Cocrystals of nonsteroidal anti-inflammatory drugs, lysine and gabapentin, pharmaceutical compositions and medical uses thereof

Abstract

The present invention relates to new co-crystals of the non-steroidal anti-inflammatory drug (NSAID) lysine and gabapentin, which belong to the class of phenylpropionic acid or phenylacetic acid derivatives, their pharmaceutical compositions and their use in the prevention, reduction or treatment of pain and / or inflammation.

Description

[Technical field]

[0001] The present invention relates to co-crystals of non-steroidal anti-inflammatory drugs (NSAIDs) belonging to the phenylpropionic acid or phenylacetic acid class, lysine and gabapentin, processes for their preparation, pharmaceutical compositions comprising said co-crystals and the use of said co-crystals or pharmaceutical compositions in the treatment of acute or chronic pain, in particular in the treatment of neuropathic or inflammatory pain. [Background technology]

[0002] Pain is the body's way of communicating that tissue damage has occurred. According to the IASP (International Association for the Study of Pain-2020) and World Health Organization definitions, pain is "an unpleasant sensory and emotional experience associated with, or similar to, actual or potential tissue damage."

[0003] The experience of pain varies from person to person and there are various ways of feeling and describing it. In general, pain conditions can be divided into acute and chronic. Acute pain is severe pain that lasts for a short period of time, typically less than three months, and is generally associated with tissue injury or localized tissue damage and inflammation. In particular, there are three different types of acute pain: somatic pain (pain felt by humans in the skin or soft tissue just below the skin), visceral pain (pain in the lining of internal organs and body cavities), and referred pain (pain associated with a location other than the source of tissue damage).

[0004] Chronic pain lasts much longer than acute pain, usually longer than 3 months. Chronic pain lacks the acute warning function of physiological nociception. In general, chronic pain can be mild or severe, persistent (e.g., arthritis) or intermittent (e.g., with migraine headaches). In particular, the peripheral nervous system (PNS) and central nervous system (CNS) are involved in generating and maintaining the sensitization of nociceptive neurons that results in chronic pain.

[0005] Chronic pain can have different etiologies and includes neuropathic pain, chronic inflammatory pain, e.g. arthritis, or pain of unknown origin such as fibromyalgia and restless leg syndrome. Chronic neuropathic pain results from lesions or diseases of the somatosensory nervous system, which provides information about the body, including the skin, musculoskeletal, and visceral organs.

[0006] Pharmacological treatment of chronic inflammatory pain usually involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Nonsteroidal anti-inflammatory drugs are usually divided according to their chemical structure into different classes, e.g., salicylates, e.g., aspirin, sodium salicylate and diflunisal, propionic acid derivatives, e.g., ibuprofen, ketoprofen, flurbiprofen and naproxen, acetic acid derivatives, e.g., diclofenac, ketorolac, indomethacin, sulindac and zomepirac, alkanones, e.g., nabumetone, and oxicams, e.g., piroxicam and tenoxicam (J Clin Pharmacol 1988 June;28(6):512-7).

[0007] NSAIDs have antipyretic, analgesic, and anti-inflammatory effects achieved by inhibition of prostaglandin synthesis. In particular, NSAIDs inhibit cyclooxygenase (COX), an enzyme that catalyzes the synthesis of cyclic endoperoxides from arachidonic acid to form prostaglandins. Nonselective NSAIDs inhibit the activity of both COX-1 and COX-2, whereas selective COX-2 inhibits only cyclooxygenase COX2.

[0008] NSAIDs are commonly used but can cause unwanted effects that are problematic as they increase the risk of gastrointestinal ulcers and bleeding, heart attacks and kidney disease. Therefore, there is a felt need to identify new therapeutic solutions for the treatment of chronic pain that do not cause the severe side effects mentioned above.

[0009] Chronic inflammatory pain states are often associated with neuroinflammation, a physiological / pathological state characterized by the infiltration of immune cells, so-called leukocytes, which release inflammatory cytokines.

[0010] Neuroinflammation also marks the activation of glial cells and the production of inflammatory mediators that modulate pain sensitivity, specifically Schwann cells in nerves, satellite glial cells in ganglia and microglia, and astrocytes and oligodendrocytes in the spinal cord and brain.

[0011] Today, there are no effective therapies for the treatment of neuroinflammatory conditions. Nonsteroidal anti-inflammatory drugs are largely ineffective in treating neuropathic pain. Gabapentin is a drug of the formula

[0012] [ka]

[0013] It is an anticonvulsant synthetic analogue of the neurotransmitter gamma-aminobutyric acid (GABA). Gabapentin is an anticonvulsant drug primarily used to treat partial seizures and neuropathic pain. Gabapentin has recently been approved for the treatment of chronic pain, especially neuropathic pain conditions. Neuropathic pain results from lesions or diseases of the somatosensory system, including peripheral fibers and central neurons, and affects 7-10% of the general population. In particular, neuropathic pain results from an imbalance in somatosensory signaling between excitatory and inhibitory, alterations in the release of ion channels and modulators. Neuropathic pain is a chronic pain characterized by complex symptoms, poor outcomes and difficult treatment decisions.

[0014] Gabapentin's mechanism of action involves binding to calcium channels in several areas of the central nervous system and spinal cord that express calcium channels, which are localized at presynaptic terminals and control neurotransmitter release.

[0015] Gabapentin is neither inhibited nor metabolized by hepatic enzymes. It is excreted by the renal system, with an elimination half-life of approximately 6 hours. Gabapentin is therefore characterized by a short half-life and, as a result, must be administered three times a day (tds).

[0016] Rapid titration can be accomplished with a dose of 300 mg once daily (often at bedtime to minimize sedation) on day 1, followed by 300 mg twice daily on day 2 and 300 mg tds on day 3. Dosage can be further increased if efficacy is not achieved at this dose.

[0017] A poor pharmacological and pharmacokinetic profile is observed when gabapentin is used alone in pain therapy. In other words, gabapentin is not completely effective when used as a monotherapy for the treatment of pain. In fact, a delayed onset of response was recorded. Gabapentin is slowly absorbed after oral administration, with maximum levels in plasma within 3-4 hours (Quintero, Journal of Experimental Pharmacology 2017:9 13-21). Moreover, gabapentin is barely active against inflammatory pain, as confirmed in the present experimental section of the carrageenan-inflamed rat model.

[0018] In addition, gabapentin is not recommended for the treatment of low back pain (Low back pain and sciatica in over 16s: assessment and management, National Institute for Health and Care Excellence NICE Guidelines 2016).

[0019] In view of the shortcomings of using gabapentin as a monotherapy for the treatment of pain, applicants have conducted several studies to improve the properties of gabapentin for use in the treatment of painful conditions.

[0020] In particular, the applicant has carried out investigations into gabapentin in combination with non-steroidal anti-inflammatory drugs, especially those belonging to the phenylpropionic acid and phenylacetic acid classes. Summary of the Invention [Means for solving the problem]

[0021] The Applicant, aiming to improve the therapy of pain conditions, has surprisingly found that non-steroidal anti-inflammatory drugs belonging to the phenylpropionic acid or phenylacetic acid class form stable co-crystals with gabapentin and lysine.

[0022] During the course of research, the applicant discovered that co-crystals of a non-steroidal anti-inflammatory drug belonging to the above mentioned class, lysine and gabapentin, exhibit surprising synergistic effects against inflammation and pain.

[0023] Indeed, when these active ingredients are associated in the cocrystals of the present invention, they exhibit greater anti-inflammatory and analgesic activity than is obtained by co-administration as separate active molecules (NSAID, gabapentin).

[0024] Thus, the cocrystals allow for the use of significantly smaller therapeutic doses of either NSAIDs or gabapentin or both, minimizing side effects. Additionally, sustained efficacy over time was observed compared to gabapentin alone.

[0025] Finally, the cocrystal improves the dissolution rate of the NSAID, especially when dissolved in an aqueous physiological environment, and enhances the absorption and / or bioavailability of the two active molecules, gabapentin and the NSAID.

[0026] Thus, an object of the present invention is a co-crystal of a non-steroidal anti-inflammatory drug (NSAID) belonging to the phenylpropionic acid or phenylacetic acid class, lysine and gabapentin, with the proviso that said non-steroidal anti-inflammatory drug is not ketoprofen.

[0027] According to an embodiment of the present invention, the nonsteroidal anti-inflammatory drug is a phenylpropionic acid derivative selected from ibuprofen, flurbiprofen, fenoprofen, indoprofen, loxoprofen, perbiprofen, and naproxen.

[0028] According to an embodiment of the invention, the nonsteroidal anti-inflammatory drug is a phenylacetic acid derivative selected from diclofenac, felbinac, ibufenac, fenclofenac, tiflac, and ketorolac.

