Synergistic admixture of gabapentin and ketoprofen, pharmaceutical composition and medical use thereof

Abstract

The present invention relates to a synergistic admixture of gabapentin and ketoprofen (preferably lysine ketoprofen), a pharmaceutical composition comprising the admixture, and the use of the admixture or pharmaceutical composition in the treatment of acute or chronic pain, particularly in the treatment of neuropathic or inflammatory pain.

Description

Technical Field

[0001] The present invention relates to a synergistic admixture of gabapentin and ketoprofen (preferably lysine ketoprofen), a pharmaceutical composition comprising the admixture, and the use of the admixture or pharmaceutical composition in the treatment of acute or chronic pain, particularly in the treatment of neuropathic or inflammatory pain. Background Art

[0002] Pain is a sensory and emotional experience usually caused by actual or potential tissue damage.

[0003] Pain conditions can be divided into acute and chronic.

[0004] Acute pain is pain that is of short duration (generally less than 3 months) and is usually associated with tissue injury, inflammation, surgical procedures, childbirth, or a transient disease process.

[0005] Chronic pain is considered to be pain that persists beyond normal healing time and therefore lacks the acute warning function of physiological pain sensation. Pain is usually classified as chronic when it persists or recurs for more than 3 months.

[0006] Chronic pain can have different etiologies, including neuropathic pain, chronic inflammatory pain (eg, arthritis), or pain of unknown origin (eg, fibromyalgia and restless legs syndrome).

[0007] Chronic neuropathic pain results from damage or disease to the somatosensory nervous system, which provides information about the body, including the skin, musculoskeletal, and internal organs. Many diseases or pathological conditions can lead to damage to sensory neurons, causing hyperalgesia or allodynia, such as low back pain, sciatica, postoperative pain, cancer pain, phantom limb pain, HIV pain, diabetic neuropathy pain, herpes zoster pain, or trigeminal neuralgia.

[0008] Chronic inflammatory pain is associated with intense inflammation of infectious, autoimmune, or metabolic etiology (such as rheumatoid arthritis) and structural changes affecting bones, joints, tendons, or muscles (such as osteoarthrosis).

[0009] Treatment for this type of pain often includes the use of nonsteroidal anti-inflammatory drugs, acetaminophen, and other disease-modifying agents.

[0010] Due to its complex etiology, the pharmacological treatment of neuropathic pain differs from that of non-neuropathic pain. Guidelines recommend the use of serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, anticonvulsants, or topical lidocaine as first- and second-line treatments for neuropathic pain, and opioids are generally recommended as second- or third-line therapies (Deng et al., BMC Anesthesiology (2016) 16:12). Acetaminophen and nonsteroidal anti-inflammatory drugs are largely ineffective for neuropathic pain.

[0011] Neuroinflammation is a physiological / pathological condition characterized by the infiltration of immune cells, activation of glial cells, and production of inflammatory mediators in the peripheral and central nervous systems.

[0012] Recent progress shows that the occurrence of neuroinflammation in the peripheral nervous system (PNS) and the central nervous system (CNS) is the cause of chronic pain caused by the sensitization of pain neurons and the maintenance of pain. Neuroinflammation occurs in the PNS (i.e., peripheral nerves and ganglia) and the CNS (i.e., spinal cord and brain), and is characterized by the increase in the infiltration of leukocytes and the production of inflammatory mediators at these positions. The transportation of different types of leukocytes occurs in the PNS and CNS, with different time data archives. Neuroinflammation is manifested as the activation of glial cells (such as Schwann cells in nerves, satellite glial cells and microglia in ganglia, and astrocytes and oligodendrocytes in spinal cord and brain). The activation of glial cells causes the production of glial mediators that can regulate pain sensitivity.

[0013] Neuroinflammation is a localized form of inflammation, which means it is more effective than systemic inflammation in causing and maintaining pain, but it is difficult to detect clinically. For example, fibromyalgia, a chronic muscle pain condition, was previously considered an atypical pain condition because no overt pathology and inflammation could be detected in affected patients. However, a recent study found neuropathy of small nerve fibers in fibromyalgia patients, which may be a consequence of chronic neuroinflammation as well as a cause. Neuroinflammation appears permanent in chronic pain patients, but also occurs in non-chronic conditions such as post-surgical pain.

[0014] The lack of efficacy of currently available therapies in treating neuroinflammatory disorders requires the discovery of new specific and safe drugs for treating the unmet medical needs associated with acute or chronic neuroinflammatory processes (Ru-Rong Jil Nat. Rev. Drug Discov. 2014 Jul;13(7):533-548).

[0015] Gabapentin is an anticonvulsant synthetic analog of the neurotransmitter gamma-aminobutyric acid (GABA) having the following formula (I):

[0016]

[0017] Although its exact mechanism of action is unknown, gabapentin appears to inhibit excitatory neuronal activity. The molecule was originally developed as a chemical analog of gamma-aminobutyric acid to reduce spinal reflexes to treat spasticity, but it was found to be inactive on the GABAergic system. Its mechanism of action involves binding to calcium channels in several areas of the central nervous system and spinal cord where they are expressed. Calcium channels are localized to presynaptic terminals where they control the release of neurotransmitters.

[0018] In 1993, gabapentin was approved for adjunctive treatment of partial epileptic seizures in adults and children. More recently, gabapentin has also been approved for the treatment of chronic pain, particularly neuropathic pain syndromes. It is also claimed to be beneficial for several other clinical conditions, such as anxiety, bipolar disorder, and hot flashes. High doses of gabapentin have also been shown to be effective in the treatment of fibromyalgia (Moore et al., Cochrane Database Syst Rev. 2014 Apr 27;(4):CD007938; Deng et al., BMC Anesthesiology (2016) 16:12).

[0019] However, many studies have shown that when gabapentin is used alone in pain treatment, the pharmacological and pharmacokinetic data profile is unsatisfactory, for example in terms of lack of efficacy, side effects or delayed response to specific types of pain. In fact, gabapentin is slowly absorbed after oral administration, with the highest level in plasma within 3-4 hours (Quintero, Journal of Experimental Pharmacology 2017: 9 13-21).

