Compositions and Methods

Abstract

The present invention relates to a solid composition containing a fat-soluble drug (such as a cannabinoid or vitamin E) and cyclodextrin, wherein the fat-soluble drug and cyclodextrin are in the form of a complex, and the molar ratio of the fat-soluble drug to cyclodextrin in the complex is about 1:2, and a method for obtaining the same.

Description

Technical Field

[0001] Related Applications The present invention relates to a solid composition containing a fat-soluble drug and cyclodextrin, a method for obtaining the same, its formulation, and its use for therapeutic purposes and non-therapeutic purposes.

Background Art

[0002] Improving the solubility of poorly water-soluble fat-soluble drugs is an ongoing challenge in pharmaceutical formulations.

[0003] Fat-soluble drugs (especially those with a logP value exceeding 1) are known to have low solubility in aqueous media. Using such drugs as therapeutic agents involves many problems due to their low solubility, resulting in a decrease in bioavailability, and thus a decrease in effectiveness and an increase in side effects.

[0004] For example, cannabinoids represent a type or group of fat-soluble drugs with low water solubility.

[0005] Cannabinoids are fat-soluble compounds contained in cannabis. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta9-THC or delta8-THC), which is the main psychoactive compound contained in cannabis. Cannabidiol (CBD) is another major component of this plant.

[0006] Certain cannabinoids may be useful for the treatment of various medical conditions such as pain, chronic pain, inflammation, alcoholism, drug addiction, depression, post-traumatic stress disorder, anxiety, multiple sclerosis, epilepsy, Parkinson's disease, etc. Cannabinoids may also be useful for improving the side effects of chemotherapy.

[0007] The endocannabinoid system (ECS) regulates many functions of the human body. The ECS plays an important role in various aspects of neural function, such as the control of movement and coordinated movement, learning and memory, emotion and motivation, addictive-like behavior, and pain regulation.

[0008] The ECS is an ecosystem consisting of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed throughout the central nervous system (including the brain) and peripheral nervous system of vertebrates.

[0009] Two major cannabinoid receptors (CBRs), CB1 and CB2, have been identified. Cannabidiol (CBD) is a naturally occurring cannabinoid that mainly binds to the CB2 receptor and is an allosteric inhibitor of the CB1 receptor.

[0010] To obtain a desirable therapeutic effect, an appropriate administration route is the key. For example, cannabinoids are formulated to be soluble in alcohol for oral administration. For example, a spray mist containing nabiximol for the relief of neuropathic pain is a spray in which CBD and THC are dissolved in a mixture of ethanol and propylene glycol at a ratio of about 1:1. Cannabinoids can be prepared for administration as an injectable formulation by dissolving them in an oil.

[0011] However, such formulations have many drawbacks, such as the problem that it is difficult to sterilize oils. Therefore, by increasing the solubility of cannabinoids, more administration forms will be possible in a safe and cost-effective way.

[0012] Therefore, there is a need for new formulations for poorly soluble lipophilic drugs such as cannabinoids (e.g., CBD) and certain vitamins (e.g., vitamin E) to increase their solubility in aqueous media, thereby enhancing drug absorption, bioavailability, and ultimately efficacy. The process for obtaining such new formulations should be low-cost, and the resulting products are preferably stable and free of toxic excipients.

SUMMARY OF THE INVENTION

[0013] The present invention aims to address the above problems by providing a solid composition comprising a lipophilic drug such as a cannabinoid and a cyclodextrin. This is achieved by the process described herein. This process allows for fine control of the complexation process and importantly results in almost complete complexation of the lipophilic drug. In existing cyclodextrin complexation processes, such a level of control is not possible, so while an improvement in the solubility of lipophilic drugs may be observed using such an approach, even if at a seemingly significant level, the product is generally a mixture of partially complexed substances, cyclodextrin starting materials, and uncomplexed drug. Thus, the improved solubility is not optimal in that not all of the available cyclodextrin is complexed with the drug, or in other words, not all of the lipophilic drug introduced into the system is complexed.

[0014] By the process described herein, it is possible to complex almost all of the lipophilic drug introduced into the system with cyclodextrin, which can result in an improvement in the water solubility of the complexed drug that is orders of magnitude greater than that achieved by the prior art compared to the uncomplexed form in some embodiments.

[0015] As is apparent from the data shown below, a composition comprising a lipophilic agent (e.g., a cannabinoid) and cyclodextrin according to the present invention can have significantly improved solubility and / or bioavailability compared to a similar composition comprising a single (i.e., "uncomplexed" or "non-polymeric") lipophilic agent (e.g., a cannabinoid).

[0016] Accordingly, a first aspect of the present invention is a solid composition comprising a lipophilic agent and cyclodextrin, wherein the lipophilic agent and cyclodextrin are in the form of a complex, and the molar ratio of the lipophilic agent to cyclodextrin in the complex is about 1:2.

[0017] A second aspect of the present invention is the solid composition according to the first aspect for use in the treatment of a disease, disorder or medical condition.

[0018] A third aspect of the present invention is a method of treating a disease, disorder or medical condition, comprising administering the solid composition of the first aspect of the present invention to a subject.

[0019] A fourth aspect of the present invention is the use of the solid composition of the first aspect of the present invention in the manufacture of a medicament for the treatment of a disease, disorder or medical condition.

[0020] A fifth aspect of the present invention is a non-therapeutic use of the solid composition of the first aspect of the present invention.

[0021] A sixth aspect of the present invention is a process for producing a solid composition comprising a lipophilic agent and cyclodextrin, wherein the lipophilic agent and cyclodextrin are in the form of a complex in a molar ratio of about 1:2, and wherein the process comprises the following steps. a. providing a lipophilic agent, b. providing cyclodextrin, c. combining the lipophilic agent and cyclodextrin in the presence of water to form a composition. d. Mixing the composition until a complex of the lipophilic agent and cyclodextrin precipitates; e. Recovering the precipitate of step d. to provide a solid composition comprising the lipophilic agent and cyclodextrin in the form of a complex.

[0022] The seventh aspect of the present invention is a solid composition obtained by the process of the sixth aspect of the present invention.

[0023] The eighth aspect of the present invention is the solid composition of the first aspect when produced by the process of the sixth aspect.

Brief Description of the Drawings

[0024]

Figure 1

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Figure 4(a)

Figure 4(b)

Figure 4(c)

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Figure 6

Figure 7

Modes for Carrying Out the Invention

[0025] According to a first aspect of the present invention, there is provided an oral solid composition comprising a lipophilic drug and cyclodextrin, wherein the lipophilic drug and cyclodextrin are in the form of a complex, and the molar ratio of the lipophilic drug and cyclodextrin in the complex is about 1:2.

[0026] The complex at a molar ratio of about 1:2 can provide certain advantages in terms of improving the solubility, and / or release profile, and / or bioavailability, and / or stability, and / or formulation for delivery, and / or commercial viability of the complexation process and the complexed product, and / or optimization of the amount of lipophilic drug complexed within a batch, and / or the ability to complex a particular lipophilic drug.

[0027] Without wishing to be bound by theory, it is believed that the dimeric complex is formed sequentially. First, a lipophilic drug such as a cannabinoid complexes with cyclodextrin in a 1:1 molar ratio to form a monomer, and then the monomer further complexes with an equivalent amount of cyclodextrin to form a dimeric complex (i.e., the molar ratio of the lipophilic drug such as a cannabinoid to cyclodextrin is about 1:2).

[0028] Therefore, when a composition containing such a dimer complex is administered in vivo, the dimer is considered to dissociate into 1 equivalent of monomer (i.e., a lipophilic drug such as a cannabinoid remains complexed with 1 cyclodextrin molecule initially) and 1 equivalent of free cyclodextrin. As a result, the technical advantage that the complex maintains solubility even after this partial dissociation is obtained, and thus the lipophilic drug is not excreted and can be absorbed into the bloodstream as a monomer or dimer complex. When absorbed into the bloodstream and diluted in plasma, more dimers dissociate into monomers. The monomers further dissociate to release lipophilic drugs such as cannabinoids. In this way, complete dissociation and release of the lipophilic drug into the bloodstream are achieved. Conversely, if the dimer immediately dissociates into free cyclodextrin and free lipophilic drug after administration in the body and before absorption into the bloodstream, the lipophilic drug simply precipitates and is excreted and cannot be used for absorption. Therefore, administration in the form of a cyclodextrin dimer can improve the solubility and / or bioavailability of the lipophilic drug.

[0029] Furthermore, in embodiments of the present disclosure, the dimer has lower water solubility compared to the monomer (i.e., a lipophilic drug complexed with cyclodextrin in a 1:1 molar ratio), which facilitates the preparation process because the dimer selectively precipitates from the aqueous reaction mixture. This may be particularly applicable when using β-cyclodextrin as the specific cyclodextrin in the complex based on its relatively low water solubility compared to other natural cyclodextrins. When using other cyclodextrins such as α- or γ-cyclodextrin, it is desirable to combine the lipophilic drug and cyclodextrin in an aqueous solvent. That is, water can be mixed with other solvents such as alcohol to appropriately change the solubility of the complex product and make it lower than its equilibrium concentration.

[0030] The term "comprising" or its variants is understood to mean that it includes the recited elements, components or steps, or groups of elements, components or steps, but does not imply excluding other elements, components or steps, or groups of elements, components or steps. The terms "comprising" or "comprises" include references to components that consist essentially of the relevant features (e.g., consisting of).

[0031] The terms "consisting" or "consists" or their variants are understood to mean that they include the recited elements, components or steps, or groups of elements, components or steps, and imply excluding other elements, components or steps, or groups of elements, components or steps.

[0032] As used herein, the term "complex" refers to a chemical complex in which the complex has one or more chemical and physical properties that are different from the properties of the individual starting chemical substances and from the properties of a mixture in which the chemical substances form the complex without interacting. "Complex" also includes inclusion complexes in which a chemical compound ("host") has a cavity that can accommodate a "guest" compound. The complex of a lipophilic agent and cyclodextrin of the present disclosure is a complex (1:2 complex or "dimer") in which the lipophilic agent is simultaneously accommodated or "hosted" within two cyclodextrin molecules. "Complex" does not include clathrates or cyclodextrin-based complexes crosslinked by, for example, crosslinked portions where cyclodextrin molecules are covalently bonded.