[0029] According to a particularly preferred embodiment of the invention, the non-steroidal anti-inflammatory drug is selected from ibuprofen and flurbiprofen. The inventive co-crystals of flurbiprofen-lysine-gabapentin (FLG) and ibuprofen-lysine-gabapentin (ILG), respectively, are characterized by the XRPD diffractogram reported in FIG. 1, and the XRPD positions and intensities shown in Tables 2-3.

[0030] Applicants have surprisingly observed that the flurbiprofen-lysine-gabapentin cocrystal and the ibuprofen-lysine-gabapentin cocrystal bear a striking similarity to one another, with XRPD diffraction peaks of greatest intensity in the regions 9-10 degrees 2-theta, 15-25 degrees 2-theta and 27-28 degrees 2-theta. The same pattern was observed in a previous cocrystal of ketoprofen-lysine-gabapentin described in International Patent Application PCT / EP2021 / 060421, which is not part of the present application.

[0031] This similarity provided clear evidence of the isostructurality of the cocrystals. Isostructurality refers to different components with similar crystal packing. When closely related molecules are introduced into the crystal lattice of a single component, the corresponding binary system can exhibit close packing [G. Portalone, Crystals, 2020, 10, 999-1012].

[0032] A further object of the present invention is a process for the preparation of the co-crystal of the invention, comprising: a) suspending a non-steroidal anti-inflammatory drug (NSAID) belonging to the phenylpropionic acid or phenylacetic acid class, lysine, and gabapentin in a suitable solvent; b) dissolving the NSAID, lysine and gabapentin, possibly with stirring and optionally by heating the suspension, until a clear solution is obtained; c) optionally cooling the resulting solution; and / or d) optionally adding an anti-solvent to provide an NSAID, lysine, and gabapentin co-crystal; The method includes:

[0033] A further object of the present invention is a pharmaceutical composition comprising the cocrystal of the present invention and at least a pharma- ceutically acceptable excipient. A further object of the present invention is a pharmaceutical composition comprising a cocrystal according to the invention and at least another pharma- ceutical active ingredient.

[0034] A further object of the invention is a cocrystal according to the invention for use in the treatment of pain and / or inflammation. A further object of the present invention is a method for the treatment of pain and / or inflammation comprising administering to a patient an effective amount of a cocrystal according to the invention.

[0035] definition For purposes of the present invention, the term "co-crystal" refers to a multi-component system in which all components, when in their pure form, are solid under ambient conditions. The components coexist at the molecular level within a single crystal. At least some of the components are linked by non-covalent, non-ionic interactions.

[0036] For the purposes of the present invention, the term "pain" refers to disorders of different natures and organs, such as: headaches, cephalalgia, both primary and therefore not related to other factors or diseases, and secondary and therefore dependent on trauma, injury and separate diseases; toothache, in the case of abscesses or caries, which cause pain in the tooth pulp with its many blood vessels and nerves; menstrual pain: pain in the abdomen and lower abdomen and headache due to hormonal changes typical during menstruation; neuralgia, or severe neuralgia, due to strain, trauma and infection; pain in the muscles, or myalgia: pain located at the muscle level when using or contacting the muscles due to contraction or trauma; osteoarticular pain, for example pain due to inflammation of the joints (for bones, cartilage, ligaments and tendons) following trauma, aging, strain and injury.

[0037] For purposes of the present invention, the term "inflammation" refers to the local response of an organism to cellular insult, manifested by capillary dilation, leukocyte infiltration, redness, heat, and pain, and serving as a mechanism to initiate elimination of injurious agents and damaged tissue.

[0038] For the purposes of the present invention, the term "pharmaceutical acceptable excipient" refers to a substance that is devoid of any pharmacological effect of its own and does not produce adverse reactions when administered to a mammal, preferably a human.

[0039] For the purposes of the present invention, the term "room temperature" means a temperature in the range of 18 to 25°C. For the purposes of the present invention, the term "anti-solvent" means a solvent in which a compound is insoluble or only slightly soluble.

[0040] In this specification and the drawings accompanying this specification, the abbreviation "Gaba" refers to gabapentin. As used herein, the terms "approximately" and "about" refer to the range of experimental error that can occur in a measurement. [Brief description of the drawings]

[0041] [Figure 1]Powder X-ray diffraction patterns of flurbiprofen-lysine-gabapentin and ibuprofen-lysine-gabapentin cocrystals. [Diagram 2] DSC thermogram of flurbiprofen-lysine-gabapentin 1:1:1 cocrystal. [Diagram 3] DSC thermogram of ibuprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 4] TG thermogram of flurbiprofen-lysine-gabapentin 1:1:1 cocrystal. [Diagram 5] TG thermogram of ibuprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 6] Raman spectrum of flurbiprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 7] Raman spectrum of ibuprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 8] FT-IR spectrum of flurbiprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 9] FT-IR spectrum of ibuprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 10] 1H-NMR spectrum of flurbiprofen-lysine-gabapentin 1:1:1 cocrystal (400 MHz, DO). [Figure 11] H-NMR spectrum of ibuprofen-lysine-gabapentin 1:1:1 cocrystal (400 MHz, DO). [Figure 12] 13C CPMAS spectrum of flurbiprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 13] Detail of the carboxylic acid region of the C CPMAS spectra of FLU-LYS-GAB, FLU·SALA, FLU·PICA, NaFLU, pure FLU, NaGAB, pure GAB, DL-LYS·2HCl, L-LYS acetate and pure L-LYS. [Figure 14]15N CPMAS spectrum of flurbiprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 15] Comparison between 15N CPMAS spectra of FLU-LYS-GAB, NaGAB, GAB, DL-LYS·2HCl, L-LYS acetate and pure L-LYS. [Figure 16] 13C CPMAS spectrum of ibuprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 17] Detail of the carboxylic acid region of the C CPMAS spectra of IBU-LYS-GAB, IBU·L-proline, NaIBU, pure IBU, NaGAB, pure GAB, DL-LYS·2HCl, L-LYS acetate and pure L-LYS. [Figure 18] 15N CPMAS spectrum of ibuprofen-lysine-gabapentin 1:1:1 cocrystal. [Figure 19] Comparison between 15N CPMAS spectra of IBU-LYS-GAB, NaGAB, GAB, DL-LYS·2HCl, L-LYS acetate and pure L-LYS. [Figure 20] 13C (150.91 MHz) CPMAS spectra of flurbiprofen-lysine-gabapentin and ibuprofen-lysine-gabapentin acquired at room temperature and a spinning speed of 20 kHz. [Figure 21] 15N (60.83 MHz) CPMAS spectra of flurbiprofen-lysine-gabapentin and ibuprofen-lysine-gabapentin acquired at room temperature and a spinning speed of 12 kHz. [Figure 22] Figure 1 shows the effect of Flur / Lys / Gaba cocrystals compared to the mixture of Flur+Lys+Gaba and the single active substances flurbiprofen, gabapentin and indomethacin, respectively, on carrageenan-induced rat paw edema. In this figure, "Gaba" refers to gabapentin. [Diagram 23]Figure 1 shows the effect of Flur / Lys / Gaba cocrystals compared to a mixture of Flur+Lys+Gaba and the single active substances flurbiprofen, gabapentin and indomethacin, respectively, on mechanical allodynia in a carrageenan-induced paw edema model in rats. In this figure, "Gaba" refers to gabapentin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] The object of the present invention is a co-crystal of a non-steroidal anti-inflammatory drug (NSAID) belonging to the phenylpropionic acid or phenylacetic acid class, lysine and gabapentin, with the proviso that said non-steroidal anti-inflammatory drug is not ketoprofen.

[0043] According to a preferred embodiment of the present invention, the molar ratio of the components of the co-crystal is 1:1:1. In line with the analyses reported in the experimental section, in the cocrystal according to the invention, the carboxyl group of a non-steroidal anti-inflammatory drug (NSAID) belonging to the class of phenylpropionic acid or phenylacetic acid is deprotonated and bound to the protonated lysine ε-NH3 through an ionic bond forming a neutral salt. + Interacts with the group.

[0044] Salts of lysine with nonsteroidal anti-inflammatory drugs (NSAIDs) belonging to the phenylpropionic acid or phenylacetic acid class, particularly flurbiprofen or ibuprofen salts containing lysine, interact with gabapentin through nonionic bonds to form stable cocrystals.

[0045] According to an embodiment of the present invention, the nonsteroidal anti-inflammatory drug is a phenylpropionic acid derivative selected from ibuprofen, flurbiprofen, fenoprofen, indoprofen, loxoprofen, perbiprofen and naproxen.

[0046] According to an embodiment of the invention, the nonsteroidal anti-inflammatory drug is a phenylacetic acid derivative selected from diclofenac, felbinac, ibufenac, fenclofenac, tiflac and ketorolac.

