solid pharmaceutical composition which are shared with the solid pharmaceutical compositions above, and/or with the solid pharmaceutical compositions produced by the methods above (e.g. the first cannabinoid extract, the second cannabinoid extract, the lipophilic solvent, the particulate porous solid, the first solid cannabinoid-containing particulate composition, the second solid cannabinoid- containing particulate composition) are as described for the methods and solid pharmaceutical compositions above.

The solid pharmaceutical composition may also contain optional components, such as emulsifier/surfactant, filler/binder, anti-caking agent, lubricant, and the like.

The optional components of the solid pharmaceutical composition which are shared with the solid pharmaceutical compositions above, and/or with the solid pharmaceutical compositions produced by the methods above (for example further cannabinoid extracts, further solid cannabinoid-containing particulate compositions, lipophilic solvent-containing particulate compositions, excipients such as emulsifier/surfactant (e.g. polyethoxylated castor oil), filler/binder (e.g. microcrystalline cellulose), anti caking agent (e.g. tricalcium phosphate), lubricant (e.g. magnesium stearate or sodium stearyl fumarate), and other excipients such as antioxidants, preservatives, glidants and the like) are also as described for the methods and solid pharmaceutical compositions above.

The present disclosure also provides kits containing different solid cannabinoid-containing particulate compositions. Such kits can be utilised for preparing oral dosage forms containing a desired amount of one or more cannabinoids which are tailored for the patient and/or the condition to be treated. By selecting and blending appropriate amounts of different cannabinoid-containing particulate compositions from the kit, tailored cannabinoid dosage forms can be produced.

Thus, there is also provided a kit for use in making a solid pharmaceutical composition for use in an oral dosage form, the solid pharmaceutical composition having a target cannabinoid profile; and the kit comprising: a first solid cannabinoid-containing particulate composition comprising a first cannabinoid extract having a first cannabinoid profile, a lipophilic solvent and a particulate porous solid; a second solid cannabinoid-containing particulate composition comprising a second cannabinoid extract having a second different cannabinoid profile, a lipophilic solvent and a particulate porous solid; and one or more containers for separate containment of the first and second solid cannabinoid-containing pharmaceutical compositions.

The features of the kit which are shared with the solid pharmaceutical compositions above, and/or with the solid pharmaceutical compositions produced by the methods above (e.g. the cannabinoid, cannabinoid extract, lipophilic solvent, particulate porous solid, first and second solid cannabinoid-containing particulate compositions) are as described for the methods and solid pharmaceutical compositions above.

Any container or containers suitable for separately storing multiple solid cannabinoid-containing particulate compositions may be used. The container(s) is/are typically suitable for preventing contamination of the particulate compositions. The container(s) will typically contain a lid or other means for preventing spillage of components and/or contamination of the contents. In some embodiments, a series of containers may be used. In some embodiments, a container having multiple chambers each for containment of a separate composition is used.

Whilst in some embodiments two solid cannabinoid-containing pharmaceutical compositions are provided in the kit, in other embodiments, more than two different solid cannabinoid-containing pharmaceutical compositions are provided. For example, in some embodiments, the kit comprises three different solid cannabinoid-containing particulate compositions. In some embodiments, the kit comprises four different solid cannabinoid-containing particulate compositions. In some embodiments, the kit comprises five different solid cannabinoid-containing particulate compositions. In some embodiments, the kit comprises a solid cannabinoid- free particulate composition, e.g. a composition which comprises a lipophilic solvent and a particulate porous solid, which is produced by adsorption of lipophilic solvent to a porous particulate solid, and which does not contain cannabinoid.

The provision of kits with a large number of different cannabinoid-containing compositions and/or which contains a solid cannabinoid-free particulate composition, facilitates production of tailored solid pharmaceutical compositions and oral unit dosage forms having tailored amounts of the cannabinoid or cannabinoids of interest.

Dilution of Cannabinoid Extracts

The present disclosure also provides methods of making tailored solid pharmaceutical compositions having a target cannabinoid profile, which are achieved by dilution of a cannabinoid extract using a lipophilic solvent, and adsorption of the appropriately diluted extract to the required quantity of a porous particulate solid. Thus, there is also provided a method of making a solid pharmaceutical composition for use in an oral dosage form, the solid pharmaceutical composition comprising one or more cannabinoids, a lipophilic solvent and a porous particulate solid; the solid pharmaceutical composition having a target cannabinoid profile; and the method comprising: diluting a cannabinoid extract with a lipophilic solvent and producing a modified cannabinoid extract; and incorporating the modified cannabinoid extract to the porous particulate solid; the cannabinoid extract having a concentration of cannabinoid such that, following dilution and incorporation, the solid pharmaceutical composition has the target cannabinoid profile.

The steps and features of the method which are shared with the methods described above, and/or with the solid pharmaceutical compositions described above (e.g. the types of cannabinoids used, analysis of the cannabinoid extracts, the target cannabinoid profile, the nature of the lipophilic solvent, the nature of the porous particulate solid) are as described for the methods and solid pharmaceutical compositions above.

