CO-CRYSTALS COMPRISING VALACYCLOVIR

FIELD OF THE INVENTION

The invention relates to a co-crystal. The invention also concerns a pharmaceutical composition comprising the co-crystal, various uses of the co-crystal, a process for producing the co-crystal, and a precursor composition for use in preparing the co-crystal.

BACKGROUND TO THE INVENTION

Valacyclovir (C13H20N6O4) is a white solid, and a prodrug of the antiviral drug acyclovir. Acyclovir triphosphate functions as a substrate for viral, but not cellular, DNA polymerase, competing with deoxyguanosine triphosphate for incorporation into the elongating chain of viral DNA. This results in chain termination, as acyclovir lacks the 3'- hydroxyl group necessary for subsequent elongation. The L-valyl ester valacyclovir (VAL), whose structure is shown in Scheme 1, has an optimal combination of side chain length and degree of branching that makes it more chemically stable in aqueous solution, whilst allowing it to be rapidly and extensively converted to acyclovir in vivo. (Beutner, K.R. Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Research 28 (1995) 281-290).

Scheme 1. Molecular structure of valacyclovir (VAL)

It is hydrolysed rapidly to acyclovir via an enzyme -mediated mechanism which is not dose limiting. The absorption of valacyclovir is improved compared to acyclovir due to a stereoselective transporter, which is then followed by the hydrolysis of the prodrug to acyclovir in vivo. (Smiley, M.L.; Murray, A.; de Miranda, P. Valacyclovir HC1

(Valtrex™): An acyclovir prodrug with improved pharmacokinetics and better efficacy for treatment of zoster. Antiviral Chemotherapy 4 Edited by I. Mills et al., Plenum Press, New York, 1996). The absolute bioavailability of valacyclovir after oral administration as a suspension is about 54%, making it a BCS class III drug (low permeability, high solubility) according to the FDA. (Office of Clinical Pharmacology Review, FDA 2007). While it is predominantly absorbed via the small intestine, the permeability of valacyclovir is concentration dependent, and significantly reduced in the presence of common peptide analogues such as amoxicillin, among others. It is also increasingly unstable at higher pH values. (Sinko, P. J.; Balimane, P.V. Carrier-Mediated Intestinal Absorption of

Valacyclovir, the L-Valyl Ester Prodrug of Acyclovir: 1. Interactions with Peptides, Organic Anions and Organic Cations in Rats. Biopharm. Drug Dispos. 19 (1998), 209- 217).

The importance of valacyclovir stems from its wide use in the treatment of a number of viral conditions, such as herpes zoster, herpes simplex, and vestibular neuritis. It has been deemed safe to use in pregnant patients, children and the elderly, and its application for the treatment of herpes simplex in immunocompromised patients has made it one of the most popular antivirals on the market. (Zuckermann, A.; Lucchetti, A.; et al. Herpes Simplex Virus (HSV) Suppression with Valacyclovir Reduces Rectal and Blood Plasma HIV-1 Levels in HIV-l/HSV-2-Seropositive Men: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. Journal of Infectious Diseases. 2007, 196, 1500-1508; Strupp, M.; Zingler, V.C. et al. Methylprednisolone, Valacyclovir, or the Combination for Vestibular Neuritis. N Engl J Med. 2004, 351 :354-61; Gross, G.; Schoefer, H,; et al.

Herpes Zoster guideline of the German Dermatological Society (DDG), Journal of Clinical Virology, 2003, 26:3, 277-289).

It is used in conjunction with prednisolone in the treatment of Bell's Palsy (Hato N, Yamada H, Kohno H, et al. Valacyclovir and Prednisolone Treatment for Bell's Palsy: A Multicenter, Randomized, Placebo-Controlled Study, Otol. Neurotol. 2007, 28, 408-413), and in the prevention of cytomegalovirus infection after renal and bone marrow transplant (Lowance, D.; Neumeyer, H-H.; et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. N. Engl. J. Med. 1999, 340, 1462-70; Ljungman, P.; de la Camara, R.; et al. Randomized study of valacyclovir as prophylaxis against

cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants. Blood, 2002, 99:8, 3050-3056). Its safety profile in pregnant patients has made it the drug of choice in the prevention of recurrent herpes during labour (Sheffield, J.S.; Hill, J.B.; et al. Valacyclovir Prophylaxis to Prevent Recurrent Herpes at Delivery: A Randomized Clinical Trial. Obstetrics and Gynecology, 2006, 108: 1, 141-147). In spite of its wide use and indisputable clinical and pharmacological relevance, a higher aqueous solubility of VAL would increase its oral bioavailability, and therefore also the effectiveness of the drug. A novel form of the drug could also obliterate the adverse effect that commonly used peptide analogues such as amoxicillin have on its permeability, not only making it more efficacious, but also allowing for combined therapy.

SUMMARY OF THE INVENTION

The invention relates to new solid forms of valacyclovir (VAL) which have significantly enhanced aqueous solubilities. Thus, co-crystals comprising VAL and particular co-crystal formers are provided which are readily soluble in water, leading to improved bioavailability of the active pharmaceutical ingredient and, consequently, increased effectiveness. Under the U.S. Food and Drug Administration's Biopharmaceutics Classification System (BCS), the co-crystals would likely be classified under class I ("high permeability, high solubility") whereas the pure API falls under class III ("low

permeability, high solubility"). The enhancement in aqueous solubility is expected to facilitate uptake of VAL in the small intestine. The enhanced solubility and bioavailablility should also enable lower concentrations of VAL to be employed in formulations than is currently possible, reducing manufacturing costs. It will also enable the development of purely aqueous formulations of VAL, which should provide various benefits including quicker absorption of the drug. The new solid forms have the potential to overcome existent and documented drug interactions between VAL and some other APIs in vivo.

