WO2022013565A1 - New curcumin co-crystals and uses - Google Patents

Abstract

The present invention relates to a co-crystal consisting essentially of curcumin and a co-crystal former, wherein the co-crystal former is a combination of nicotinamide and isonicotinamide, or wherein the co-crystal former is proline. The structures of the co-crystals have been elucidated and shown to contain slip planes and other structural features which provide a benefit for pharmaceutical compositions containing the co-crystals.

Description

NEW CURCUMIN CO-CRYSTALS AND USES

Field of the Invention The present invention relates to novel co-crystals consisting essentially of cureumin and a co-crystal former, wherein the co-crystal former is a combination of nicotinamide and isonicotinamide, or wherein the co-crystal former is proline. The invention aiso relates to pharmaceutical and nutraceutical compositions containing these co-crystals and their use in medicine, such as in the treatment of cancer, rheumatoid arthritis, and depression.

Background of the invention

Cureumin ((1 E,6E)-1 ,7-bis (4-hydroxy-3-methoxyphenyl)-1 ,6-heptadiene-3,5-dione) is a solid yellow compound that is a component of the Indian spice turmeric. The hydrocarbon skeleton exhibits tautomerism at the carbonyl groups, with the keto-enol form being the dominant form in solution due to the resonance stabilization that results from the intramolecular hydrogen bonding. The keto-enol form (1b) is more energetically stable than the diketone form (1a) in the solid phase. Three reactive functional groups, namely the diketone moiety and the two phenolic groups, determine the activity of cureumin.

Cureumin is derived from the rhizome of Curcuma longa and has been traditionally used in the treatment of skin wounds, inflammation, tumours etc. It is a powerful antioxidant with the ability to scavenge free radicals generated in the body as a result of various metabolic processes, it is also well known for its anti-inflammatory, anti-angiogenic and immunomodulatory effects. Commercially available cureumin contains a mixture of about 75% cureumin, about 15% demethoxycurcumin and about 5% bisdemethoxycurcumin. Research on cureumin over the past decade has demonstrated the ability of this compound to modulate multiple cellular targets, and hence shown that it has potential as a preventive and therapeutic against a broad range of diseases. The compound possesses a broad range of biological activities that include antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities (see Jamvval, R. Journal of Integrative Medicine, 2018, 18, pp. 367-374).

In particular, curcumin is used for treatment of various diseases like arthritis, gastrointestinal upset and the like, Curcumin is available in the form of a dietary supplement because of its antioxidant benefits as it provides protection against cell- damaging free radicals. However, the extent to which the human body benefits from consumption of curcumin is limited because of the poor bioavailability of curcumin. The poor bioavaiiability is due, in part, to poor solubility (< 8 pm mL·¹ in water), low permeability and absorption, and rapid metabolism (short elimination half-life < 2h), Although curcumin actively inhibits proliferation in cancer cells in vitro, it has poor solubility, bioavaiiability and half-life in vivo and clinical trials have failed to show any meaningful activity.

Following oral administration, curcumin must be absorbed at a suitable rate, distributed in adequate concentration in the blood and then remain in the system for a sufficient period at an effective concentration to provide the desired clinical benefits. The poor solubility of curcumin presents challenges for the provision of an adequate therapy.

To improve the bioavaiiability of curcumin, numerous approaches have been undertaken mainly to increase solubility and protection from acidic pH in the gastrointestinal tract. Said approaches include methods such as amorphisation, nanopartic!e formation, and eutectic formation.

US 2007/0148263 relates to a formulation of curcuminoid (defined as a mixture of curcumin, demethoxycurcumin and bisdidemethoxycurcumin) with the essential oil of turmeric to enhance the bioavaiiability of curcumin and to augment the biological activity of curcumin. The disadvantage of this invention is that this formulation is also highly hydrophobic, insoluble, has strong turmeric oil aroma and acts by inhibiting glucuronidation, an important in vivo detoxifying mechanism.

WO 2007/101551 discloses phospholipid complexes of curcumin for improved bioavaiiability, and WO 2010/013224 describes the formation of chitosan bound curcumin nanoparticles with an enhancement of 10-fold bioavaiiability upon oral administration to rats. US 9,447,050 describes solid forms of curcumin.

Notwithstanding the poor bioavaiiability of curcumin, curcumin also possesses poor tableting properties. Tablets are however the most favourable dosage forms for patients. Additionally, tablets are also the most economical dosage forms for formulation from an industrial standpoint. The ability of a pharmaceutical powder to exhibit plastic deformation upon compression at a specific pressure to form a tablet is essential for good tablet formation (tabletability). For example, paracetamol form 1 is known to have poor tabletting properties, and problems with chipping arise for tablets that are product by compression without a large amount of binders (Karki S., et al. Adv Mater. 2009; 21 (38-39):39G5-3909). Since cureumin has poor tabletability, tablets comprising curcumin may require high amounts of auxiliary ingredients, such as binders, which may limit the amount of active ingredient, i.e. curcumin, present in the formulation. Thus, alternative methods of increasing the tabletability of curcumin are needed.

The international patent application with published no, WO 2012/138907 relates to cocrystals of curcumin with co-formers selected from nicotinamide, 2-amido benzimidazole and L-lysine, The international patent application with published no. WO 2015/052588 discloses co-crystals of curcumin with nicotinamide and curcumin with isonicotinamide. However, none of these publications discloses the atomic arrangement of these crystal forms, nor do they mention whether there are any changes in terms of tabletability or bioavaiiability of curcumin.

There remains a need for developing novel solid forms of curcumin having improved bioavaiiability properties as well as better tableting properties.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Disclosure of the Invention

According to a first aspect of the invention there is provided a co-crystai having at least one slip plane and consisting essentially of curcumin and a co-crystal former, wherein the co-crystal former is a combination of nicotinamide and isonicotinamide, or wherein the cocrystal former is proiine.

These eo-crystais are hereinafter referred to as the “co-crystals of the invention”. it has surprisingly been found that the co-crystals of the invention possess better tabletability properties compared to crystalline curcumin and may also have increased bioavailability compared to crystalline curcumin. The co-crystals of the Invention are therefore suitable for enteral administration. The 3D arrangements of the molecules in the co-crystals of the invention have been elucidated and the co-crystals have been shown to contain a reliable slip plane. Without wishing to be bound by theory, it is believed that the presence of a reliable slip plane contributes to the advantageous properties (e.g. improved tabletability) of the co-crystals described here.

The term “co-crystal” as employed herein will be understood by the skilled person to mean a solid consisting of, or consisting essentially of, a crystalline material composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. Co-crystals typically take a different crystalline form from that associated with any of the individual ingredients, and the co-crystals frequently have significantly different physical properties compared to the individual components, such as solubility, dissolution rate, chemical stability, mechanical behaviour, moisture uptake, etc.