In cases where the solid pharmaceutical composition produced by the method contains excipients such as emulsifier, filler/binder, anti-caking agent, lubricant, glidants and the like, the optional components (for example excipients such as emulsifier (e.g. polyethoxylated castor oil), filler/binder (e.g. microcrystalline cellulose), anti-caking agent (e.g. tricalcium phosphate), lubricant (e.g. magnesium stearate or sodium stearyl fumarate), and other excipients such as antioxidants, preservatives, glidants and the like) are also as described for the methods and solid pharmaceutical compositions above. For example, where the solid pharmaceutical composition produced by the method comprises an emulsifier/surfactant (e.g. such that the composition is self-emulsifying), in some embodiments the emulsifier/surfactant (e.g. polyethoxylated castor oil) is admixed with cannabinoid extract in the presence of lipophilic solvent, prior to incorporation onto/into the porous particulate solid. Dosage Forms

The solid pharmaceutical compositions find use in oral dosage forms, e.g. oral unit dosage forms such as capsules, tablets and the like. Accordingly, there is also provided a method of making a dosage form for oral administration, comprising carrying out a method of making a solid pharmaceutical composition as defined herein, and converting the solid pharmaceutical composition into a dosage form for oral administration.

There is also provided a dosage form for oral administration, comprising a solid pharmaceutical composition as defined herein.

Examples of such oral dosage forms include capsules, tablets, strips, caplets, powders, lozenges, sachets and suspensions. For example, the oral dosage form may be a capsule, such as a hard gelatine capsule or a soft gelatine capsule, or a hydroxypropyl methylcellulose capsule, or a pullulan capsule. In some embodiments, the dosage form is a capsule having a shell which comprises gelatin. In some embodiments, the dosage form is a capsule which comprises hydroxypropyl methyl cellulose. In some embodiments the oral dosage form is a tablet, such as an effervescent tablet. In some embodiments, the oral dosage form is a powder. For example it may be a powder in unit dosage form, present in a sachet. It may be an effervescent powder for example, or a powder for suspension. In some embodiments, the oral dosage form is a sub-lingual or buccal delivered form for local adsorption.

In some embodiments, the oral dosage form is an immediate release dosage form, such as an immediate release capsule. Immediate release capsules include those containing capsule shells formed of excipients such as gelatin or hydroxypropyl methyl cellulose (HPMC).

In some embodiments, the oral dosage form is a modified release dosage form, such as a modified release capsule. Such dosage forms contain excipients that may facilitate sustained/extended release of active from the dosage form over a period of time following oral administration, and/or which may facilitate delayed release of the active from the dosage form. For example, an enteric-coated capsule may be utilised, i.e. a capsule (such as a gelatin or HPMC capsule) which is treated/coated with a material to prevent or reduce degradation in the stomach but permits release of the active further on in the gastrointestinal tract, e.g. in the small intestine. For example, the dosage form may incorporate or comprise a coating that prevents or reduces degradation of the dosage form in an acidic environment. Examples of such coatings include polymers of methacrylic acid and/or methacrylate esters. These are typically anionic polymers containing carboxylate functional groups which tend to be stable at strongly acidic pH but dissolve at weakly acidic, neutral or alkaline pH. Such coatings may be sold under the Eudragit® trade name, for example

In some embodiments, the dosage form is a unit dosage form, e.g. such as a capsule, tablet, caplet, or sachet containing a predetermined dose of cannabinoid- containing solid pharmaceutical composition. In some embodiments, the unit dosage form (e.g. capsule) contains 1 mg of CBD, or 2.5 mg of CBD, or 5 mg of CBD, or 10 mg of CBD, or 20 mg of CBD, or 50 mg of CBD, or 100 mg of CBD, or 150 mg of CBD. In some embodiments, the unit dosage form contains 1 mg of THC, or 2.5 mg of THC, or 5 mg of THC, or 10 mg of THC, or 20 mg of THC, or 40 mg of THC. In some embodiments, the unit dosage form contains CBD and THC, for example in a weight ratio of at least 20:1, at least 1:20, in a weight ratio in the range of from 20:1 to 1:20, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1 about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, or about 1:20.

In some embodiments, the dosage form is a unit dosage form (e.g. capsule), at least 70% by weight of all cannabinoids present in the unit dosage form is CBD, and no other cannabinoid is present in the unit dosage form at more than 5% by weight.

In some embodiments, the dosage form is a unit dosage form (e.g. capsule), at least 70% by weight of all cannabinoids present in the unit dosage form is THC, and no other cannabinoid is present in the unit dosage form at more than 5% by weight.

Any suitable method for producing the oral dosage forms from the solid pharmaceutical composition may be used. For example, in the case of a capsule oral dosage form, the solid pharmaceutical composition may be filled into capsules, e.g. using an encapsulation machine. The filled capsules may then be packaged in a suitable container (e.g. in blister packs, and further in a carton).

Kits for Dosing Different Cannabinoids

The ability to produce tailored solid cannabinoid-containing pharmaceutical compositions and dosage forms containing them also extends to the provision of kits containing multiple dosage forms, each having a different cannabinoid profile. One such example is a kit containing a first set of capsules which contain a first target cannabinoid profile (e.g. 20mg/270mg of CBD, at least 70% by weight of all cannabinoids present in the dosage form is CBD, with no other cannabinoid being present at more than 5% by weight), and containing a second set of capsules which contain a second target cannabinoid profile (e.g. 20mg/270mg of THC, at least 70% by weight of all cannabinoids present in the dosage form is THC, with no other cannabinoid being present at more than 5% by weight). Such a kit finds use in dosage regimes which require dosing of different cannabinoid therapies at different points in time, e.g. dosing of CBD during the daytime (e.g. in the morning and/or in the afternoon) and dosing of THC in the evening, prior to sleep.