The invention results from the inventors' findings that stable co-crystals comprising valacyclovir can be produced, by employing mellitic acid or L-ascorbic acid as the co-crystal former, and that the resulting co-crystals are readily soluble in water. These findings were unexpected and unique to VAL, similar but unsuccessful studies having been carried out at the same time on the structurally similar antivirals, famciclovir and ganciclovir.

Accordingly, the invention provides a co-crystal, which co-crystal comprises valacyclovir and a co-crystal former, which co-crystal former is mellitic acid or L-ascorbic acid.

The invention further provides a pharmaceutical composition which comprises a co-crystal, which co-crystal comprises valacyclovir and a co-crystal former, which co- crystal former is mellitic acid or L-ascorbic acid. Further provided is a co-crystal of the invention, or a pharmaceutical composition of the invention, for use in a method of treatment of the human or animal body by therapy.

The invention also provides a co-crystal of the invention, or a pharmaceutical composition of the invention, for use in the treatment or prevention of a viral infection or a viral disease. The viral disease may for instance be a viral disease after renal or bone marrow transplants, or a viral disease recurring during labour.

Also provided is a co-crystal of the invention, or a pharmaceutical composition of the invention, for use in the treatment or prevention of herpes zoster, herpes simplex, vestibular neuritis or cytomegalovirus.

The invention further provides the use of a co-crystal of the invention or the use of a pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment or prevention of a viral infection or a viral disease. The viral disease may for instance be a viral disease after renal or bone marrow transplants, or a viral disease recurring during labour, in the human or animal body.

Further provided is the use of a co-crystal of the invention or the use of a pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment or prevention of herpes zoster, herpes simplex, vestibular neuritis or cytomegalovirus .

The invention also provides a method of treating a patient suffering from or susceptible to a viral infection or a viral disease, which method comprises administering to said patient an effective amount of a co-crystal of the invention, or an effective amount of a pharmaceutical composition of the invention. The viral disease may for instance be a viral disease after renal or bone marrow transplants, or a viral disease recurring during labour.

The invention also provides a method of treating a patient suffering from or susceptible to herpes zoster, herpes simplex, vestibular neuritis or cytomegalovirus, which method comprises administering to said patient an effective amount of a co-crystal of the invention, or an effective amount of a pharmaceutical composition of the invention.

In another aspect, the invention provides a process for producing a co-crystal, which co-crystal comprises valacyclovir and a co-crystal former, which co-crystal former is mellitic acid or L-ascorbic acid, which process comprises:

applying a mechanical force to a sample which comprises solid valacyclovir, a solid co-crystal former, and a solvent, wherein the co-crystal former is mellitic acid or L- ascorbic acid. The invention also provides a composition for forming a co-crystal, which composition comprises valacyclovir and a co-crystal former, which co-crystal former is mellitic acid or L-ascorbic acid.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows the infrared (IR) spectrum of the 1 : 1 VAL/mellitic acid co-crystal (middle trace) and those of the API and the co-crystal former (upper and lower traces respectively).

Fig. 2 shows the IR spectrum of the 1 : 1 VAL/L-ascorbic acid co-crystal (middle trace) and those of the API and the co-crystal former (upper and lower traces respectively).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a co-crystal.

The term "co-crystal" (or "cocrystal") as used herein means a solid that is a crystalline single phase material comprising two or more different molecular and/or ionic compounds which are neither solvents nor simple salts (S. Aitipamula et al. "Polymorphs, Salts, and Cocrystals: What's in a Name?", Cryst. Growth Des., 2012, 12 (5), pp 2147- 2152). The two or more different molecular and/or ionic compounds in a co-crystal are generally compounds which are themselves solid at room temperature (i.e. solids at 22 °C). They are typically present in the co-crystal in a definite stoichiometric ratio.

In the co-crystals of the present invention, one of the two or more different molecular and/or ionic compounds is an API, and another of the two or more different molecular and/or ionic compounds is a co-crystal former. Indeed, the co-crystals of the present invention are pharmaceutical co-crystals. A pharmaceutical co-crystal is a crystalline single phase material comprising an API and one or more unique co-crystal formers, typically in a stoichiometric ratio.

Each of the one or more co-crystal formers is a molecular or an ionic compound that is a solid at room temperature. Solvates (including hydrates) of an API that do not further comprise a co-crystal former are therefore not considered to be co-crystals. A pharmaceutical co-crystal may however include one or more solvent (e.g. acetonitrile, or water) molecules in the crystal lattice which comprises the API and the one or more unique co-crystal formers.

Co-crystals can be constructed through several types of interaction, including hydrogen bonding (H-bonding), pi stacking, and van der Waals forces. However, co- crystals often rely on hydrogen-bonded assemblies between neutral molecules of an API and another (co-crystal former) component.

In the co-crystals of the present invention, the API is VAL, and the co-crystal former is mellitic acid or L-ascorbic acid.

Thus, the present invention provides a co-crystal, which co-crystal comprises valacyclovir and a co-crystal former, which co-crystal former is mellitic acid or L-ascorbic acid.

The molecular structure of valacyclovir is shown in scheme 1, above.

Mellitic acid (benzenehexacarboxylic acid) and L-ascorbic acid (Vitamin C) have the following structures, respectively:

Mellitic acid L-ascorbic acid

Usually, the co-crystal of the invention comprises only one co-crystal former which is one of mellitic acid and L-ascorbic acid.