The co-crystals of the present invention contain curcumin together with one or more other components. These one or more other components are referred to as “co-formers” (or cocrystal formers) and are present in the crystal lattice in a fixed stoichiometric ratio relative to the curcumin. By virtue of forming a co-crystal, the present invention also provides a route for providing curcumin having a lower content of demethoxycurcumin and bisdemethoxyeurcumin. Co-crystal formation with curcumin has been found to be favoured over demethoxycurcumin and bisdemethoxyeurcumin.

A co-crystal of a drug (an active nufraceufical ingredient or an active pharmaceutical ingredient) is a distinct chemical composition between the drug and co-former, and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the drug and co-former individually. Unlike salts, which possess a neutral net charge, but which are comprised of charge-balanced components, co-crystals are comprised of neutral species. Thus, unlike a salt, one cannot determine the stoichiometry of a co-crystal based on charge balance. Indeed, one can often obtain cocrystals having stoichiometric ratios of drug to co-former of greater than or less than 1 :1.

The process of co-crystallisation for curcumin has now been found to change various properties of the curcumin, such as its bioavailability and its capability to exhibit plastic deformation upon compression at a specific pressure. The improvements in the mechanical properties are believed to arise from the altering of the molecular packing within the crystals. The co-crystals of the present invention contain new slip planes or other structural features which are believed to facilitate an improvement in mechanical properties as the slip planes facilitate the sliding of the layers within the crystal and thereby ease plastic deformation.

The term “slip” refers to the translational motion of neighbouring lattice planes relative to each other in response to a compression force. Such planes are termed “slip planes”. Slip planes may also be defined as crystallographic planes in the crystal structure which contain the weakest interaction between the adjacent planes and are accounted by the highest molecular density and largest d-spaeing, as compared to the other planes in that crystal (Shariare, M.H., et ai., Pharm. Res. 2012, 29, 319-331). A family of slip planes, together with the slip direction, is termed a “slip system”. The lattice structure of cureumin form 1 lacks a reliable slip plane, and this material has been found to have poor plasticity. Direct comparison with the co-crystals of the invention shows that the latter contain reliable slip planes and exhibit better plasticity.

The co-crystals of the present invention have been found to comprise both cureumin and the co-crystal former(s) in a molar ratio that is typically from 1 :1 to 1 :3, preferably about 1 :2. When the co-crystal former is a combination of nicotinamide and isonicotinamide, a ternary system is formed and a ratio of 1 :2 in this context indicates that one molecule of cureumin is present for each pair of nicotinamide and/or isonicotinamide molecules.

In an alternative first aspect of the invention, there is provided a co-crystal consisting essentially of cureumin and co-crystal former, wherein the co-crystal former is a combination of nicotinamide and isonicotinamide, or wherein the co-crystal former is proiine and the molar ratio of cureumin and proline is from 1 :1 to 1 :3. The structures of these co-crystals, which may include a slip plane or another relevant structural feature, provide for improved compression properties which aid tabletabiiity. In one embodiment, the molar ratio of cureumin and co-former(s) in the co-crystal is from 1 :1 to 1 :3, preferably about 1 :2. For example, when the co-crystal former is a combination of nicotinamide and isonicotinamide, the molar ratio of cureumin to the combination of nicotinamide and isonicotinamide is from 1 :0.5 to 1 :1 ,5, preferably about 1 :1 , Preferably, the nicotinamide and isonicotinamide are present in roughly equal quantities, such that the total amount of nicotinamide in the co-crystal is between 45% and 55% of the total amount of nicotinamide and isonicotinamide combined. Binary Curcumin Co-crystais with Proiine

The applicant has identified a further novel co-crystal comprising curcumin and a coformer, in which the co-former is proiine. As proline contains a single chiral centre, the compound has two enantiomeric forms known as L-proline and D-proline. In particular embodiments of the invention in which the co-former is proiine, the co-former is predominantly one of the two enantiomers of proiine (preferably L-proline). For example, the proiine co-former may be enanfiomericai!y enriched by at least 70%, at least 80%, at least 90% or at least 95%.

The molar ratio of curcumin and proiine is typically about 1 :2. For the avoidance of doubt, the term “CURPRO” as used herein refers to a co-crystal consisting essentially of curcumin and proiine, wherein the molar ratio is about 1 :2.

The CURPRO co-crystal of the invention has an X-ray powder diffraction pattern having characteristic peaks at about 5.4° (±0.2°), 7.1° (±0.2°), 16.3° (±0.2°) and 22.9° (±0.2°) 2Q. in contrast, curcumin has an X-ray powder diffraction pattern having characteristic peaks at about 8.0° (±0.2°), 8.9° (±0.2°), 17.3° (±0.2°), and 25.3° (±0.2°) 2Q and proiine has an X-ray powder diffraction pattern having characteristic peaks at about 18.0° (±0.2°), 19.5° (±0.2°), 22.7° (±0.2°), and 24.9° (±0.2°) 2Q. Ail X-ray powder diffraction peak positions mentioned herein were determined using Cu K-alpha radiation with a wavelength of 1.54060 A.

The CURPRO co-crystal of the Invention may further be characterised by an FTIR spectrum exhibiting peaks at 3200 cm^-1 (±3 cm^-1), 1513 cm^-1 (±3 cm^-1) and 1411 cm^-1 (±3 cm^-1). Notably, curcumin is characterised by an FTIR spectrum exhibiting a characteristic peak at 3508 cm^-1 (±3 cm^-1), Proiine is characterised by an FTIR spectrum exhibiting characteristic peaks at 1548 cm^-1 (±3 cm^-1) and 1448 cm^-1 (±3 cm^-1), which correspond to the asymmetric and the symmetric stretching of COO- group, respectively.

The CURPRO co-crystal of the invention may also be characterised by a differential scanning calorimetry curve having an onset of melting in the range 171 to 175 °C.

The CURPRO co-crystal of the invention is obtainable by crystallisation of a mixture comprising curcumin and proiine in ethanol or methanol. Single crystals of the CURPRO co-crystal of the invention (comprising curcumin and L-proline) have been formed and the structure has been elucidated. The CURPRO cocrystals have the orthorhombic space group P2i2i2i with the following single crystal lattice parameters: a = 5.61 A, b = 21.42 A, c = 24.82 A. While the crystallographic information disclosed herein for the cureumin-proline co-crystal has been obtained using L-proline, the skilled person would appreciate that corresponding co-crystal formation with D-proiine may also be achieved. in the CURPRO binary co-crystal, proiine molecules are stacked on top of each other to form a double ladder-like structure as shown in Figure 3. Every four molecules in the ladders are connected with two curcumin molecules: each of them has a slight pitch (angle = 36.8°). The ladder assembly facilitate the compression of the lattice as a result of the lower energy barrier for movement, in addition to the non-pianar curcumin giving some flexibility and better tolerability to accommodate more pressure when stressed. XRPD was performed before and after compression to ensure that no phase transformation has occurred.