Accordingly, in another aspect, there is also provided a kit comprising: a first dosage form for oral administration, comprising a solid pharmaceutical composition comprising a cannabinoid having a first cannabinoid profile, a lipophilic solvent, and a particulate porous solid; a second dosage form for oral administration comprising a solid pharmaceutical composition comprising a cannabinoid having a second different cannabinoid profile, a lipophilic solvent, and a particulate porous solid; and one or more containers for separate containment of the dosage forms.

For the kit of this aspect, in some embodiments the first cannabinoid profile is that the first dosage form comprises CBD, and/or the second cannabinoid profile is that the second dosage form comprises THC. In some embodiments, the first cannabinoid profile is that the first dosage form comprises at least 0.25 mg CBD, at least 0.5mg CBD, at least 0.75mg CBD, at least lmg CBD, at least 1.5mg CBD, at least 2 mg CBD, at least 2.5mg CBD, at least 3 mg CBD, at least 4mg CBD, at least 5mg CBD, at least lOmg CBD, at least 20 mg of CBD, at least 50 mg of CBD, at least 100 mg of CBD, or about 150 mg of CBD, CBD in an amount within the range of from lmg to 150mg, from lmg to lOOmg, from lmg to 50 mg, from lmg to 20 mg, from lmg to 5 mg, about 0.25mg CBD, about 0.5mg CBD, about 0.75mg CBD, about lmg CBD, about 1.5mg CBD, about 2mg CBD, about 2.5mg CBD, about 3mg CBD, about 4mg CBD, about 5 mg CBD, about lOmg CBD, about 20 mg CBD, about 40mg CBD, about 50 mg CBD, about lOOmg CBD, about 150 mg CBD and/or the second cannabinoid profile is that the second dosage form comprises at least 0.25 mg THC, at least 0.5mg THC, at least 0.75mg THC, at least lmg THC, at least 1.5mg THC, at least 2 mg THC, at least 2.5mg THC, at least 3 mg THC, at least 4mg THC, at least 5mg THC, at least lOmg THC, at least 20mg THC, at least 40mg THC, THC in an amount within the range of from lmg to 40mg, from lmg to 20mg, from lmg to 5 mg, about 0.25mg THC, about 0.5mg THC, about 0.75mg THC, about lmg THC, about 1.5mg THC, about 2mg THC, about 2.5mg THC, about 3mg THC, about 4mg THC, about 5 mg THC, about lOmg THC, about 20 mg THC, or about 40 mg THC.

In some embodiments, the first cannabinoid profile is that the weight ratio of CBD to THC in the first dosage form is at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 10:1, at least 20:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 15:1, or about 20:1, and/or that the second cannabinoid profile is that the weight ratio of THC to CBD in the second dosage form is at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 10:1, at least 20:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 15:1, or about 20:1.

In some embodiments, the first cannabinoid profile is that at least 35%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by weight of all cannabinoid present in the first dosage form is CBD, or that substantially all of the cannabinoid present in the first dosage form is CBD, and/or that the second cannabinoid profile is that at least 35%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by weight of all cannabinoid present in the second dosage form is THC, or that substantially all of the cannabinoid present in the second dosage form is THC.

In some embodiments, the first cannabinoid profile is that less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than 95% by weight of all cannabinoid present in the first dosage form is THC, and/or the second cannabinoid profile is that less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than 95% by weight of all cannabinoid present in the second dosage form is CBD.

In some embodiments, the first cannabinoid profile is that at least 70% by weight of all cannabinoid present in the first dosage form is CBD, and at least 70% by weight of all cannabinoid present in the second dosage form is THC. In some embodiments, the first cannabinoid profile is that at least 70% by weight of all cannabinoids present in the first dosage form is CBD, and that no other cannabinoid is present in the first dosage form at more than 5% by weight, and at least 70% by weight of all cannabinoids present in the second dosage form is THC, and that no other cannabinoid is present in the second dosage form at more than 5% by weight.

The dosage forms may for example be any of the oral dosage forms described above. In some embodiments, the dosage forms are unit dosage forms. In some embodiments, the dosage forms are capsules.

Whilst in some embodiments two sets of oral dosage forms may be provided in the kit (e.g. two sets of capsules), in other embodiments where required by the dosage regimen, three or more different sets of oral dosage forms may be provided, each dosage form having a different cannabinoid profile.

Any container or containers suitable for separately storing multiple sets of dosage forms such as capsules may be used. In some embodiments, the container is a blister pack. In some embodiments, multiple blister packs are used. For example, in some embodiments a first blister pack containing capsules of first dosage forms is provided together with a second blister pack containing capsules of second dosage forms. In some embodiments a single blister pack is provided containing capsules of first dosage forms in one section of the blister pack (e.g. the top half) and containing capsules of second dosage forms in another section of the blister pack (e.g. the bottom half).

The container or containers are typically labelled or produced in a manner which allows identification of the respective dosage forms.

Kits for Immediate and Modified Release Oral Dosage Forms

There is also provided a kit comprising: an immediate release dosage form for oral administration, comprising a solid pharmaceutical composition comprising a cannabinoid extract, a lipophilic solvent, and a particulate porous solid; a modified release dosage form for oral administration comprising a solid pharmaceutical composition comprising a cannabinoid extract, a lipophilic solvent, and a particulate porous solid; and one or more containers for separate containment of the immediate release and modified release dosage forms.

The kits allow for administration of cannabinoid therapy which provides for both rapid onset of therapeutic effects, and for sustained duration of activity.