Thus, typically, the co-crystal comprises only one of mellitic acid and L-ascorbic acid.

The co-crystal of the present invention may or may not further comprise one or more solvent molecules. When the co-crystal of the invention comprises more than one solvent molecule, the solvent molecules may be molecules of the same solvent (for instance, molecules of acetonitrile, or molecules of water) or molecules of two or more different solvents (for instance, one or more molecules of acetonitrile and one or more molecules of water). The stoichiometric ratio of the one or more solvents to VAL in the co- crystal (solvent molecules : VAL molecules) may, for instance be from 10: 1 to 1 :4, for example from 5 : 1 to 1 :2, or for instance from 3: 1 to 1 : 1.

The co-crystal of the invention may, for instance, consist of: (i) VAL; (ii) the co- crystal former which is one of mellitic acid and L-ascorbic acid; and, optionally, (iii) one or more solvents. The co-crystal may, for instance, consist of: (i) VAL; (ii) the co-crystal former which is one of mellitic acid and L-ascorbic acid; and (iii) one or more solvents.

The one or more solvents may for instance be selected from polar solvents, e.g. from acetonitrile and water. The one or more solvents may, for instance, be selected from polar aprotic solvents, an example of which is acetonitrile. The one or more solvents may for instance be selected from organic solvents. The organic solvents may for instance comprise, or be, polar aprotic organic solvents. The one or more solvents may for example comprise acetonitrile. The one or more solvents may comprise a polar protic solvent, for instance water.

The stoichiometric ratio of the one or more solvents to VAL in the co-crystal (solvent molecules: VAL molecules) may, for example, be from 10: 1 to 1 :4, for example from 5 : 1 to 1 :2, or for instance from 3: 1 to 1 : 1.

The one or more solvents may consist of a single solvent. Thus, the co-crystal of the invention may consist of: (i) VAL, (ii) a co-crystal former which is one of mellitic acid and L-ascorbic acid, and (iii) a solvent.

The solvent may, for example, be a polar solvent, for instance acetonitrile or water. It may, for instance, be a polar aprotic solvent, for instance acetonitrile. It may, for instance, be a polar protic solvent, for instance water.

The solvent may be an organic solvent. The solvent may for instance be, a polar aprotic organic solvent. The solvent may for example be acetonitrile.

In some embodiments, the co-crystal of the present invention does not comprise a solvent. Accordingly, the co-crystal of the invention may comprise valacyclovir, a co- crystal former which is mellitic acid and L-ascorbic acid, and no solvent.

The co-crystal of the invention may, for instance, consist of: (i) VAL and (ii) a co- crystal former which is one of mellitic acid and L-ascorbic acid.

Mellitic acid as the co-crystal former

In one preferred embodiment of the co-crystal of the invention, the co-crystal former is mellitic acid.

Accordingly, in a preferred embodiment, the invention provides a co-crystal, which co-crystal comprises valacyclovir in any form and a co-crystal former, which co-crystal former is mellitic acid.

Usually, the molar ratio of the valacyclovir to the mellitic acid in the co-crystal is from 2: 1 to 2:7. The molar ratio of the valacyclovir to the mellitic acid in the co-crystal may, for instance, be 1 :3. Typically, however, the molar ratio of the valacyclovir to the mellitic acid in the co-crystal is 1 : 1.

Usually, the co-crystal of the invention in which the co-crystal former is mellitic acid has a melting point within the temperature range of from 132 °C to 153 °C. It often, for instance, has a melting point within the temperature range of from 137 °C to 147 °C. More typically, the co-crystal has a melting point within the temperature range of from 139 °C to 145 °C. The melting point may, for instance, be 143 °C. The melting point may, for instance, be 142 °C.

The term "melting point", as used herein throughout, refers to the melting point as the Clear Point, i.e. the point at which the sample becomes a clear liquid and no solid particles remain, as determined under standard atmospheric pressure (1013 mbar) in an open vessel. This can be measured using, for instance, a Stuart SMP40 melting point apparatus which employs optical sensors to detect melting. An open melting point glass capillary filled with the co-crystal sample up to ca. 2cm in height is placed into the analysing chamber of the apparatus and, under standard atmospheric pressure, the sample is heated at a heating rate of 5°C per minute to raise the temperature of the sample from about 25°C to a temperature above the melting point; the clear point is determined by the optical sensors of the apparatus.

The co-crystal of the invention, in which the co-crystal former is mellitic acid, may be characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at at least one of the following two theta values: 3.5°±0.2°, 6.9°±0.2°, 8.0°±0.2°, 15.3°±0.2°, 16.4°±0.2°, 20.2°±0.2°, 23.6°±0.2° and 26.9°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least two of the aforementioned two theta values, for instance at at least three of the aforementioned two theta values, or for example at at least four of the aforementioned two theta values.

Often, for instance, the co-crystal of the invention, in which the co-crystal former is mellitic acid, is characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises peaks at at least five of the following two theta values: 3.5°±0.2°, 6.9°±0.2°, 8.0°±0.2°, 15.3°±0.2°, 16.4°±0.2°, 20.2°±0.2°, 23.6°±0.2° and 26.9°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least six of the aforementioned two theta values, for instance at at least seven of the aforementioned two theta values. The co-crystal of the invention, in which the co-crystal former is mellitic acid, is typically characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at each of the following two theta values: 3.5°±0.2°, 6.9°±0.2°, 8.0°±0.2°, 15.3°±0.2°, 16.4°±0.2°, 20.2°±0.2°, 23.6°±0.2° and 26.9°±0.2°.