[0020] Gabapentin plasma levels do not increase proportionally if the dose is increased, so careful titration on an individual basis is required at the start of treatment; gabapentin does not bind to plasma proteins.

[0021] Gabapentin is neither inhibited nor metabolized by liver enzymes; in addition, gabapentin can be excreted by the renal system with an excretion half-life of approximately 6 hours. The most common side effects of gabapentin are drowsiness (20%), dizziness (18%), ataxia (13%), and fatigue (11%).

[0022] Because of the short half-life of gabapentin, its oral dose is administered three times a day (tds). Rapid titration can be achieved using the following doses: 300 mg once a day on the first day (usually at bedtime to minimize sedation), followed by 300 mg twice a day on the second day, and 300 mg three times a day on the third day. If efficacy is not achieved at this dose, the dose can be further increased.

[0023] The recommended starting dose for the treatment of neuropathic pain is 300 mg three times a day, titrated if necessary to a maximum of 3600 mg / day, but

[0024] Doses as high as 4200 mg have been reported when limited or no efficacy was observed (MARose, Anaesthesia, 2002, 57, pp. 451-462).

[0025] For example, gabapentin is not recommended for the treatment of low back pain because it has shown little efficacy and is associated with an increased risk of side effects (Low back pain and sciatica in over 16s: assessment and management, National Institute for Health and Care Excellence NICE Guidelines 2016).

[0026] Furthermore, gabapentin has little activity against inflammatory pain, which was also confirmed in the carrageenan inflammatory rat model in this experimental section.

[0027] It has also been shown that the therapeutic effect of gabapentin in the treatment of osteoarthritis only begins after 3 months of long-term administration (Enteshari-Moghaddam et al., Clinical Rheumatology 2019:38, 2873-2880).

[0028] Applicants have conducted studies with the goal of increasing the activity of gabapentin against painful conditions, extending efficacy to other pain syndromes, and potentially reducing dose-related side effects.

[0029] In particular, Applicants investigated the combination of gabapentin with ketoprofen, in particular with ketoprofen lysine.

[0030] Ketoprofen ((RS)-2-(3-benzoylphenyl)-propionic acid) is a well-established nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties and has the formula II

[0031]

[0032] Due to its high tolerability, ketoprofen is one of the most widely used nonsteroidal anti-inflammatory drugs in clinical practice, both for the treatment of severe inflammatory conditions and for analgesia and antipyretics by inhibiting the body's production of prostaglandins, prostacyclins, and thromboxanes.

[0033] Ketoprofen is commonly prescribed for inflammatory pain associated with arthritis, severe dental pain, treatment of musculoskeletal pain, neuropathic pain (eg, sciatica), postherpetic neuralgia, and referred pain from radiculopathy.

[0034] The ketoprofen pharmaceutical composition currently in use contains a racemate as an active ingredient, in which two enantiomers S(+) and R(-) are present in an equimolecular ratio.

[0035] Ketoprofen pharmaceutical compositions currently available for oral use contain the active ingredient as the free acid, which exhibits very low solubility in water and therefore low bioavailability.

[0036] In order to improve the dissolution and bioavailability of the active ingredient, salts of ketoprofen are also advantageously used. These salts are used, for example, for the treatment of rheumatoid and chronic pathological symptoms (needing large doses, continuous and prolonged administration of the drug) by oral administration, and for pain manifestations requiring an immediate analgesic effect.

[0037] In particular, the salts of ketoprofen with lysine, in particular with the natural amino acid L-lysine, while presenting a parallel pharmaceutical data profile and similar anti-inflammatory-analgesic efficacy, offer the following advantages compared to the free acid: a much higher solubility in water allowing rapid and almost complete absorption of the compound to ensure rapid onset of action, and greater gastric tolerance.

[0038] As described in European patent applications Nos. EP18215336.1, PCT / EP2019 / 025464 and EP19219293.8, ketoprofen and lysine can be combined to form salts or co-crystals in different crystalline forms (polymorphs) depending on the process conditions. Summary of the invention

[0039] Applicants have unexpectedly discovered in these investigations that admixtures of gabapentin and ketoprofen, preferably in the form of ketoprofen lysine salt or co-crystals, exhibit surprising biological effects.

[0040] In this regard, Applicants have observed a synergistic effect on inflammation and pain when gabapentin is combined with ketoprofen.

[0041] Furthermore, the combination of gabapentin and ketoprofen prolonged the duration of the effect on inflammation and pain.

[0042] Finally, administration of gabapentin in combination with ketoprofen increased the brain penetration of gabapentin compared with gabapentin alone.

[0043] The greater efficacy, increased brain penetration and duration of the combination could allow for lower therapeutic doses of gabapentin, less frequent administration, and thus fewer side effects and overall improved patient compliance.

[0044] Therefore, a first object of the present invention is a blend of gabapentin and ketoprofen, wherein the ketoprofen is preferably lysine ketoprofen.

[0045] A further object of the present invention is the admixture according to the invention for use as a medicament, preferably for use in preventing, reducing or treating pain and / or inflammation.

[0046] A further object of the present invention is a pharmaceutical composition comprising the admixture according to the invention and at least one pharmaceutically acceptable excipient.

[0047] A further object of the present invention is the pharmaceutical composition according to the invention, which further comprises at least one further pharmaceutically active ingredient.

[0048] A further object of the present invention is a kit comprising gabapentin and ketoprofen, preferably lysine ketoprofen.

[0049] A further object of the present invention is a method for treating pain and / or inflammation, which comprises administering to a patient simultaneously, separately or sequentially an effective amount of gabapentin and ketoprofen, preferably lysine ketoprofen.

[0050] definition

[0051] For the purpose of the present invention, the term "pharmaceutically acceptable excipient" refers to a substance that does not have any pharmacological effect by itself and does not produce adverse reactions when administered to mammals, preferably humans.

[0052] For the purposes of the present invention, the term "admixture" refers to a physical admixture or mixture of at least two ingredients, which can be produced, for example, by simple dry blending. A physical admixture does not consist of a complex or co-crystal that may be obtained from the ingredients under conditions other than dry blending (e.g., by co-crystallization, wet blending, or co-grinding). The ingredients of the admixture are not within a single crystal at the molecular level.