The solid pharmaceutical compositions used in the kits may be a solid pharmaceutical composition as described above, and the components of the solid pharmaceutical compositions (e.g. the cannabinoid extracts, the lipophilic solvent and the particulate porous solid) may also be as described above. The solid pharmaceutical compositions may also contain excipients such as an emulsifier/surfactant (e.g. polyethoxylated castor oil), a filler, binder and/or anti-caking agent (e.g. microcrystalline cellulose and/or tricalcium phosphate) and/or a lubricant (e.g. magnesium stearate, sodium stearyl fumarate) as described above.

The dosage forms may for example be any of the oral dosage forms described above. In some embodiments, the dosage forms are unit dosage forms. In some embodiments, the dosage forms are capsules. In some embodiments, the immediate release dosage form is an immediate release capsule, and the modified release dosage form is a modified release capsule, for example an immediate release capsule and/or modified release capsule as described above.

Any container or containers suitable for separately storing multiple sets of dosage forms such as capsules may be used. In some embodiments, the container is a blister pack. In some embodiments, multiple blister packs are used.

Stability of Compositions and Oral Dosage Forms

It has been found that capsules containing solid pharmaceutical compositions comprising a cannabinoid, lipophilic solvent and porous particulate solid exhibit excellent storage stability properties, with low levels of degradation of cannabinoid.

Accordingly, there is also provided a solid pharmaceutical composition or dosage form as described herein, wherein the solid pharmaceutical composition, dosage form or kit comprises a cannabinoid, and wherein following storage of the solid pharmaceutical composition, unit dosage form or kit for a period of 3 months at 25°C and 60% relative humidity, the amount of the cannabinoid in the solid pharmaceutical formulation, unit dosage form or kit decreases by no more than 10 wt% or 10mol%.

In some embodiments, the cannabinoid is CBD. In some embodiments, the cannabinoid is THC. In some embodiments, the cannabinoid is a mixture of CBD and THC.

In some embodiments, the amount of cannabinoid in the solid pharmaceutical formulation, unit dosage form or kit decreases by no more than 7.5 wt% or 7.5mol% following storage for a period of 3 months at 25°C.

In some embodiments, the amount of cannabinoid in the solid pharmaceutical formulation, unit dosage form or kit decreases by no more than 5 wt % or 5mol% following storage for a period of 3 months at 25°C.

In some embodiments, the amount of cannabinoid in the solid pharmaceutical formulation, unit dosage form or kit decreases by no more than 3 wt% or 3mol% following storage for a period of 3 months at 25°C.

Adherence is an issue which can be associated with some cannabinoid- containing formulations. Cannabinoids can adhere to some materials, e.g. some plastics. When in solution, through fluid dynamics, some active molecules will come into contact with the container. The present solid compositions, which contain the cannabinoid taken up onto/into the porous particulate solid, are understood to protect and/or house the cannabinoid active, providing limited opportunity for contacting of cannabinoid to materials and/or adherence to those materials.

Therapeutic Methods

It will be appreciated that the cannabinoid-containing solid pharmaceutical compositions and dosage forms may be used therapeutically and prophylactically, e.g. in connection with those diseases, disorders and conditions for which administration of a cannabinoid may be beneficial. This includes, for example, treating or lessening the severity of one or more symptoms associated with such a disease, condition or disorder. Examples of such conditions include inflammatory disorders, neurological disorders, psychiatric disorders, malignancies, immune disorders, metabolic disorders, nutritional deficiencies, infectious diseases, gastrointestinal disorders, cardiovascular disorders, cancer, and pain, including chronic and neuropathic pain.

Accordingly, there is provided a method of preventing, treating and/or lessening the severity of a disease, disorder or condition in a subject, wherein the disease disorder or condition is selected from the group consisting of an inflammatory disorder, a neurological disorder, a psychiatric disorder, a malignancy, an immune disorder, a metabolic disorder, a nutritional deficiency, an infectious disease, a gastrointestinal disorder, a cardiovascular disorder, cancer, and pain, and wherein the method comprises administering to the subject in need thereof an effective amount of a solid pharmaceutical composition or dosage form as defined herein.

There is also provided use of a solid pharmaceutical composition, kit or dosage form as defined herein, in the manufacture of a medicament for preventing, treating, and/or lessening the severity of a disease, disorder or condition, wherein the disease or disorder is selected from the group consisting of an inflammatory disorder, a neurological disorder, a psychiatric disorder, a malignancy, an immune disorder, a metabolic disorder, an infectious disease, a gastrointestinal disorder, a cardiovascular disorder, cancer, and pain.

There is also provided a solid pharmaceutical composition or a dosage form as defined herein for use in preventing, treating and/or lessening the severity of a disease, disorder or condition in a subject, wherein the disease is selected from the group consisting of an inflammatory disorder, a neurological disorder, a psychiatric disorder, a malignancy, an immune disorder, a metabolic disorder, a nutritional deficiency, an infectious disease, a gastrointestinal disorder, a cardiovascular disorder, cancer, and pain.