Ternary Curcumin Co-crystals with Nicotinamide and isonicotinamide

The applicant has identified a novel co-crystal comprising curcumin and a co-former, in which the co-former is a combination of nicotinamide and isonicotinamide. The molar ratio of curcumin, nicotinamide and isonicotinamide is typically about 1 :1 :1. For the avoidance of doubt, the term “CURNICISN” as used herein refers to a co-crystal essentially consisting of curcumin, nicotinamide and isonicotinamide, wherein the molar ratio is about 1 :1 :1.

The CURNICISN co-crystal has an X-ray powder diffraction pattern having characteristic peaks at about 4.5° (±0,2°), 6,0° (±0.2°), and 26,8° (±0.2°) 2Q. In contrast, crystalline curcumin “form G has an X-ray powder diffraction pattern having characteristic peaks at about 8,0° (±0.2°), 8,9° (±0.2°), 17,3° (±0.2°), and 25.3° (±0,2°) 2Q, nicotinamide has an X-ray powder diffraction pattern having characteristic peaks at about 14.9° (±0.2°), 26.0° (±0.2°), 26.5° (±0.2°), and 27.9° (±0.2°) 2Q, and isonicotinamide has an X-ray powder diffraction pattern having characteristic peaks at about 17.9° (±0,2°), 21.0° (±0.2°), 23.6° (±0.2°), and 26.1 ° (±0.2°) 2Q.

The CURNICISN co-crystal of the invention may also be characterised by an FTIR spectrum exhibiting peaks at 3505 cm^-1 (±3 cm^-1), 3165 cm^-1 (±3 cm^-1), 2932 cm^-1 (±3 cm^-1) and 1660 cm^-1 (±3 cm^-1). Notably, curcumin is characterised by an FTIR spectrum exhibiting a characteristic peak at 3508 cm^-1 (±3 cm^-1). Nicotinamide is characterised by an FTIR spectrum exhibiting characteristic peaks at 3335 cm^-1 (±3 cm^-1), 3145 cm^-1 (±3 cm^-1), and 1673 cm^-1 (±3 cm^-1). Isonicotinamide is characterised by an FTIR spectrum exhibiting characteristic peaks at 3363 cm^-1 (±3 cm^-1), 3178 cm^-1 (±3 cm^’1), and 1656 cm^-1 (±3 cm^-1),

The CURN!C!SN co-crystal of the invention may also be characterised by a differential scanning calorimetry curve having an endothermic peak in the range 95 to 99 °C.

The CURN!C!SN co-crystal of the invention is obtainable by crystallisation of a mixture comprising curcumin, nicotinamide and isonicotinamide in ethyl acetate or propyl acetate. Typically, the components are dissolved in the solvent, optionally with heating, and the crystals are allowed to form by slow evaporation of the solvent.

The CURNiCISN co-crystal of the invention is also obtainable by crystallisation of a mixture comprising curcumin, nicotinamide and isonicotinamide in a solvent, such as ethyl acetate, using an antisolvent, such as hexane. Typically, the compounds are dissolved in the solvent, e.g. at about 60 °C, before the antisolvent is added to form the co-crystals. The co-crystals are then separated from the solvent mixture by any conventional method, such as filtration.

Single crystals of the CURNICISN co-crystal of the invention have been formed so that the crystal structure can be elucidated. The CURNICISN co-crystals have the space group triciinic P-1 with the following single crystal lattice parameters: a = 5.13 A, b = 16.72 A, c = 21.49 A, a = 109.3°, b = 96.6°, and g = 96.5°.

The crystal structure of curcumin form 1 lacks a reliable slip plane, and this material has been found to have poor plasticity, while the co-crystals of the invention contain reliable slip planes and exhibit better plasticity. X-ray crystallographic studies of curcumin form 1 , the most stable crystalline form of curcumin, show that curcumin molecules are connected through hydrogen bonding between the enoi-hydroxyl and the phenyl-hydroxyl to form layers. From each layer, half of each curcumin molecule is protruding out to form a rough edge of the layer. Moreover, the phenyl rings of the neighbouring curcumin molecules are not lying in the same plane. The neighbouring layer of curcumin molecules is facing the opposite direction, and the protruding halves of the curcumin molecules are also in the opposite direction. This three-dimensional intersecting herring bone structure therefore lacks a reliable slip plane to ease the sliding of layers upon the application of a compression force.

Unlike curcumin form 1 , the co-crystals of the invention possess a slip plane as exemplified in Figure 4 for CURNICiSN showing a curcumin/niGotinamide/isonicotinamide ternary cocrystal of the invention having a main slip plane (0 -1 2) found by direct visualisation. Without wishing to be bound by theory, it is believed that the presence of the voids in the curcumin/nicotinamide/isonicotinamide ternary co-crystals described herein facilitate the sliding of the layers around this plane, without causing a collapse in the voids. This is supported by powder X-ray diffraction (XRPD) analysis which showed no phase transformation after compression. The strong hydrogen bonding between the amide groups of nicotinamide and isonieotinamide are believed to strengthen the intraiayer interaction, while the interlayer interaction employing weak C-H interactions may facilitate interlayer sliding.

The co-crystais of the invention have been surprisingly found to exhibit advantageous properties, including an increased bioavailability and/or solubility of the curcumin from the curcumin co-crystal compared to the bioavailability and/or solubility of curcumin from a crystal consisting of curcumin. Curcumin in its solid form has poor bioavailability and water solubility. Various methods of solubilising curcumin have been investigated such as the use of surfactants and micelles. These techniques have however not been successful as a metasiab!e solution is typically formed with uncontrolled re-precipitation which results in dissolution drop off.

The bioavailability of a drug is the amount of an enterally administered dose that reaches the systemic circulation in an unchanged form. Therefore, sufficient bioavailability is important to achieve a therapeutically active concentration at the site of action. Both drug release from the formulation and the stability of the formulation will affect its bioavailability. It is therefore important that the drug formulation should rapidly release a sufficient quantity of the drug, in vitro drug release can be measured using tests known in the art.

The co-crystals of the invention may be made by any method known to the skilled person. In a second aspect of the invention, there is provided a process for preparing a co-crystal of the invention, wherein the process comprises the steps of dissolving curcumin and the co-crystal former in a solvent, and allowing the solvent to partially or fully evaporate so that crystals form. There are various methods of co-crystallisation such as solution, cooling, wet and neat grinding, and slurry co-crystallisation. The outcome of the crystallisation process can be controlled through an understanding of the phase solubility diagrams that give an idea about the landscape of the co-crystallisation technique used and the thermodynamics controlling the process. Despite the various methods of co-crystallisation, crystallisation from solution remains the most popular and most desirable from an industrial point of view due to economic reasons. The main driving force for obtaining a co-crystal resembles that of obtaining a mono-component crystal; supersaturation followed by crystal nucieation and growth, it is vital to facilitate the conditions that lead to the formation of nuclei of the cocrystal rather than nuclei of the constituents.

Co-crystals are typically most readily obtained from solvent evaporation of the solution containing the components in the desired stoichiometric ratio.