[0047] In the co-crystals according to the invention, the chiral carbons of the NSAID, if present, may be optically pure (S) or (R) or racemic (S,R) or in the form of any mixture of stereoisomers.

[0048] In the cocrystals of the present invention, lysine can be racemic (S,R) lysine, (S) lysine or (R) lysine, or any mixture thereof, and is preferably the natural amino acid (S)-lysine, also designated L-lysine.

[0049] According to a particularly preferred embodiment, the nonsteroidal anti-inflammatory drug is selected from flurbiprofen and ibuprofen. According to another preferred embodiment, the nonsteroidal anti-inflammatory drug is flurbiprofen.

[0050] In the co-crystal according to this embodiment, the flurbiprofen can be racemic (S,R) flurbiprofen, (S)-flurbiprofen or (R)-flurbiprofen or any mixture thereof.

[0051] In the co-crystals according to this embodiment, lysine can be racemic (S,R) lysine, (S) lysine or (R) lysine, or any mixture thereof, and is preferably the natural amino acid (S)-lysine, also named L-lysine.

[0052] In one embodiment, a cocrystal of the invention comprises (S,R)-flurbiprofen. In one embodiment, a cocrystal of the invention comprises (S,R)-lysine. In one embodiment, a cocrystal of the invention comprises (S,R)-flurbiprofen and (S,R)-lysine.

[0053] According to another preferred embodiment, the nonsteroidal anti-inflammatory drug is ibuprofen. In the co-crystal according to this embodiment, the ibuprofen can be racemic (S,R) ibuprofen, (S)-ibuprofen or (R)-ibuprofen or any mixture thereof.

[0054] Also, in the co-crystals according to the present embodiments, lysine can be racemic (S,R) lysine, (S) lysine or (R) lysine, or any mixture thereof, and is preferably the natural amino acid (S)-lysine, also named L-lysine.

[0055] In one embodiment, a cocrystal of the invention comprises (S,R)-ibuprofen. In one embodiment, a cocrystal of the invention comprises (S,R)-lysine. In one embodiment, a cocrystal of the invention comprises (S,R)-ibuprofen and (S,R)-lysine.

[0056] The co-crystals of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. The co-crystals of the present invention are readily available and stable. The cocrystals of the present invention exhibit improved pharmaceutical properties, pharmacokinetics and efficacy in pain conditions, as described in the Experimental section below.

[0057] The co-crystals of the present invention are characterized by a common XRPD pattern, in particular the following common XRPD diffraction peaks: 9.3, 17.1, 18.5, 19.8, 22.1, 24.1, 24.9, 27.9 degrees 2-theta ±0.4 degrees 2-theta.

[0058] Other polymorphs of this co-crystal are also within the scope of the present invention. According to one embodiment, the co-crystal of flurbiprofen, lysine and gabapentin of the present invention is characterized by the following XRPD diffraction peaks: 9.3, 10.4, 15.2, 16.0, 17.2, 18.3, 18.8, 19.7, 20.7, 21.9, 24.0, 24.8, 27.9, and 29.0 degrees 2-theta ± 0.2 degrees 2-theta, and preferably further characterized by the following XRPD diffraction peaks: 6.9, 10.9, 12.2, 25.5, 26.3, 29.8, 31.5, 33.0, 34.0, 35.9, 37.5, 39.2 and 40.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0059] According to this embodiment, the cocrystal of flurbiprofen, lysine and gabapentin of the present invention has a DSC thermogram in FIG. 2 with a peak of the endothermic shape of the cocrystal corresponding to a melting point of 163.48° C.±0.5° C. with an onset of 161.59° C.±0.5° C., a TGA thermogram in FIG. 4, FT Raman and FT-IR spectra with typical absorption bands reported in FIGS. 6 and 8, and a solution in FIG. 10. 1 H-NMR spectra and relative assignments in Table 10, solid-state Figs. 13 Further characterized by C CPMAS and relative assignments in Table 12 and / or 15N CPMAS spectra in Figures 14 and 15.

[0060] According to another embodiment, the co-crystal of ibuprofen, lysine and gabapentin of the present invention is characterized by the following XRPD diffraction peaks: 9.5, 10.3, 15.9, 17.1, 17.6, 18.7, 20.0, 22.3, 24.1, 25.1, 25.6, 27.9 and 28.6 degrees 2-theta ± 0.2 degrees 2-theta, and preferably is further characterized by the following XRPD diffraction peaks: 6.9, 12.0, 14.7, 26.3, 30.6, 31.1, 32.3, 33.1, 34.5, 35.3, 36.6, 38.6, 39.0, 41.1, and 48.9 degrees 2-theta ± 0.2 degrees 2-theta. According to this embodiment, the cocrystal ibuprofen, lysine and gabapentin of the present invention has a DSC thermogram in FIG. 3 with a peak of the endothermic shape of the cocrystal corresponding to a melting point of 165.60° C.±0.5° C. with an onset of 161.60° C.±0.5° C., a TGA thermogram in FIG. 5, FT Raman and FT-IR spectra with typical absorption bands reported in FIGS. 7 and 9, and a solution in FIG. 11. 1 H-NMR spectra and relative assignments in Table 11, solid state in Figs. 13 Further characterized by C CPMAS and relative assignments in Table 13, and / or the 15N CPMAS spectra in Figures 18 and 19.

[0061] The cocrystals having the XRPDs shown above are observed to be isostructural cocrystals, particularly the flurbiprofen-lysine-gabapentin cocrystal and the ibuprofen-lysine-gabapentin cocrystal.

[0062] Isostructurality refers to different components with similar crystal packing: if closely related molecules are introduced into the crystal lattice of a single component, the corresponding binary system can exhibit close packing (G. Portalone, Crystals, 2020, 10, 999-1012).

[0063] Isostructural cocrystals, which contain similar structural blueprints, can exhibit commonly modified pharma- ceutical relevant properties due to the presence of varying coformers and minor changes in their conformation and packing. In many cases, isostructural cocrystals have similar lattice parameters, including space groups, defined as isomorphs, and generally exhibit identical X-ray diffraction patterns [FY Wang, Q. Zhang, Z. Zhang, X. Gong, JRWang and X. Mei, Cryst. Eng. Comm, 2018, 20, 5945-5948]. The isostructurality of the cocrystals was demonstrated by XRPD pattern comparison and further confirmed by 13C and 15N-CPMAS NMR spectra (see Experimental Section).

[0064] The XRPD diffractograms of the cocrystals are very similar (Figure 1, XRPD), with the major peak reflections in the 14-22 degrees 2-theta region having similar intensities. This similarity provides clear evidence of the isostructural nature of the cocrystals.

[0065] Furthermore, in the 13C and 15N-CPMAS NMR spectra of the two cocrystals (see Figures 20 and 21), many of the resonances coincide. A careful analysis of the signals points out that all of the repeating signals in the aliphatic region (below 80 ppm) correspond to the aliphatic C nuclei of LYS and GAB. The most obvious differences are in the aromatic range (110-170 ppm), which makes sense since the aromatic carbons are of different NSAIDs. Most notably, the same similarity can be observed in the carboxylic acid region, with the carboxylic acid resonances of FLU-LYS-GAB and IBU-LYS-GAB.

[0066] The same striking spectral similarity can be observed in the 15N CPMAS spectra of the samples. All these spectral similarities indicate that the FLU-LYS-GAB and IBU-LYS-GAB crystal systems are homogeneous phases, characterized by very similar local environments, especially for LYS and GAB, as well as comparable vibrational behavior.

[0067] A further object of the present invention is the co-crystal of the present invention for use as a medicine. The medical use may be curative, prophylactic or palliative. The applicant has observed that the association of the two active ingredients in the same crystal presents several advantages for this medical use: First, a co-crystal containing an NSAID, lysine and gabapentin behaves as a single chemical entity, thus facilitating treatment and resulting in fewer side effects relative to treatment with gabapentin and an NSAID alone.

[0068] Cocrystals comprising an NSAID, lysine and gabapentin may be advantageously used to prevent, reduce or treat pain and / or inflammation, said pain being acute or chronic pain.

[0069] According to a preferred use, the cocrystals containing NSAID, lysine and gabapentin are used for neuropathic or inflammatory pain.Indeed, the association of the two active ingredients into one unique species may allow for better pharmacokinetics / pharmacodynamics (PKPD), including better penetration of the blood-brain barrier, helping to treat neuropathic pain.

[0070] Preferably, the pain is selected from headache, toothache, menstrual pain, muscle pain, neuropathic pain, pain associated with nerve inflammation, diabetic neuropathy, cancer pain, osteoarthritis, lower back pain, sciatica, fibromyalgia, trigeminal neuralgia, post-surgical and post-operative pain, post-herpetic neuralgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, phantom limb pain and HIV pain.

[0071] According to one embodiment, the daily dosage of the cocrystal for a human is preferably provided in an amount of 50-250 mg per day, more preferably 100-200 mg per day relative to flurbiprofen, preferably 1-4 times per day.