[0053] For the purposes of the present invention, the term "ketoprofen lysine" refers to both ketoprofen lysine salt and co-crystals of ketoprofen and lysine, the co-crystals being any polymorph or solvated form, preferably co-crystals as described in European Patent Application Nos. EP18215336.1, PCT / EP2019 / 025464 and EP19219293.8.

[0054] For the purposes of the present invention, the term "ketoprofen lysine co-crystal Form I" refers to the co-crystals described in EP18215336.1 and PCT / EP2019 / 025464.

[0055] For the purposes of the present invention, the term "ketoprofen lysine co-crystal Form IV" refers to the co-crystal described in EP19219293.8.

[0056] For the purposes of the present invention, the term "ketoprofen lysine salt" refers to the salt of ketoprofen with lysine.

[0057] For the purposes of the present invention, the term "room temperature" refers to a temperature range of 18 to 25°C.

[0058] For the purposes of the present invention, the term "co-crystal" refers to a multi-component system in which all components are solid when present in their pure form under ambient conditions. The components coexist within a single crystal at the molecular level. At least some of the components are linked by non-covalent, non-ionic interactions.

[0059] For the purposes of the present invention, the term "pain" refers to pain caused by disturbances of different nature and origin, for example: headache or headache: primary (and therefore independent of other factors or diseases) and secondary (therefore dependent on trauma, injury and obvious diseases); toothache: in the case of abscesses or caries, pain arises in the pulp of the tooth, which has many blood vessels and nerves; menstrual pain: abdominal and lower abdominal pain and headache caused by hormonal changes typical during menstruation; neuralgia, or intense nerve pain caused by strains, trauma and infection; muscle pain, or myalgia: pain located at the level of the muscle when the muscle is used or touched, due to sudden contraction or trauma; bone and joint pain, such as inflammation of the joints (to bones, cartilage, ligaments and tendons) after trauma, old age, strains and injuries.

[0060] For purposes of the present invention, the term "inflammation" refers to the organism's localized response to cellular injury, characterized by capillary dilation, leukocyte infiltration, redness, heat and pain, and serves as a mechanism to initiate elimination of noxious agents and damaged tissue.

[0061] The terms "about" and "approximately" herein refer to the range of experimental errors that may occur in the measurements. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 : 1:1 admixture of ketoprofen lysine cocrystal Form I and gabapentin 1 H-NMR spectrum (400 MHz, D 2 O).

[0063] Figure 2 : DSC thermogram of ketoprofen lysine cocrystal Form I.

[0064] Figure 3 : DSC thermogram of gabapentin.

[0065] Figure 4: Paw volume (ml) versus time (hours) after intraplantar injection of 1% carrageenan, administration of vehicle, 1:1 admixture of ketoprofen lysine cocrystal Form I and gabapentin (KL Co-xx-GAB MIX), ketoprofen lysine cocrystal Form I (KL Co-xx), or gabapentin (GAB) in the carrageenan-induced rat paw edema model. P < 0.05 was considered statistically significant, calculated using two-way ANOVA with Bonferroni post hoc test. * Compared to vehicle, $ Compared to gabapentin, ° Compared to KL Co-xx.

[0066] Figure 5 : Bar graph of % inhibition of paw volume induced by vehicle, 1:1 admixture of ketoprofen lysine cocrystal Form I and gabapentin (KL Co-xx-GAB MIX), ketoprofen lysine cocrystal Form I (KL Co-xx), gabapentin (GAB) at 3, 4 and 5 hours after carrageenan injection in the carrageenan-induced rat paw edema model. In the figure, the % inhibition value of vehicle is zero. P < 0.05 was considered statistically significant and was calculated using two-way ANOVA and Bonferroni post hoc test. * Compared to vehicle, $ Compared to gabapentin, ° Compared to KL Co-xx.

[0067] Fig. 6A and Figure 6B : Shows that compared with vehicle (rice starch), two different doses ( Fig. 6A and Figure 6B ) of ketoprofen lysine cocrystal Form I (KL Co-xx), 1:1 admixture of ketoprofen lysine cocrystal Form I and gabapentin (KL Co-xx-GAB MIX), or gabapentin (GAB) at 1, 3, and 6 hours after administration on mechanical allodynia, measured as 50% withdrawal threshold (g). All values ​​represent the mean ± SEM of each group. One-way ANOVA and Dunnett's test were used to compare between vehicle control group and compound treatment group. Differences were considered significant at the level of P < 0.05: * compared to vehicle, ° compared to KL Co-xx, $ compared to gabapentin.

[0068] Figure 7 : Bar graph of brain penetration (brain / plasma %) of gabapentin alone (gabapentin) or as a 1 :1 admixture with ketoprofen lysine cocrystal Form I (KL Co-xx-GAB MIX) when gabapentin was administered orally.

[0069] Explanation of symbols in the figure: GAB gabapentin; KL lysine ketoprofen; Co-xx cocrystal; MIX admixture; KLCo-xx ketoprofen lysine cocrystal; KL-GAB Co-xx ketoprofen lysine gabapentin cocrystal; KL Co-xx-GABMIX admixture of ketoprofen lysine cocrystal and gabapentin. DETAILED DESCRIPTION

[0070] An object of the present invention is a blend of gabapentin and ketoprofen, preferably a blend of gabapentin and lysine ketoprofen.

[0071] Preferably, the molar ratio of the components of the admixture is between 100:1 and 1:100, between 50:1 and 1:50, more preferably between 20:1 and 1:20, even more preferably between 10:1 and 1:10, still more preferably between 5:1 and 1:5, and most preferably between 2:1 and 1:2. In a preferred embodiment, the molar ratio in the admixture is about 1:1.

[0072] The 1:1 admixture of the present invention is characterized by Figure 1 of 1 H-NMR and relative assignments in Table 2.

[0073] In the admixtures of the present invention, the gabapentin may be in any crystalline form.

[0074] In the admixtures of the present invention, gabapentin may be used in a neutral form (zwitterionic inner salt) or in any acidic or basic salted form, such as gabapentin hydrochloride or gabapentin sodium salt.

[0075] Preferably, the neutral form of gabapentin is used.