Usually, the co-crystal of the invention in which the co-crystal former is mellitic acid is characterized by an infrared spectrum which comprises peaks at:3438.15cm ^" ^cm ^"1 , 3321.33cm- ¹ ±15cm- ¹ , llW.SOcm-^lScm- ¹ , 1090.47cm- ¹ ±15cm- ¹ and 889.34cm ^" ^lScm ^"1 .

Often, for instance, the co-crystal is characterized by an infrared spectrum which comprises peaks at 3438.15cm ^"1 ±10cm ^"1 , 3321.33cm ^"1 ±10cm ^"1 , ^^.SOcm^ilOcm ^"1 , 1090.47cm ^"1 ±10cm ^"1 and 889.34cm ^"1 ±10cm ^"1 . Said infrared spectrum is typically recorded by performing infrared spectroscopy on a pellet which comprises, and more typically consists essentially of, or consists of: KBr and the co-crystal.

The co-crystal of the invention in which the co-crystal former is mellitic acid preferably has a melting point as defined above, and is preferably characterized by a powder X-ray diffraction pattern as defined above and by an infrared spectrum as defined above.

The co-crystal of the invention, in which the co-crystal former is mellitic acid, may or may not further comprise one or more solvent molecules.

The co-crystal may, for instance, consist of: (i) VAL; (ii) mellitic acid; and, optionally, (iii) one or more solvents.

For instance, the co-crystal may consist of: (i) VAL; (ii) mellitic acid; and (iii) one or more solvents.

The one or more solvents may consist of a single solvent. Thus, the co-crystal of the invention may consist of: (i) VAL, (ii) mellitic acid; and (iii) a solvent. The one or more solvents, or the (single) solvent, may be as further defined hereinbefore.

In some embodiments, the co-crystal of the invention, in which the co-crystal former is mellitic acid, does not comprise a solvent. Accordingly, the co-crystal of the invention may comprise valacyclovir in any form, mellitic acid and no solvent. The co- crystal of the invention may, for instance, consist of: (i) VAL and (ii) mellitic acid.

Usually, the molar ratio of the VAL to the mellitic acid in the co-crystal is from 2: 1 to 2:7. The molar ratio of the VAL to the mellitic acid in the co-crystal may, for instance, be 1 : 1 , or 1 :3. L-ascorbic acid as the co-crystal former

In one preferred embodiment of the co-crystal of the invention, the co-crystal former is L-ascorbic acid.

Accordingly, in a preferred embodiment, the invention provides a co-crystal, which co-crystal comprises valacyclovir in any form and a co-crystal former, which co-crystal former is L-ascorbic acid.

Usually, the molar ratio of the VAL to the L-ascorbic acid in the co-crystal is from 2:1 to 2:7. The molar ratio of the VAL to the L-ascorbic acid in the co-crystal may, for instance, be 1 : 1 or 1 :2.

Usually, the co-crystal of the invention in which the co-crystal former is L-ascorbic acid has a melting point within the temperature range of from 146°C to 166°C. It often, for instance, has a melting point within the temperature range of from 151 °C to 166 °C, from 151 °C to 163 °C, for instance from 151 °C to 161 °C. The melting point may, for instance, be 156-163 °C or 157-163 °C. More typically, the co-crystal has a melting point within the temperature range of from 153 °C to 159 °C. The melting point may, for instance, be 155- 156 °C. Alternatively, it may be 155-163 °C.

The co-crystal of the invention, in which the co-crystal former is L-ascorbic acid, may be characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at at least one of the following two theta values: 8.6°±0.2°, 10.5°±0.2°, 10.9°±0.2°, 12.1°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.4°±0.2°, 19.8°±0.2°, 20.9°±0.2°, 23.8°±0.2°, 25.1°±0.2°, 26.0°±0.2°,

26.9°±0.2°, 27.8°±0.2°, 29.7°±0.2°, 30.3°±0.2°, 31.7°±0.2°, 32.9°±0.2°, 34.3°±0.2°,

35.0°±0.2°, 40.9°±0.2° and 41.4°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least two of the aforementioned two theta values, for instance at at least three of the aforementioned two theta values, or for example at at least four of the aforementioned two theta values.

Often, for instance, the co-crystal of the invention, in which the co-crystal former is L-ascorbic acid, is characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises peaks at at least five of the following two theta values: 8.6°±0.2°, 10.5°±0.2°, 10.9°±0.2°, 12.1°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.4°±0.2°, 19.8°±0.2°, 20.9°±0.2°, 23.8°±0.2°, 25.1°±0.2°,

26.0°±0.2°, 26.9°±0.2°, 27.8°±0.2°, 29.7°±0.2°, 30.3°±0.2°, 31.7°±0.2°, 32.9°±0.2°,

34.3°±0.2°, 35.0°±0.2°, 40.9°±0.2° and 41.4°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least seven of the

aforementioned two theta values, for instance at at least eight of the aforementioned two theta values, or for example at at least nine of the aforementioned two theta values.

The co-crystal of the invention, in which the co-crystal former is L-ascorbic acid, is typically characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at each of the following two theta values: 8.6°±0.2°, 10.5°±0.2°, 10.9°±0.2°, 12.1°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.4°±0.2°, 19.8°±0.2°, 20.9°±0.2°, 23.8°±0.2°, 25.1°±0.2°, 26.0°±0.2°,

26.9°±0.2°, 27.8°±0.2°, 29.7°±0.2°, 30.3°±0.2°, 31.7°±0.2°, 32.9°±0.2°, 34.3°±0.2°,

35.0°±0.2°, 40.9°±0.2° and 41.4°±0.2°.