[0033] As used herein in connection with drugs that complex with cyclodextrin, the term "lipophilic" is broadly construed as a compound having poor water solubility such that the drug requires complexation with cyclodextrin to improve its solubility for formulation or delivery in the body. In certain embodiments, this term may relate to Class II or Class III compounds as defined and measured under the Biopharmaceutics Classification System (BCS) that classifies drugs based on both solubility and permeability. In certain embodiments, a lipophilic agent can have a logP of from 3 to 9, preferably from 4 to 8, more preferably from 5 to 8, or from 5 to 7. In certain embodiments, a lipophilic agent can have a size of from 100 g / mol to 700 g / mol, preferably from 200 g / mol to 600 g / mol. In certain embodiments, for a lipophilic agent, any two or more of the following descriptions may apply. That is, being a Class II or Class III compound of the BCS, and / or having a logP of from 100 g / mol to 700 g / mol, preferably from 200 g / mol to 600 g / mol, and / or having a logP of from 5 to 8, including from 3 to 9, preferably from 4 to 8, more preferably from 5 to 7, any two or more thereof.

[0034] As used herein in connection with the process of the sixth aspect in which a complex of a lipophilic agent and cyclodextrin precipitates, the term "precipitates" means that the complex is formed in solution and drops out of the solution as a solid complex. While the reaction to form the complex is still proceeding, preferably both the lipophilic agent and cyclodextrin are in a saturated state in the solution, and thus during this period, the precipitation of the complex may not reduce the concentration of either starting material or the dissolved complex, but nevertheless, for the purposes herein, it is considered precipitation.

[0035] In a first aspect of the invention, the composition comprises a complex between a lipophilic agent and cyclodextrin.

[0036] Properly, the lipophilic drug and cyclodextrin form an inclusion complex, where the "host" is the cyclodextrin and the "guest" is the lipophilic drug.

[0037] Cyclodextrin (CD) is a group of cyclic oligosaccharides consisting of a large cyclic ring of glucose subunits linked by α-1,4 glycosidic bonds. Cyclodextrins are used in pharmaceutical development to improve the water solubility, dissolution rate, and absorbability of many lipophilic drugs. Cyclodextrins, which are hydrophobic on the inside and hydrophilic on the outside, can form inclusion complexes with some known hydrophobic compounds under appropriate conditions.

[0038] However, until the present disclosure, it has not been recognized that by controlling aspects of the process conditions when forming the complex of the lipophilic drug and cyclodextrin, important additional benefits can be brought to the final solid composition of the complex of the lipophilic drug and cyclodextrin. Conventional methods of using CD to improve the solubility of lipophilic compounds lack fine control. Therefore, although the inclusion complex often shows an improvement in solubility compared to the uncomplexed or simply lipophilic compound, this improvement is not optimized, and the complexes generally vary in quality and purity and lack pharmaceutical-grade reproducibility. For example, cannabidiol (CBD) has been complexed with CD, and the solubility of the final product in water is up to 10 times improved compared to CBD alone. However, the processes exemplified here show that unexpectedly, even greater improvements and orders-of-magnitude enhancements can be achieved. This is based on significantly increasing the degree of complexation of CBD within the complexation system, resulting in a higher-purity product. Furthermore, some lipophilic compounds have been thought to not complex well with CD, but the approach described herein has been shown to have a much broader applicability than expected through the understanding and manipulation of the underlying complexation dynamics.

[0039] In one embodiment, the cyclodextrin is selected from the group consisting of natural α-, β-, γ-cyclodextrins, and methyl β-cyclodextrin, and preferably the cyclodextrin is a natural α-, β-, or γ-cyclodextrin. More preferably, the cyclodextrin is natural β-cyclodextrin.

[0040] In another embodiment, the cyclodextrin is hydroxypropylated-β-cyclodextrin or sulfobutylated-β-cyclodextrin.

[0041] In a preferred embodiment of the present disclosure, the cyclodextrin is a natural α-, β- or γ-cyclodextrin, where "natural" means that the cyclodextrin is not modified. Such natural cyclodextrins do not include cross-linked cyclodextrins.

[0042] As shown herein, various types of lipophilic drugs / compounds can be complexed with CD using this process.

[0043] Preferably, the size of the lipophilic drug is smaller than the size of the cavity of the CD, such as β-cyclodextrin. Preferably, the lipophilic drug is 100 - 700 g / mol. More preferably, the lipophilic drug is 200 - 600 g / mol, or 300 - 600 g / mol, or 300 - 550 g / mol, or 250 - 550 g / mol.

[0044] In an embodiment, the lipophilic drug is classified into Class II or III using the Biopharmaceutics Classification System (BCS).

[0045] Preferably, the lipophilic agent has at least one carbon chain with a length of at least 3 carbon atoms, and when the lipophilic agent forms a complex with CD, the 3-carbon chain is close to the protons at the 3-position and / or 5-position of the sugar ring of CD. More preferably, such a lipophilic agent has a logP of 3 or more, and logP is, for example, between 3 and 9, preferably between 3 and 8, more preferably between 3 and 7.

[0046] In an embodiment, the lipophilic agent is a compound having a phenol ring, which may be substituted and / or fused with another ring. The phenol ring or the further fused ring may be substituted with an alkyl chain or an alkenyl chain. Preferably, the lipophilic agent has at least a 3-carbon chain, and when the lipophilic agent is in a complex with CD, at least one 3-carbon chain is close to the protons at the 3-position and / or 5-position of the sugar ring of the CD cavity.

[0047] Preferably, the lipophilic agent is the only active agent in the composition.

[0048] Preferably, the lipophilic agent is a cannabinoid or vitamin E (or a vitamin E derivative) or curcumin (or a curcumin analog or derivative). Preferably, the vitamin E derivative is selected from tocopherol acetate, tocopherol glucoside, tocopherol phosphate, tocopherol nicotinate and / or succinate tocopherol. Preferably, the vitamin E derivative is succinate tocopherol. This composition may have any of the appropriate features described in the following sixth aspect (process for producing a solid composition containing a lipophilic agent and cyclodextrin).

[0049] Those skilled in the art will understand that these classes of compounds share structurally important similarities (cannabinoids, tocopherols and curcumin, and similar compounds).

[0050] Suitably, the lipophilic agent further has a size smaller than the size of the cavity of the CD, such as β-cyclodextrin. Preferably, the lipophilic agent has a molecular weight of 100 to 700 g / mol. More preferably, the lipophilic agent has a molecular weight of 200 to 600 g / mol. Further, such a lipophilic agent optionally has a logP between 3 and 9, preferably between 3 and 8, more preferably between 3 and 7, or between 4 and 9, preferably between 4 and 8, more preferably between 4 and 7, or between 5 and 9, preferably between 5 and 8, more preferably between 5 and 7.

[0051] The structure of vitamin E is shown below (with minor variations in ring substitution that provide different forms of tocopherol).

Chemical formula

[0052] The structure of curcumin is shown below, and those skilled in the art will understand the presence of the keto-enol form.

Chemical formula

[0053] The structural similarity between these compounds and the cannabinoids (described below) is apparent.

[0054] Although not wishing to be so limited, cannabinoids represent one class or group of lipophilic agents suitable for use in the present invention. Cannabinoids are compounds contained in the cannabis plant or synthetic compounds that can interact with the endocannabinoid system. As used herein, the term "cannabinoid" includes lipophilic compounds found in cannabis. At least 113 distinct cannabinoids have been isolated from cannabis.

[0055] As used herein, "cannabinoid" includes classical cannabinoids and non-classical cannabinoids. Classical cannabinoids are structurally related to THC. Non-classical cannabinoids (cannabimimetics) include aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, arylsulfonamides, and eicosanoids related to endocannabinoids.

[0056] In one embodiment, the cannabinoid is selected from the group consisting of cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), and THC. THC includes delta-9-tetrahydrocannabinol and its derivatives (such as THCA-A, THCA-B, THCV, etc.). In embodiments of the present disclosure, the cannabinoid is preferably selected from CBD, CBG, and delta-9-tetrahydrocannabinol. Most preferably, the cannabinoid is CBD and / or delta-9-tetrahydrocannabinol.

[0057] In another embodiment, the cannabinoid is cannabinol (CBN) or tetrahydrocannabinol (THC) and includes delta-9-tetrahydrocannabinol.

[0058] The cannabinoid family is large and encompasses a certain degree of structural diversity, but those skilled in the art will understand that there are also important common structural features. For example, the structures of the most important cannabinoids are shown below. Important common structural features are apparent, including but not limited to the substitution of a carbon chain on the central phenol ring.

Chemical formula

[0059] From the examples shown herein, it is clear that the size and lipophilicity of cannabinoids are particularly suitable for complexation with CD using the processes of the present disclosure.

[0060] Thus, in embodiments where the fat-soluble agent is a cannabinoid, the cannabinoid may comprise the following structural formula I. [Chemical Formula] In the formula, R 1 and R 3 may each independently be selected from hydrogen and carboxy, R 2 is C 2 -C 8 alkyl, R 4 may be selected from hydrogen or C 2 -C 8 alkyl, R 5 is C 2 -C 12 alkyl or alkenyl and C 6 carbocyclic, or alternatively R 4 and R 5 may be joined to form one or two ring structures, wherein each of the foregoing groups may optionally be substituted or unsubstituted.

[0061] In an embodiment, R 2 is C 3 -C 5 alkyl, including n-propyl, n-butyl and n-pentyl.

[0062] In an embodiment, R 5 is unsubstituted or methyl-, ethyl- or propyl-substituted C 8 -C 12 alkenyl, or substituted cyclohexenyl.

[0063] R 4 and R 5 are joined to form one or two ring structures, in which case they may form a fused bicyclic system. The bicyclic system is preferably as shown for THC and CBN in the above structure.

[0064] As used herein, the "molar ratio" refers to the ratio of the number of moles of the compounds forming the complex.

[0065] According to the present invention, the molar ratio of a fat-soluble drug such as a cannabinoid to cyclodextrin is about 1:2. An advantage of the present disclosure is that the provided molar ratio (i.e., 1:2, fat-soluble drug:CD) can be obtained with high purity. That is, a complex of 1:2 is provided as a high-purity composition.

[0066] As used herein, a complex in which a fat-soluble drug (e.g., a cannabinoid) and cyclodextrin form a complex at a molar ratio of about 1:2 refers to a complex in which two individual cyclodextrin molecules are complexed with one cannabinoid molecule. Thus, the cyclodextrin is uncrosslinked cyclodextrin (i.e., the cyclodextrin is not crosslinked cyclodextrin). "Crosslinked cyclodextrin" includes cyclodextrin dimers in which two molecules of cyclodextrin are covalently bonded by a linker.

[0067] In an embodiment of the first aspect, at least 80% by weight of the fat-soluble drug such as a cannabinoid and cyclodextrin in the dry solid composition are present in the complex at a molar ratio of about 1:2.