[0076] Gabapentin may be in any polymorphic form.

[0077] In the admixture of the present invention, ketoprofen may be used as a free acid, as a salt with a pharmaceutically acceptable base, or as a co-crystal.

[0078] Examples of ketoprofen salts are ketoprofen sodium, ketoprofen tromethamine or ketoprofen salts with basic amino acids such as lysine.

[0079] In the admixture of the present invention, the ketoprofen may be racemic (S,R)-ketoprofen, (S)-ketoprofen or (R)-ketoprofen or any admixture thereof.

[0080] In one embodiment, the ketoprofen is (S)-ketoprofen (also known as dexketoprofen).

[0081] Preferably, in the admixture of the present invention, the ketoprofen is lysine ketoprofen.

[0082] In the admixture of the present invention, the ketoprofen lysine may be any crystal form of ketoprofen lysine salt, ketoprofen lysine co-crystal, or a mixture thereof.

[0083] In one embodiment, the ketoprofen lysine is a ketoprofen lysine co-crystal, preferably ketoprofen lysine co-crystal Form I or ketoprofen lysine co-crystal Form IV.

[0084] In one embodiment, the ketoprofen lysine is ketoprofen lysine salt.

[0085] Ketoprofen lysine salt can be prepared as described, for example, in GB1497044A and BE882889.

[0086] Ketoprofen lysine cocrystal Form I can be prepared as described, for example, in European Patent Application Nos. EP18215336.1 and PCT / EP2019 / 025464.

[0087] Ketoprofen lysine co-crystal Form IV can be prepared as described, for example, in European patent application EP19219293.8.

[0088] The components of the admixtures of the present invention may be in unsolvated form as well as in solvated form (including hydrated form). Preferably, they are in unsolvated form.

[0089] In the admixture lysine ketoprofen of the present invention, lysine may be racemic (S,R)-lysine, (S)-lysine or (R)-lysine, or any admixture thereof, preferably the natural amino acid (S)-lysine (also known as L-lysine).

[0090] In one embodiment, the ketoprofen is in the (S) configuration.

[0091] In another embodiment, the ketoprofen is in the racemic configuration.

[0092] In one embodiment, the lysine is in the (S) configuration.

[0093] In one embodiment, the admixture of the present invention comprises (S)-ketoprofen and / or (S)-lysine.

[0094] As will be described in the experimental section below, the admixture of the present invention shows improved efficacy in painful conditions compared to gabapentin or ketoprofen alone. The two active ingredients act synergistically, resulting in a higher and longer-lasting analgesic effect than when used alone.

[0095] Based on the above, the daily dose of each active ingredient in the mixture according to the present invention may be lower than the daily dose of the active ingredient usually employed when not used in combination.

[0096] Therefore, a further object of the present invention is the admixture according to the invention for use as a medicament.

[0097] The medical use of the admixtures of the present invention may be therapeutic, prophylactic or palliative.

[0098] Preferably, the admixture according to the present invention is used for the prevention, reduction or treatment of pain and / or inflammation.

[0099] The admixtures of the present invention are preferably used for use in the treatment of pain, preferably acute or chronic pain.

[0100] Preferably, the pain is selected from the group consisting of headache, toothache, menstrual pain, muscle pain, neuropathic pain, diabetic neuropathy, cancer pain, osteoarthritis, low back pain, sciatica, fibromyalgia, trigeminal neuralgia; postoperative and postoperative pain, postherpetic neuralgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, phantom limb pain or HIV pain.

[0101] Preferably, the admixtures of the present invention are administered orally.

[0102] The combination of the two active ingredients in the admixture of the invention presents several advantages for the medical use of the invention.

[0103] As noted above, gabapentin and ketoprofen are complementary to each other particularly in the treatment of pain, but may also be complementary to each other in the treatment of a variety of other diseases or conditions.

[0104] Another advantage is that the combination of the two active ingredients in the admixture allows for better pharmacokinetics / pharmacodynamics (PKPD), including better penetration of the blood-brain barrier, which is of great help in the treatment of pain.

[0105] As shown in the pain and inflammation prediction test of the present invention, the admixture of the present invention shows synergistic activity of the active ingredients gabapentin and ketoprofen.

[0106] This unexpected synergistic effect may provide enhanced clinical efficacy, or reduce the required dosage of each compound, resulting in fewer side effects, while maintaining or enhancing the clinical effectiveness of the compounds and treatments, compared to the individual components of the admixture administered alone.

[0107] For example, patients may experience an improved reduction in the frequency and severity of pain and / or inflammation. In addition, patients may benefit from the longer duration of action of the admixture treatment compared to treatment with gabapentin or ketoprofen or lysine ketoprofen alone.

[0108] Preferably, the daily dosage of the admixture according to the invention for humans is: an amount of ketoprofen calculated in the form of the acid is between 25 and 200 mg, preferably between 50 and 150 mg, more preferably 50 mg, and an amount of gabapentin is between 5 and 500 mg, preferably between 100 and 300 mg, more preferably 300 mg, 1 to 8 times a day, preferably 1 to 4 times a day.

[0109] It is not only necessary for a skilled person (such as a physician or veterinarian) to determine the preferred route of administration and the corresponding dosage form and amount, but said skilled person must also determine the dosage regimen.

[0110] The daily dose for humans and animals may differ depending on factors having their basis in the respective species or other factors (eg age, sex, weight or degree of disease, etc.).

[0111] A further object of the present invention is a pharmaceutical composition comprising the admixture of gabapentin and ketoprofen as defined above and at least one pharmaceutically acceptable excipient.

[0112] Preferably, the pharmaceutical composition is used for treating pain (preferably acute or chronic pain and inflammation, preferably neuroinflammation).

[0113] Preferably, the pain is selected from the group consisting of headache, toothache, menstrual pain, muscle pain, neuropathic pain, diabetic neuropathy, pain associated with neuroinflammation, cancer pain, osteoarthritis, low back pain, sciatica, fibromyalgia, trigeminal neuralgia; postoperative and postoperative pain, postherpetic neuralgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, phantom limb pain or HIV pain.

[0114] For example, a composition according to the invention may contain 0.5-60% by weight of an admixture as defined herein and 40-99.5% by weight of one or more pharmaceutically acceptable excipients.