The CURNICISN co-crystals of the invention are obtainable by crystallisation of a mixture comprising curcumin, nicotinamide and isonicotinamide in propyl acetate or, particularly, ethyl acetate.

A bulk amount of the CURNICISN co-crystal of the invention as powder may be obtainable by dissolving curcumin, nicotinamide and isonicotinamide in ethyl acetate or propyl acetate. Approximately equimolar amounts of curcumin, nicotinamide and isonicotinamide is preferably used. A suitable temperature for dissolving a mixture of curcumin, nicotinamide and isonicotinamide in ethyl acetate or propyl acetate is from about 50 °C to about 75 °C, preferably about 60 °C. The solvent from the so-obtained solution may then be evaporated slowly by keeping the mixture in an open vessel under atmospheric conditions until the co-crystals are formed, preferably with slow cooling if the solvent was heated for the dissolution step. The so-formed co-crystals may be isolated by techniques known in the art, such as filtration or decantation.

The CURPRO co-crystals of the invention are obtainable by crystallisation of a mixture comprising curcumin and proline in ethanol or methanol. The curcumin and proiine may be dissolved together in ethanol at a temperature of from about 40 °C to about 65 °C, preferably about 50 °C. Solvent evaporation may then take place to form crystals, preferably without cooling the mixture. The CURPRO co-crystals of the invention are also obtainable by freeze drying an ethano!ic solution comprising curcumin and proline, optionally at a 1 :2 molar ratio and a pressure of about 0.8 bar and a temperature of from about -75 °C to about -85°C.

Medicinal uses

As indicated herein, the co-crystal of the invention, and compositions (e.g, tablets and capsules) containing the same, are useful as pharmaceuticals or nutraceuticals.

Thus, according to a third aspect of the invention there is provided a co-crystal of to the invention, i.e. a co-crystal as hereinbefore defined optionally including any embodiments and particular features thereof, for use in medicine. The co-crystals of the invention may also be incorporated into any suitable composition for administration either as a pharmaceutical or a nutraceutical, and said compositions may be useful in medicine or as nutraceuticals. The co-crystals of the invention are particularly suited for incorporation into tablets. Therefore, in a particular embodiment, there is provided a co-crystal according to the invention, a pharmaceutical or nutraceutical composition according to the invention, or a tablet according to the invention, for use as a medicament.

Compositions comprising co-crystals of the invention are especially suited for enteral administration (e.g. for oral or rectal delivery). The increased curcumin bioavailabiiity observed for the co-crystals of the invention may then be used to provide a benefit to the recipient in terms of an increase in the amount of curcumin delivered to the body for a given formulation size.

Pharmaceutical compositions containing the co-crystal of the invention are useful in the treatment or prevention of diseases for which curcumin is known to have potential clinical use, for example as an anti-inflammatory agent, an antioxidant, an antiviral agent, an antibacterial agent, an antifungal agent, an anti-angiogenic agent, an immunomodulator and an anticancer agent. Diseases and conditions that may be treated by the co-crystals of the invention include skin wounds, inflammation, gastrointestinal upset, and particularly arthritis, depression, and cancer, as well as others that are known to the skilled person such as those described in Kunnumakkara A.B. et a!., Br. J. Pharmacol. 2017 Jun; 174(11): 1325-1348. The pharmaceutical compositions described here may be particularly useful in the treatment or prevention of rheumatoid arthritis. Thus, according to a fourth aspect of the invention, there is provided a method of treating or preventing a disease selected from the group consisting of arthritis, depression, and cancer, said method comprising administering to a patient in need thereof a therapeutically effective amount of a co-crystal of the invention. Similarly, the present invention relates to the use of a co-crystal of the invention in the manufacture of a medicament for treating or preventing arthritis, depression, and cancer. in a particular embodiment the co-crystal of the invention may be useful in the treatment of cancer wherein the cancer is selected from the group consisting of cervical cancer, breast cancer, lung cancer, haemato!ogiea! cancer, gastric cancer, colorectal cancer, skin cancer, pancreatic cancer and intestinal cancer.

The skilled person will understand that references herein to the “treatment” of a particular condition (or, similarly, to “treating” that condition) take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.

The skilled person will understand that references herein to “prevention” of a particular condition (and, similarly, to “preventing” that condition) take their normal meanings in the art. In particular, these terms may refer to achieving a reduction in the likelihood of developing the relevant condition or symptoms associated with the relevant condition (for example, a reduction of at least 10% when compared to the baseline level, such as a reduction of at least 20% or, more particularly, a reduction of at least 30%). Similarly, the term “preventing” may also be referred to as “prophylaxis” of the relevant condition, and vice versa.

According to a fifth aspect of the invention, there is provided a pharmaceutical or nutraceutical composition comprising a co-crystal of the invention and one or more pharmaceutically acceptable excipients. The pharmaceutical and nutraceutical compositions of the present invention encompass any composition made by admixing a co-crystal of the invention and one or more pharmaceutically acceptable excipients. The term “nutraceutical composition” refers to a medicinally or nutritionally functional food or dietary supplement.

Pharmaceutically acceptable excipients (i.e. excipients that are suitable for use in the compositions of the fifth aspect of the invention) include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dlcalcium phosphate, tricalcium phosphate, mannitol, sorbitol and sugar: binders such as acacia, guar gum, tragacanth, gelatine, polyvinylpyrrolidones, hydroxypropyi celluloses, hydroxypropylmethyi celluloses and pregeiatinized starch; disintegrants such as starch, sodium starch giycoiate, pregelatinized starch, crospovidones, croscarmeilose sodium and colloidal silicon dioxide; lubricants such as stearic acid, talc, magnesium stearate and zinc stearate; glidants such as colloidal silicon dioxide; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, complex forming agents such as various grades of cyc!odextrins and resins; release rate controlling agents such as hydroxypropyi celluloses, hydroxymethyl celluloses, hydroxypropyi methylce!iuioses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, and waxes. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, film coating agents, plasticizers, colorants, flavouring agents, sweeteners, viscosity enhancers, preservatives, and antioxidants. in a particular embodiment, the co-crystal of the invention is incorporated into a capsule, tablet, a melt tablet, or provided in the form of a dispersible powder or granules. Capsules containing the co-crystals of the invention may contain a mixture of dry ingredients including said co-crystals or may contain the co-crystals suspended in a liquid, preferably glycerol or an oil. The co-crystals of the invention may also be provided in the form of suppositories for rectal administration. in a particularly preferred embodiment, there is provided a tablet comprising a co-crystal of the invention. Said tablet may contain an enteral pharmaceutical or nutraceutical composition which itself comprises a co-crystal of the invention. The co-crystals of the invention may be present in tablets in an amount of at least about 30% (w/w), at least about 40% (w/w), at least about 50% (w/w), at least about 60% (w/w), at least about 70% (w/w), at least about 80% (w/w), at least about 85% (w/w), at least about 90% (w/w), at least about 95% (w/w), or at least about 99% (w/w). The co-crystals of the invention may be present in tablets in an amount of up to about 100% (w/w), up to about 99% (w/w), up to about 95% (w/w), up to about 90% (w/w), or up to about 80% (w/w).