In view of the current understanding regarding clinical applications of cannabinoids, the solid pharmaceutical compositions and oral unit dosage forms as described herein may for example be applicable to diseases, disorders or conditions such as depression, sleeping disorders, eating disorders, cancer, multiple sclerosis, graft versus host disease (GVHD), Parkinson's, epilepsy, autism, tuberculosis, ulcerative colitis, morbus Crohn, inflammatory bowel disorder (IBD), irritable bowel syndrome (IBS), appetite stimulant, appetite depressant, obesity, diabetes, nausea, neuropathic pain, anxiety, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), gastrointestinal disorders, hypertension, incontinence, pruritus, arthritis, arthrosis, rheumatic inflammation, insomnia, mycosis, local and/or chronic pain, inflammation, attention deficit and hyperactivity disorder (ADDH), vomiting, atopic dermatitis, fibromyalgia, autoimmune deficiency syndrome (AIDS), mood disorders, erectile dysfunction, cancer, premature ejaculation, bone growth, and treatment resistant epilepsy, in particular treatment resistant childhood epilepsy.

In some embodiments, the subject to whom the cannabinoid is administered is an animal, e.g. a mammal. In some embodiments the subject is a human. In other embodiments the subject is a non-human animal, e.g. a non-human mammal.

The dose or frequency of administering the solid pharmaceutical composition or the oral dosage formulation as described herein may for example be dependent on factors such as the age, weight, general physical condition of the subject, or other clinical symptoms specific to the subject to be treated. Pharmacokinetic and Release Properties

It has been found that dosage forms comprising solid pharmaceutical compositions which contain cannabinoid, lipophilic solvent and porous particulate solid release cannabinoid effectively under aqueous conditions.

Accordingly, there is also provided a solid pharmaceutical composition or dosage form as defined herein, wherein following contacting of the composition or unit dosage form with an aqueous environment, at least 50% by weight of cannabinoid is released within 1 hour.

In some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by weight of cannabinoid is released within 1 hour. The term “released” refers to cannabinoid being present in the aqueous environment, rather than incorporated into and/or onto or in some manner physically and intimately associated with the porous particulate solid. The amount of cannabinoid released at a given time may for example be measured by determining the concentration of cannabinoid in the aqueous environment.

In some embodiments, the solid pharmaceutical composition or oral unit dosage form comprises CBD, and wherein following contacting of the solid pharmaceutical composition or oral unit dosage form with an aqueous environment, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% by weight of the CBD is released within 1 hour. In some embodiments, at least 50% by weight of the CBD is released within 45 minutes, within 30 minutes, within 20 minutes or within 15 minutes.

In some embodiments, at least 70% by weight of all cannabinoids present in the solid pharmaceutical composition or dosage form is CBD, and no other cannabinoid is present in the solid pharmaceutical composition or dosage form at more than 5% by weight, and wherein following contacting of the solid pharmaceutical composition or dosage form with an aqueous environment, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% by weight of the CBD is released within 1 hour. In some embodiments, at least 50% by weight of the CBD is released within 45 minutes, within 30 minutes, within 20 minutes or within 15 minutes. In some embodiments, the solid pharmaceutical composition or oral unit dosage form comprises THC, and wherein following contacting of the solid pharmaceutical composition or oral unit dosage form with an aqueous environment, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% be weight of the THC is released within 1 hour. In some embodiments, at least 50% by weight of the THC is released within 45 minutes, within 30 minutes, within 20 minutes or within 15 minutes.

In some embodiments, at least 70% by weight of all cannabinoids present in the solid pharmaceutical composition or dosage form is THC, and no other cannabinoid is present in the solid pharmaceutical composition or dosage form at more than 10% by weight or at more than 5% by weight, and wherein following contacting of the solid pharmaceutical composition or dosage form with an aqueous environment, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% by weight of the THC is released within 1 hour. In some embodiments, at least 50% by weight of the THC is released within 45 minutes, within 30 minutes, within 20 minutes or within 15 minutes.

Tests for determining release profiles of active ingredient from pharmaceutical compositions and dosage forms (e.g. capsules) in an aqueous environment are known in the art. For example, dissolution tests for tablets and capsules is described in the British Pharmacopeia (see Appendix XII B. Dissolution). In some embodiments, dissolution testing is carried out in accordance with the British Pharmacopeia Dissolution Test for Tablets and Capsules. In some embodiments, dissolution testing is carried out in accordance with the British Pharmacopeia Dissolution Test for Tablets and Capsules, using Apparatus 2 (Paddle apparatus). In some embodiments, the aqueous environment is 0.5% aqueous hexadecyltrimethylammonium bromide comprising a phosphate buffer at pH 6.8, and wherein the contacting is carried out at 37°C ± 0.5°C with stirring at 100 rpm.

It is expected that, due to the provision of compositions and unit dosage forms which release cannabinoid quickly on contact with aqueous environment, the solid pharmaceutical compositions and dosage forms of the present disclosure provide predictable and high oral bio availability of cannabinoid following oral administration, and provide a good pharmacokinetic profile of the active. For example, the compositions and dosage forms may achieve one or more of the following compared with administration of a comparable dose of cannabinoid by a conventional oral dosage formulation such as an oil: a) higher plasma C _max of cannabinoid; b) increased AUC; and c) improved Tmax. This may in turn enable dosing of lower amounts of cannabinoid compared with existing conventional oral formulations.

The compositions and dosage forms are also expected to provide reduced variability in pharmacokinetic parameters of the active over a course of therapy involving repeated administrations, given that the compositions and dosage forms have precisely controlled amounts of cannabinoid active, and have good storage stability properties.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Examples

The following examples are to be understood as illustrative only. They should therefore not be construed as limiting the invention in any way.

