Use of cocrystals of tramadol and celecoxib to treat pain while reducing the abuse liability of tramadol

Abstract

The present invention relates to the use of a co-crystal of tramadol and celecoxib to treat pain with preventing the risk of dependence on tramadol, to treat pain with a reduced abuse liability of tramadol, to treat pain with a reduced incidence of dependence on tramadol, to treat pain with preventing dependence on tramadol, to treat pain in patients with or at risk of dependence on tramadol, to treat pain with inhibiting, delaying, reducing or halting dependence on tramadol, or to treat pain with a reduced incidence of dependence on tramadol.

Description

[Technical Field]

[0001] The present invention relates to the use of a co-crystal of tramadol and celecoxib to treat pain with preventing the risk of dependence on tramadol, to treat pain with a reduced abuse liability of tramadol and a reduced incidence of dependence on tramadol, to treat pain with preventing dependence on tramadol, to treat pain in patients with or at risk of dependence on tramadol, to treat pain while preventing, delaying, reducing or halting dependence on tramadol, or to treat pain with a reduced incidence of dependence on tramadol. [Background technology]

[0002] Pain is a complex response that has been functionally classified into sensory, autonomic, motor, and emotional components. The adaptive component is thought to be the activation of endogenous pain modulation and motor planning of escape responses, while the sensory aspect includes information about the location and intensity of the stimulus. The emotional component is thought to include appraisals of the unpleasantness and threat of the pain, as well as negative emotions evoked by memories and situations of painful stimuli.

[0003] In general, pain conditions can be classified as chronic or acute. Chronic pain includes neuropathic pain and chronic inflammatory pain, such as arthritis or pain of unknown origin (e.g., fibromyalgia). Acute pain usually occurs following non-neural tissue injury, such as tissue damage or inflammation due to surgery, or migraine.

[0004] Recently, cocrystals of tramadol and celecoxib have been discovered for use in the treatment of pain. Examples of such cocrystals are published in WO 2011 / 044962 and are highly useful in the treatment of pain, particularly chronic and acute moderate to severe pain.

[0005] Tramadol is a centrally acting analgesic with two distinct synergistic mechanisms of action. It is a weak opioid agonist selective for the μ receptor and a reuptake inhibitor of noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT). Its analgesic potency is said to be approximately one-tenth that of morphine. Tramadol is used to treat both moderate to (moderately) severe acute and chronic pain. Tramadol is considered a relatively safe analgesic and is widely used.

[0006] The main side effects of tramadol treatment, especially in the early stages of treatment, are nausea, dizziness, and vomiting. At therapeutic doses, tramadol does not cause clinically relevant respiratory depression. However, tramadol is contraindicated in patients with impaired respiratory function. Tramadol is generally considered a medication with a lower addictive potential compared to morphine. However, evidence suggests that tramadol dependence can develop with prolonged use (7 weeks to several months or more). Dependence on tramadol can occur within the recommended dosage range, particularly at or above maximum doses. Dependence occurs at doses above maximum and, rarely, at therapeutic doses. Symptoms of tramadol toxicity are similar to those of other opioid analgesics but may include serotonergic and noradrenergic components. Symptoms include central nervous system (CNS) depression and coma, tachycardia, cardiovascular collapse, seizures, and respiratory depression leading to respiratory arrest. Fatal poisoning is rare and appears to be associated with large tramadol overdoses.

[0007] According to the U.S. Drug Enforcement Administration (DEA), drugs, substances, and specific chemicals used to create drugs are classified into five different classifications or schedules depending on the drug's acceptable use and its potential for abuse or dependence. Abuse rates are a determining factor in drug scheduling; for example, Schedule I drugs have a high risk of abuse and can produce severe psychological and / or physical dependence. As drugs move down the schedule, down to Schedule II, Schedule III, etc., their abuse potential also changes, with Schedule V drugs representing the least potential for abuse. Lists of drugs and their schedules are listed alphabetically in the Controlled Substances Act (CSA) Schedules or CSA Schedules. These lists include basic or parent chemicals; their salts, isomers, and isomeric salts, esters, ethers, and derivatives are also classified as controlled substances, although they are not necessarily listed. These lists are intended as a general guide and are not a comprehensive list of all controlled substances.