[0068] In a more specific embodiment, at least 85% by weight of the fat-soluble drug such as a cannabinoid in the composition and cyclodextrin are present in the complex at a molar ratio of about 1:2, at least 90% by weight, preferably at least 95% by weight, more preferably at least 98% by weight, for example at least 99% by weight. In certain embodiments, substantially all of the fat-soluble drug such as a cannabinoid and cyclodextrin in the dry solid composition are present in the complex at a molar ratio of about 1:2.

[0069] This weight % relates to all of the lipophilic agent such as cannabinoid and cyclodextrin present in the dry solid composition (i.e., including the complex in both ratios of 1:2 and 1:1, as well as the uncomplexed lipophilic agent such as cannabinoid and cyclodextrin).

[0070] In other words, the complex with a molar ratio of about 1:2 between a lipophilic agent such as cannabinoid and cyclodextrin accounts for at least 80% by weight (e.g., at least 90% or 95% or 98% or 99%, or almost all) of the total amount of the lipophilic agent such as cannabinoid and cyclodextrin present in the dry solid composition.

[0071] "Weight percent" or "wt%" refers to the proportion of a particular substance within a mixture, measured by weight or mass.

[0072] In an embodiment of the first aspect, at least 80 mol% (at least 85 mol%, preferably at least 95 mol%, more preferably at least 98 mol%, e.g., at least 99 mol%, etc.) of the lipophilic agent such as cannabinoid and cyclodextrin in the composition is present in the complex at a molar ratio of about 1:2.

[0073] The term "mol%" refers to the proportion of a particular substance within a mixture, measured in moles.

[0074] The term "about" when modifying a numerical value or a value is used herein to refer to a value within ±10% of the specified value.

[0075] In an embodiment, the solid composition of the first aspect may include a complex between a lipophilic agent such as a cannabinoid with a logP between about 3 and about 8 and an unmodified α-, β- or γ-cyclodextrin. Here, the molar ratio of all fat-soluble drugs such as cannabinoids and at least 80% by weight (such as at least 90% or 95% or 98% or 99% or almost all) of α-, β- or γ-cyclodextrin present in the dry solid composition is about 1:2. Preferably, the cyclodextrin is unmodified β-cyclodextrin. Preferably, the size of the fat-soluble drug is 100-700 g / mol, more preferably 200-600 g / mol or 250-550 g / mol.

[0076] In an embodiment, the solid composition of the first aspect consists of a complex between a fat-soluble drug such as a cannabinoid having a logP between about 3 and about 8 and an unmodified α-, β- or γ-cyclodextrin, Here, the molar ratio of all fat-soluble drugs such as cannabinoids and at least 80% by weight (such as at least 90% or 95% or 98% or 99% or almost all) of α-, β- or γ-cyclodextrin present in the dry solid composition is about 1:2. Preferably, the cyclodextrin is unmodified β-cyclodextrin. Preferably, the size of the fat-soluble drug is 100-700 g / mol, more preferably 200-600 g / mol or 250-550 g / mol.

[0077] An advantage of the process of the present disclosure is that it provides high control over the complexation process. While other approaches may provide random mixtures of various molar ratios of fat-soluble compounds and CDs, uncomplexed fat-soluble compounds, and uncomplexed CDs, this approach can obtain the desired complex product in high purity without the need for later complex additional purification steps.

[0078] In one embodiment, the solid composition of the first aspect consists of a complex between a fat-soluble drug such as a cannabinoid having a logP between about 3 and about 8, or between about 3 and about 7, and unmodified β-cyclodextrin, Here, at least 90 wt%, or 95 wt%, or 98 wt%, or 99 wt%, and even almost all of the total fat-soluble agents such as cannabinoids and β-cyclodextrin present in the dry solid composition are present in the complex in a molar ratio of about 1:2. Optionally, the fat-soluble agent is selected from the group consisting of CBD, δ-9-THC, CBG, CBN, vitamin E (or vitamin E derivative), and curcumin (or curcumin analog or derivative). Preferably, the size of the fat-soluble agent is 100-700 g / mol, more preferably 200-600 g / mol or 250-550 g / mol.

[0079] The solid composition of the present invention can be formulated with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means any diluent or excipient such as a filler or binder that is compatible with the other components of the composition and not harmful to the recipient. The pharmaceutically acceptable carrier can be selected according to standard pharmaceutical practice based on the desired route of administration.

[0080] The composition of the first aspect of the present invention can be easily recovered as a solid composition such as a precipitate and does not require a large amount of water or other solvents, so it can be easily dried. And they can be accurately measured and formulated according to the desired route of administration. Commercially available cannabinoid formulations rely on liquid formulations using solvents designed to maximize the dissolution of fat-soluble cannabinoids. This solid composition can be prepared into an aqueous formulation due to the improved solubility profile provided, and as a result, it is possible to directly administer pharmaceutical-grade formulations for injection or solid-form compositions.

[0081] The composition of the first aspect of the present invention may be prepared in a pharmaceutically acceptable dosage form via oral, intravenous, subcutaneous, transdermal, sublingual, topical, ophthalmic (e.g., via eye drops), or any other parenteral route. The resulting pharmaceutical composition includes compositions in the form of tablets, capsules, or elixirs for oral administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Alternatively, particularly when the composition of the first aspect of the present invention acts locally, such a composition may be formulated for topical administration.

[0082] In one embodiment, the composition of the first aspect is formulated in a liquid form suitable for oral ingestion or injection, or in a form suitable for topical administration. These liquid preparations may contain stabilizing components and / or buffering components and are dispensed as unit doses in the form of ampoules or vials. The liquid form (i.e., solution) can also be prepared as a dry preparation so that it can be immediately reconstituted with a suitable solvent before use.

[0083] In some embodiments, the composition of the first aspect is formulated as an eye drop.

[0084] In some embodiments, the composition of the first aspect is formulated as an injection, such as an injection suitable for administration to the face.

[0085] In one embodiment, the composition of the first aspect is formulated for oral administration, for example, as tablets, capsules, pellets, gums, or powders, preferably as tablets or capsules. "Oral composition" and "oral administration" mean that the composition is suitable for swallowing.

[0086] Tablets, capsules, pellets, and gums can be prepared using binders such as syrups, acacia, gelatin, sorbitol, tragacanth, cellulose, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, or silica, and surfactants such as sodium lauryl sulfate.

[0087] The composition of the first aspect can also be formulated as a liquid composition for oral administration. For example, this composition may be provided in the form of a syrup or a suspension, such as a solution or a suspension, which contains the composition of the first aspect of the present invention, and the remaining components of the formulation consisting of sugars or sugar alcohols, as well as a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If necessary, such liquid formulations may include colorants, flavors, saccharin and carboxymethyl cellulose, or other thickening agents. Liquid formulations for oral administration can also be prepared in the form of dry powders which are reconstituted with a suitable solvent before use.

[0088] In some embodiments, the composition of the first aspect is formulated as a drop.

[0089] The composition may also be formulated with an agent that reduces the degradation of substances by processes other than the normal metabolism of the patient, such as an antibacterial agent, or an inhibitor of protease enzymes that may be present in symbiotic or parasitic organisms that inhabit the patient's body or on the patient's body surface or inside the body and that can degrade the compound.

[0090] The formulated composition may be administered once, twice, three times, or four times a day.

[0091] It will be understood that the therapeutic uses of the solid composition of the first aspect are not particularly limited. Indeed, the disclosure of the present invention provides a platform approach that can complex a wide range of lipophilic agents with CDs. The complexed lipophilic agent is released in vivo in the normal way to exert a therapeutic effect without interference from the CD. Thus, the therapeutic use depends entirely on the particular lipophilic agent complexed to the solid composition of the first aspect and simply follows its already known and verified efficacy. This approach, among other advantages, simply enables the improvement of the formulation and delivery of known drugs.

[0092] The effective dosage is obvious to those skilled in the art and depends on several factors such as age, gender, weight, disease, etc., and can be determined by medical practitioners.

[0093] In one embodiment of the present invention, the formulated composition is administered at least once a day. Preferably, it is administered as a once-daily dose. The once-daily dosage is preferably 5 mg to 1000 mg, more preferably 10 mg to 500 mg, still more preferably 15 mg to 200 mg, for example 20 mg to 150 mg. Exemplary dosages are 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 500 mg, 1000 mg.

[0094] In one embodiment of the present invention, the formulated composition contains a fat-soluble drug such as a cannabinoid between 10 mg and 1000 mg, such as between 20 mg and 900 mg, between 30 mg and 800 mg, between 40 mg and 700 mg, between 50 mg and 600 mg, between 60 mg and 500 mg, between 70 mg and 400 mg, between 80 mg and 300 mg, and between 90 mg and 200 mg. Preferably, the composition contains a fat-soluble drug such as a cannabinoid between 200 mg and 750 mg, more preferably a fat-soluble drug such as a cannabinoid between 300 mg and 600 mg.

[0095] Suitably, the formulated composition contains a fat-soluble drug in an amount exceeding 10 mg, such as a cannabinoid in an amount exceeding 20 mg, 50 mg, 100 mg, 200 mg, or 250 mg. Suitably, the formulated composition contains a fat-soluble drug less than 1000 mg, such as a cannabinoid less than 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, or 300 mg. Any of the above-mentioned lower or upper limits may be combined with each other, and they are disclosed herein.

[0096] In one embodiment of the present invention, the formulated composition is administered at least twice a day. Preferably, each dose is from 2 mg to 500 mg, more preferably from 3 mg to 300 mg, still more preferably from 5 mg to 200 mg. Exemplary doses are 5 mg, 10 mg, 20 mg, 50 mg, or 100 mg.

[0097] In one embodiment of the present invention, the formulated composition is administered at least three times a day. Preferably, each dose is from 2 mg to 350 mg, more preferably from 3 mg to 200 mg, still more preferably from 5 mg to 100 mg. Exemplary doses are 5 mg, 10 mg, 20 mg, 50 mg, or 100 mg.

[0098] Preferably, the dosing schedule is such that the total daily dose of a fat-soluble agent such as a cannabinoid does not exceed 1000 mg.

[0099] A second aspect of the present invention is a solid composition according to the first aspect for use in the treatment of a disease, disorder or medical condition.

[0100] In one embodiment of the present invention, the composition is administered in an effective amount to treat a disease or disorder associated with the endocannabinoid system.

[0101] In some embodiments, the solid composition of the first aspect is for use as a pharmaceutical. In alternative embodiments, there is provided the use of the solid composition of the first aspect in the manufacture of a pharmaceutical. In alternative embodiments, there is provided a method of treatment comprising administering the composition of the first aspect to a patient.