Example 1: Analysis of Cannabinoid Content in Cannabinoid Extracts

For preparation of solid pharmaceutical compositions, amounts of active ingredients were obtained as cannabinoid extracts containing certain amounts of cannabinoid agent(s). Cannabinoid content in cannabinoid extracts was analysed by validated methodology that included HPLC analysis.

Two different representative batches of cannabinoid extracts, Batch A and Batch B, were assayed, and the results are shown in Tables 1 and 2. Table 1. Analysis of cannabinoid content in Batch A

Table 2. Analysis of cannabinoid content in Batch B

The assays showed that batch A predominantly contained THC, and batch B predominantly contained CBD.

Example 2: Preparation of Solid Pharmaceutical Compositions and Oral Dosage Forms

Solid pharmaceutical compositions including the amounts of active ingredients and excipients as described in the tables below were prepared according to the following procedures.

A required amount of a cannabinoid resin according to Example 1, containing CBD, THC or a 1:1 mixture of CBD:THC, was placed into a stainless steel or glass container. Approximately half of the required amount of medium chain triglyceride (MCT) was transferred into the container with the resin and a suitable size magnetic stirring bar or blender was placed into the container. The mixture was stirred slowly at a speed which avoids formation of a vortex until the resin has dissolved. Vitamin E may optionally be added into the container. The remainder of the MCT was then added to the container, and the mixture was blended until homogenous. Amounts of cannabinoid and MCT were used so as to make up 60 mg of the solid pharmaceutical composition. For example, cannabinoid may be present in a resin at about 80% by weight of the resin, with the remainder being MCT. In the case of preparing a solid pharmaceutical composition containing e.g. 10 mg cannabinoid, for example, 12.25 mg of an 80% strength resin was used, and an additional amount of 47.75 mg MCT was also used to make up the combined total of 60 mg. This is reported in the table below as 10 mg API and 50mg MCT. The required amount of emulsifier/surfactant (polyoxyl castor oil: Kolliphor ^® EL) was added to the lipophilic solution of the cannabinoid(s) and blended for 10-30 minutes at a speed which avoids vortexing.

The required amount of colloidal anhydrous silica was transferred to the blender and the pre-defined amount of lipophilic solution of the cannabinoid(s) was added dropwise at a rate of approximately 60-360 drops per minute to the silica which was under continuous stirring at an impeller speed of between 150 to 400 rpm.

After the lipophilic solution had been added, the mixture was blended for about 10 minutes at an impeller speed of 200-1000 rpm. Any lumps were removed by passing the solid self-emulsifying composition through a 425 micron aperture sieve.

Prior to addition of the excipients, each of the dry powder excipients was sieved through a 425 micron aperture sieve. The pre-sieved microcrystalline cellulose and tricalcium phosphate were transferred to the blender and spread over the solid self- emulsifying composition bed. The impeller speed was then set to between 200 and 500 rpm and the mixture was blended for approximately 15-30 minutes until a homogeneous blend was achieved. The pre-sieved magnesium stearate, or the pre-sieved sodium stearyl fumarate, was then transferred to the blender, the impeller speed was set to between 200 and 500 rpm and the mixture was blended for 120 to 300 seconds. The final master blend was then discharged into a suitable intermediate bulk container for transport and/or storage.

The final master blend may be processed in an encapsulation machine to fill hard shell gelatin capsules (i.e. oral unit dosage forms). The filled hard shell gelatin capsules may then be packaged in blister packs and further packaged in approved size “shelf-ready” cartons.

Solid Pharmaceutical Composition 1

Solid Pharmaceutical Composition 2

Solid Pharmaceutical Composition 3

Solid Pharmaceutical Composition 4

Solid Pharmaceutical Composition 5

Solid Pharmaceutical Composition 6

Solid Pharmaceutical Composition 7

Solid Pharmaceutical Composition 8

Solid Pharmaceutical Composition 9

Solid Pharmaceutical Composition 10

Example 3: Preparation of Solid Pharmaceutical Composition and Capsule Dosage Form from Multiple Cannabinoid Extracts

A free-flowing self-emulsifying powder composition is produced having a target cannabinoid profile of: 1.4% w/w cannabidiol (CBD), 1.4% w/w of delta-9- tetrahydrocannabinol (THC), at least 70% by weight of all cannabinoid being either CBD or THC, and no other cannabinoid being present in more than 5% by weight. lg of a first cannabinoid extract having cannabinoid content as described above for Batch A of Example 1 (i.e. having 74.7% w/w THC and no more than 5% w/w of any other cannabinoid) is diluted with 5g medium chain triglycerides to provide a liquid having 12.5% w/w CBD. lg of a second cannabinoid extract having cannabinoid content as described above for Batch B of Example 1 (i.e. having 75.4% w/w CBD and no more than 5% w/w of any other cannabinoid) is diluted with 5.05g medium chain triglycerides to provide a liquid having 12.5% w/w CBD. 3g of each liquid is mixed together, lg of polyoxyl castor oil is added, and the resulting mixture blended until homogeneous, providing 7g of a modified cannabinoid extract containing 5.4% w/w CBD and 5.4% w/w THC.

The modified cannabinoid extract is added dropwise with continuous stirring to 6g of colloidal anhydrous silica (Aeroperl 300 Pharma®), the resulting mixture is stirred for a period of 30 minutes, and then held for a further period of 2 hours, to provide a solid composition which is filtered through a 425 micron aperture sieve, and provides 13g of a solid particulate composition containing 2.9 % w/w CBD and 2.9% w/w THC.