[0008] Tramadol is a Schedule IV listed drug with low abuse potential and low risk of dependence.

[0009] According to the FDA's official definition, drugs with abuse potential generally include drugs that act on the central nervous system, producing euphoria (and other mood changes), hallucinations, and effects comparable to those of central nervous system depressants or stimulants. Therefore, if a drug acts on the CNS, any new drug product containing that drug must undergo a thorough evaluation for abuse potential and is subject to regulation (in the United States, the Controlled Substances Act (CAS) (see 21 U.S.C. 811)). Drug abuse is defined as the intentional, nontherapeutic use of a drug or drug product, even if only once, to achieve a desired psychological or physiological effect. Abuse potential, therefore, refers to the risk that a particular CNS-active drug or drug product may be abused. Drug abuse is a serious public health problem that affects nearly every community and home in some way. Each year, drug abuse causes millions of serious illnesses or injuries to Americans. Drugs of abuse include methamphetamines, anabolic steroids, club drugs, cocaine, heroin, inhalants, marijuana, and prescription drugs, including opioids. Drug abuse also contributes to many important societal problems, such as drug-induced driving, violence, and stress. Various types of treatments exist to treat drug abuse, one of which is to reduce the abuse potential of drugs by altering their pharmacokinetics.

[0010] The World Health Organization (WHO) defines drug dependence as the repeated use of drugs despite the knowledge and experience of adverse effects. Drug dependence is a chronic, relapsing disorder characterized by a lack of control over drug use, compulsive drug-seeking and craving, continued use despite adverse effects, and a physiological and / or psychological dependence on the drug. Drug abuse and drug dependence are public health problems.

[0011] On the other hand, opioid drugs such as tramadol are essential in the clinical management of pain syndromes.

[0012] Therefore, there is a continuing and urgent need to find alternative or improved pharmacological agents that are effective in treating pain while reducing the potential for drug abuse. This certainly applies to tramadol, which is widely used as a relatively safe analgesic. Summary of the Invention [Problem to be solved by the invention]

[0013] While investigating the potential of E-58425 in treating pain, applicants emphasized that it may help reduce the abuse liability of tramadol by modifying its pharmacokinetics.

[0014] The present invention thus relates to reducing the abuse liability of tramadol by administering a cocrystal of tramadol HCl and celecoxib. Accordingly, an important aspect of this application relates to a cocrystal of (rac) tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain while reducing the abuse liability of tramadol.

[0015] It has surprisingly been found that cocrystals of tramadol and celecoxib, such as cocrystal E-58425, treat pain while reducing abuse liability based on altered pharmacokinetic profiles compared to tramadol alone or compared to the combination of tramadol and celecoxib.

[0016] Abuse potential for opioids is typically measured using validated measures of subjective pharmacodynamic (PD) effects (e.g., drug preference, drug-induced high) as well as peak plasma concentrations (C max ) and T max C expressed as maxThe opioid abuse rate is assessed using selected pharmacokinetic properties of the opioid, such as the time to reach a certain level of pain (Harris et al., Pain Medicine; 18: 1278-1291 (2017) and Kopecky et al.; The Journal of Clinical Pharmacology, 57(4) 500-512 (2017)). From a pharmacokinetic perspective, this literature includes a C index called the Abuse Quotient (AQ) for opioids. max / T max It has been reported that there is a high correlation between the ratio and pharmacodynamic effect, with higher AQ indicating greater abuse potential.

[0017] In this context, Harris et al. evaluated the oral abuse potential and pharmacokinetics of intact, chewed, or finely ground hydrocodone compared with hydrocodone solution or placebo. The results of the pharmacokinetic analysis were calculated using the formula C max / T max These results indicate that the rate of hydrocodone absorption, expressed as a pharmacodynamic measure of abuse potential, decreased along with the rate of increase in plasma opioid concentrations (C max / T max ) is positively correlated with the likelihood of abuse.