[0115] The choice of excipient will to a large extent depend on factors such as the particular mode of administration, its effect on solubility and stability, and the nature of the dosage form.

[0116] The pharmaceutical composition 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.Preferably, the pharmaceutical composition according to the invention is administered orally.

[0117] The pharmaceutical composition of the present invention is preferably for oral administration, preferably an oral solid composition or a liquid composition.

[0118] Preferably, the solid composition is a capsule, a pill, a tablet, a cachet, a chewable dosage form, a lozenge, a granule, a suspension, an emulsion, a spray, a powder.

[0119] The powder is preferably suitable for reconstitution with a liquid medium.

[0120] When the pharmaceutical composition is a powder, it can be prepared, for example, by dry mixing the powders of the individual active ingredients in a conventional mixer, such as a fixed shell mixer (e.g., an impeller mixer, a ribbon or a screw mixer) or a rotating shell mixer (e.g., a drum, cross-flow, double cone and double shell) under conditions and times within the skill of the art.

[0121] Preferably, the oral solid composition of the present invention comprises per dosage form an amount of ketoprofen calculated in acid form of between 25 and 200 mg, preferably between 50 and 150 mg, more preferably 50 mg, and / or an amount of gabapentin per dosage form of between 50 and 500 mg, preferably between 100 and 300 mg, more preferably 300 mg.

[0122] The pharmaceutical composition may additionally contain one or more pharmaceutically acceptable excipients, such as fillers, binders, glidants, disintegrants, flow regulators and release agents.

[0123] Suitable excipients are disclosed, for example, in “Handbook of Pharmaceutical Excipients”, 3rd edition, published by AH Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London.

[0124] Suitable fillers include, for example, lactose (monohydrate, spray dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dihydrate, and dibasic calcium phosphate.

[0125] The amount of filler may be 0-80% by weight, preferably 10-60% by weight, based on the total weight of the composition.

[0126] Suitable binders are, for example, polyvinylpyrrolidone, microcrystalline cellulose hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sugars, dextran, corn starch, gelatin, polyethylene glycol, natural and synthetic gums, pregelatinized starch.

[0127] The amount of the binder may be 0-80 wt %, preferably 10-60 wt %, based on the total weight of the composition.

[0128] Binders are generally used to impart cohesiveness to tablet formulations.

[0129] Suitable glidants are, for example, alkaline earth metal salts of fatty acids (eg, stearic acid), such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate.

[0130] The amount of the glidant may be 0-2 wt%, preferably 0.5-1.5 wt%, based on the total weight of the composition.

[0131] Suitable disintegrants include, for example, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, crosslinked polyvinyl pyrrolidone (crospovidone), sodium carboxymethyl glycolate, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, sodium alginate and sodium bicarbonate.

[0132] The amount of the disintegrant may be 0-20 wt%, preferably 1-15 wt%, based on the total weight of the composition.

[0133] Suitable flow regulators are, for example, colloidal silicon dioxide. The amount of flow regulator may be 0-8 wt%, preferably 0.1-3 wt%, based on the total weight of the composition.

[0134] Suitable release agents include, for example, talc. The amount of the release agent may be 0-5% by weight, preferably 0.5-3% by weight, based on the total weight of the composition.

[0135] The solid composition may be coated, preferably film-coated.

[0136] Suitable coating agents are, for example, cellulose derivatives, poly(meth)acrylates, polyvinyl pyrrolidone, polyvinyl acetate phthalate, and / or shellac or natural rubber (eg carrageenan).

[0137] In many cases it will be advantageous or even necessary to deliver the admixtures of the invention in solid form, for example by installation of a solid implant composition into an appropriate body tissue or cavity.

[0138] The implant may comprise a matrix of biocompatible and bioplastic material in which particles of the admixture of the invention are dispersed, or possibly droplets or separate chambers of a liquid mixture of the admixture of the invention are trapped. Desirably, the matrix will be broken down and completely absorbed by the body. The composition of the matrix is ​​also preferably selected to provide controlled release, sustained release and / or delayed release of the admixture of the invention over an extended period of time.

[0139] Alternatively, the admixtures of the invention may be formulated as a solid, semisolid, or thixotropic liquid and administered as an implanted depot to provide modified release of the active compound.

[0140] The compositions of the invention may be administered topically to the skin or mucosa, ie, dermally, epidermally, sub-epidermally or transdermally.

[0141] The compositions of the present invention may be administered sublingually or by suppository.

[0142] Typical formulations for this purpose include pour-on, spot-on, dip, spray, mousse, shampoo, powder formulations, gel, hydrogel, lotion, cream, ointment, dusting powder, dressing, foam, film, skin patch, wafer, implant, reservoir, sponge, fiber, bandage, microemulsion, orodispersible granules. Liposomes may also be used.

[0143] The pharmaceutical composition of the present invention may be a solid composition for the extemporaneous preparation of a solution for oral or parenteral administration (eg to be administered by intramuscular, intraperitoneal or intravenous injection).

[0144] The pharmaceutical composition of the present invention can be prepared by methods well known to those skilled in the art.

[0145] The compositions of the invention may be of the immediate release, delayed release, modified release, sustained release, pulsed release or controlled release type.

[0146] According to a further embodiment, the pharmaceutical composition of the present invention may comprise the admixture of the present invention and at least one other pharmaceutically active ingredient.

[0147] The additional pharmaceutically active ingredient will be determined by the circumstances under which the therapeutic agent of the invention is to be administered.

[0148] A further object of the invention is a kit comprising gabapentin and ketoprofen lysine.

[0149] Preferably, in the kit of the present invention, the molar ratio of gabapentin to lysine ketoprofen is between 100:1 and 1:100 or 50:1 and 1:50, preferably between 20:1 and 1:20, more preferably between 10:1 and 1:10, still more preferably between 5:1 and 1:5, most preferably between 2:1 and 1:2.

[0150] In a preferred embodiment, the molar ratio in the kit is about 1:1.

[0151] A further object of the present invention is a method for treating pain and / or inflammation, which comprises administering to a patient simultaneously, separately or sequentially an effective amount of gabapentin and ketoprofen, preferably lysine ketoprofen.