The co-crystal of the invention, in which the co-crystal former is L-ascorbic acid, may be characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at at least one of the following two theta values: 8.6°±0.2°, 10.5°±0.2°, 12.1°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.4°±0.2°, 19.8°±0.2° and 23.8°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least two of the aforementioned two theta values, for instance at at least three of the aforementioned two theta values, or for example at at least four or at least five of the aforementioned two theta values. It may for instance be characterized by a said powder X-ray diffraction pattern comprising peaks at each of the aforementioned two theta values.

Usually, the co-crystal of the invention in which the co-crystal former is L-ascorbic acid is characterized by an infrared spectrum which comprises peaks at 3523cm ^"1 ±15cm ^"1 , 3446cm- ¹ ±15cm- ¹ , 3408cm- ¹ ±15cm ^"1 , SS ^cm^ilScm ^"1 and 1099cm ¹ ±15cm ¹ .

Often, for instance, the co-crystal is characterized by an infrared spectrum which comprises peaks at 3523cm ^"1 ±10cm ^"1 , 3446cm ^"1 ±10cm ^"1 , 3408cm ^"1 ±10cm ^"1 , 3319cm ^" ^lOcm ^"1 and 1099cm ^"1 ±10cm ^"1 . Said infrared spectrum is typically recorded by performing infrared spectroscopy on a pellet which comprises, and more typically consists essentially of, or consists of: KBr and the co-crystal.

The co-crystal of the invention in which the co-crystal former is L-ascorbic acid preferably has a melting point as defined above for that co-crystal, and is preferably characterized by a powder X-ray diffraction pattern as defined above for that co-crystal and by an infrared spectrum as defined above for that co-crystal.

The co-crystal of the invention, in which the co-crystal former is L-ascorbic acid, may or may not further comprise one or more solvent molecules. The co-crystal may, for instance, consist of: (i) VAL; (ii) L-ascorbic acid; and, optionally, (iii) one or more solvents.

For instance, the co-crystal may consist of: (i) VAL; (ii) L-ascorbic acid; and (iii) one or more solvents.

The one or more solvents may consist of a single solvent. Thus, the co-crystal of the invention may consist of: (i) VAL, (ii) L-ascorbic acid; and (iii) a solvent.

The one or more solvents, or the (single) solvent, may be as further defined hereinbefore.

In some embodiments, the co-crystal of the invention, in which the co-crystal former is L-ascorbic acid, does not comprise a solvent. Accordingly, the co-crystal of the invention may comprise valacyclovir in any form, L-ascorbic acid and no solvent. The co- crystal of the invention may, for instance, consist of: (i) VAL and (ii) L-ascorbic acid.

Usually, the molar ratio of the valacyclovir to the L-ascorbic acid in the co-crystal is from 2: 1 to 2:5. The molar ratio of the valacyclovir to the L-ascorbic acid in the co- crystal may, for instance, be 1 : 1. The molar ratio of the valacyclovir to the L-ascorbic acid in the co-crystal may, for instance, be 1 :2.

Process

The co-crystal of the invention can be produced by applying a mechanical force to a sample comprising solid valacyclovir in any form, the solid co-crystal former, and a solvent. An embodiment of this process is referred to as a "solvent-assisted grinding".

Accordingly, the invention provides a process for producing a co-crystal, which co- crystal comprises valacyclovir and a co-crystal former, which co-crystal former is mellitic acid or L-ascorbic acid, which process comprises: applying a mechanical force to a sample which comprises solid valacyclovir in any form, a solid co-crystal former, and a solvent, wherein the co-crystal former is mellitic acid or L-ascorbic acid.

Applying the mechanical force to the sample may for instance comprise grinding, milling or crushing the sample. Often, it comprises grinding the sample.

The sample to which the mechanical force is applied is typically a paste, and applying the mechanical force to the sample typically produces a powder from the paste.

The process of the invention may therefore comprise:

(i) preparing said sample which comprises solid valacyclovir, the solid co- crystal former, and the solvent, by: (a) applying a mechanical force to a mixture of solid valacyclovir and the solid co-crystal former, and

(b) adding a solvent to the mixture to form a paste; and

(ii) applying a mechanical force to the paste thus formed, to produce a powder.

Typically, the solvent comprises an organic solvent or water. The solvent may for instance comprise, or be, a polar, aprotic organic solvent. The solvent may for example comprise, or be, acetonitrile. The solvent may for instance comprise, or be, a polar, protic solvent. The solvent may for example comprise, or be, water.

The amount of solvent in the sample is typically from 15 % by weight (wt%) to 90 % by weight (wt%), based on the total weight of the sample, and is more typically from 15 wt% to 80 wt%. The amount of solvent in the sample may for instance be from 20 wt% to 70 wt%, or for instance from 20 wt% to 60 wt%, for example from 25 wt% to 50 wt%.

The balance of the sample is typically made up of the valacyclovir solid and the co- crystal former.

The molar ratio of valacyclovir to the co-crystal former in the sample may be from 2:1 to 2:7. For instance, the co-crystal former may be mellitic acid and said molar ratio may be from 2: 1 to 2:7, and is preferably 1 : 1. Alternatively, for instance, the co-crystal former may be L-ascorbic acid and said molar ratio may be from 2: 1 to 2:7, and is preferably 1 : 1 or 1 :2.