[0102] Preferably, the solid composition is used in the treatment of a disease or disorder associated with the endocannabinoid system.

[0103] "Patient" and "subject" are used interchangeably and refer to the subject to whom the composition of the first aspect of the present invention is administered. Preferably, the subject is a human.

[0104] Diseases or disorders related to the endocannabinoid system are selected from the group consisting of anxiety, insomnia, epilepsy, neuropathic pain, opioid addiction, PTSD, IBD, stroke, acne, dermatitis, psoriasis, ADHD, SARS, inflammatory diseases, and chronic pain.

[0105] In a preferred embodiment, the disease or disorder related to the endocannabinoid system is selected from the group consisting of anxiety and insomnia.

[0106] In one embodiment, the cannabinoid is the sole active agent in the composition. "The sole active agent" means that the composition does not contain other components that can be used for the treatment or prevention of neurofibromatosis.

[0107] To treat a disease or disorder related to the endocannabinoid system, the solid composition of the first aspect of the present invention is used in a chronic dosing regime, i.e., a chronic and long-term treatment. This treatment plan is preferably continued for at least 1 month, preferably at least 2 months, for example at least 3 months.

[0108] According to a third aspect of the present invention, a method of treating a disease, disorder or medical condition is provided, which includes administering the solid composition of the first aspect of the present invention to a subject.

[0109] In an embodiment of the third aspect, the disease, disorder or medical condition is determined by selecting a lipophilic agent based on its known efficacy.

[0110] In an embodiment of the third aspect, the disease, disorder or medical condition is related to the endocannabinoid system.

[0111] Embodiments of the third aspect of the present invention may have any of the features described for the first and second aspects of the present invention.

[0112] Administration is directed to the solid composition of the first aspect, it being understood that this does not require the composition to still be in solid form. That is, the solid composition of the first aspect is formulated into one form or another suitable for the desired route of administration. For this reason, it may be necessary to formulate the solid composition of the first aspect into a solution prior to administration. This and similar approaches are encompassed by the step of "administering to a subject the solid composition of the first aspect of the invention".

[0113] According to a fourth aspect of the invention, there is provided the use of a solid composition of the first aspect (including alternative first aspects) in the manufacture of a medicament for the treatment of a disease, disorder, or medical condition.

[0114] In embodiments of the fourth aspect, the disease, disorder or medical condition is determined by being selected based on the known effectiveness of a lipophilic agent.

[0115] In embodiments of the fourth aspect, the disease, disorder or medical condition is related to the endocannabinoid system.

[0116] Embodiments of the fourth aspect of the invention may have any of the features described for the first to third aspects of the invention. This includes, but is not limited to, the final form of the medicament being solid.

[0117] According to a fifth aspect of the invention, there is provided a non-therapeutic use of the solid composition of the first aspect of the invention.

[0118] Suitably, the non-therapeutic use may be in the form of a cosmetic, supplement, nutraceutical, nutritional purpose, or beverage.

[0119] In some embodiments, the use is as a cosmetic such as anti-acne, anti-aging, eczema, dry skin, sunburn, psoriasis or fungal infection.

[0120] In some embodiments, the use is as a supplement. A supplement is a substance known to be used to add nutrients to a person's diet or to reduce the risk of health problems.

[0121] As used herein, a "nutritional supplement" is a product derived from food that, in addition to the basic nutritional value contained in the food, is said to provide health benefits. A beverage is a liquid intended for human consumption. The compositions of the present invention may be mixed with one or more liquids to form a beverage.

[0122] Preferably, the non-therapeutic use is as a nutritional supplement or for nutritional supplementation. Embodiments of the fifth aspect of the present invention may have any of the appropriate features described for the first to third aspects of the present invention.

[0123] According to a sixth aspect of the present invention, there is provided a process for producing a solid composition comprising a fat-soluble agent and cyclodextrin, wherein the fat-soluble agent and cyclodextrin are in the form of a complex in a molar ratio of about 1:2, wherein the process comprises the following steps. a. providing a fat-soluble agent, b. providing cyclodextrin, c. combining the fat-soluble agent and cyclodextrin in the presence of water to form a composition, d. mixing the composition until a precipitate of the complex of the fat-soluble agent and cyclodextrin forms, e. recovering the precipitate of step d. to provide a solid composition comprising the fat-soluble agent and cyclodextrin in the form of a complex.

[0124] In embodiments, the fat-soluble agent and cyclodextrin are in a saturated solution in step c. Advantageously, the saturated state promotes complete complexation of the fat-soluble agent and cyclodextrin.

[0125] In an embodiment, the cyclodextrin is at least slightly in excess over the lipophilic drug. Thereby, substantially all of the lipophilic drug is consumed and incorporated into the complex, and a high-purity product can be obtained. When the cyclodextrin is slightly in excess, when all of the lipophilic drug has been consumed, the cyclodextrin may be present in the solution, and the complex can be recovered as the sole solid product. When the cyclodextrin is in excess and some remains as a solid, separating it from the complex based on respective solubilities etc. is the simplest purification step.

[0126] Prior art approaches (e.g., Mannila, J. et al., J. Pharm Sci, Vol. 96, No. 2, 2007) rely on the "precipitation complex formation" reaction first described by Higuchi et al. (1965 Advances in analytical chemistry instrumentation, Wiley and sons, pp. 117 - 212). However, this approach relies on adding the active compound to be complexed in excess to a highly diluted solution of cyclodextrin. Thereafter, the reaction is left to form the complex. The inventor has discovered that this approach may require a very long time for the reaction to proceed. Therefore, in the conventional approach, when recovering the material in a relatively short time, a large amount of the precipitated active compound is inevitably recovered, which may contain some precipitated cyclodextrin, and furthermore, it has been found that the amount of the actually complexed material, which may itself exhibit complexes with different molar ratios, may be unclear. When measuring the active compound in such a product, the detected level simply represents all the compounds present in various free and complexed forms and does not accurately represent the level of complexation. Furthermore, in Mannila's precipitation method, a consistent and highly reliable high-purity 1:2 complex of lipophilic drug and cyclodextrin cannot be obtained, so the advantages described above for such a complex cannot be achieved.

[0127] In this approach, by saturating the lipophilic drug and cyclodextrin, the reaction can proceed and be completed within an appropriate time. Therefore, a high-purity and highly reproducible complex can be obtained. Also, by maintaining both the lipophilic drug and cyclodextrin in a saturated solution state, easy and almost complete precipitation of the complex product is ensured until the excess starting material(s) in the system are consumed and dissolved. This approach and advantage are demonstrated in the examples of this specification where, for example, CBD and β-cyclodextrin are complexed. These materials are used in a complexation approach by precipitation method, and it has been confirmed that the solubility of the final material is improved (for example, from about 0.2 micromoles for CBD to about 3 micromoles for the final mixed product), but in this method, a CBD:CD complex is obtained, and its water solubility is shown to be in the range of 1.5 - 2.7 millimoles (at 35 - 40 °C, i.e., body temperature, and higher solubility is obtained at higher temperatures). Such a significant increase in solubility is only observed when the prior art precipitation method complex, in fact, not all CBD was complexed with CD. In this method, a solid composition is provided in which almost all CBD is complexed with the desired CBD:CD in a molar ratio of 1:2.

[0128] Without wishing to be bound by theory, the process of the sixth aspect of the present invention is efficient. This is because the equilibrium concentration of the desired dimer complex is greater than the solubility of that dimer complex product in the reaction medium. Simply put, this means that during the reaction, the complex product always precipitates, and lipophilic drugs such as cyclodextrin and cannabinoid are always dissolved to replace the cyclodextrin and lipophilic drugs such as cannabinoid lost from the liquid phase by precipitation. Furthermore, this means that the concentration of all species in the liquid phase remains constant until the excess material is consumed. Therefore, the dimer can be consistently and reliably achieved based on these saturation, solubility, and concentration dynamics parameters that have not been evaluated in the art until now.

[0129] This process enables the formation of a lipophilic drug:cyclodextrin inclusion complex (i.e., a dimer complex) in a 1:2 molar ratio, as detailed in the Examples section and shown in Figure 3. As described above, in the 1:2 complex, it is thought that when the dimer dissociates, the lipophilic drug remains complexed with one cyclodextrin molecule (i.e., the 1:2 drug:CD dimer dissociates into 1 equivalent of a 1:1 drug:CD monomer and 1 equivalent of cyclodextrin). This allows for absorption into the bloodstream. Otherwise, if only monomers were initially formed and administered, the monomers would directly dissociate into free cyclodextrin and free lipophilic drug, and the lipophilic drug would precipitate and be excreted and thus not absorbed. Therefore, the 1:2 dimer is particularly important for drugs with low water solubility to be delivered in vivo.

[0130] The novel process described herein surprisingly enables the highly controlled formation of the described dimer complex, thereby leading to the completion of the formation with predictability and reproducibility. This significantly improves the solubility and / or bioavailability of the lipophilic drug when delivered to a subject. The surprising advantage that substantially complete complexation of the lipophilic drug is achieved by controlling these saturation / concentration and excess substance parameters was not previously known. Such an advantage is not obtained with approaches of the prior art that rely on dilute (i.e., unsaturated) solutions of the lipophilic drug / cyclodextrin.

[0131] The solid composition formed by this manufacturing method can have improved stability in aqueous and acidic media (e.g., during and after preparation and in the human stomach).

[0132] Furthermore, the dimer has lower water solubility compared to the monomer (i.e., the lipophilic drug complexed with cyclodextrin in a 1:1 molar ratio), and since the dimer selectively precipitates from the aqueous reaction mixture, the preparation step is facilitated.

[0133] Furthermore, the fat-soluble drug (i.e., guest molecule) may be less soluble than both the cyclodextrin and the complex of the formed monomer or dimer. Complexation of the fat-soluble drug with cyclodextrin promotes the continuous dissolution of the fat-soluble drug in the solution. The dimer has lower solubility than free cyclodextrin.

[0134] The measurement of logP can be performed by various methods well known to those skilled in the art. To form a drug:cyclodextrin complex, the lipophilicity of the drug must be suitable for interacting with the hydrophobic interior of the cyclodextrin. In one embodiment, the fat-soluble drug has a logP between 1 and 10.

[0135] Suitably, the fat-soluble drug has a logP value greater than 1, such as greater than 2, greater than 3, greater than 4, or greater than 5. Suitably, the fat-soluble drug has a logP less than 10, such as less than 9, less than 8, or less than 7. Any of the above lower or upper limits may be combined with each other, and they are disclosed herein.