[0072] According to another embodiment, the daily dosage of the cocrystal for a human is preferably provided in an amount of 200-800 mg per day, more preferably 400-600 mg per day relative to ibuprofen, preferably 1-4 times per day.

[0073] A daily dosage of the cocrystals according to the present invention for humans advantageously provides a much lower total amount of gabapentin compared to the usual dosage of gabapentin when used alone.

[0074] A further object of the present invention is a process for the preparation of the co-crystal of the invention, comprising: a) suspending a non-steroidal anti-inflammatory drug (NSAID) belonging to the phenylpropionic acid or phenylacetic acid class, lysine, and gabapentin in a suitable solvent and stirring the resulting mixture at room temperature until a clear solution is obtained; b) dissolving the NSAID, lysine and gabapentin, possibly with stirring and optionally by heating the suspension, until a clear solution is obtained; c) optionally cooling the solution obtained in b), and / or d) optionally adding an anti-solvent to provide an NSAID, lysine, and gabapentin co-crystal. The method includes:

[0075] According to an embodiment of the invention, the non-steroidal anti-inflammatory drug according to step a) is a phenylpropionic acid derivative selected from ibuprofen, flurbiprofen, fenoprofen, indoprofen, loxoprofen, perbiprofen and naproxen.

[0076] According to another embodiment of the invention, the nonsteroidal anti-inflammatory drug is a phenylacetic acid derivative selected from diclofenac, felbinac, ibufenac, fenclofenac, tiflac, and ketorolac.

[0077] According to a preferred embodiment, said non-steroidal anti-inflammatory drug is selected from flurbiprofen, ibuprofen, diclofenac and naproxen, even more preferably from ibuprofen and flurbiprofen.

[0078] In this method, the starting material for the NSAID can be an NSAID free acid or an NSAID salt. In the case of an NSAID free acid or an NSAID salt other than lysinate, the lysine is preferably added to the neutral form of the lysine. The lysine is preferably used in the same molar amount of the NSAID.

[0079] The NSAID salt may preferably be flurbiprofen lysinate or ibuprofen lysinate. In step a) of the process, the molar ratio of gabapentin to NSAID is preferably between 1:1 and 1.5:1, more preferably between 1:1 and 1.2:1, even more preferably about 1:1.

[0080] In a preferred embodiment, the molar ratio of NSAID:lysine:gabapentin in step a) is about 1:1:1. Suitable solvents for use in step a) of the process according to the invention are water, alcohols, preferably methanol and ethanol, esters, preferably ethyl acetate, ethers, preferably tetrahydrofuran and tert-butyl methyl ether, or aromatic solvents, preferably toluene.

[0081] Step b) can be carried out at room temperature or with heating, preferably at the reflux temperature of the solvent. Preferably, the clear solution of step b) contains said NSAID in a molar concentration of 1 mol, lysine in a molar concentration of 1 to 1.5 mol / mol relative to the NSAID, more preferably 1 mol / mol, and gabapentin in a molar concentration of 1 to 1.5 mol / mol relative to the NSAID, more preferably 1 mol / mol.

[0082] Preferably, the solution from step b) is kept at room temperature or cooled and filtered. Preferably, step b) is carried out with stirring. The stirring step of step b) is preferably carried out for a period of between 10 minutes and 30 minutes.

[0083] Optionally, in step d), precipitation of the co-crystal is preferably by addition of an anti-solvent such as ethyl acetate and tetrahydrofuran. Preferably, the poor solvent can be added in a volume ratio of 1:1 to 16:1 relative to the volume of the solution.

[0084] According to one embodiment, in step a) of the method according to the invention, the NSAID and lysine may be present as preformed salts or co-crystals in any polymorphic form. The starting materials for the production of the co-crystals of the present invention can be prepared according to previously published methods of synthesis well known to organic chemists.

[0085] According to alternative embodiments, said NSAID is a free acid and / or said lysine is in neutral form. In this preparation method, gabapentin is preferably used in its neutral form (zwitterionic inner salt) or in any acid or base salt form, for example as gabapentin hydrochloride or gabapentin sodium salt.

[0086] Preferably, gabapentin is used in its neutral form. The gabapentin can be in any polymorphic form. The method provides the co-crystals of the present invention in high yields, which is simple and easily scalable at an industrial level.

[0087] The present invention further relates to a pharmaceutical composition comprising the above-mentioned nonsteroidal anti-inflammatory drug (NSAID) belonging to the class of phenylpropionic acid or phenylacetic acid, a cocrystal of lysine and gabapentin, and at least one pharma- ceutically acceptable excipient.According to an embodiment of the present invention, the nonsteroidal anti-inflammatory drug in the pharmaceutical composition is a phenylpropionic acid derivative selected from ibuprofen, flurbiprofen, fenoprofen, indoprofen, loxoprofen, perbiprofen and naproxen.

[0088] According to another embodiment of the invention, the nonsteroidal anti-inflammatory drug in the pharmaceutical composition is a phenylacetic acid derivative selected from diclofenac, felbinac, ibufenac, fenclofenac, tiflac and ketorolac.

[0089] According to a particularly preferred embodiment, the pharmaceutical composition comprises a flurbiprofen-lysine-gabapentin co-crystal. According to another particularly preferred embodiment, the pharmaceutical composition comprises an ibuprofen-lysine-gabapentin cocrystal.

[0090] The nonsteroidal anti-inflammatory drug in the co-crystal present in the pharmaceutical composition of the present invention is not ketoprofen. The compositions according to the invention may contain 6 to 60% by weight of a co-crystal as defined herein, and 40 to 94% by weight of one or more pharma- ceutically acceptable excipients.

[0091] The choice of excipient can vary widely, depending on factors such as the particular mode of administration, solubility and stability effects, and the nature of the dosage form. The pharmaceutical compositions according to the invention may be in any form suitable for administration to humans and / or animals, preferably humans, including infants, children and adults, and may be produced by standard procedures known to those skilled in the art.

[0092] The pharmaceutical compositions of the present invention are preferably oral solid compositions such as capsules, pellets, tablets, cachets, chewable dosage forms, powders, lozenges, granules, orally soluble granules, suspensions, emulsions, sprays, or dry powder forms to be reconstituted with a liquid medium.

[0093] The pharmaceutical composition may further contain one or more pharma- ceutically acceptable excipients, such as fillers, binders, glidants, disintegrants, flow regulators, release agents, and the like. Suitable excipients are disclosed, for example, in the "Handbook of Pharmaceutical Excipients", 3rd Edition, published by AH Kibbe, American Pharmaceutical Association, Washington, USA, and the Pharmaceutical Press, London.

[0094] Suitable fillers are, for example, lactose (monohydrate, spray dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dicalcium phosphate dihydrate and calcium hydrogen phosphate.

[0095] The filler may be present in an amount of 0-80% by weight, preferably 10-60% by weight, of the total weight of the composition. Suitable binders are, for example, polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sugars, dextran, corn starch, gelatin, polyethylene glycol, natural and synthetic gums, pregelatinized starch.

[0096] The binder may be present in an amount of 0 to 80% by weight, preferably 10 to 60% by weight, of the total weight of the composition. Binders are commonly used to impart cohesive properties to tablet formulations.

[0097] Suitable glidants are, for example, alkaline earth metal salts of fatty acids such as stearic acid, for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate.

[0098] The glidant may be present, for example, in an amount of 0 to 2% by weight, preferably 0.5 to 1.5% by weight of the total weight of the composition. Suitable disintegrants are, for example, croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, sodium alginate and sodium bicarbonate.

[0099] The disintegrant may be present in an amount of 0-20% by weight, preferably 1-15% by weight of the total weight of the composition. A suitable flow regulator is, for example, colloidal silica. The flow regulator may be present in an amount of 0 to 8% by weight, preferably 0.1 to 3% by weight, of the total weight of the composition.

[0100] A suitable releasing agent is for example talcum. The releasing agent may be present in an amount of 0 to 5% by weight, preferably 0.5 to 3% by weight, of the total weight of the composition. The solid composition may be coated, preferably film coated.

[0101] Suitable coating agents are, for example, cellulose derivatives, poly(meth)acrylates, polyvinylpyrrolidones, polyvinyl acetate phthalates, and / or shellac or natural gums, such as carrageenans.

[0102] The pharmaceutical composition of the present invention may be a solid implant composition, in which the cocrystal is in solid form. The composition may be incorporated into a body tissue or cavity. The implant may comprise a matrix of a biocompatible and bioerodible material in which particles of the cocrystals of the invention are dispersed, or possibly globules or isolated cells of a liquid mixture of the cocrystals are entrapped. Desirably, the matrix is ​​broken down and completely absorbed by the body. The composition of the matrix is ​​also preferably selected to provide controlled, sustained, and / or delayed release of the cocrystals of the invention over an extended period of time.