[0152] Experimental Section

[0153] The following describes the manufacture, analytical characterization, and biological characterization of the blend of gabapentin and ketoprofen of the present invention.

[0154] 1. Preparation of admixtures of gabapentin and ketoprofen lysine cocrystal Form I

[0155] The mixture was prepared by dry mixing Ketoprofen Lysine Cocrystal Form I (prepared as described in European Patent Application Nos. EP18215336.1 and PCT / EP2019 / 025464) and Gabapentin (from Spectrum) in a 1:1 molar ratio in a powder mixer supplied by Cavicchi SpA.

[0156] 2. Thermal analysis

[0157] DSC analysis

[0158] The analysis was performed using a DSC Mettler Toledo DSC1 instrument.

[0159] The sample was weighed in an aluminum pan sealed with an aluminum lid. The analysis was performed by heating the sample from 25°C to 320°C at 10 K / min under the conditions shown in Table 1 below:

[0160] Table 1

[0161]

[0162]

[0163] Ketoprofen lysine cocrystal form I ( Figure 2 ) and gabapentin ( Figure 3 ) samples were analyzed.

[0164] 3. NMR analysis

[0165] The results were recorded on a Bruker Avance3 400 MHz instrument with tetramethylsilane (TMS) as internal standard in the indicated solvents. 1 H-NMR spectroscopy. Chemical shifts are reported in parts per million (ppm) relative to an internal standard. Abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, br = broad. The unit of coupling constants (J values) is Hertz (Hz).

[0166] Admixture of Ketoprofen Lysine Cocrystal Form I and Gabapentin 1 H-NMR spectroscopy

[0167] Admixture of Ketoprofen Lysine Cocrystal Form I and Gabapentin 1H-NMR spectroscopy confirmed that ketoprofen lysine cocrystal Form I and gabapentin were present in the sample at a molar ratio of 1:1.

[0168] The multiples and attributions of the signals are reported in Table 2 below:

[0169] Table 2: 1 H-NMR

[0170] δppm multiple Attribution 7.76-7.78 m,2H Ar KET 7.68-7.72 m,2H Ar KET 7.60-7.63 m,2H Ar KET 7.47-7.57 m,3H Ar KET 3.70 t,J=6.4Hz,1H CH-LYS 3.69 Quartet, J = 7.2 Hz, 1H CH-KET 2.98 t,J=7.6Hz,2H <![CDATA[CH 2 -LIGHT]]> 2.96 s,2H <![CDATA[CH 2 -GAB]]> 2.38 s,2H <![CDATA[CH 2 -GAB]]> 1.79-1.92 m,2H <![CDATA[CH 2 -LIGHT]]> 1.68 Quintet, J = 7.6 Hz, 2H <![CDATA[CH 2 -LIGHT]]> 1.40 d,J=7.2Hz,3H <![CDATA[CH 3 -AND]]> 1.29-1.52 m,12H <![CDATA[5CH 2 -GAB;CH 2 -LYS]]>

[0171] Ketoprofen lysine cocrystal form I and gabapentin admixture 1 H-NMR spectrum (400 MHz, D 2 O) is shown in Figure 1 middle.

[0172] 4. In vivo study of inflammatory pain induced by intraplantar injection of carrageenan in rats

[0173] 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 06.00 h) and standard environmental conditions (room temperature 22 ± 1 °C, humidity 60 ± 10%) for at least 1 week before experimental use. Rat chow and tap water were freely available. The experimental procedures were approved by the Animal Ethics Committee of the University of Campania “Luigi Vanvitelli”. Animal care complied with the provisions of the Italian legislative decree (DL 116 / 92) and the European Commission Directive (OJ of ECL 358 / 1, 18 / 12 / 86) on the protection of experimental animals. Every effort was made to minimize animal suffering and the number of animals used.

[0174] Peripheral inflammatory pain was induced by a single intraplantar injection of 1% λ-carrageenan (100 μl per rat in 0.9% sodium chloride) in the left hind paw of each animal.

[0175] 1h before injection of carrageenan, vehicle (2 capsules filled with Avicel PH101), ketoprofen lysine cocrystal form I (47.1mg / kg, 1 capsule), gabapentin (20.4mg / kg, 2 capsules) and 1:1 admixture of gabapentin and ketoprofen lysine cocrystal form I (47.1mg / kg+20.4mg / kg, 2 capsules) were orally administered. The paw volume of the animals was measured by an organ plethometer (Ugo Basile, Varese, Italy) before injection of carrageenan (0h) and at different time intervals after injection of carrageenan (1, 2, 3, 4, 5 and 6h after carrageenan). Edema was expressed as the average increase (ml) in paw volume relative to control animals. The percentage of edema inhibition was calculated by the following equation:

[0176] Edema inhibition % = (Vc-Vt / Vc) × 100,

[0177] Where Vc is the edema volume of the control group, and Vt is the edema volume of the treated group.

[0178] The results of the above tests are shown in Figure 4 and Figure 5 .

[0179] exist Figure 4 The time course of the anti-inflammatory effect of a 1:1 blend of gabapentin and ketoprofen lysine cocrystal Form I compared to ketoprofen lysine cocrystal Form I, gabapentin and vehicle on paw swelling (paw volume in ml) in rats following intraplantar injection of 1% carrageenan is reported in .

[0180] exist Figure 5 A bar graph of the % inhibition of paw volume by a 1:1 blend of gabapentin and ketoprofen lysine cocrystal Form I compared to ketoprofen lysine cocrystal Form I, gabapentin and vehicle at 3, 4 and 5 hours after carrageenan injection is reported in FIG.

[0181] exist Figure 4 and Figure 5 In the graphs, each time point or bar represents the mean ± SEM of 6 rats per vehicle and 8 rats per drug. P < 0.05 was considered statistically significant and was calculated using two-way ANOVA and Bonferroni post hoc test. Legend of symbols: * compared to vehicle, $ compared to gabapentin, ° compared to ketoprofen lysine cocrystal.

[0182] from Figure 4 and Figure 5 It was shown that ketoprofen lysine cocrystal form I attenuated carrageenan-induced edema, whereas gabapentin was less effective.