The process of the invention typically further comprises:

(a) adding further solvent to the powder thus produced to form a further paste;

(b) applying a mechanical force to the further paste to produce a powder; and

(c) optionally repeating step (a) and then step (b), once, or more than once.

The further solvent may comprise an organic solvent or water. The further solvent may for instance comprise, or be, a polar, aprotic organic solvent. The further solvent may for example comprise, or be, acetonitrile. The further solvent may for instance comprise, or be, a polar, protic solvent. Typically both the solvent and the further solvent comprise, or are, water.

The process may further comprise isolating a co-crystal produced thereby.

Precursor composition for producing a co-crystal

The invention also provides a composition for forming a co-crystal, which composition comprises valacyclovir in any form and a co-crystal former, which co-crystal former is mellitic acid or L-ascorbic acid. The composition is usually a mixture of solid valacyclovir and the solid co-crystal former.

The composition of the invention may further comprise a solvent. Typically, the solvent comprises an organic solvent or water. The solvent may for instance comprise, or be, a polar, aprotic organic solvent. The solvent may for example comprise, or be, acetonitrile. The solvent may for instance comprise, or be, a polar, protic solvent. The solvent may for example comprise, or be, water.

When the composition further comprises a solvent, the composition may be a paste.

When the composition further comprises a solvent, the amount of solvent in the composition is typically from 15 % by weight (wt%) to 90 % by weight (wt%), based on the total weight of the composition, and is more typically from 15 wt% to 80 wt%. The amount of solvent in the composition may for instance be from 20 wt% to 70 wt%, or for instance from 20 wt% to 60 wt%, for example from 25 wt% to 50 wt%.

When the composition further comprises a solvent, the balance of the composition is typically made up of the valacyclovir and the co-crystal former.

The molar ratio of valacyclovir to the co-crystal former in the composition may be from 2: 1 to 2:7. For instance, the co-crystal former may be mellitic acid and said molar ratio may be from 2: 1 to 2:7, and is preferably 1 : 1. Alternatively, for instance, the co- crystal former may be L-ascorbic acid and said molar ratio may be from 2: 1 to 2:7, and is preferably 1 : 1 or 1 :2.

Therapeutic uses and pharmaceutical compositions

The co-crystals of the present invention are therapeutically useful. The present invention therefore provides a co-crystal, which co-crystal comprises valacyclovir and a co-crystal former, which co-crystal former is mellitic acid or L-ascorbic acid, for use in a method of treatment of the human or animal body by therapy. The co-crystal may be as further defined anywhere herein.

Also provided is a pharmaceutical composition which comprises a co-crystal, which co-crystal comprises valacyclovir and a co-crystal former, which co-crystal former is mellitic acid or L-ascorbic acid. The co-crystal may be as further defined anywhere herein. The pharmaceutical composition typically further comprises a pharmaceutically acceptable diluent, excipient or carrier. In a preferred embodiment, the pharmaceutically acceptable diluent, excipient or carrier does not comprise an organic solvent. Preferably, the pharmaceutically acceptable diluent, excipient or carrier is aqueous. The pharmaceutical composition of the invention typically contains up to 85 wt% of the co-crystal of the invention. More typically, it contains up to 50 wt% of a co-crystal of the invention, for instance up to 30 wt%, or up to 15 wt% of a co-crystal of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free.

Also provided is a pharmaceutical composition of the invention as defined herein, for use in a method of treatment of the human or animal body by therapy.

The co-crystals of the invention are useful in treating or preventing viral infections and viral diseases. They are, for instance, useful in treating or preventing a viral infection, a viral disease, a viral disease after renal or bone marrow transplants, a viral disease in immunocompromised patients, or a viral disease recurring during labour. The co-crystals of the invention are, for instance, useful in treating or preventing herpes zoster, herpes simplex, vestibular neuritis or cytomegalovirus infections in the human or animal body.

The present invention therefore provides a co-crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, for use in the treatment or prevention of a viral infection, a viral disease, a viral disease after renal or bone marrow transplants, a viral disease in immunocompromised patients, or a viral disease recurring during labour, in the human or animal body.

Also provided is a method for treating a patient suffering from or susceptible to a viral infection, a viral disease, a viral disease after renal or bone marrow transplants, a viral disease in immunocompromised patients, or a viral disease recurring during labour, in the human or animal body, which method comprises administering to said patient an effective amount of a co-crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein.

Further provided is the use of a co-crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein in the manufacture of a medicament for use in treating or preventing a viral infection, a viral disease, a viral disease after renal or bone marrow transplants, a viral disease in immunocompromised patients, or a viral disease recurring during labour, in the human or animal body..

Non-limiting examples of viral infections and diseases that can be treated or prevented using the co-crystals and the pharmaceutical compositions of the invention are systemic (internal) and topical (skin) diseases: herpes zoster, herpes simplex, vestibular neuritis and cytomegalovirus, genital herpes, recurrent herpes during labour, herpes simplex in immunocompromised patients (for example HIV positive patients), and cytomegalovirus infection after transplantation (such as renal or bone marrow transplants). The co-crystal of the invention may also be used in conjunction with prednisolone to treat Bell's palsy.

The co-crystal of the invention may also be used to treat unusually severe viral skin conditions.

More typically, the disease or condition is herpes zoster or herpes simplex.

Accordingly, the invention also provides a co-crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, for use in the treatment or prevention of herpes.

Also provided is a method for treating a patient suffering from or susceptible to herpes, which method comprises administering to said patient an effective amount of a co- crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein.