[0103] Alternatively, cocrystals of the invention can be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. The compositions may be administered topically to the skin or mucosa, that is, transdermally, transepidermally, subepidermally or transdermally.

[0104] The compositions may be administered sublingually or via a suppository. Typical formulations for this purpose include pour-ons, spot-ons, dips, sprays, mousses, shampoos, powders, gels, hydrogels, lotions, creams, ointments, dusting powders, bandages, foams, films, skin patches, wafers, implants, depots, sponges, fibers, bandages, microemulsions, orosoluble granules. Liposomes may also be used.

[0105] Pharmaceutical compositions of the present invention may be solid compositions for extemporaneous preparation of a solution for oral or parenteral administration, for example to be administered by intramuscular, intraperitoneal or intravenous injection. The pharmaceutical compositions of the present invention can be prepared by methods well known to those skilled in the art.

[0106] The compositions of the present invention may be in the immediate, delayed, modified, sustained, pulsed or controlled release form. According to further embodiments, a pharmaceutical composition of the invention may comprise a cocrystal of the invention and at least another pharma- ceutical active ingredient.

[0107] The other pharma- ceutical active ingredients will be determined by the context in which the therapeutic agent of the present invention is to be administered. According to the present invention, the pharmaceutical composition may be used for the prevention, reduction or treatment of pain and / or inflammation, said pain being acute or chronic pain.

[0108] According to a preferred use, the composition is used for the prevention, alleviation and / or treatment of neuropathic or inflammatory pain. The pain is selected from headache, toothache, menstrual pain, muscle pain, neuropathic pain, pain associated with nerve inflammation, diabetic neuropathy, cancer pain, osteoarthritis, lower back pain, sciatica, fibromyalgia, trigeminal neuralgia, post-surgical and post-operative pain, post-herpetic neuralgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, phantom limb pain or HIV pain.

[0109] A further object of the present invention is a method for the prevention, reduction or treatment of pain and / or inflammation, comprising the step of administering to a subject, preferably a human, in need of the prevention, reduction or treatment of pain and / or inflammation an effective amount of a cocrystal of the present invention and / or a pharmaceutical composition comprising said cocrystal.

[0110] In particular, the method allows for the prevention, relief or treatment of headache, toothache, menstrual pain, muscle pain, neuropathic pain, pain associated with neuroinflammation, diabetic neuropathy, cancer pain, osteoarthritis, lower back pain, sciatica, fibromyalgia, trigeminal neuralgia, post-surgical and post-operative pain, post-herpetic neuralgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, phantom limb pain or HIV pain. In particular, patients benefit from a longer duration of action from treatment with the cocrystal than treatment with gabapentin or an NSAID or combinations thereof.

[0111] This is within the ordinary skill of a person of ordinary skill in the art, such as a physician, to determine the preferred route of administration and the corresponding suitable dosage forms and dosing regimens. For example, the daily dosage for humans and animals may vary depending on factors such as age, sex, weight or the degree of disease.

[0112] According to one embodiment of the method for the prevention, reduction, or treatment of pain and / or inflammation, the cocrystal and / or pharmaceutical composition may be administered in combination with one or more other drugs useful in the prevention, reduction, or treatment of pain and / or inflammation. EXAMPLES

[0113] Experimental section Described below is the preparation of cocrystals of an NSAID, lysine and gabapentin, their analysis and biological characterization.

[0114] 1. Synthesis of Cocrystal NSAID-Lysine-Gabapentin The NSAID (3.3 mmol, 1.0 equiv.) was dissolved in 6 mL of ethanol. To the resulting solution, 50% w / w D,L-lysine in water (1.0 equiv.) was added and the solution was stirred for 10 min. Then, 1.0 equiv. of gabapentin was added. Solid precipitation was carried out for approximately 30 min and the suspension was stirred (300 rpm) at 25° C. for 5 h. The solid product was isolated by vacuum filtration on a filter paper and then squeezed under a stream of nitrogen for approximately 10 min. The solid was gently crushed and then dried at 40° C. and 30 mbar overnight to obtain the desired product as a white solid of NSAID-lysine-gabapentin cocrystals (yield: 75-90%).

[0115] Flurbiprofen-lysine-gabapentin cocrystals and ibuprofen-lysine-gabapentin cocrystals were synthesized according to the procedures described above and subjected to the following analyses. 2.XRPD analysis XRPD analysis was performed with the following instruments and conditions reported in Table 1 below.

[0116] [Table 1-1]

[0117] [Table 1-2]

[0118] The powder X-ray diffraction patterns of the flurbiprofen-lysine-gabapentin 1:1:1 and ibuprofen-lysine-gabapentin 1:1:1 cocrystals are reported in FIG. The XRPD peak listings for the co-crystals are reported in Tables 2 and 3 below.

[0119] [Table 2]

[0120] [Table 3]

[0121] The XRPD diffractograms of flurbiprofen-lysine-gabapentin and ibuprofen-lysine-gabapentin were very similar, with major peak reflections in the 9-10 degrees 2-theta, 15-25 degrees 2-theta, and 27-28 degrees 2-theta regions, respectively, with similar intensities (see Figure 1 and Tables 2 and 3). This similarity provided clear evidence of the isostructural nature of the cocrystals.

[0122] 3.Thermal analysis DSC analysis The analysis was carried out using the instrument DSC Mettler Toledo DSC1.

[0123] The samples were weighed into aluminum pans sealed with aluminum covers. The analysis was carried out by heating the samples from 25° C. to 320° C. at 10° K / min under the conditions shown in Table 3a below.

[0124] [Table 3a]

[0125] The analysis was performed on samples of flurbiprofen-lysine-gabapentin cocrystal (Figure 2) and ibuprofen-lysine-gabapentin (Figure 3). The DSC profile of flurbiprofen-lysine-gabapentin showed an endothermic event at 163.48 °C (onset 161.59 °C, delta H = 153.58 J / g) associated with sample melting and decomposition (Figure 2). The DSC profile of ibuprofen-lysine-gabapentin showed an endothermic event at 165.60 °C (onset 161.60 °C, delta H = 157.73 J / g), while above 120 °C multiple partially overlapping endothermic peaks were detectable for the decomposition step (Figure 3). Surprisingly, flurbiprofen-lysine-gabapentin and ibuprofen-lysine-gabapentin showed similar enthalpies of fusion (153.58 and 157.73 J / g), further supporting their isostructural packing. Furthermore, the lower melting endotherm of the cocrystal is expected to improve the solubility / dissolution profile of the native drug [(a) M K Mishra, P. Sanphui, U. Ramamurty and G R Desiraju, Cryst. Growth Des., 2014, 14, 3054-3061; (b) P. Sanphui, N R Goud, U B R Handavilli and A. Nangia, Cryst. Growth Des., 2011, 11, 4135-4145].

[0126] thermogravimetric analysisTGA The analysis was carried out using the instrument Mettler Toledo TGA / DSC1. The samples were weighed into aluminum pans sealed with aluminum perforated covers. The analysis was carried out by heating the samples from 25° C. to 320° C. at 10° / min under the conditions shown in Table 4 below.

[0127] [Table 4]

[0128] TGA analysis of the flurbiprofen-lysine-gabapentin cocrystal showed only a 1.686% weight loss before the melting point, confirming that the cocrystal was nearly free of solvent (Figure 4). TGA analysis of the ibuprofen-lysine-gabapentin cocrystal showed a loss of 8.007 wt %, confirming the loss of water of solvation (FIG. 5).

[0129] 4. FT-Raman and FT-IR FT-Raman Raman spectra were recorded on a Nicolet iS50 FT-IR spectrometer. The excitation source was a Nd-YAG laser (1064 nm) in the backscattering (180°) configuration. The diameter of the focused laser beam was approximately 50 mm and the spectral resolution was 4 cm. -1 The spectra were recorded with the laser power at the sample approximately 100 mW.

[0130] FT-IR The analysis was carried out using the instrument Thermo Nicolet iS50-ATR module spectrometer equipped with a Smart Performer Diamond, DTGS KBr detector, IR source, KBr beam splitter under the conditions shown in Table 5 below.

[0131] [Table 5]

[0132] The Raman spectra of the flurbiprofen-lysine-gabapentin and ibuprofen-lysine-gabapentin cocrystals are reported in FIGS. 6 and 7, and the peak listings are reported in Tables 6 and 7.

[0133] [Table 6]

[0134] [Table 7]

[0135] The FT-IR spectra of the flurbiprofen-lysine-gabapentin and ibuprofen-lysine-gabapentin cocrystals are shown in FIGS. 8 and 9, and the peak listings are reported in Tables 8 and 9.