Although it is stated that the tablets described herein consist essentially of co-crystals of the invention, said tablets may also contain one or more excipients which do not substantially alter the biological efficacy of the active ingredient (i.e. the curcumin). Therefore, the tablets described herein may contain one or more diluents (e.g. di-calcium phosphate, calcium carbonate, microcrystai!ine cellulose), one or more binders (e.g. acacia), one or more anti-caking agents (e.g. silicon dioxide, stearic acid, magnesium stearate), and one or more coatings (e.g. hydroxypropyi methylceilulose, glycerine).

In embodiments of the invention, the tablet containing a co-crystal of the invention has a tensile strength of at least 1 MPa, such as at least 2 MPa. Particularly, the tablet may have a tensile strength from about 1 to about 10 MPa.

Tablets are the most commonly opted formulation for administration of pharmaceutically active ingredients to humans, and an adequate mechanical strength is a key requirement for efficacy and patient compliance. The tensile strength can give an idea about the mechanical behaviour of the compacted curcumin and the cocrystals taking into account the geometry of the formed tablets alongside the breaking force. A tablet with tensiie strength larger than 1.7 MPa is generally considered to be capable of withstanding mechanical stress, i.e. they are less susceptible to breakage or cracking, e.g. during manufacturing, packaging, shipping and handling. The breaking force may be measured by subjecting the tablets to radial hardness force, and the tensile strength may then be calculated according to the following formula:

s is the tensiie strength, F is the breaking force, D is the diameter, and T Is the thickness.

Tablets may be made by filling a tablet die with an appropriate amount (e.g. 1QQ mg) of a suitable mixture of ingredients, and then compacting the mixture under pressure (e.g. 200 MPa) and at a suitable compression speed (e.g. 1 mm/min).

Depending on the disorder and the patient to be treated, as well as the route of administration, co-crystals of the invention may be administered at varying therapeutically effective doses to a patient in need thereof. Determination of an effective amount of the compound is within the capability of those skilled in the art. The dosage may be determined by the timing and frequency of administration. In the case of oral administration, the dosage can vary from about 1 mg to about 2000 mg per day of a cocrystal of the invention. Preferably, tablets comprising the co-crystals of the invention comprise from 200 to 1500 mg curcumin, such as from 500 to 1000 mg.

In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. For example, Kunnumakkara A.B. et ai., Br. J. Pharmacol. 2017 Jun; 174(11): 1325-1348 summarises a number of clinical studies involving curcumin and outlines doses which were found to be both tolerated and clinically efficacious. The dosages mentioned herein are exemplary only; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

As used herein, the term “about” or “approximately”, when used together with a number value (e.g. 5, 10%, 1/3) refers to a range of numeric values that can be less or more than the number. For example, "about 5" refers to a range of numeric values that are 10%, 5%, 2%, or 1% less or more that 5, e.g, a range of 4.5 to 5.5, or 4.75 to 5.25, or 4.9 to 5.1 , or 4.95 to 5.05. In some instances, "about 5" refers to a range of numeric values that are 2% or 1% less or more that 5, e.g. a range of 4.9 to 5.1 or 4.95 to 5.05. When the term “about” in the context of a ratio, this means that each component in the ratio may independently vary by ±10%, 5%, 2%, or 1%. For example, a reference to a three-component product in which the molar ratio is “about 1 :1 :1” includes such a product in which the molar ratio is 1 :11 :0.9.

For the avoidance of doubt, the skilled person will understand that references herein to cocrystals of particular aspects of the invention (such as the first aspect of the invention, i.e. referring to a co-crystal having at least one slip plane and consisting essentially of curcumin and a co-crystal former, wherein the co-crystal former is a combination of nicotinamide and isonicotinamide, or wherein the eo-crystai former is proiine) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention.

Unless stated to the contrary, any use of the words such as "including," "containing," "comprising" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.

The co-crystals of the invention are stated to consist essentially of curcumin and a co- crystal former, in this context, the term “consists essentially of (and similar) does not exclude the possibility that the co-crystals contain further components, but that the only additional components that may be present are those that do not material affect the essential characteristics of the co-crystal. Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention (particularly those of sufficient stability to allow for isolation thereof).

Figures

Preferred, non-limiting embodiments of the invention will now be described by way of example, with reference to the accompanying drawings in which:

Figure 1 shows the characteristic powder X-ray diffraction (XRPD) patterns of curcumin (top), L-proline (middle) and CURPRO (bottom). The XRPD diffraetogram was obtained using CuKal radiation. The y-axis shows the intensity (counts) and the x-axis shows the 20-angles (°),

Figure 2 shows the characteristic XRPD patterns of the following (top to bottom): curcumin, nicotinamide, co-crystal of nicotinamide and isonicotinamide, isonicotinamide, co-crystal of curcumin and isonicotinamide, and CURNICISN. The XRPD diffraetogram was obtained using CuKal radiation. The y-axis shows the intensity (counts) and the x-axis shows the 20-angles (°).

Figure 3 shows the crystal structure of CURPRO.

Figure 4 shows the crystal structure of CURNICISN.

Figure 5 shows stacked representative IR spectrum for each curcumin (top), proline (middle), and CURPRO (bottom).

Figure 6 shows stacked representative !R spectrum for each curcumin (top), nicotinamide (lower middle), isonicotinamide (bottom), and CURNICISN (upper middle).

Figure 7 shows a differential scanning calorimetry (DSC) diagram of a representative sample of CURPRO (bottom) and its coformers proline (top) and curcumin (middle).

Figure 8 shows a DSC diagram of a representative sample of CURNICISN (bottom) and Its coformers curcumin (lower middle) nicotinamide (upper middle) and isonicotinamide (top). Figure 9 shows the dissolution profiie of curcumin, CURPRO, and CURNICiSN in 30% ethanol.

Figure 10 shows the dissolution profile of Gurcumin and CURPRO in 10% ethanol.

Figure 11 shows the dissolution profile of curcumin and CURNICISN in 10% ethanol.

Figure 12 shows the tabietability profile of curcumin, curcumin and proline as a physical mixture, curcumin and nicotinamide and isonicotinamide as a physical mixture, CURPRO, CURNICISN.

Examples

The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention.

Methods

1) Powder X-ray diffraction

A Bruker D8 Discover Powder X-ray diffractometer was used to obtain the XRPD pattern for curcumin, the coformers and the co-crystals. Diffraction patterns were obtained across the 2Q range of 3 to 40° with a step of 0,2 and 2-second time count per step and a wavelength of 1.54060 A. EVA software package was used to analyse the data.