[0183] In addition, if Figure 4 The rat paw edema curve and Figure 5 As can be appreciated, the result is that the anti-inflammatory effect of the 1:1 blend of ketoprofen lysine cocrystal Form I and gabapentin of the present invention is not only higher than the sum of the effects of the individual actives gabapentin and ketoprofen lysine cocrystal Form I, but even more unexpectedly, it lasts much longer. This trend indicates that the duration of the therapeutic effect is prolonged, longer than the duration of the therapeutic effect of each active administered alone.

[0184] Nerve ligation-induced neuropathic pain

[0185] Test substances were provided by Dompé Farmaceutici SpA, gabapentin was purchased from Spectrum (Cat# G1092), and rice starch for the vehicle control group was obtained from Sigma (Cat# S7260).

[0186] pass Gabapentin alone, ketoprofen lysine co-crystal Form I alone, or a 1:1 blend of gabapentin and ketoprofen lysine co-crystal Form I of the present invention were orally administered in size 9 gelatin capsules. Based on the recommended dose, 1-3 capsules were given per rat.

[0187] Male Sprague Dawley rats weighing 180 ± 20 g were provided by BioLasco, Taiwan, China (under the permission of Charles River Laboratories). The space allocation for 2-3 animals was 45 × 25 × 21 cm. All animals were kept in a temperature (20-24 ° C) and humidity (30%-70%) controlled environment with a light / dark cycle of 12 h. Free access to standard laboratory diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved water were allowed. All aspects of this work (including feeding, experiments and animal disposal) were carried out in our AAALAC-accredited experimental animal facility in accordance with the "Guide for the Care and Use of Laboratory Animals: Eighth Edition" (National Academies Press, Washington, DC, 2011). In addition, the animal care and use program was reviewed and approved by the IACUC of Pharmacology Discovery Services China Taiwan, Ltd.

[0188] On day 0, the left sciatic nerve was exposed at the level of the mid-thigh under sodium pentobarbital [50 mg / kg, intraperitoneal (IP)] anesthesia. Four chromic gut sutures were tied loosely around the nerve, approximately 1 millimeter (mm) apart. The animals were then socially housed in cages with soft bedding for 13 days before assessing mechanical allodynia.

[0189] Rats were placed on a wire mesh rack in an inverted Plexiglas cage and allowed to acclimate for 20 to 30 minutes. Mechanical touch-evoked pain thresholds were assessed by manual Von Frey testing using the Chaplan up / down method. Animals were given 20-30 minutes to acclimate to the wire mesh racks in each compartment prior to behavioral testing. The paw was touched with a series of 8 manual von Frey fibers [3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1.0 g), 4.31 (2.0 g), 4.56 (4.0 g), 4.74 (6.0 g), 4.93 (8.0 g), and 5.18 (15.0 g)] of increasing stiffness logarithmically. The manual Von Frey fiber was applied vertically to the mid-plantar surface from below the mesh bottom with sufficient force to cause slight deformation of the paw and maintained for approximately 6-8 seconds. A positive response was scored if the paw was withdrawn sharply; walking was considered a vague response, in which case the stimulus was reapplied. Mechanical thresholds [50% withdrawal threshold (g)] were assessed using the up / down method according to the procedure described by Chaplan (1994).

[0190] The resulting positive and negative response patterns were tabulated using the following convention: X = retracted; O = not retracted, and the 50% response threshold was interpolated using the following formula:

[0191] Mechanical threshold = (10[Xf+kδ]) / 10000,

[0192] Where Xf = the value of the last von Frey filament used (in logarithmic units);

[0193] k = the tabulated value for the positive / negative response pattern; and

[0194] δ = mean difference between stimuli (in log units) (here 0.224).

[0195] Mechanical allodynia was assessed in all rats to obtain the preoperative allodynia threshold on day -1 (preoperative baseline). Rats were preselected for the experiment only if the pain threshold on day 13 after nerve ligation (pre-treatment) was reduced by 10 g of force relative to the response of a single paw before nerve ligation (pre-surgery), i.e., the presence of allodynia was evident. Rats were randomly assigned to balanced treatment groups based on pre-drug mechanical allodynia scores. Compounds were administered orally (PO) in size 9 gelatin capsules or the recommended formulation. Mechanical allodynia was assessed again on day 14 after surgery, 1, 3, and 6 hours after administration of the test article, vehicle, or reference compound.

[0196] The results are shown in Fig. 6A and Figure 6B middle.

[0197] In particular, Fig. 6AData from the following groups are shown: Ketoprofen lysine cocrystal Form I (KL Co-xx) [15.7 mg / kg, PO via capsule], 1:1 blend of ketoprofen lysine cocrystal Form I and gabapentin (KL Co-xx-GAB MIX) [15.7+6.8 mg / kg, PO via capsule], gabapentin [6.8 mg / kg, PO via capsule], and vehicle [rice starch, PO via capsule].

[0198] Figure 6B Data from the following groups are shown: Ketoprofen lysine cocrystal Form I (KL Co-xx) [47.1 mg / kg, PO via capsule], 1:1 blend of Ketoprofen lysine cocrystal Form I and gabapentin (KL Co-xx-GAB MIX) [47.1+20.4 mg / kg, PO via capsule], gabapentin [20.4 mg / kg, PO via capsule], and vehicle [rice starch, PO via capsule].

[0199] All values ​​represent the mean ± standard error of the mean (SEM) of each group. One-way ANOVA and Dunnett's test were used to compare between vehicle control group and compound-treated group. The level of P < 0.05 was considered significant. Statistical analysis was performed by GraphPad Prism 5.0. Symbol description: * compared with vehicle, $ compared with gabapentin, ° compared with ketoprofen lysine cocrystal.

[0200] from Fig. 6A and 6B The results showed that administration of the admixture of the present invention (KL Co-xx-GAB MIX) significantly reduced the number of ipsilateral paw withdrawals compared to Ketoprofen Lysine Cocrystal Form I and Gabapentin alone. Statistically significant analgesic effects were observed at 1, 3, and 6 hours after administration using the admixture of the present invention (Ketoprofen Lysine Cocrystal Form I and Gabapentin 47.1+20.4 mg / kg).