[0136] [Table 8]

[0137] [Table 9]

[0138] Even in the Raman and FT-IR spectra, significant similarities within the cocrystals were observed, with some differences that could be due to the presence of different NSAIDs. All the spectra seemed to indicate that the two crystal systems were characterized by very similar local environments, especially for lysine and gabapentin, and showed comparable vibrational behavior.

[0139] 5. Liquid and Solid State NMR 1 H-nuclear magnetic resonance (NMR) spectra were recorded in the indicated solvents with tetramethylsilane (TMS) as internal standard on a Bruker Avance3 400 MHz instrument. Chemical shifts are reported in parts per million (ppm) relative to the internal standard. Abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, br = broad. Coupling constants (J values) are given in Hertz (Hz).

[0140] Solid state of the sample 13 The C CPMAS spectra are 1 H and 13 The data were obtained on a Jeol ECZR600 instrument operating at 600.17 and 150.91 MHz for the C nucleus. The powder samples were loaded into a cylindrical zirconium rotor with an od of 3.2 mm and a volume of 60 μl. Samples were collected from each batch and used without further preparation to load the rotor.13 C CPMAS spectrum was recorded using a 2.1 μs 90° 1 H pulses and a ramp cross-polarization pulse sequence with a contact time of 3.5 ms were used at room temperature at a spinning rate of 20 kHz. Optimal recycle delays of 5.7 to 100 s were used for the cocrystals, and 2200 to 20 for the number of scans. For each spectrum, a two-pulse phase-modulated (TPPM) decoupling scheme was used with a radio frequency field of 108.5 kHz. 13 The C chemical shift scale was calibrated through the methylene signal of external standard glycine (at 43.7 ppm). 13 C T1 1 For H analysis, 12 spectra were acquired for 350 scans with different relaxation delays, included in the range 0.1-60 s, and calculated by Delta v5.2.1 software through an exponential algorithm. 1 H pulses and a ramp cross-polarization pulse sequence with a contact time of 2 ms were used, acquired at room temperature and a spinning rate of 20 kHz.

[0141] Flurbiprofen-Lysine-Gabapentin 1 H-NMR spectrum Cocrystal 1 H-NMR spectra confirmed the coexistence in the samples of flurbiprofen-lysine-gabapentin with a 1:1:1 stoichiometry.

[0142] The signal multiplicities and assignments consistent with the atom numbering shown in Scheme 1 are reported in Table 10: Scheme 1. Chemical structure and atom numbering of flurbiprofen-lysine-gabapentin

[0143] [ka]

[0144] [Table 10]

[0145] Flurbiprofen-Lysine-Gabapentin Cocrystal 1 The H-NMR spectrum (400 MHz, DO) is shown in FIG. Ibuprofen-Lysine-Gabapentin 1 H-NMR spectrum Ibuprofen-Lysine-Gabapentin Cocrystal 1 H-NMR spectra confirmed the coexistence in the sample of ibuprofen-lysine-gabapentin with 1:1:1 stoichiometry.

[0146] The signal multiplicities and assignments consistent with the atom numbering shown in Scheme 2 are reported in Table 11: Scheme 2. Chemical structure and atom numbering of ibuprofen-lysine-gabapentin

[0147] [ka]

[0148] [Table 11]

[0149] Ibuprofen-Lysine-Gabapentin Cocrystal 1 The H-NMR spectrum (400 MHz, DO) is shown in FIG. Solid state of the cocrystal flurbiprofen-lysine-gabapentin 13 C CPMAS spectrum The new homogeneous phase of flurbiprofen-lysine-gabapentin is 13 The stoichiometry was estimated to be 1:1:1, with one independent molecule of flurbiprofen, lysine, and gabapentin in the unit cell, as confirmed by C-CPMAS spectroscopy.

[0150] In Table 12 below, specific solid-state 13 C NMR signals are summarized.

[0151] [Table 12]

[0152] From the 13C SSNMR analysis, the carboxylic acid / carboxylate moieties of the material are involved in a variety of different interactions (Figures 12 and 13): · Pure flurbiprofen (FLU) exhibits a carboxylic acid homodimer in its crystal structure, resulting in a relevant signal at 183.4 ppm.

[0153] Flurbiprofen sodium salt (NaFLU, Figure 13) presents a reduced carboxylate peak at 183.9 ppm; In two flurbiprofen cocrystals reproduced from the literature (salicylamide, FLU·SALA and picolinamide, FLU·PICA), the neutral COOH moiety of flurbiprofen participates in hydrogen bonds with the aromatic N of the two amides. The corresponding signals resonate at 178.6 (FLU·SALA) and 177.8 (FLU·PICA) ppm, respectively.

[0154] Pure gabapentin (GAB) is a zwitterion containing a COO- moiety that resonates at 179.0 ppm; as the sodium salt (NaGAB), a neutral NH2 moiety is present in place of the NH3+ group, but still has a carboxylate group that resonates at 183.4 ppm.

[0155] ·Zwitterionic L-lysine (L-LYS) is characterized by a carboxylate signal at 176.7 ppm, whereas the double hydrochloride salt of DL-lysine (DL-LYS·2HCl) presents a neutral COOH group and its peak is reduced to 171.7 ppm.

[0156] The spectrum of flurbiprofen-lysine-gabapentin (FLU-LYS-GAB) features three distinct peaks in the carboxylic acid region at 181.3, 179.5 and 178.2 ppm. Considering the chemical shifts of the starting materials, it is reasonable to assume that they belong to flurbiprofen, gabapentin and lysine, respectively.

[0157] 15N CPMAS analysis was performed on the cocrystal as well as NaGAB, and a comparison of these spectra, along with those of L-LYS and GAB, are presented in Figures 14 and 15. Flurbiprofen-lysine-gabapentin exhibits three distinct 15N resonances at 37.6, 30.2 and 21.6 ppm, confirming the presence of single independent molecules of lysine (occupying two signals) and gabapentin (occupying one) in the unit cell. The chemical shifts suggest that in the cocrystal, the α-N and ε-N of lysine and the nitrogen of gabapentin are deprotonated (i.e., in the form of NH3+) (Figures 14 and 15).

[0158] Solid state of cocrystal ibuprofen-lysine-gabapentin 13 C CPMAS spectrum The new homogeneous phase of ibuprofen-lysine-gabapentin is 13 The stoichiometry was estimated to be 1:1:1, with one independent molecule of ibuprofen, lysine, and gabapentin in the unit cell. 13 C NMR signals are summarized.

[0159] [Table 13]

[0160] FIG. 16 shows the structure of ibuprofen-lysine-gabapentin cocrystals. 13 C CPMAS NMR spectrum is presented. Ibuprofen-Lysine-Gabapentin 13For C CPMAS NMR, two signals due to ibuprofen (IBU) appear at 182.8 and 181.3 ppm (Figure 17). The first chemical shift is very similar to that of pure ibuprofen (182.9 ppm), where the COOH moiety is involved in homodimer interactions, and to that of the carboxylate group of ibuprofen sodium salt (NaIBU) at 183.4 ppm. This suggests that it corresponds to a carboxylate moiety, as further indicated by the very low chemical shift of the neutral COOH of ibuprofen in cocrystal with L-proline (176.7 ppm). For the other three carboxylic acid signals, all considerations made for flurbiprofen-lysine-gabapentin apply here as well. The same can be true for the 15N CPMAS spectrum, presented in Figures 18 and 19.

[0161] The 13C CPMAS spectra of the cocrystals of flurbiprofen-lysine-gabapentin and ibuprofen-lysine-gabapentin are very similar as shown in Figure 20. Many of the signals of the two cocrystals (highlighted by dashed lines in Figure 20) coincide. A careful analysis of the signals indicates that all of the repeating signals in the aliphatic region (below 80 ppm) correspond to the aliphatic C nuclei of lysine and gabapentin. The most obvious differences concern the aromatic range (110-170 ppm), which makes sense since the two different NSAIDs contain aromatic carbons. Most notably, the same similarity can be observed in the carboxylic acid region, with the carboxylic acid signals of flurbiprofen-lysine-gabapentin also appearing for ibuprofen-lysine-gabapentin.

[0162] The same striking spectral similarity (highlighted by the dashed line) can be observed in the 15N CPMAS spectrum of the sample (Figure 21). From the 13C and 15N data, the local environment of the lysine and gabapentin fragments appears to be the same for the two crystal forms. In all cases, gabapentin is a zwitterion, while lysine is a normal COO - and α-NH3 +The ε-N of the lysine and the COOH group of the NSAID share a carboxylic acid proton.

[0163] The results strongly suggested the occurrence of proton transfer from the COOH moiety of flurbiprofen and ibuprofen, which transformed into a carboxylate moiety, to the ε-NH2 of lysine, which is the only possible acceptor.