2) Single Crystal X-ray Diffraction (SC-XRD)

Bruker D8 Venture system was used to acquire the X-ray diffractions of the singie crystals. The measurements were conducted at a temperature of 173 K. Bruker Saint software was used to integrate the frames. Isotropic and anisotropic refinement of the non-hydrogen atoms was done first then hydrogen atoms were positioned by the aid of the electron density map.

3) Fourier Transform Infrared Spectroscopy (FTIR)

IR spectra of the starting materials and the co-crystals were collected using a Bruker Alpha Platinum ATR instrument. The samples were scanned in the region 400-4000 cm^·1, with a total of 64 scans per spectrum and the spectra were analysed using the software OPUS- 7. 4) Differential scanning calorimetry (DSC)

The melting temperatures and the TGA of curcumin, the coformers and the co-crystal powder were generated using Netzsch STA449F3. The scan was done at a rate of 10°c/min and from 50-200°c, under N₂gas flow of 50ml/min.

5) Solubility measurements

The coformers L-proiine, nicotinamide and isonicotinamide, were weighed in excess and suspended in a known volume of the solvents: ethanol, water, 10% ethanol and 30% ethanol. The solubility was then measured using UV spectrophotometry.

Example 1 - Preparation of curcumin-i-proline co-crystals (CURPRO)

Curcumin (36.8 mg) and L-proline (23 mg) we re dissolved in 5 ml_ ethanol at 50°C until a clear solution was obtained. The solution was left to evaporate at the same temperature. After five days, the single crystals were collected and analysed.

The co-crystal was also obtained by freeze drying the ethanolic solution of the 1 :2 molar amounts of curcumin: L-proline, at a pressure of Q.81 bar and a temperature of -81 °C. Single crystals of CURPRO have been formed and the structure has been elucidated. The CURPRO co-crystals have the orthorhombic space group P2i2i2i with the following single crystal lattice parameters: a = 5.61 A, b = 21.42 A, c = 24,82 A.

The CURPRO co-crystals were found to comprise atoms at atomic positions relative to the origin of the unit cell as set forth in Table 1.

Table 1 : Atomic positions for CURPRO

In this structure, each phenolic hydroxyl of curcumin form a H-bond with the carbonyl group of one proline molecule via 0(7).,.H(05) and Q(9),..H(Q1). In addition, proline molecules form a 1 D chain, and these chains form a double column-llke structure through a series of hydrogen bonding interactions; H(N1)...G10, H(N1)...08, N1...H(07), 07...H(N2), and H(N2),..09, Curcumin and proline molecules form a tape (wave-like shape) that is connected to the next antiparallel tape by the H-bond N1(H1M)...G8 between two proline molecules and the weak C30(H30A),,.C9 and C30(H30A)...C8 bonds. One molecule of curcumin is anchored between the columnar network by hydrogen bonding and the stacks of curcumin are connected through week hydrophobic interactions.

The CURPRO co-crystal has an X-ray powder diffraction pattern having characteristic peaks at about 5.4° (±0.2°), 7.1° (±0.2°), 16.3° (±0.2°) and 22.9° (±0.2°) 28. The XRPD trace is shown in Figure 1.

FT!R characterisation of the CURPRO co-crystal showed peaks at 3200 cm^-1 (±3 cm^-1), 1513 cm^-1 (±3 cm^-1) and 1411 cm^-1 (±3 cm^-1). The IR spectrum is shown in Figure 5. DSC investigations for the CURPRO co-crystal resulted in a curve having curve having an onset of melting in the range 171 to 175 °C. The DSC curve is shown in Figure 7.

Example 2 - Preparation of curcumin-nicotinamide-isonicotinamide co-crystals fCURNICISN) by solvent evaporation

Equivalent molar amounts of curcumin (38.83 mg), nicotinamide (12.22 mg) and isonicotinamide (12.22 mg) were dissolved in 4 mi ethyl acetate at 60°C for 2 hours, to aid dissolution, until the solution became clear. The solution was left to evaporate in a water bath preheated at 60°C and kept cooling down gradually to room temperature. Single crystals were harvested after a week and analysed. A bulk amount of the powder co-crystal was prepared in the same way using either ethyl acetate or propyl acetate but without the slow cooling step. The powder was analysed using XRPD. Single crystals of CURNICiSN have been formed and the structure has been elucidated. The CURNICiSN co-crystals have the space group triclinic P-1 with the following single crystal lattice parameters: a = 5,13 L, b = 16.72 L, e = 21.49 A, a = 109.3°, b = 96.6°, and Y = 96.5°. The atomic positions relative to the origin of the unit cell as set forth in Table 2.

In this structure, each curcumin molecule binds to a dimer of isonicotinamide-nicotinamide molecules through hydrogen bond formation. An aromatic nitrogen of one of the co-former molecules binds to a curcumin phenolic hydroxyi, through 0(2)-H(2G).,.N(9), to form the robust hydroxyl-pyridine heterosynthons. The amide groups of both nicotinamide and isonicotinamide interact to form the robust amide-amide homosynthon through 0(8)- H(80)...0(1Q) and 0(9)-H(90)...0(7) resulting in a ladder structure of curcumin, nicotinamide and isonicotinamide and a column of nicotinamide and isonicotinamide dimers. The layers of curcumin, nicotinamide, and isonicotinamide are stacked in a parallel fashion by means of the hydrophobic interaction C(2G)-H(2QB)...Q(5) and the hydrogen bond between nicotinamide molecules through N(4)-H(4M).,.Q(5).

Separate characterization of single crystal co-crystals of curcumin and Isonicotinamide (in a 1 :2 ratio; data not shown here) showed considerable structural similarities with the CURNiCISN co-crystal. NIC:!SN dimers and ISN:ISN dimers in both cocrystals are connected by the same hydrogen bond amide:amide homosynthons. The stacking interactions are aiso similar between the dimers. However, in the CURNiCISN cocrysta!, curcumin molecules are almost in plane with the NIC:!SN dimers but form a ladder shape due to the position of the nitrogen atom in nicotinamide molecules, whereas curcumin molecules are out of plane in the binary (eurcumin-isonieotinamide) co-crystals.

The CURNICISN co-crystal has an X-ray powder diffraction pattern having characteristic peaks at about 4.5° (±0.2°), 6.0° (±0.2°), and 26.8° (±0.2°) 2Q. The XRPD trace is shown in Figure 2,

FTIR characterisation of the CURNICISN co-crystals showed peaks at 3505 cm^-1 (±3 cm^-1), 3165 cm^-1 (±3 cm^-1), 2932 cm^-1 (±3 cm^-1) and 1660 cm^-1 (±3 cm^-1). The IR spectrum is shown in Figure 6.

DSC investigations for the CURNICISN co-crystal resulted in a curve having an endothermic peak in the range 95 to 99 °C. The DSC curve is shown in Figure 8.