[0201] Gabapentin and a 1:1 admixture of gabapentin and ketoprofen lysine cocrystal Form I administered as capsules in rats Determination of plasma and brain levels after oral administration

[0202] The aim of this study was to determine the brain penetration of a physical mixture of gabapentin and ketoprofen lysine cocrystal Form I after administration in capsules to rats compared to gabapentin alone.

[0203] Sprague Dawley male rats (weight 310 g at the time of treatment) were used in this study. The animals were originally supplied by Harlan, Italy. Upon receipt from the supplier, the animals were immediately subjected to a health check and received. The animals were housed in groups of three in cages appropriate for the species and were routinely housed in the following environment, except for short periods when the experimental procedures required otherwise. The animals were acclimated to local housing conditions for approximately 5 days.

[0204] Animals were housed in a single dedicated room with air conditioning providing a minimum of 15 air changes per hour. Environmental control was set to maintain the temperature within the range of 22°C, relative humidity within the range of 50-60%, and automatically controlled cycles of approximately 12 hours of light and 12 hours of darkness. Throughout the study, food (Mucedola standard GLP diet) and water were freely available. All animals were weighed on the day of each treatment. Throughout the study, clinical signs were regularly monitored to assess any reaction to the treatment. Before the experiment, each animal was uniquely identified using a color spray on the back.

[0205] At the end of the study, the animals were sacrificed by exsanguination under anesthesia.

[0206] The experiments were conducted in accordance with Italian law DLvo 4marzo 2014, n.26.

[0207] The experimental protocol involved sampling blood and brain tissue from the animals according to Tables 3 and 4 below, and analyzing the samples as described below.

[0208] Table 3: Blood sampling

[0209] Animal / time point 4 / 1 time point Time 2h Fasting requirements Not required Collection site Animals will be bled from the tail vein Collection tube Lithium heparin anticoagulant Target HP 70μL Sample identification Label display: study number, animal ID, test project ID, sampling time Sample Request Store on ice and centrifuge at +4°C for 10 minutes at 3000 g Final sample storage conditions -20℃ until bioanalysis

[0210] Table 4: Brain tissue sampling

[0211] Animal / time point 4 / 1 time point Time 2hr Fasting requirements Not required Sample processing Brains were washed in saline, dried, weighed and placed in tubes. Sample identification Label display: study number, animal ID, test project ID, sampling time Sample Request Store on ice and centrifuge at +4°C for 10 minutes at 3000 g Final sample storage conditions -20℃ until bioanalysis

[0212] Prepare 1 mg / mL stock solutions of Ketoprofen Lysine Cocrystal Form I and Gabapentin in MeOH, and prepare a mixed stock solution by diluting the two aforementioned stock solutions to achieve a final concentration of 100 μg / mL for each analyte. Prepare 2 mg / mL and 1 mg / mL stock solutions of DF1681Y and Gabapentin Impurity A in MeOH, respectively. Prepare a mixture of both in ACN to a final concentration of 5000 and 500 ng / mL, respectively (mixed IS).

[0213] Calibration curves and QC samples were prepared in rat blank plasma by spiking 2 μL of each stock solution in 18 μL plasma. Spiked plasma samples were added to 200 μL of mixed IS and centrifuged at 9000 g for 5 min at 5 °C. Samples from the oral treatment group were prepared at a 1:10 dilution in blank plasma, and 20 μL of diluted plasma was processed as described above. 100 μL of extracted samples were then diluted in 120 μL of mobile phase A.

[0214] The collected brain was homogenized in ammonium formate 10 mM buffer, 1 g / 5 mL. Samples, as well as calibrators and QC samples, were prepared by adding 20 μL of brain homogenate to 200 μL of mixed IS and centrifuged at 9000 g for 5 min at 5°C. 100 μL of the extracted sample was then diluted in 120 μL of mobile phase A.

[0215] Gabapentin levels in rat plasma were measured after administration of two individual gabapentin capsules and a 1:1 admixture capsule of ketoprofen lysine cocrystal Form I and gabapentin as a physical mixture. The percentage ratio of gabapentin concentrations in brain to plasma is reported as Figure 7 middle.

[0216] Gabapentin brain and plasma concentrations were assessed 2 hours later and showed that gabapentin had a brain / plasma penetration of 37.8% when administered alone and 58.8% when administered as an admixture with ketoprofen lysine cocrystal Form I ( Figure 7 ). Interestingly, administration of a blend of gabapentin and ketoprofen lysine cocrystal Form I increased the brain penetration of gabapentin compared to administration of gabapentin alone.

Claims

1. A blend of gabapentin and ketoprofen, wherein the ketoprofen is a co-crystal of ketoprofen and lysine.

2. The admixture according to claim 1, wherein the molar ratio of the components is between 100:1 and 1:

100.

3. The admixture according to claim 1 or 2, wherein the ketoprofen is (S)-ketoprofen.

4. The admixture of claim 1 or 2, wherein the lysine is (S)-lysine.

5. Use of the admixture according to claim 1 in the preparation of a medicament for preventing, reducing or treating pain and / or inflammation.

6. The use according to claim 5, wherein the pain is acute or chronic pain.

7. The use according to claim 6, wherein the pain is selected from the group consisting of: dental pain, menstrual pain, muscle pain, neuropathic pain, cancer pain, low back pain, fibromyalgia, phantom limb pain or HIV pain.

8. The use according to claim 6, wherein the pain is selected from the group consisting of pain associated with neuroinflammation, postoperative pain, post-herpetic neuralgia, sciatica and trigeminal neuralgia.

9. The use according to claim 6, wherein the pain is selected from the group consisting of pain caused by diabetic neuropathy, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and frozen shoulder.

10. The use according to claim 6, wherein the pain is headache.

11. The use according to claim 5, wherein the admixture is administered orally.

12. A pharmaceutical composition comprising the admixture according to any one of claims 1 to 4 and at least one pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12, comprising 0.5-60 wt% of the admixture and 40-99.5 wt% of one or more pharmaceutically acceptable excipients.

14. The pharmaceutical composition according to claim 12 or 13, which is an oral solid composition or a liquid composition.

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