[0164] In line with solid-state 13C and 15N NMR analyses, in the present cocrystals, the carboxyl groups of flurbiprofen and ibuprofen are deprotonated and protonated through ionic bonds to form neutral salts, forming lysine ε-NH3 + The lysine neutral salts of flurbiprofen and ibuprofen interact with gabapentin through non-ionic bonds forming stable co-crystals.

[0165] 6. In vivo research Inflammatory pain induced by intraplantar injection of carrageenan in rats Male Wistar rats (270–280 g) (Envigo, Italy) were housed 2–3 per cage under controlled lighting (12:12 h light:dark cycle; lights on at 6.00 h) and standard environmental conditions (room temperature 22 ± 1 °C, humidity 60 ± 10%) for at least 1 week before their use in the experiments. Rat food and tap water were made available ad libitum. The procedures were approved by the Animal Ethics Committee "Luigi Vanvitelli" of the University of Campania. Animal care complied with the regulations of the Italian Decree for the Protection of Laboratory Animals (DL116 / 92) and the European Commission Directive (ECL358 / 1 OJ, 18 / 12 / 86). All efforts were made to minimize animal suffering and the number of animals used.

[0166] A method for testing carrageenan-induced rat paw edema. Peripheral inflammatory pain was induced in the left hind paw of each animal by a single intraplantar injection of 1% λ-carrageenan (100 μl for each rat in 0.9% NaCl) (Sigma-Aldrich, St. Louis, MO) by using a 30G insulin syringe according to a previous study (Hajhashemi V et al. The role of central mechanisms in the anti-inflammatory effect of amitriptyline on carrageenan-induced paw edema in rats. Clinics (Sao Paulo), 2010). Vehicle or drugs were administered orally 1 h before carrageenan injection. Paw volumes were measured with a plethysmometer (Ugo Basile, Varese, Italy) before injection (0 h) and after injection of carrageenan at different time intervals (1, 3 and 5 h after carrageenan). Edema is expressed as the average increase in paw volume (ml) relative to the control animal group. The percentage inhibition of edema was calculated by the following equation: Inhibition of edema % = [(Vc-Vt) x 100-100 (where Vc is the edema volume of the control group and Vt is the edema volume of the treatment group.) After 5 hours, the animals were sacrificed with a lethal dose of urethane and the paws and stomach were dissected for morphological and biochemical evaluation.

[0167] mechanical allodynia Mechanical allodynia was assessed using the up-down method (Chaplan, SR et al., (1994) Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55-63). All animals were allowed to acclimate for approximately 30-45 min on an elevated mesh platform in an enclosure (Ugo Basile, Italy). A von Frey filament calibrated for rats (Stoelting, Wood Dale, IL, bending force ranging from 4 g to 100 g) was applied for 3-4 s to the mid-plantar surface of the hind paw (Nour Elhouda Saidi et al., Unilateral 6-Hydroxydopamine-Lesioned Rat as Relevant Model to Study the Pain Related to Parkinson's Disease, NEUROLOGY AND NEUROBIOLOGY (2019), ISSN 2613-7828). Thresholds were taken as the minimum force (g) that elicited scratching or licking of the stimulated hind paw. Animals were tested at baseline (0 h) before carrageenan injection and at 1, 3, and 5 h after carrageenan.

[0168] Experimental groups and drugs Vehicle 1 (torpac capsule filled with Avicel PH101, 1 cps) (n=4); Vehicle 2 (Ethanol / 0.9% saline, 1:19, 100ul) (n=4); Indomethacin in Vehicle 2 (10mg / Kg, 100ul) (n=8); Flurbiprofen (5mg / Kg, 1 cps) (n=8); Gabapentin (3.51mg / Kg, 1 cps) (n=8); Flur+Lys+Gaba mixture (11.50mg / Kg, 1 cps) (n=8); Flur / Lys / Gaba cocrystal (11.50mg / Kg, 1 cps) (n=8). The weight ratio of flurbiprofen, lysine and gabapentin in the Flur+Lys+Gaba mixture is 1:1:1.

[0169] Relative efficacy of a single oral dose of Flur / Lys / Gaba cocrystal and flurbiprofen alone on carrageenan-induced paw edema in rats A single dose of either vehicle (capsule or ethanol / 0.9% saline, ig) did not affect the increase in thickness of the rats' left paw induced by intraplantar carrageenan injection (4.71±0.17 mm, 3 hours after carrageenan) compared to the untreated contralateral paw. Notably, a time-dependent paw swelling was observed starting at 1 hour, with a peak of edema 5 hours after carrageenan injection (9.55±0.47 mm, p<0.0001; n=8) (Figure 22). A single dose of flurbiprofen (5 mg / Kg), administered 1 hour before carrageenan injection, significantly reduced the thickness of the rats' paws (6.5±0.28 mm, p=0.028, n=8, 5 hours after carrageenan) compared to the vehicle-treated group (Figure 22, Table 14), with a reduction in paw volume of -32.0% (Table 15).

[0170] Table 14 below reports the statistics of paw thickness in different groups of animals treated with vehicle, flurbiprofen alone, gabapentin, indomethacin, Flur+Lys+Gaba mixture or Flur / Lys / Gaba cocrystals after intraplantar injection of 1% carrageenan. Each time point represents the mean value ± SEM of 8 rats per group. P<0.05 was considered statistically significant and was calculated using two-way ANOVA followed by Tukey's post-hoc test.

[0171] °°°°p<0.0001 vs. contralateral side; * p<0.05, ** p<0.01 and *** p<0.001 vs. vehicle and # p<0.05 and ## p<0.01 vs. Gaba. In Table 14 below, "ns" stands for "not significant."

[0172] [Table 14]

[0173] [Table 15]

[0174] On the other hand, administration of Flur / Lys / Gaba (11.5 mg / Kg) cocrystals significantly reduced paw thickness (5.51 ± 0.42 mm 5 hours after carrageenan; p = 0.0003, n = 8) with a percentage inhibition of paw volume of -42.27% compared to vehicle-treated rats (Figure 22, Table 15). Similarly, indomethacin (10 mg / Kg, ig), used as the reference drug in this study, significantly reduced paw thickness at all observation time points (5.69 ± 0.27 mm 5 hours after carrageenan; p = 0.0002, n = 8) with a percentage decrease of paw volume of -40.45% compared to the vehicle-treated group (Figure 22, Table 15). Finally, gabapentin alone at 3.51 mg / Kg was only able to reduce paw swelling 5 hours after carrageenan injection (7.45±0.26 mm 5 hours after carrageenan; p=0.0284, n=8), with a percentage reduction in volume of -17.27% (Figure 22, Table 15). Two-way ANOVA analysis showed a significant effect of treatment (F6,49=57.48, P<0.0001), a significant effect of time (F3,147=45.10, P<0.0001), and a significant interaction of the factors time x treatment (F18,147=7.042, P<0.0001) was observed.

[0175] Relative efficacy of a single oral dose of Flur / Lys / Gaba cocrystals and flurbiprofen alone on mechanical allodynia in a carrageenan-induced paw edema model in rats In another set of experiments, single oral doses (ig) of flurbiprofen (5mg / Kg) and Flur / Lys / Gaba cocrystals (11.5mg / Kg, cps) were tested against indomethacin (10mg / kg), gabapentin (3.51mg / Kg) or vehicle (capsule or ethanol / 0.9% saline) on mechanical allodynia in carrageenan-injected animals. Specifically, analysis was performed at baseline (0), before intraplantar injection of carrageenan, and 1, 3 and 5 hours after carrageenan using manual Von Frey filaments. We observed that the mechanical withdrawal threshold was significantly decreased in the ipsilateral paw starting 1 hour after carrageenan and was maintained until the end of observation (5 hours) in vehicle-treated animals (8.25±1.61 g 3 hours after carrageenan, p<0.0001; n=8) compared to baseline (80±7.56 g, time 0) (FIG. 23). No changes were observed on the contralateral side of carrageenan injection (85±7.31 g 3 hours after carrageenan). A single oral administration of flurbiprofen showed a strong anti-inflammatory effect after carrageenan injection of the paw, but no significant anti-allodynic effect. Indeed, flurbiprofen failed to increase the paw withdrawal threshold in rats 3 hours after carrageenan injection (44.62±14.43 g, p=0.2802; n=8) compared to vehicle-injected animals (FIG. 23). Furthermore, animals treated with indomethacin (10 mg / Kg) showed no significant tendency to increase paw thresholds 3 hours after carrageenan (36 ± 7.21 g, p = 0.0567; n = 8). In contrast, Flur / Lys / Gaba cocrystals induced a reduction in mechanical allodynia from 1 hour after carrageenan injection until the end of the experiment, reaching a peak 3 hours after carrageenan injection (85.75 ± 9.86 g, p = 0.001; n = 8) compared to vehicle-injected animals (Figure 23). Finally, gabapentin (3.51 mg / Kg) administration showed a tendency to reduce mechanical allodynia, with a peak time 3 hours after carrageenan injection (66.5 ± 11 g, p = 0.0109; n = 8) (Figure 24).Two-way ANOVA analysis showed a significant effect of treatment (F6,49=22.13, P<0.0001), a significant effect of time (F3,147=39.29, P<0.0001) and a significant interaction of the factor time x treatment (F18,147=2.30, P=0.0035) was observed. Table 16 below shows the statistics of paw withdrawal threshold (g) in the different groups of animals. P<0.05 was considered statistically significant and was calculated using two-way ANOVA followed by Tukey's post-hoc test. p<0.0001 vs. contralateral. * p<0.05, ** p<0.01 and *** p<0.001 vs. vehicle and #p<0.05 and ##p<0.01 vs. Gaba.