[0136] Preferably, the logP of the fat-soluble drug is 3 or more, such as between 3 and 9, preferably between 3 and 8, more preferably between 3 and 7, or between 4 and 9, preferably between 4 and 8, more preferably between 4 and 7, or between 5 and 9, preferably between 5 and 8, more preferably between 5 and 7.

[0137] The size of the fat-soluble drug must be suitable for the drug to fit into the cavity of the cyclodextrin. Suitably, the fat-soluble drug has a size smaller than the size of the cavity of β-cyclodextrin.

[0138] Preferably, the lipophilic agent has a size greater than 100 g / mol, such as greater than 150 g / mol, greater than 200 g / mol, or greater than 250 g / mol. Appropriately, the lipophilic agent has a size less than 700 g / mol, such as less than 650, less than 600, less than 550, less than 500, less than 450, less than 400, or less than 300 g / mol. Any of the above lower or upper limits may be combined with each other, and they are disclosed herein.

[0139] Preferably, the lipophilic agent is from 100 to 700 g / mol. More preferably, the lipophilic agent is from 200 to 600 g / mol, or from 300 to 600 g / mol, or from 300 to 550 g / mol, or from 250 to 550 g / mol.

[0140] The lipophilic agent of the sixth aspect can be the same as that described in any one or more of the embodiments of the first aspect.

[0141] Appropriately, the dimer complex (lipophilic agent: CD 2 ) has lower solubility than the monomer complex (lipophilic agent: CD), which enables the dimer to precipitate easily in the manufacturing process.

[0142] Appropriately, the dimer complex (lipophilic agent: CD 2 ) has lower solubility than cyclodextrin, which enables such a complex to precipitate easily in the manufacturing process.

[0143] While not wishing to be bound by theory, water enables the occurrence of complex formation and is thus thought to act as a mediator or catalyst. However, when a large amount of water is present (i.e., when the concentration of the lipophilic agent and / or cyclodextrin is low), the reaction mixture is too diluted and the reaction does not occur, occurs too slowly, or does not complete properly. This is the case for the precipitation complex formation approach of the prior art. The fastest rate is obtained when the reactants, cyclodextrin and the lipophilic drug, are kept at their saturation concentrations.

[0144] Preferably, in step d., the mixing of the composition is continued until a solid precipitate is formed. Depending on the case, it may take from 0 to 48 hours, for example from 0 to 24 hours, or from 0 to 12 hours. Appropriately, the mixing is carried out for at least 2 hours, preferably at least 4 hours, preferably at least 6 hours, for example at least 8 hours. Appropriately, the mixing is carried out for 24 hours or less, preferably 20 hours or less, more preferably 16 hours or less, for example 12 hours or less. To avoid doubt, either of these lower or upper limits may be used in combination.

[0145] The inventor has confirmed that the addition order of the fat-soluble drug and cyclodextrin does not affect the reaction. That is, this process functions whether the fat-soluble drug is added to water first and then cyclodextrin is added, or cyclodextrin is added to water first and then the fat-soluble drug is added, or both are added simultaneously.

[0146] A "saturated solution" contains the maximum concentration of solute dissolved in a solvent. As used herein, a "saturated solution" refers to a solution containing an excess of undissolved solute. The degree of saturation can be measured by any technique known in the art. For example, the degree of saturation may be determined visually or calculated using the solubility value of the solute.

[0147] Appropriately, the amounts of the fat-soluble drug and cyclodextrin exceed their relative solubilities in the respective water or water mixture. Appropriately, the concentration of the fat-soluble drug in the composition of step c. is in a saturated state. Appropriately, the concentration of cyclodextrin in the composition of step c. is in a saturated state.

[0148] The saturation of the solution can be maintained by having an excess of the fat-soluble drug and / or cyclodextrin present in the reaction vessel. Thereby, when complex formation proceeds and the complex precipitates, the excess fat-soluble drug and / or cyclodextrin dissolves further. Preferably, cyclodextrin is contained in excess in the compositions of steps c. and d.

[0149] In one embodiment, the composition of step c is a solution in which substantially all of the lipophilic drug is dissolved in the solution and / or a solution in which substantially all of the cyclodextrin is dissolved in the solution.

[0150] In a preferred embodiment, the composition of step c contains an excess of undissolved lipophilic drug and / or cyclodextrin. The excess material dissolves when the complex product precipitates, thereby allowing further complexation to continue. Those skilled in the art will understand that the absolute amount can be calculated based on the desired amount of the product according to the present disclosure.

[0151] In one embodiment, the composition of step c contains undissolved lipophilic drug between 0.01% and 20%, 0.05% and 15%, 0.1% and 10%, 0.2% and 5%, 0.25% and 3%, or 0.3% and 2% by weight of the composition and / or undissolved cyclodextrin between 2% and 90%, for example between 2% and 80%, 3% and 70%, 5% and 60%, 10% and 60%, 15% and 50%, or 20% and 40% by weight of the composition. Suitably, the composition of step c contains undissolved lipophilic drug and cyclodextrin between 2% and 90%, for example between 2% and 80%, 3% and 70%, 5% and 60%, 10% and 60%, 15% and 50%, or 20% and 40% by weight of the composition. Preferably, the composition of step c contains undissolved lipophilic drug and / or cyclodextrin between 2% and 60% by weight of the composition.

[0152] A further advantage of the process described herein is that it is not necessary to dissolve a large amount of cyclodextrin in a large amount of water to produce the complex, and thus the subsequent drying time and cost are significantly reduced compared to other methods. The cyclodextrin only needs to be a saturated solution in water regardless of the volume of the system. As described above, when the cyclodextrin in the saturated solution binds to the lipophilic drug and precipitates from the liquid phase, an excess of undissolved cyclodextrin may be desirable to maintain saturation.

[0153] The cyclodextrin of the sixth aspect may be any one or more of the embodiments described in the first aspect. In a preferred embodiment of the sixth aspect, the cyclodextrin is natural α-, β- or γ-cyclodextrin, where "natural" means that the cyclodextrin is not modified. Preferably, the cyclodextrin of the sixth aspect is natural β-cyclodextrin.

[0154] A further advantage of the process of the sixth aspect of the present invention is that it is not necessary to micronize or nanonize the lipophilic drug and the cyclodextrin before dissolving them in a solvent (here water), thus enabling a simpler and more efficient process compared to methods that require micronizing or nanonizing the substrate.

[0155] Another way to monitor the concentration of the lipophilic drug and / or CD is to measure the refractive index (RI) (which is commonly used and known in the art). Appropriately, in step d., CD is continuously added to the starting CD:CBD mixture of step c. until the refractive index (RI) of the CD is no longer detected. This means that all CD molecules in the solution have been complexed. Other methods, including HPLC, can also be used to indicate the progress of the complexation.

[0156] By using the measurement of RI (e.g., using an RI meter) in combination with the molar ratio of the cannabinoid to the cyclodextrin, the desired 1:2 complex can be formed and the point in time when the reaction is complete can be identified. When the reaction mixture is diluted to be within the dissolution range of the total amount of cyclodextrin during the reaction, the RI decreases as the reaction progresses. When the decrease in RI stops and reaches a stable state, the reaction is complete because the cyclodextrin is no longer complexed. Therefore, step d. may include performing one or more RI measurements. By using this method, each batch will contain the same amount of dimer, and there is an advantage that consistency between batches can be ensured, in contrast to batches with different dimer and monomer contents.

[0157] In a preferred embodiment, in step d., mixing is continued until the cyclodextrin concentration is no longer saturated. This indicates that the cyclodextrin in the solid phase is substantially left without being incorporated into the composition (i.e., continue mixing until almost all cyclodextrin is included in the solid complex precipitate). Achieving such control of reactivity provides a very efficient process and is advantageous in ensuring consistency between batches of materials.

[0158] Suitably, in step c., the temperature of the water exceeds 25 °C, for example, exceeds 30 °C, 35 °C, 40 °C, 45 °C, 65 °C, 75 °C, 100 °C. Desirably, it is 35 °C or higher, more desirably 45 °C or higher. Suitably, the temperature of the water is about 50 °C. Desirably, it is less than 80 °C, more desirably less than 70 °C.

[0159] Heating is not essential but can provide advantages in accelerating complexation and / or obtaining a high-purity complex product.

[0160] Without being bound by theory, for some cyclodextrins, when step c. is carried out with only water, the solubility of the resulting complex is high compared to its equilibrium concentration, so the yield of the subsequent dimer complex may be low. Therefore, in such cases, the solubility and equilibrium concentration in step c. can be changed by adding ethanol to the water. This increases the solubility of the lipophilic drug and decreases the solubility of cyclodextrin and the dimer complex, thus improving the yield of the solid dimer product. Thus, in some embodiments, in step c., the lipophilic drug and cyclodextrin are mixed with a mixture of water and ethanol to form a composition. In a particular embodiment, the mixture of water and ethanol contains ethanol between 1 and 40% by weight, preferably ethanol between 5% and 30% by weight, most preferably ethanol between 10% and 30% by weight. In such embodiments, it is desirable that the cyclodextrin is α-cyclodextrin or γ-cyclodextrin.

[0161] Suitably, step e. may be carried out using standard techniques such as filtration, removal of supernatant by decantation, centrifugation, etc. Suitably, the newly formed solid precipitate is purified by removing excess moisture by known drying methods such as freeze-drying or air-drying. It will be appreciated that the solid composition of the first aspect is effectively obtained by precipitation of the complex product. The present invention is not particularly limited by the method of recovering the precipitated solid composition product, and in certain embodiments, it can even be transferred, modified or used in the precipitated form from step d. Recovery may include methods of directly recovering the solid precipitate or, alternatively, removing the aqueous or liquid phase in which the precipitate is present.

[0162] A further advantage of the process described herein is that the product obtained in step e. is a solid and can be purified using standard techniques. Other known cyclodextrin complexes need to be maintained in liquid form because water cannot be removed efficiently or cost-effectively. The solid product of the present invention has advantages compared to liquid products, which lie in the fact that solids are easy to transport and have improved stability because they are in an inert powder form rather than a liquid form.

[0163] In some embodiments, in step d., the lipophilic drug and cyclodextrin (i.e., dimer) in the form of the complex are formed in a solid phase that exceeds 30% by weight relative to the liquid. This is highly advantageous because the solid can be easily recovered by physical means such as filtration.

[0164] In certain embodiments, the process further includes steps of drying and grinding.

[0165] In one embodiment, the solid composition obtained by the process of the present invention is suitable for oral administration.

[0166] In some embodiments, the method further f. forming a tablet, capsule, pellet, gum, or powder comprising a solid composition containing the fat-soluble drug and cyclodextrin extracted in step e., preferably forming a tablet or capsule.