9g of pre- sieved microcrystalline cellulose and 4g of pre- sieved granular tricalcium phosphate are added, and the mixture is blended for 30 minutes. 200 mg of pre-sieved sodium stearyl fumarate is added, and the mixture is blended for 5 minutes, producing 26.2g of a free-flowing powder containing 1.4 % w/w CBD and 1.4% w/w THC.

The solid pharmaceutical composition is filled into gelatin capsule at an amount of 270 mg per capsule.

Example 4: Preparation of Solid Pharmaceutical Composition and Capsule Dosage Form from Multiple Cannabinoid Extracts

A free-flowing self-emulsifying powder composition is produced having a target cannabinoid profile of: 4.2% w/w of delta-9-tetrahydrocannabinol (THC), 1.4% w/w of cannabidiol (CBD), at least 70% by weight of all cannabinoid being either CBD or THC, and no other cannabinoid being present in more than 5% by weight.

3g of a first cannabinoid extract having cannabinoid content as described above for Batch A of Example 1 (i.e. having 74.7% w/w THC and no more than 5% w/w of any other cannabinoid) is diluted with 3.05g medium chain triglycerides to provide 6g of liquid having 37.0% w/w THC. To 3g of the liquid is added 0.5g of polyoxyl castor oil, and the resulting mixture blended until homogeneous, providing 3.5g of a liquid containing 31.7% w/w THC. The liquid is added dropwise with continuous stirring to 3g of colloidal anhydrous silica (Aeroperl 300 Pharma®), the resulting mixture is stirred for a period of 30 minutes, and then held for a further period of 2 hours, to provide a solid composition which is filtered through a 425 micron aperture sieve, and provides 6.5g of a solid particulate composition containing 17.1 % w/w THC. lg of a second cannabinoid extract having cannabinoid content as described above for Batch B of Examples 1 (i.e. having 75.4% w/w CBD and no more than 5% w/w of any other cannabinoid) is diluted with 5.05g medium chain triglycerides to provide a liquid having 12.5% w/w CBD. To 3g of the liquid is added 0.5g of polyoxyl castor oil, and the resulting mixture blended until homogeneous, providing 3.5g of a liquid containing 10.7% w/w CBD. The liquid is added dropwise with continuous stirring to 3g of colloidal anhydrous silica (Aeroperl 300 Pharma®), the resulting mixture is stirred for a period of 30 minutes, and then held for a further period of 2 hours, to provide a solid composition which is filtered through a 425 micron aperture sieve, and provides 6.5g of a solid particulate composition containing 5.8 % w/w CBD.

The solid particulate compositions are blended together in a mixer with stirring for a period of 30 minutes.

9g of pre- sieved microcrystalline cellulose and 4g of pre- sieved granular tricalcium phosphate are added, and the mixture is blended for 30 minutes. 200 mg of pre-sieved sodium stearyl fumarate is added, and the mixture is blended for 5 minutes, producing 26.2g of a free-flowing powder containing 4.2% w/w THC and 1.4% w/w CBD.

The solid pharmaceutical composition is filled into gelatin capsule at an amount of 270 mg per capsule.

Example 5: Preparation of Solid Pharmaceutical Composition and Capsule Dosage Form from Cannabinoid Extract

A free-flowing self-emulsifying powder composition is produced having a target cannabinoid profile of: 1.4% w/w of delta-9-tetrahydrocannabinol (THC), at least 70% by weight of all cannabinoid being THC, and no other cannabinoid being present in more than 5% by weight. lg of a first cannabinoid extract having cannabinoid content as described above for Batch A of Example 1 (i.e. having 74.7% w/w THC and no more than 5% w/w of any other cannabinoid) is diluted with 5g medium chain triglycerides to provide a liquid having 12.5% w/w THC. To 3g of the liquid is added lg of polyoxyl castor oil, and the resulting mixture blended until homogeneous, providing 4g of liquid. Analysis of the liquid indicates that it contains 9.4% w/w THC. 3g of medium chain triglycerides is added to further dilute the THC, and the mixture stirred. Analysis of the liquid indicates that is contains 5.4% w/w THC.

The modified cannabinoid extract is added dropwise with continuous stirring to 6g of colloidal anhydrous silica (Aeroperl 300 Pharma®), the resulting mixture is stirred for a period of 30 minutes, and then held for a further period of 2 hours, to provide a solid composition which is filtered through a 425 micron aperture sieve, and provides 13g of a solid particulate composition containing 2.9 % w/w THC.

9g of pre- sieved microcrystalline cellulose and 4g of pre- sieved granular tricalcium phosphate are added, and the mixture is blended for 30 minutes. 200 mg of pre-sieved sodium stearyl fumarate is added, and the mixture is blended for 5 minutes, producing 26.2g of a free-flowing powder containing 1.4% w/w THC.

The solid pharmaceutical composition is filled into gelatin capsule at an amount of 270 mg per capsule.

Example 6: Analysis of Cannabinoid Content of Solid Pharmaceutical Compositions in Oral Unit Dosage Forms

Cannabinoid content was analysed in the solid pharmaceutical compositions contained in capsules (oral unit dosage forms) as prepared in Example 2.