Example 3 - Preparation of curcumin-nicotinamide-isonicotinamide co-crystals (CURNICISN) using an antisolvent

Ethyl acetate and hexane were chosen as the solvent and antisoivent, respectively, Curcumin (36,8 mg), nicotinamide (24.4 mg) and isonicotinamide (24,4 mg) were dissolved in 5 ml ethyl acetate at 60 °C with continuous stirring for 2 hours until the solution became clear. Ten millilitres of the antisolvent, hexane, were poured gradually to the solvent with continuous stirring for 10 minutes after the antisolvent addition. When the hexane was added gradually, the yellow solution of ethyl acetate and the three components turned hazy, and fine particles could be seen followed by precipitation of a yellow powder on the bottom of the flask. The resulting powder was then filtered and analysed using PXRD, DSC and IR to confirm the production of the cocrystal.

Example 4 - In vitro dissolution tests

Dissolution tests were done using the dissolution tester (model DIS 6000, Copley) USB II. The dissolution media was pre-warmed, degassed, and dispensed using the "Dissomate" Media Preparation from Copley. Calibration curve for curcumin in 10% ethanol: water were constructed in triplicates using UV spectrophotometer (Malvern). Calibration curves construction in 10% ethanol

A known amount of curcumin was dissolved in pure ethanol. Then 1 ml of this solution was mixed with 10 ml 30% ethanol. Then 100 mI of this solution was mixed with 3 ml of 10% ethanol. Then six calibration standards were produced by serial dilutions. The standards were then measured using UV, and the absorbance was plotted against curcumin concentration.

For both calibration curves, regression factor (r²) was taken as the acceptance criteria. Each curve was done in triplicates.

Calibration curves construction in 30%, ethanol

A known amount of curcumin was dissolved in 30% ethanol to prepare the stock solution. Then serial dilution was done to prepare six calibration standards. The standards were then measured using UV, and the absorbance was plotted against curcumin concentration.

Powder dissolution in 10% and 30% ethanol dissolution media

For the powder dissolution study, the powder was first sieved using 200 pm mesh sieve to reduce the effect of particle size on the dissolution rate.

Equal amount to 18.5 mg was weighed for the three compounds (curcumin, co-crystals, and the physical mixture) and placed in dialysis bags (cut-off 12kDa). The bags were then placed in 900 ml of 30% ethanol dissolution media at 37°C and stirring rate of 100 rpm. The software was automated to withdraw a sample every 10 min, then UV absorbance was measured. Due to the slow diffusion from the dialysis bags, the experiment was allowed to proceed for 10 hours, and the solid residue was analysed using XRPD.

The equivalent amount to 30 mg was weighed for the three compounds (curcumin and cocrystals, and the physical mixture) and placed directly onto the 500 ml of 10% ethanol dissolution media at 37°C and stirring rate of 150 rpm. The software was automated to withdraw a sample every 10 min, then UV absorbance was measured. The experiment was continued for 10 hours, and the solid residue was analysed using XRPD.

Results 30% ethanol

The (AUG 0-10 h) was 221.86 mg hr/L for curcumin, 309 mg hr/L for the CURN!CISN cocrystals, and 627 mg hr/L for the CURPRO cocrystals, as sho wn in Figure 9 and Table 3. The overall amount of curcumin dissolved from the cocrysta! powders was found to be higher than that from curcumin powder in the 10 hour-time course, Additionally, the concentrations of dissolved curcumin from the cocrystal powders were consistently higher than that of curcumin at every time point until the stoppage of the experiment.

Table 3: Curcumin concentrations in μg/ml at different time points after the dissolution of curcumin, CURPRO, and CURNICiSN co-crystals in 30% ethanol media

Results - 10% ethanol

The peak solubilities were achieved after 3 h for curcumin (0,65 pg/mi), alter 2.5 h for the curcumin-proline physical mixture (0.9 μg/ml), and after 6 h for CURPRO cocrystals (2.8 μg/ml), as shown in Figure 10.

The peak solubilities were achieved after 3 h for curcumin (0.65 μg/ml), after 4 h for the curcumin-nicotinamide-isonicotinamide physical mixture (1.04 μg/ml), and after 4 h for CURNICISN cocrystals (1.05 pg/mi), as shown in Figure 11.

CURPRO cocrystals showed the best maximum solubility that is about 4.3 times better than curcumin alone. Additionally, the cocrystals were constantly better dissolving than curcumin at each time point as seen in Table 4. in fact, the concentration of curcumin in the CURPRO cocrystals solution after 20 minutes of the beginning of the experiment is 8.3 times higher than that of curcumin aione solution. For CURPRO, the physical mixture of the two co-crystal components did not exhibit the same dissolution enhancement as that of the co-crystal. This proves that this dissolution improvement is a direct result of the cocrystallisation, and the inclusion of L-proline in the crystal lattice with curcumin. The XRPD at the end of the experiment has shown a complete transformation of the cocrystals into curcumin form 1. Nevertheless, the supersaturation state has remained for at least 48 hr with no sign of the famous spring and parachute effect that was expected for the incongruentiy dissolving cocrystals.

Table 4: Curcumin concentrations in μg/ml at different time points after the dissolution of curcumin, CURPRO, and CURNICiSN co-crystals in 10% ethanol media

Example 5 - Tabletabilitv

Tablet preparation

Curcumin, co-crystals and the physical mixtures of curcumin and co-former(s) were triturated using mortar and pestle to reduce the effect of size and morphology on powder compaction.

Approximately 100 mg of the solid materials were weighed and manually filled into a tablet die and compacted into tablets under two different pressures (100 and 200 MPa) using a laboratory scale Gamlen tabletting machine. Both die cavity and punches were lubricated with a thin film of paraffin oil between each compression. The compression speed wa s fixed at 1 mm/min. The tablets were then left to rest for 24 hours, before measuring their thickness, diameter, and the breaking force. Curcumin tablets were frequently found to suffer capping upon ejection, unlike the CURPRO and CURNICISN tablets. The breaking force was measured by subjecting the tablets to radial hardness force using a Copley crush tester.

The tablets were placed bet ween the two jaws of the machine, and the crushing force required to crack the tablets using a force application speed of 10 mm/min was recorded. Tablets were tested in triplicate for each powder at each compression pressure. The tensile strength is calculated from the force in kg, the thickness, and the diameter of the tablets.

The XRPD before and after compaction was undertaken and the data were compared and checked for any phase transformation. Results

Curcumin was shown to exhibit inferior tabletability properties compared to both CURPRO and CURNICISN. For tablets compressed at 200 MPa, the tablet diameters ranged from 5.99 to 6.21 mm, and the tablet thicknesses ranged from 2.44 to 3.19 mm. For tablets compressed at 100 MPa, the tablet diameters ranged from 6.02 to 6.08 mm, and the tablet thicknesses ranged from 2.89 to 3.53 mm. Tensile strength results are shown in tables 5 and 6.

Table 5: tensile strength of tablets at compressed 200MPa

Table 6: tensile strength of tablets compressed at 100MPa

The tensile strength of tablets containing the co-crystais was much higher than tablets containing curcumin as seen in Figure 12. While tablets containing the physical mixtures had an improved tensile strength compared to tablets lacking the co-former(s), the strength was still below 1 MPa and therefore outside of the acceptable range. This tabletability improvement proves that the manufacturability of curcumin is better in the form of cocrystal instead of a pure crystalline ‘form T curcumin.