[0167] Alternatively, this process further f. combining the solid composition containing the fat-soluble drug and cyclodextrin extracted in step e. with a suitable carrier to form a gel, cream, or beverage. Such carriers include, but are not limited to, glycerol, glycerol monostearate, sodium citrate, citric acid, stearic acid, palmitic acid, substitute beeswax, acacia gum, sorbitol, malic acid, soybeans, lecithin, mannitol, flavorings, phenylalanine, propylene glycol, polyethylene glycol, water, sodium, castor oil, methylparaben, or propylparaben.

[0168] In one embodiment of the sixth aspect, the fat-soluble drug is a cannabinoid, vitamin E or a vitamin E derivative, or a vitamin D derivative, vitamin A or a vitamin A derivative, a sterol or a sterol derivative, an antibiotic, curcumin or a curcumin analog or derivative, a non-steroidal anti-inflammatory drug (NSAID), artemisinin or an artemisinin derivative. Preferably, the fat-soluble drug is a cannabinoid or vitamin E, preferably a cannabinoid, more preferably a cannabinoid selected from the group consisting of CBD, CBN, CBG, and THC.

[0169] Suitably, the cannabinoid is cannabidiol (CBD), cannabinol (CBN), or tetrahydrocannabinol (THC), preferably CBD or THC. In a preferred embodiment, the cannabinoid is CBD.

[0170] Suitably, the vitamin E derivative may be selected from tocopheryl acetate, tocopherol glucoside, tocopheryl phosphate, tocopheryl nicotinate and / or tocopheryl succinate. Preferably, the vitamin E derivative is tocopheryl succinate.

[0171] Suitably, the cyclodextrin is selected from the group consisting of natural α-, β-, γ-cyclodextrins, and methyl β-cyclodextrin, and preferably, the cyclodextrin is natural α-, β-, or γ-cyclodextrin. More preferably, the cyclodextrin is natural β-cyclodextrin.

[0172] In another embodiment, the cyclodextrin is hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin.

[0173] To avoid misunderstanding, the process of the sixth aspect of the present invention may include any of the features described above for the first to fifth aspects, and also includes the fat-soluble drug described in any embodiment of the first aspect.

[0174] The seventh aspect of the present invention is a solid composition obtained (for example, obtained) by the process of the sixth aspect of the present invention.

[0175] The solid composition of the seventh aspect of the present invention may have any of the features described above for the first to sixth aspects of the present invention.

[0176] The eighth aspect of the present invention is a solid composition of the first aspect when produced by the process of the sixth aspect.

[0177] The solid composition of the eighth aspect of the present invention may have any of the features described above for the first to sixth aspects of the present invention.

[0178] The present invention will be further described using the following non-limiting examples.

[0179] Those skilled in the art will understand that various different embodiments and examples can be constructed with different combinations of optional features being used and not limited to those shown herein.

Example

[0180] Example 1: Preparation of CBD: Cyclodextrin Complex 100 ml of water was heated to 50 °C, and 40 g of β-cyclodextrin was added while stirring. Stirring was continued throughout the entire process of the reaction. The amount of β-cyclodextrin dissolved in water was monitored until saturation as indicated by a stable cyclodextrin concentration was reached. 6 g of cannabidiol was added, and the amount of β-cyclodextrin dissolved in water was monitored again. After confirming that the concentration of the dissolved cyclodextrin decreased to a minimum value and remained constant, cyclodextrin was gradually added in 0.5 g increments until the concentration of the dissolved cyclodextrin reached 20 g / L. After the mixture was cooled to 20 °C, the liquid phase was removed by vacuum filtration. Then, the filter cake was completely dried on zeolite.

[0181] Solubility Profile of β-CD in the Presence of CBD Figure 1 shows that when increasing and adding β-cyclodextrin in the presence of a certain amount of CBD, its solubility showed a characteristic shape. The black squares (CD alone) indicate that the concentration measured by RI increased until saturation was reached, and then did not change even when more cyclodextrin was added.

[0182] However, in the presence of CBD, cyclodextrin showed the same solubility curve as before, but only up to a certain point. When more cyclodextrin was added at about 20 mM, the amount of actually dissolved cyclodextrin decreased, and continued to decrease until the concentration of dissolved cyclodextrin reached 5 - 10 mM. After that, even when cyclodextrin was added, there was little change in the concentration of dissolved cyclodextrin until about 80 mM of cyclodextrin was added. This indicates that the stoichiometric ratio of CBD to CD was 1:2, that is, at this point, all CBD was complexed with cyclodextrin. When more cyclodextrin was added after this point, since there was no more CBD to bind, it could dissolve, and the dissolution concentration began to increase again.

[0183] Example 2: Preparation of Succinate Tocopherol (Vitamin E): Cyclodextrin Complex 100 ml of water was heated to 50 °C, and 40 g of β - cyclodextrin was added while stirring. Stirring was continued throughout the entire process of the reaction. The amount of β - cyclodextrin dissolved in water was monitored until saturation, indicated by a stable cyclodextrin concentration. 9.4 g of succinate tocopherol was added, and the amount of β - cyclodextrin dissolved in water was monitored again. After confirming that the concentration of dissolved cyclodextrin decreased to the minimum value and remained constant, cyclodextrin was gradually added in 0.5 g increments until the concentration of dissolved cyclodextrin reached 20 g / L. After the mixture was cooled to 20 °C, the liquid phase was removed by vacuum filtration. Then, the filter cake was completely dried on zeolite.

[0184] The solubility of CD in the presence of succinate tocopherol is shown in Figure 2. The solubility of CD follows a profile similar to that of Example 1 using CBD.

[0185] Example 3: Preparation of Curcumin: Cyclodextrin Complex Curcumin (0.6 g) was added to 50 ml of water at 35 °C and mixed with stirring. β-Cyclodextrin powder was sequentially added to the mixture in 0.1 g portions, allowing the system to reach equilibrium between each addition. The equilibrium state was determined by the stable RI measurement values. The RI measurement values were recorded during the subsequent addition. Thereafter, the concentration of the dissolved CD was plotted against the cumulative amount of cyclodextrin added.

[0186] The product (curcumin: cyclodextrin 1:2 dimer) was separated by the same method as in Example 1.

[0187] Example 4: Preparation of CBG: cyclodextrin complex 32 g of β-cyclodextrin was placed in a beaker and water was added to make the total volume 400 ml. The mixture was heated to 55 °C with stirring and 3 g of CBG was added. Samples were taken at regular intervals, diluted 1 / 5 with water at 20 °C, and the RI of the diluted samples was measured. The reaction was stopped when the RI of the diluted sample decreased to 0.3 and became constant, indicating that the reaction was complete. The reaction mixture was cooled to room temperature (about 20 °C), and then the solid phase was recovered by filtration. The filtrate contained unreacted dissolved β-cyclodextrin, which was discarded.

[0188] A 1:2 CBG:CD dimer product was obtained.

[0189] Figure 7 shows the solubility of β-cyclodextrin in the presence of CBG.

[0190] Example 5: Preparation of CBD:α-CD dimer complex and CBD:γ-CD dimer complex In the complex formation reaction, the equilibrium concentration of the dimer complex formed needs to exceed the solubility of these complex products in the reaction medium in order to obtain a high yield of the dimer complex. When α- or γ-cyclodextrin is used to complex with CBD and the reaction medium is water, these conditions cannot be satisfied, and therefore the reaction yield is low.

[0191] When the complex formation reaction is successful, it is indicated by a decrease in the refractive index at the end.

[0192] In the next experiment, replacing water as the reaction medium with a diluted ethanol solution (i.e., a mixture of water and ethanol) was investigated. The presence of ethanol in the aqueous reaction medium increases the solubility of CBD and decreases the solubility of cyclodextrin and the CBD / cyclodextrin complex.

[0193] Either α- or γ-cyclodextrin was added to an aqueous ethanol solution in the presence of a certain amount of CBD to test whether an aqueous ethanol solution was used as the reaction medium. If the reaction was successful, it was indicated by a decrease in the refractive index after incubation overnight at 25°C.

[0194] Results

Table 1

[0195] In the above table, "O / N" means overnight.

[0196] Conclusion By using aqueous ethanol as the reaction medium, the relative solubility of the reaction species changed, and the relative solubility of the cyclodextrin / CBD complex products became lower than the equilibrium concentration of those products. As a result, the reaction proceeded completely and was successfully completed.

[0197] Both dimer products (i.e., CBD:α-cyclodextrin and CBD:γ-cyclodextrin) were successfully prepared in high yields (complex formation efficiency exceeding 90%).

[0198] Stoichiometric evaluation of the CBD:CD complex The results of this experiment are shown in Figure 3.

[0199] β-Cyclodextrin was divided and added to water at 50 °C, and while stirring, it was added to a solution containing either 0.00635 mol of CBD, 0.0127 mol of CBD, 0.0254 mol of CBD, or 0.0381 mol of CBD. The concentration of cyclodextrin was measured after each addition. The results show that the concentration of dissolved cyclodextrin increases linearly until it reaches approximately 0.014 M. This indicates that the reaction between CD and CBD hardly occurs when the CD concentration is less than 0.014 M. Conversely, when CD is added in excess of 0.014 M, the concentration of (dissolved) CD in water decreases rather than increases, and this trend continues until the molar ratio of CD to CBD is approximately equal. When the molar ratio of CBD to CD is in the range of 1 to 2, the CD concentration in water remains constant even when CD is added. This suggests that within this molar ratio range, there is an equilibrium between CBD:CD monomers, CBD:CD 2 dimers, and CD in the solution. When CD is added to a mixture with a CD:CBD ratio exceeding 2, as a result, the CD concentration in water increases again. This indicates that the previous equilibrium is not maintained and that free CD is present in the solution.

[0200] In conclusion, for the complex formation reaction of CD / CBD, the concentration of CD needs to exceed a minimum amount. This reaction proceeds stepwise, first forming monomers (CBD:CD), and then dimers (CBD:CD 2 ). The CBD:CD monomers, CBD:CD 2 dimers, and CD form a stable equilibrium in the solution.

[0201] Evaluation of the stability of the CBD / CD dimer complex A stability test was conducted on a technical batch in which the CBD:β-CD dimer product was encapsulated in two-piece hard shell capsules (420 mg per capsule).

[0202] The stability test was carried out for 3 months under the conditions of 25 °C / 60% relative humidity and 40 °C / 75% relative humidity, and analysis by HPLC-UV / MS was performed at each time point of t = 0, 1, 2, and 3 months.