Further provided is the use of a co-crystal of the invention as defined herein, or of a pharmaceutical composition of the invention as defined herein, in the manufacture of a medicament for use in the treatment or prevention of herpes.

Administration

Co-crystals of the present invention are typically administered to a subject in the form of a pharmaceutical composition of the invention. Such pharmaceutical compositions may be administered to the subject by any acceptable route of administration including, but not limited to oral, nasal, topical (including transdermal) and parenteral modes of administration. Further, the compositions of the invention may be administered, for example orally, in multiple doses per day, in a single daily dose or a single weekly dose. It will be understood that any form of the active agents used in the composition of the invention, (i.e. free base, pharmaceutically acceptable salt, solvate, etc.) that is suitable for the particular mode of administration can be used in the pharmaceutical compositions discussed herein.

The pharmaceutical compositions of this invention typically contain a

therapeutically effective amount of a co-crystal of the invention. Those skilled in the art will recognize, however, that a pharmaceutical composition may contain more than a therapeutically effective amount, i.e., bulk compositions, or less than a therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount. In one embodiment, the composition will contain from about 0.01-95 wt % of a co-crystal of the invention, including, from about 0.01-30 wt %, such as from about 0.01-10 wt %, with the actual amount depending upon the formulation itself, the route of administration, the frequency of dosing, and so forth. In another embodiment, a composition suitable for topical application, for example, comprises from about 0.01-30 wt % of a co-crystal of the invention with yet another embodiment comprising from about 0.01-10 wt % active agent.

Any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention. The choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular subject or type of medical condition or disease state. In this regard, the preparation of a suitable composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, carriers or excipients used in such compositions are commercially available. By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20 ^th Edition, Lippincott Williams & White, Baltimore, Md. (2000); and H. C. Ansel et al, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7 ^th Edition, Lippincott Williams & White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; compressed propellant gases, such as chlorofluorocarbons and hydrofluorocarbons; and other non-toxic compatible substances employed in pharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly and intimately mixing or blending the co-crystal of the invention with a pharmaceutically acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture may then be shaped or loaded into tablets, capsules, pills, canisters, cartridges, dispensers and the like using conventional procedures and equipment. The pharmaceutical compositions of the invention, which comprise a co-crystal of the invention, are often suitable for oral or topical administration. The pharmaceutical composition may be for administration by tablet or ointment. Suitable compositions for oral administration may be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; suspensions; emulsions; elixirs or syrups; and the like; each containing a predetermined amount of the co-crystal of the invention.

When intended for oral administration in a solid dosage form (i.e., as capsules, tablets, pills and the like), the composition will typically comprise the co-crystal of the invention and one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate. Solid dosage forms may also comprise: fillers or extenders, such as starches, microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and/or sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and/or glycerol monostearate; absorbents, such as kaolin and/or bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the

pharmaceutical compositions. Exemplary coating agents for tablets, capsules, pills and like, include those used for enteric coatings, such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymers, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, and the like. Examples of

pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol, and the like; and metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid, phosphoric acid, and the like.

Compositions may also be formulated to provide slow or controlled release of the co-crystal of the invention using, by way of example, hydroxypropyl methyl cellulose in varying proportions or other polymer matrices and/or microspheres. In addition, the pharmaceutical compositions of the invention may contain opacifying agents and may be formulated so that they release the active agent only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active agent can also be in micro-encapsulated form, if appropriate, with one or more of the above- described excipients.

Suitable liquid dosage forms for oral administration include, by way of illustration, pharmaceutically acceptable emulsions, microemulsions, suspensions, syrups and elixirs. Suspensions may contain the co-crystal of the invention and suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

When intended for oral administration, the pharmaceutical compositions of the invention may be packaged in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for dosing a subject, i.e., each unit containing a

predetermined quantity of the active agents calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units. For example, such unit dosage forms may be capsules, tablets, pills, and the like.

Compositions of the invention can also be administered parenterally (e.g., by subcutaneous, intravenous, intramuscular, or intraperitoneal injection). For such administration, the co-crystal of the invention are provided in a sterile suspension, or emulsion. Parenteral formulations may also contain one or more solubilizers, stabilizers, preservatives, wetting agents, emulsifiers, and dispersing agents. These formulations may be rendered sterile by use of a sterile injectable medium, a sterilizing agent, filtration, irradiation, or heat.

Compositions of the invention can also be administered transdermally using known transdermal delivery systems and excipients. For example, the co-crystal of the invention can be admixed with permeation enhancers, such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like, and incorporated into a patch or similar delivery system. Additional excipients including gelling agents, emulsifiers and buffers, may be used in such transdermal compositions if desired.

The present invention is further illustrated in the Example which follows: EXAMPLE

Co-crystal syntheses

Co-crystals were prepared in three definite stoichiometries: 1 :1, 1 :2 and 1 :3 by solvent- assisted grinding. Stoichiometric amounts of the coformer and the API were ground together for a short period of time. Two drops of water (in total ca. 100 mg of water*) were pipetted onto the ground mixture, turning into a paste which re-formed a powder upon further grinding due to evaporation of the solvent. In total, each API and coformer mixture was ground for a period of 10 minutes. (*One drop of water has a volume of ca. 0.05 mL, and the density of water is 1.00 g/mL, meaning that two drops of water weigh ca. 100 mg.)

Co-crystals of VAL and two different co formers respectively were produced by the above method. Thus: (1) co-crystals of valacyclovir and mellitic acid (in a 1 : 1 molar ratio) were produced, as were (2) co-crystals of valacyclovir and L-ascorbic acid (in a 1 : 1 and 1 :2 molar ratio).