Overcoming the poor tableting properties of curcumin is a prerequisite for intact tablets, which could, in principle, be achieved by the use of additional excipients that improve the powder compression. However, the use of additional excipients will inevitably reduce the drug loading in tablets, which is not ideal in the case of curcumin where a huge dose is already required to allow sufficient amount of the drug to dissolve and reach plasma to exert its therapeutic effect. These results show that co-crystailisation offer an interesting alternative role to the excessive use of excipients. In the case of CURPRO and CURNICISN cocrystals, both the dissolution rate and the tableting behaviour of curcumin have been improved, thus theoretically the drug loading should also be improved.

Example 8 - Tablet formulation of CURPRO and CURNICISN

The CURPRO and CURNICISN co-crystals can be formulated together with appropriate excipients into a tablet, as shown in Table 7 below.

Table 7: Formulation of curcumin co-crystals

Abbreviations

The following abbreviations may be used herein. SC-XRD single crystal X-ray diffraction

XRPD powder X-ray diffraction NiC nicotinamide ISN isonicotinamide PM physical mixture PRO L-proiine CUR curcumin FT-IR Fourier transform infrared DSC differential scanning calorimetry API active pharmaceutical ingredient AUC area under the curve

Claims

Claims

1. A co-crystal having at least one slip plane and consisting essentially of eurcumin and a co-crystal former, wherein the co-crystal former is a combination of nicotinamide and isonicotinamide, or wherein the co-crystal former is proline,

2. The co-crystal consisting essentially of eurcumin and a co-crystal former, wherein the co-crystal former is a combination of nicotinamide and isonicotinamide, or wherein the co-crystal former is proiine and the molar ratio of eurcumin and proiine is from 1 :1 to 1 :3.

3. The co-crystal according to Claim 1 or Claim 2 wherein the bioavaiiability and/or solubility of the eurcumin is increased compared to the bioavaiiability and/or solubility of eurcumin from a crystal consisting of eurcumin.

4. The co-crystal according to any one of Claims 1 to 3, wherein the co-crystal former is a combination of nicotinamide and isonicotinamide.

5. The co-crystal according to Claim 4, wherein the molar ratio of eurcumin and nicotinamide and isonicotinamide is about 1 :1 :1.

6. The co-crystal according to Claim 4 or Claim 5, wherein the co-crystal has an X- ray powder diffraction pattern having characteristic peaks at about 4.5° (±0,2°), 6.0° (±0.2°), and 26.8° (±0.2°) 2Q.

7. The co-crystal according to any one of Claims 4 to 6, which is further characterised by an FTIR spectrum exhibiting peaks at 3505 cm^-1 (±3 cm^-1), 3165 cm^-1 (±3 cm^-1), 2932 cm^-1 (±3 cm^-1) and 1660 cm^-1 (±3 cm ¹),

8. The co-crystal according to any one of Claims 4 to 7, characterised by a differential scanning calorimetry curve having an endothermic peak in the range 95 to 99 °C.

9. The co-crystal according to any one of Claims 4 to 8, which is obtainable by crystallisation of a mixture comprising eurcumin, nicotinamide and isonicotinamide in ethyl acetate or propyl acetate.

10. The co-crystal according to any one of Claims 4 to 9, wherein the space group of the co-crystal is triciinic P-1 with the following single crystal lattice parameters: a = 5.13 A, b = 16.72 A, c = 21.49 A, a = 109.3°, b = 96.6°, and g = 96.5°.

11. The co-crystal according to any one of Claims 1 to 3, wherein the co-crystal former is proline.

12. The co-crystal according to Claim 11 , wherein the molar ratio of curcumin and proiine is about 1 :2.

13. The co-crystal composition according to Claim 11 or Claim 12, wherein the cocrystal has an X-ray powder diffraction pattern having characteristic peaks at about 5.4° (±0.2°), 7.1° (±0.2°), 16.3° (±0.2°) and 22.9° (±0.2°) 2Q.

14. The co-crystal according to any one of Claims 11 to 13, which is further characterised by an FTIR spectrum exhibiting peaks at 3200 cm^-1 (±3 cm^-1), 1513 cm^-1 (±3 cm^-1) and 1411 errr¹ (±3 cm^-1),

15. The co-crystal according to any one of Claims 11 to 14, characterised by a differentiai scanning calorimetry curve having an onset of melting in the range 171 to 175 °C.

16. The co-crystal according to any one of Claims 11 to 15, which is obtainable by crystallisation of a mixture comprising curcumin and proiine in ethanol or methanol, preferably at about 50 °C.

17. The co-crystal according to any one of Claims 11 to 16, wherein the space group of the co-crystal is orthorhombic P2i2i2i with the following single crystal lattice parameters: a = 5.61 A, b = 21 ,42 A, c = 24.82 A,

18. A pharmaceutical or nutraceutical composition comprising a co-crystal as defined in any one of Claims 1 to 17 and one or more pharmaceutically acceptable excipients, optionally wherein the composition is in the form of a tablet.

19. A tablet comprising the co-crystai as defined in any one of Claims 1 to 17 or the pharmaceutical or nutraceutical composition as defined in Claim 18, wherein the tablet comprises at least about 90% by weight of said co-crystals.

20. A tablet comprising the co-crystai as defined in any one of Claims 1 to 17 or the pharmaceutical or nufraceufical composition as defined in Claim 18, wherein the tablet has a tensile strength of at least 1 MPa.

21. A process for preparing a co-crystal according to any one of Claims 1 to 3, wherein the process comprises the steps of: dissolving curcumin and the co-crystal former in a solvent, and allowing the solvent to evaporate.

22. A co-crystai as defined in any one of Claims 1 to 17, a pharmaceutical or nutraeeutica! composition as defined in Claim 18, or a tablet as defined in Claim 19 or Claim 20, for use as a medicament.

23. A co-crystai as defined in any one of Claims 1 to 17, a pharmaceutical or nutraeeutica! composition as defined in Claim 18, or a tablet as defined in Claim 19 or Claim 20, for use in treating or preventing a disease selected from the group consisting of rheumatoid arthritis, depression, and cancer.

24. A method of treating or preventing a disease selected from the group consisting of arthritis, depression, and cancer, said method comprising administering to a patient in need thereof a therapeutically effective amount of a co-crystal as defined in any one of Claims 1 to 17, a pharmaceutical or nutraceutical composition as defined in Claim 18, or a tablet as defined in Claim 19 or Claim 20.

25. The co-crystal for use, composition for use, or tablet for use according to Claim 23, the method according to Claim 24, wherein the cancer is selected from the group consisting of cervical cancer, breast cancer, lung cancer, baematological cancer, gastric cancer, colorectal cancer, skin cancer, pancreatic cancer, and intestinal cancer.