[0203] At each time point, the capsules were taken out of the humidity chamber and prepared according to the following procedure. The sample was prepared in a 250 ml volumetric flask. This volume was found to be sufficient to keep the CBD concentration in each capsule within the calibration range during the initial investigation. The capsules were opened by separating both sides of the case, and the contents were carefully transferred to the flask. The inside of the case was washed three times with a 50:50 methanol / water solution, and the washing liquid was poured into the flask to ensure that the remaining powder was also recovered. As a result, a turbid solution was formed. Then, each sample solution was sonicated for 30 minutes using a Fisherbrand ultrasonic disruptor at a frequency of 37 kHz and an output of 40%. After sonication, the resulting solution became transparent, indicating that the CBD / CD complex had completely dissolved.

[0204] After sonication, the sample was cooled to room temperature, and then additional 50:50 methanol / water solution was added to make up to the mark. The flask was inverted 10 times to confirm that the sample solution was well mixed, and then aliquots were taken and filled into HPLC vials. For each sample, two sets of HPLC vials were prepared, one for analysis and the other for cryopreservation in case re - implementation was required. All sample analyses were performed on the same day as the samples were prepared, and new calibrations were performed for each measurement of each sample set. Using the regression line (obtained from the injection of the certified reference material) for each calibration, the CBD concentration in the sample was calculated, and based on this, the mass of CBD in each capsule was calculated.

[0205] Thereafter, the samples were analyzed using the HPLC - UV / MS method shown in the following table.

Table 2

[0206] A new calibration was performed for each analyzed sample set, and the CBD concentration in the 250 ml sample solution was calculated using the corresponding regression equation. Then, the mass of CBD in each capsule was calculated.

[0207] Throughout the tests, good reproducibility and accuracy were shown in all calibrations, and the R 2 value was over 0.9998.

[0208] The UV chromatogram and the MS total ion chromatogram (TIC) were examined and compared with the injection data of the pure CBD standard substance and all the samples analyzed. No additional peaks that were not present in the chromatogram of the standard substance were observed in the chromatograms of the samples. This suggests that there are no decomposition products in the samples analyzed at each time point and during the test period.

[0209] DSC analysis of the CBD / CD complex Differential scanning calorimetry (DSC) was used to evaluate the physical state of CBD in the CBD:CD dimer product prepared according to Example 1 above.

[0210] 5 - 10 mg of the powder was accurately weighed, sealed in an aluminum pan, and then subjected to one heating ramp at a heating rate of 20 °C / min in the range from 10 °C to 100 °C. The heating rate of 20 °C / min has been found to be optimal for the detection of crystallinity in the formulations prepared by Koch et al. (Koch et al., 2020, Int. J. Pharm. 119812). Therefore, this method was applied to this test. The DSC measurements were collected using a Netzsch STA449 F1 Jupiter DSC / TGA and Netzsch software Proteus - 61 (connect the Autosampler to the STA449F1 on the USB client for data collection and perform data processing with Proteus Analysis). Prior to sample analysis, a blank correction was performed using an empty aluminum pan (with a perforated lid) under the same measurement conditions. The DSC profiles of the raw materials of CBD and CD, and the CBD / CD complex are shown in Figures 4(a) - (c), respectively.

[0211] Figure 4 shows that the CBD / CD complex exhibits the same glass transition as the CD raw material. Figure 4(c) shows that there is no transition in the same region of the CBD raw material (68 °C), suggesting that CBD is completely complexed.

[0212] Solubility evaluation of the CD:CBD dimer complex (UV analysis) The concentration of the CD:CBD dimer complex was measured using UV analysis. This was done by using a solution prepared by dissolving 10 g of the dimer complex produced according to Example 1 in 200 ml of water, gradually increasing the temperature of the solution with a hot plate stirrer, and then gradually decreasing it.

[0213] The solubility profile is shown in Figure 5. The solubility profile shows an unexpected pattern, with the solubility of the complexed CBD during heating appearing to increase almost exponentially. However, a different trend was observed during cooling. Instead, the CBD dimer remained in solution for some time and the solubility appeared to decrease slowly as the temperature decreased. This is different from normal because the solubility during cooling is usually thought to show the opposite behavior to that during heating.

[0214] The CD:CBD dimer showed a solubility of 1.6 mM at approximately 37 °C (i.e., body temperature), and when the solution was heated to above 60 °C and then cooled to body temperature, the solubility increased to 2.7 mM. This result shows that the solubility of the dimer is significantly increased compared to free CBD, which is known to have a solubility of only about 0.2 μM. This also suggests that the dimer complex has a much higher bioavailability compared to free CBD.

[0215] The maximum solubility of the CD:CBD dimer measured in this experiment was approximately 15 mM - 17 mM during the cooling cycle from 90 °C to 70 °C.

[0216] Phase solubility diagram The phase solubility diagram of CBD / CD is shown in Figure 6. A representative literature on the creation of the phase diagram is the research by Takeru Higuchi and Kenneth Connors (Advances in Analytical Chemistry Instrumentation, 1965, 4, 117 - 212). Using the method of Higuchi and Connors, CBD / CD is expected to show an obvious type B complex formation behavior as described on page 148 of Higuchi et al.'s paper.

[0217] Surprisingly, contrary to previous literature, the phase solubility diagram in Figure 6 shows type A P phase solubility behavior. This means that for many lipophilic drugs (including CBD, curcumin, tocopherol, etc.), the stoichiometric ratio (plural possible) of the complex cannot be estimated using the standard Higuchi and Connors phase solubility diagram. The increase in solubility estimated using the Higuchi and Connors phase solubility diagram may be significantly underestimated, and the amount of cyclodextrin required to achieve solubility is likely to be significantly overestimated.

[0218] Evaluation of Bioavailability Two-piece hard shell capsules were prepared, each containing 100 mg of cannabidiol or 417 mg of the CBD:CD complex prepared according to Example 1 (50 mg in terms of CBD). Fasted subjects were orally administered one cannabidiol capsule (100 mg of cannabidiol) or two cannabidiol / cyclodextrin capsules (a total of 100 mg in terms of cannabidiol). The capsules were taken with one standard cup of water. Capillary blood was collected 1 hour after ingestion, and the amounts of cannabidiol and its metabolites in the blood were analyzed by an accredited testing institution.

[0219]

Table 3

[0220] The results indicate that in capillary blood, when using cannabidiol / cyclodextrin dimer (complex) as compared to natural cannabidiol, the CBD concentration increased by 4-fold and the total CBD and its metabolites increased by 5-fold.

[0221] Conclusion It was shown that by complexing a fat-soluble drug (e.g., CBD or vitamin E) and cyclodextrin at a molar ratio of 1:2, it is possible to prepare a stable solid composition for oral administration. The obtained solid composition has improved bioavailability and can be used for oral administration without being excreted.

[0222] List of items of the embodiment 1. A solid composition comprising a fat-soluble drug and cyclodextrin, wherein the fat-soluble drug and cyclodextrin are in the form of a complex, and the molar ratio of the fat-soluble drug to cyclodextrin in the complex is about 1:2.

[0223] 2. The solid composition according to item 1, wherein at least 80% by weight of the fat-soluble drug and the cyclodextrin in the solid composition are contained in the form of the complex at a molar ratio of about 1:2.

[0224] 3. The solid composition according to item 1 or item 2, wherein at least 90% by weight of the fat-soluble drug and the cyclodextrin in the solid composition are contained in the form of the complex at a molar ratio of about 1:2.

[0225] 4. The solid composition according to any one of the above items, wherein at least 95% by weight of the fat-soluble drug and the cyclodextrin in the solid composition are contained in the form of the complex at a molar ratio of about 1:2.

[0226] 5. The solid composition according to any one of the above items, wherein at least 97% by weight of the fat-soluble drug and the cyclodextrin in the solid composition are contained in the form of the complex at a molar ratio of about 1:2.

[0227] 6. The solid composition according to any one of the preceding items, wherein at least 98% by weight of the fat-soluble drug and the cyclodextrin in the solid composition are contained in the form of the complex in a molar ratio of about 1:2.

[0228] 7. The solid composition according to any one of the preceding items, wherein at least 99% by weight of the fat-soluble drug and the cyclodextrin in the solid composition are contained in the form of the complex in a molar ratio of about 1:2.

[0229] 8. The solid composition according to any one of the preceding items, wherein the fat-soluble drug is the only therapeutic active ingredient in the solid composition.

[0230] 9. The solid composition according to any one of the preceding items, wherein the solid composition contains 20 mg to 300 mg of the fat-soluble drug, preferably 40 mg to 200 mg, more preferably 50 mg to 150 mg of the fat-soluble drug.

[0231] 10. A preparation comprising the solid composition according to any one of Items 1 to 9.

[0232] 11. The preparation according to Item 11, wherein the solid composition is formulated into tablets, capsules, pellets, gums, powders, gels, creams, pastes, eye drops, lozenges, oral solutions, beverages, functional foods, or injections.

[0233] 12. The preparation according to Item 11 or Item 12, wherein the preparation contains 20 mg to 300 mg of the fat-soluble drug, preferably 40 mg to 200 mg of the fat-soluble drug, more preferably 50 mg to 150 mg of the fat-soluble drug.

[0234] 13. The solid composition according to any one of the preceding items, which is used for the treatment of diseases, disorders or medical conditions.

[0235] 14. A method for treating a disease, disorder or medical condition, comprising administering the solid composition according to any one of Items 1 to 9.

[0236] 15. Use of the solid composition according to any one of items 1 to 9 in the manufacture of a medicament for the treatment of a disease, disorder or medical condition.

[0237] 16. A solid composition for use according to item 13, a method according to item 14, or use according to item 15, wherein the disease, disorder or medical condition is one in which the fat-soluble drug is known to be effective.

[0238] 17. A solid composition for use according to item 16, a method or use, wherein these diseases, disorders or medical conditions are related to the endocannabinoid system, related to vitamin deficiency (e.g., vitamin E deficiency), or responsive to treatment with an antioxidant (e.g., curcumin).

[0239] 18. A solid composition for use according to item 16, a method or use, wherein the disease, disorder or medical condition is selected from the group consisting of anxiety, insomnia, epilepsy, neuropathic pain, opioid dependence, PTSD, IBD, stroke, acne, dermatitis, wrinkles, psoriasis, ADHD, SARS, inflammatory diseases, and chronic pain.

[0240] 19. Non-therapeutic use of the solid composition according to any one of items 1 to 9.

[0241] 20. The non-therapeutic use according to item 19, wherein the use is as part of a cosmetic formulation, supplement, functional food or nutritional food, or beverage.