The masses of the API (anhydrous valacyclovir) and the coformer that were ground together were as follows:

Valacyclovir: mellitic acid (1 : 1 molar ratio) = 40.0 mg : 42.1 mg. Thus, the total weight of the sample after adding the first two drops of solvent (but before further grinding) was 182.1 mg, assuming a mass of 100 mg for two drops of water.

Valacyclovir: L-ascorbic acid (1 : 1 molar ratio) = 40.0 mg : 21.7 mg. Thus, the total weight of the sample after adding the first two drops of solvent (but before further grinding) was 161.7 mg, assuming a mass of 100 mg for two drops of water.

Valacyclovir: L-ascorbic acid (1 :2 molar ratio) = 40.0 mg : 43.4 mg. Thus, the total weight of the sample after adding the first two drops of solvent (but before further grinding) was 183.4 mg, assuming a mass of 100 mg for two drops of water. Comparative synthesis examples

Co-crystals containing famciclovir or ganciclovir could not be produced using the solvent- drop assisted grinding method described above.

Furthermore, 1 :1, 1 :2 and 1 :3 molar ratio mixtures of each API (VAL, famciclovir, and ganciclovir) and the selected coformer were also prepared, and placed in glass vials (75 x 25 mm) together with 5 ml of solvent. In contrast to solvent-assisted grinding, this conventional method (commonly known as slurry) yielded no co-crystals for any of the three APIs tested, including VAL.

VAL forms

Anhydrous valacyclovir was employed in the solvent-assisted grinding co-crystal syntheses described in this Example. However, the HC1 salt or a hydrated form could readily have been employed successfully, in the same syntheses, instead of the anhydrous form. Indeed, either of the VAL forms (anhydrous, hydrated, or HC1 salt) can be used as the starting material because water was employed as the solvent in the synthesis method, so the presence of water does not change the result. Moreover, in the solvent-assisted grinding synthesis methods, the VAL comes out of the solid state (and is thus no longer in an anhydrous or hydrated or salt form) because it becomes dissolved in the solvent (water) present before it combines with the co-crystal former to form the co-crystal product. The same co-crystal would therefore be produced irrespective of the particular VAL form employed as the starting material.

Characterisation techniques

IR spectroscopy

Figure 1 compares the IR spectrum of the 1 : 1 VAL/mellitic acid co-crystal (middle trace) with those of the API and coformer (upper and lower traces respectively). Table 1. The labelled peaks of the IR spectra of the co-crystal and its components.

Figure 2 compares the IR spectrum of the 1 : 1 VAL/L-ascorbic acid co-crystal (middle trace) with those of the API and co former (upper and lower traces respectively).

Table 2. The peaks labelled on the IR spectra of the co-crystal and its components.

Melting point

Melting points were determined under standard atmospheric pressure (1013 mbar) in an open vessel. In particular, the melting point of each co-crystal was determined using a Stuart SMP40 melting point apparatus, which uses optical sensors to detect melting. In terms of sample preparation, open melting point glass capillaries were filled with the co- crystal sample up to ca. 2cm in height and then placed into the analysing chamber of the apparatus. Under standard atmospheric pressure, the sample was heated at a heating rate of 5°C per minute to raise the temperature of the sample from about 25°C to a temperature above the melting point. Thus, melting curves were recorded using a heating rate of 5°C/min. The melting point was determined to be the Clear Point; the point at which the sample becomes a clear liquid and no solid particles remain.

Table 3. The melting point of the synthesized co-crystals compared to the theoretical mpt.

of the co-crystal and the individual mpts. of the API and coformer.

PXRD analysis

An X-ray powder diffraction pattern of each of the selected co-crystal samples was recorded at room temperature on a STOE Stadi P diffractometer using Cu Και radiation source (λ = 1.5460 A) from a curved germanium (111) monochromator and a

stationary/fixed omega image plate PSD generating 40 kV. The powder diffraction data were collected covering a range of 3 - 50° along 2theta in steps of 0.015 every 300 seconds. In the event of an unknown pattern generated, the program DASH 3.3.3. (David, W. I. F.; Shankland, K.; van de Streek, J.; Pidcock, E.; Motherwell, W. D. S.; Cole, J. C. DASH: a program for Crystal Structure Determination from Powder Diffraction Data. J. Appl. Cryst. 2006, 39, 910 - 915) was utilised for indexing and unit cell refinement. Table 4. Some characteristic PXRD peaks of valacyclovir co-crystals with corresponding coformers.

Mellitic Acid L- Ascorbic Acid

1 3.48 8.61

2 6.89 10.49

3 8.01 12.13

4 15.33 14.52

5 16.44 16.40

6 20.16 17.40

7 23.62 19.76

8 26.92 23.78

Solubility testing

The aqueous solubilities of the co-crystals produced as described above, namely the co- crystals of valacyclovir and mellitic acid (1 : 1 molar ratio) and the co-crystals of valacyclovir and L-ascorbic acid (1 : 1 and 1 :2 molar ratios), were tested. All three co- crystals were found to be readily soluble in water. Solubility tests showed a solubility of over 160mg in 1 mL of water. The results suggested that the co-crystals of the invention would likely fall within class I of the U.S. Food and Drug Administration's

Biopharmaceutics Classification System (BCS). This is in contrast to valacyclovir itself, which has an aqueous solubility of 50 mg mL ^"1 , and falls in class III of the BCS. Guidance on the BCS can be found on the website of the U.S. Food and Drug Administration, at the following URL:

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedica lProductsandTobacco/CDE R/ucml28219.htm