[0176] In Table 16 reported below, "ns" stands for "not significant difference."

[0177] [Table 16]

[0178] 7. Determination of plasma exposure parameters of NSAIDs and gabapentin after oral administration as capsules in rats The aim of this study was to determine the pharmacological parameters of NSAIDs, particularly flurbiprofen and ibuprofen, and gabapentin in the NSAID-lysine-gabapentin cocrystal, in comparison with a physical mixture of the NSAID, lysine and gabapentin.

[0179] Male Sprague-Dawley rats (weight 310 g at time of procedure) were used in this study. The animals were originally supplied by Harlan, Italy. Upon receipt from the supplier, the animals were subjected to health examination and acceptance. The animals were housed in groups of three in cages appropriate for the species and were routinely kept in the following environment except for short periods when the experimental procedures dictated otherwise. The animals were allowed to acclimate to the local housing conditions for approximately 5 days.

[0180] Animals were housed in a single, exclusive air-conditioned space providing a minimum of 15 air changes / hour. Environmental controls were set to maintain temperature within the range of 22°C and relative humidity within the range of 50-60%, with an automatically controlled approximately 12-hour light and 12-hour dark cycle. Food (Mucedola Standard GLP diet) and water were available ad libitum during the study. All animals were weighed on the day of each treatment. Clinical signs were monitored at regular intervals throughout the study to assess any reactions to treatment. Each animal was uniquely identified with a color spray on its back prior to the experiment.

[0181] At the end of the study, the animals were sacrificed by exsanguination under anesthesia. The experiments were performed in accordance with the Italian law DLvo4 marzo 2014, n.26. The experimental protocol consisted of blood and brain tissue sampling in the animals according to Tables 17 and 18 below, and analysis of the samples as described below.

[0182] [Table 17]

[0183] [Table 18]

[0184] As shown in Table 18, following oral administration of flurbiprofen / lysine / gabapentin cocrystals and the physical mixture of flurbiprofen, lysine and gabapentin, Flur+Lys+Gaba, given via one capsule / animal, the systemic exposure parameters of gabapentin were higher, reaching statistical significance (t-test=0.017).

[0185] For flurbiprofen, Cmax was higher for the cocrystal compared to the mixture, the difference reaching statistical significance (t-test = 0.023). Therefore, a higher Cmax of the co-crystal compared to the mixture represents an improved pharmacokinetic profile that can lead to better pharmacological efficacy.

Claims

1. A co-crystal of a non-steroidal anti-inflammatory drug (NSAID) belonging to the class of phenylpropionic acid or phenylacetic acid, lysine and gabapentin, provided that the non-steroidal anti-inflammatory drug is not ketoprofen, the co-crystal.

2. The co-crystal according to claim 1, wherein the molar ratio of the components of the co-crystal is 1:1:

1.

3. The co-crystal according to any one of claims 1 or 2, wherein the non-steroidal anti-inflammatory drug belonging to the class of phenylpropionic acid derivatives is selected from ibuprofen, flurbiprofen, fenoprofen, indoprofen, loxoprofen, perbiprofen, and naproxen.

4. The co-crystal according to any one of claims 1 or 2, wherein the non-steroidal anti-inflammatory drug belonging to the class of phenylacetic acid derivatives is selected from diclofenac, felbinac, ibufenac, fenclofenac, tiflurac, and ketorolac.

5. The co-crystal according to any one of claims 1 or 2, wherein the non-steroidal anti-inflammatory drug is selected from flurbiprofen and ibuprofen.

6. The co-crystal according to any one of claims 1 or 2, characterized by having the most intense XRD diffraction peaks in the regions of 9-10 degrees 2-theta, 15-25 degrees 2-theta, and 27-28 degrees 2-theta.

7. The co-crystal according to any one of claims 1 or 2, characterized by the following common XRD diffraction peaks: 9.3, 17.1, 18.5, 19.8, 22.1, 24.1, 24.9, 27.9 degrees 2-theta ± 0.4 degrees 2-theta.

8. The co-crystal according to claim 1 or 2, wherein the NSAID is flurbiprofen, characterized by the following XRD diffraction peaks: 9.3, 10.4, 15.2, 16.0, 17.2, 18.3, 18.8, 19.7, 20.7, 21.9, 24.0, 24.8, 27.9, and 29.0 degrees 2-theta ± 0.2 degrees 2-theta, and preferably further characterized by the following XRD diffraction peaks: 6.9, 10.9, 12.2, 25.5, 26.3, 29.8, 31.5, 33.0, 34.0, 35.9, 37.5, 39.2, and 40.8 degrees 2-theta ± 0.2 degrees 2-theta.

9. The following: The DSC thermogram reported in Figure 2, characterized by a melting peak at 163.48 °C ± 0.5 °C. The TGA thermogram reported in FIG. 4, the FT Raman and FT-IR spectra of FIGS. 6 and 8, The solution of FIG. 10 １ the H-NMR spectrum and the signals in Table 10 Solid state of FIG. 12 １３ 13C CP / MAS spectrum and signals of Table 12, and / or 15N CP / MAS spectrum of FIG. 14 The cocrystal according to claim 8, further characterized by one or more of

10. The NSAID is ibuprofen, characterized by the following XRPD diffraction peaks: 9.5, 10.3, 15.9, 17.1, 17.6, 18.7, 20.0, 22.3, 24.1, 25.1, 25.6, 27.9 and 28.6 degrees 2-theta ± 0.2 degrees 2-theta, preferably further characterized by the following XRPD diffraction peaks: 6.9, 12.0, 14.7, 26.3, 30.6, 31.1, 32.3, 33.1, 34.5, 35.3, 36.6, 38.6, 39.0, 41.1, and 48.9 degrees 2-theta ± 0.2 degrees 2-theta, The cocrystal according to claim 1 or 2.

11. The following: The DSC thermogram reported in FIG. 3, characterized by a melting peak at 165.60 ° C. ± 0.5 ° C., The TGA thermogram reported in FIG. 5, the FT Raman and FT-IR spectra of FIGS. 7 and 9, The solution of FIG. 11 １ the H-NMR spectrum and the signals in Table 11 Solid state of FIG. 16 １３ C CP / MAS spectrum and signals in Table 13, and / or 15N CP / MAS spectrum of FIG. 18 The cocrystal according to claim 10, further characterized by one or more of

12. The cocrystal according to any one of claims 1 or 2, wherein the lysine is (S,R)-lysine.

13. A pharmaceutical composition comprising the cocrystal according to any one of claims 1 or 2 and at least one pharmaceutically acceptable excipient.

14. The pharmaceutical composition according to claim 13 for use as a medicament.

15. The pharmaceutical composition according to claim 13 for use in the prevention, alleviation or treatment of pain and / or inflammation, preferably acute or chronic pain.

16. The pain is neuropathic or inflammatory pain, selected from headache, toothache, menstrual pain, muscle pain, neuropathic pain, pain associated with neuroinflammation, diabetic neuropathy, cancer pain, osteoarthritis, low back pain, sciatica, fibromyalgia, trigeminal neuralgia, postoperative and post-operative pain, post-herpetic neuralgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, phantom limb pain or HIV pain, The pharmaceutical composition for use according to claim 15.

17. A method for the preparation of the cocrystal according to any one of claims 1 or 2, comprising a) suspending a non-steroidal anti-inflammatory drug (NSAID) belonging to the class of phenylpropionic acid or phenylacetic acid, lysine, and gabapentin in a suitable solvent; b) dissolving the NSAID, lysine, and gabapentin by heating the suspension optionally with stirring until a clear solution is obtained; c) optionally cooling the solution; and / or d) optionally adding a poor solvent to provide an NSAID, lysine, and gabapentin co-crystal A method comprising the steps of. **Claim 18** The method according to claim 17, wherein the solvent used in step a) is selected from water, alcohol, preferably methanol and ethanol, ester, preferably ethyl acetate, ether, preferably tetrahydrofuran and tert-butyl methyl ether, and aromatic solvent, preferably toluene. **Claim 19** The pharmaceutical composition according to claim 13 for use in the treatment of pain and / or inflammation.

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