[0242] 21. A process for producing a solid composition comprising a fat-soluble drug and cyclodextrin, wherein the fat-soluble drug and the cyclodextrin are in the form of a complex in a molar ratio of about 1:2, The process comprises the following, a. Providing the fat-soluble drug, b. Providing the cyclodextrin, c. combining the fat-soluble agent and the cyclodextrin in the presence of water to form a composition; d. mixing the composition until a complex precipitate of the fat-soluble agent and cyclodextrin forms; e. recovering the precipitate of step d. to provide the solid composition comprising the fat-soluble agent and the cyclodextrin in the form of the complex.

[0243] 22. The process according to item 21, wherein the mixing and / or stirring step is carried out in a temperature range between 25°C and 70°C, such as between 30°C and 70°C, between 40°C and 70°C, between 45°C and 70°C, between 25°C and 60°C, between 30°C and 60°C, between 40°C and 60°C, or between 45°C and 60°C.

[0244] 23. The process according to item 21 or item 22, wherein the amount of the fat-soluble agent and / or the amount of the cyclodextrin exceeds their respective relative solubilities in the composition of step c.

[0245] 24. The process according to any one of items 21 to 23, wherein the concentration of the fat-soluble agent in the composition of step c. is in a saturated state.

[0246] 25. The process according to any one of items 21 to 24, wherein the concentration of the cyclodextrin in the composition of step c. is in a saturated state.

[0247] 26. The process according to any one of items 21 to 25, wherein undissolved fat-soluble agent and / or cyclodextrin is present in the binding step, and when complexation proceeds and the solid composition precipitates, additional fat-soluble agent and / or cyclodextrin dissolves.

[0248] 27. The process according to any one of items 21 to 26, wherein the cyclodextrin is in molar excess with respect to the fat-soluble agent in the binding step and / or the mixing step.

[0249] 28. In step d., the mixing is continued until substantially no uncomplexed (i.e., free) cyclodextrin and no uncomplexed (i.e., free) lipophilic drug are present in the composition, according to any one of items 21 to 27.

[0250] 29. An RI (refractive index) meter is used to indicate the completion of the complexation, according to any one of items 21 to 28.

[0251] 30. At least 80%, or at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99% by weight of the lipophilic drug and the cyclodextrin in the solid composition are present in the complex in a molar ratio of about 1:2, according to any one of items 21 to 29.

[0252] 31. Step d is carried out in an aqueous alcohol (e.g., aqueous ethanol) solution, according to any one of items 21 to 30.

[0253] 32. A solid composition obtainable by the process of any one of items 21 to 31.

[0254] 33. A solid composition manufactured by the process of any one of items 21 to 31.

[0255] 34. In any one of the above items, the cyclodextrin is natural (unmodified) α-, β-, or γ-cyclodextrin.

[0256] 35. In any one of the above items, the cyclodextrin is natural (unmodified) β-cyclodextrin.

[0257] 36. In any one of the above items, the lipophilic drug has a size smaller than the size of the cavity of the cyclodextrin such as β-cyclodextrin.

[0258] 37. In any one of the above items, the fat-soluble drug is between 100 and 700 g / mol, more preferably between 200 and 600 g / mol, or between 250 and 550 g / mol.

[0259] 38. In any one of the above items, the fat-soluble drug has a logP of 3 or more, for example, between 3 and 9, preferably between 3 and 8, and more preferably between 3 and 7.

[0260] 39. In any one of the above items, the fat-soluble drug has at least one carbon chain with a length of at least 3 carbon atoms.

[0261] 40. In any one of the above items, the fat-soluble drug is a compound having a phenol ring, which is further substituted or fused with another ring.

[0262] 41. In any one of the above items, the fat-soluble drug is a compound having a phenol ring substituted with an alkyl chain or an alkenyl chain.

[0263] 42. In any one of the above items, the fat-soluble drug is a compound having a phenol ring substituted with an alkyl chain or an alkenyl chain with a length of at least 3 carbons.

[0264] 43. In any one of the above items, the fat-soluble drug is a compound having the structure of Formula I below.

Chemical formula

[0265] 44. The compound of item 43, wherein R 2 is C 3 -C 5 alkyl and includes n-propyl, n-butyl and n-pentyl.

[0266] 45. The compound of item 43 or item 44, wherein R 5 is C 8 -C 12 alkenyl and is unsubstituted, substituted with methyl, ethyl or propyl, or substituted with substituted cyclohexenyl.

[0267] 46. The compound of any one of items 43 to 45, wherein when R 4 and R 5 combine to form one or two ring structures, a fused bicyclic system is formed.

[0268] 47. In any one of the aforementioned items, the fat-soluble agent is selected from the group consisting of cannabinoids, vitamin E or vitamin E derivatives, vitamin D or vitamin D derivatives, vitamin A or vitamin A derivatives, curcumin or curcumin derivatives, sterols or sterol derivatives, antibiotics, non-steroidal anti-inflammatory agents (NSAIDs), and artemisinin or artemisinin derivatives.

[0269] 48. In any one of the above items, the fat-soluble drug is a vitamin E derivative selected from tocopherol acetate, tocopherol glucoside, tocopherol phosphate, tocopherol nicotinate and / or succinic acid tocopherol, and preferably, the vitamin E derivative is succinic acid tocopherol.

[0270] 49. In any one of the above items, the fat-soluble drug is a cannabinoid selected from the group consisting of cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG) and δ-9-tetrahydrocannabinol (THC).

Claims

Claim 1 A process for producing a solid composition comprising a lipophilic agent and cyclodextrin, wherein the lipophilic agent and the cyclodextrin are in the form of a complex in a molar ratio of about 1:2, the process comprises the following steps: a. providing the lipophilic agent; b. providing the cyclodextrin; c. combining the lipophilic agent and the cyclodextrin in the presence of water to form a composition; d. mixing the composition until a precipitate of the complex of the lipophilic agent and cyclodextrin forms; e. recovering the precipitate of step d to provide the solid composition comprising the lipophilic agent and the cyclodextrin in the form of the complex. Claim 2 The process according to claim 1, wherein the concentration of the lipophilic agent in the liquid phase of the composition in step c is in a saturated state. Claim 3 The process according to claim 1 or claim 2, wherein the concentration of the cyclodextrin in the liquid phase of the composition in step c is in a saturated state. Claim 4 The process according to any one of the preceding claims, wherein the amount of the lipophilic agent and / or the amount of the cyclodextrin exceeds their relative solubility in the composition of step c. Claim 5 The process according to any one of the preceding claims, wherein undissolved lipophilic agent and / or cyclodextrin is present in the binding step so that as the complexation proceeds and the solid composition precipitates, additional lipophilic agent and / or cyclodextrin dissolves. Claim 6 The process according to any one of the preceding claims, wherein in the binding step c and / or the mixing step d, the cyclodextrin is in molar excess over the lipophilic agent. Claim 7 The process according to any one of the preceding claims, wherein in step d, the mixing is continued until the cyclodextrin is no longer saturated in the liquid phase of the composition. Claim 8 The process according to any one of the preceding claims, wherein at least 80% by weight of the lipophilic agent and the cyclodextrin in the precipitate is present in the complex in the molar ratio of about 1:

2. Claim 9 The process according to any one of the preceding claims, wherein step d is carried out in an aqueous alcohol solution. Claim 10 The process according to any one of the preceding claims, wherein the combining and / or mixing step is carried out at a temperature between 25°C and 70°C.

11. The process according to any one of the preceding claims, wherein the cyclodextrin is a natural (unmodified) α-, β- or γ-cyclodextrin.

12. The process according to any one of the preceding claims, wherein the lipophilic agent has a size between 200 and 600 g / mol.

13. The process according to any one of the preceding claims, wherein the lipophilic agent has a logP between 3 and 8.

14. The process according to any one of the preceding claims, wherein the lipophilic agent is selected from the group consisting of cannabinoids, vitamin E or vitamin E derivatives, vitamin D or vitamin D derivatives, vitamin A or vitamin A derivatives, curcumin or curcumin derivatives, sterols or sterol derivatives, antibiotics, non-steroidal anti-inflammatory agents (NSAIDs), and artemisinin or artemisinin derivatives.

15. The process according to any one of the preceding claims, wherein the lipophilic agent is a cannabinoid selected from the group consisting of cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG) and δ-9-tetrahydrocannabinol (THC).

16. The process according to any one of the preceding claims, wherein the lipophilic agent and the cyclodextrin are in the form of a complex in a molar ratio of about 1:

2.

17. A solid composition comprising a lipophilic agent and a cyclodextrin, wherein the lipophilic agent and the cyclodextrin are in the form of a complex, and the lipophilic agent and the cyclodextrin in the complex are in a molar ratio of about 1:

2.

18. The solid composition according to claim 17, wherein at least 80% by weight of the lipophilic agent and the cyclodextrin in the solid composition are in the form of the complex in the molar ratio of about 1:

2.

19. The solid composition according to claim 17 or claim 18, wherein the cyclodextrin is a natural (unmodified) α-, β- or γ-cyclodextrin.

20. The solid composition according to any one of claims 17 to 19, wherein the lipophilic agent has a size between 200 and 600 g / mol.

21. The solid composition according to any one of claims 17 to 20, wherein the fat-soluble drug has a logP between 3 and 8.

22. The solid composition according to any one of claims 17 to 21, wherein the fat-soluble drug is selected from the group consisting of cannabinoids, vitamin E or vitamin E derivatives, vitamin D or vitamin D derivatives, vitamin A or vitamin A derivatives, curcumin or curcumin derivatives, sterols or sterol derivatives, antibiotics, non-steroidal anti-inflammatory agents (NSAIDs), and artemisinin or artemisinin derivatives.

23. The solid composition according to any one of claims 17 to 22, wherein the fat-soluble drug is a cannabinoid selected from the group consisting of cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), and δ-9-tetrahydrocannabinol (THC).

24. The solid composition according to any one of claims 17 to 23, wherein the fat-soluble drug is the only therapeutically active drug in the solid composition.

25. A formulation comprising the solid composition according to any one of claims 17 to 24.

26. The solid composition according to any one of claims 17 to 24, or the formulation according to claim 25, for use in the treatment of a disease, disorder or medical condition.

27. A method of treating a disease, disorder or medical condition comprising administering the solid composition according to any one of claims 17 to 24 or the formulation according to claim 25.

28. The solid composition for use according to claim 26 or the method according to claim 27, wherein the disease, disorder or medical condition is related to the endocannabinoid system, or is related to vitamin deficiency (such as vitamin E deficiency), or responds to treatment with an antioxidant (such as curcumin).

29. A non-therapeutic use of the solid composition according to any one of claims 17 to 24.

30. A solid composition obtainable by or manufactured by the process according to any one of claims 1 to 16.

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