Solid pharmaceutical compositions were analysed for cannabinoid content by validated HPLC assays. To obtain samples suitable for HPLC analysis, a capsule content (i.e. solid pharmaceutical composition comprising oral unit dosage forms) was transferred into a vessel, to which HPLC grade methanol was added. The resulting mixture was submitted to ultrasonication for at least 30 minutes, before being centrifuged at 16400 rpm for 5 minutes. Add methanolic KOH, mix and allow to stand for 10 minutes before neutralising with HC1, before being centrifuged at 16400rpm for 5 minutes. The supernatant was transferred into a HPLC vial. The resulting soluble components were analysed for their cannabinoid content by validated HPLC-UV analysis. Results of assays for a representative batch of solid oral dosage forms comprising the solid pharmaceutical composition 4 of Example 2 (containing lOmg THC and lOmg CBD) are shown in Table 3.

Solid pharmaceutical compositions were also analysed for common pathogens using validated microbiological assays. Results of assays for a representative batch of solid oral dosage forms comprising the solid pharmaceutical composition 4 of Example 2 (containing lOmg THC and lOmg CBD) are shown in Table 4.

Solid pharmaceutical compositions were also analysed for homogeneity in loading between two different loading levels and different batches (4 of potency level 1 for solid pharmaceutical composition 7 described above and 3 of potency level 2 for solid pharmaceutical composition 9 as described above). The relative standard deviation (RSD) is extremely low for all batches indicating a very low degree of variation between batches, as is shown in Table 5. Further to this, to indicate homogeneity following capsule filling, capsule weights (capsule (with their inherent variability) plus powder) for 2230 capsules in a batch were tested and provided a minimum weight of 323 mg, a maximum of 374.1, a mean of 356.2, a standard deviation of 8.3 and an RSD of 2.3% again indicating a high degree of homogeneity and consistency between capsules within a batch.

Table 3. Analysis of cannabinoid content in the solid pharmaceutical composition containing lOmg THC and lOmg CBD

Table 4. Microbiological analysis of the solid pharmaceutical composition containing lOmg THC and lOmg CBD

Table 5. Analysis of homogeneity of CBD and THC loaded at 1:1 ratio where: Level = batch number indicating potency i.e. Level 2 higher loading of CBD/THC than Level 1;

T = top value; M = middle value; B = bottom value; and Av = average value. Example 7: Stability of Cannabinoid Agents in Oral Unit Dosage Forms A study was carried out to determine the stability of cannabinoid agents contained in capsule oral dosage forms as prepared in Example 2, when subjected to storage in blister packs.

Representative capsule oral unit dosage forms containing 2.5mg THC or 2.5mg CBD were stored in blister packs at the temperature of 25 C and relative humidity of 60% (conditions defined under ICH guidelines for stability testing), and analysed for cannabinoid content. The results are shown in Table 6.

Table 6. Analysis of cannabinoid content in capsule oral dosage forms containing 2.5mg THC or 2.5mg CBD over the period of 6 months storage in blister packs

The results indicate that, following storage in blister packs over a period of 6 months under ICH-defined conditions for stability testing, the capsule oral dosage forms retained high levels of cannabinoid content. Example 8: Time-Dependent In Vitro Release of Cannabinoid Agents from Oral Unit Dosage Forms

A study was carried out to determine the rate of release of cannabinoid agents from capsule oral unit dosage forms as prepared in Example 2. Dissolution was performed on CBD or THC-containing capsules using pH 6.8 phosphate buffer and 0.5% hexadecyltrimethylammonium bromide (cetyltrimethylammonium bromide, CTAB) as dissolution media.

The tests were carried out in accordance with the Dissolution Test for Tablets and Capsules (Dissolution Test for Solid Dosage Forms) as per the British

Pharmacopoeia, Appendix XII B. Dissolution. Apparatus 2 (Paddle apparatus was used)

Dissolution media was prepared by dissolving 34g potassium dihydrogen phosphate and 4.5g of sodium hydroxide in 5L of water. pH was adjusted to pH 6.8 ±0.05 with phosphoric acid or sodium hydroxide solution. 25g of CTAB was added and the solution mixed thoroughly. The media was filtered under vacuum through a Millipore 0.45 pm HVLP filter prior to use.

500mL of the dissolution media was transferred to 6 separate vessels and allowed to equilibrate at 37°C. An additional quantity of 900mL dissolution media was transferred to a further vessel.

Six capsules each containing lOmg CBD and 10 mg THC, and the composition of Example 2 (prepared in analogous manner to solid pharmaceutical composition 1), were placed in separate stainless steel sinkers, and dropped into separate dissolution vessels, and the tests commenced immediately. Test parameters were as follows:

Table 7. Dissolution test parameters 10 mL sample was withdrawn from each vessel at the timepoints indicated in the table below, filtered through a 0.45 pm nylon filter, analysed by HPLC. The volume withdrawn was replaced with 10 mL dissolution media from the further vessel. The test was repeated with a further batch of 6 capsules (12 capsules in total). Results are shown in Table 8 and indicate the % cannabinoid released.

Table 8. In vitro dissolution profile of cannabinoid agents from oral dosage forms containing lOmg THC and lOmg CBD The results show that the cannabinoid agents are released from capsule oral unit dosage forms at a high rate, with approximately 50% dissolved after 15 minutes.

A similar in vitro release experiment was also carried out on a THC:CBD 2.5 mg:2.5 mg composition with the results shown in Table 9.

Table 9. In vitro dissolution profile of cannabinoid agents from oral dosage forms containing 2.5mg THC and 2.5mg CBD

The results show that the cannabinoid agents are released from the capsule oral unit dosage forms at a high rate with the majority having been released by 30 min and very high levels of release in under 60 min.