[0018] Kopecky et al. reported that the abuse index is a measure of the relationship between administration and T max The study states that the mean rate of increase in plasma concentration between doses is the degree of increase in plasma concentration between doses, and that this value is thought to be related to the drug's abuse potential.

[0019] Harriet de Wit et al. (Psychopharmacology; 107: 352-358 (1992)) note that certain pharmacokinetic properties of drugs are thought to explain differences in the abuse liability of drugs. One of these properties is the rate at which the drug is delivered to the central nervous system. The abuse liability of various drugs within the same class is thought to vary depending on this property, and various routes of administration are thought to be associated with different abuse liability for similar reasons.

[0020] "Abuse liability" is defined as the tendency of a drug to produce compulsive use and to produce dependence, or the dependence potential of a drug. This term is used interchangeably with "dependence potential."

[0021] "Abuse potential" or "potential for abuse" refers to the likelihood that abuse will occur for a particular drug or agent that has central nervous system activity.

[0022] "Abuse" is defined as the intentional, non-therapeutic use of a drug, even if only once, to obtain a desired psychological or physiological effect; that is, using a drug in an unintended or unrecommended manner. Abuse can lead to dependence.

[0023] "(Drug) dependence" is defined as compulsive drug use despite harmful consequences, characterized by an inability to stop using the drug.

[0024] Therefore, C max The large T max There seems to be a high tendency for abuse of drugs with small size. max / T max AQ is therefore a determinant of how addictive a drug is, with a lower AQ indicating a lower tendency to abuse.

[0025] Surprisingly, it was found that cocrystal E-58425 exhibited a better (lower) AQ ratio compared to tramadol alone or compared to the combination of tramadol and celecoxib (administered as marketed pharmaceuticals), leading to the conclusion that cocrystal E-58425 treats pain with reduced abuse liability compared to tramadol alone or compared to the combination of tramadol and celecoxib.

[0026] In a first main aspect A), the present application relates to a co-crystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain while reducing the abuse liability of tramadol.

[0027] The present application therefore relates in its main aspect A) to a method for treating pain while reducing the abuse liability of tramadol, said method comprising administering to a subject a therapeutically effective amount of a co-crystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof.

[0028] For purposes of this application, "treating pain while reducing the abuse liability of tramadol" is defined as treating a patient suffering from pain to improve their condition by administering a therapeutically effective amount of a cocrystal while simultaneously reducing the potential for abuse of tramadol. In this context, "prevent" is understood to mean reducing the risk of developing dependence when using the cocrystal compared to the risk when using tramadol alone or in combination with celecoxib to provide at least equivalent pain treatment efficacy.

[0029] In a further aspect B), the present application also relates to a co-crystal of (rac)-tramadol HCl with celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain while reducing the dependence on tramadol.

[0030] The present application therefore also relates in this aspect B) to a method for treating pain while preventing tramadol dependence, said method comprising administering to a subject a therapeutically effective amount of a cocrystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof.

[0031] In this application, "preventing tramadol dependence and treating pain" is defined as treating a patient suffering from pain and improving symptoms by administering a therapeutically effective amount of a cocrystal while simultaneously preventing dependence on tramadol. In this context, "prevent" is understood to mean that the risk of developing dependence when using the cocrystal is lower than the risk when using tramadol alone or in combination with celecoxib to achieve at least the same pain treatment effect.

[0032] In a further aspect C), the present application also relates to a co-crystal of (rac)-tramadol HCl with celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain and / or simultaneously preventing the risk of dependence on tramadol.

[0033] The present application therefore relates in this aspect C) to a method for treating pain and / or simultaneously preventing the risk of dependence on tramadol, said method comprising administering to a subject a therapeutically effective amount of a cocrystal of (rac)-tramadol HCl and celecoxib or a pharmaceutically acceptable derivative thereof.

[0034] In this application, "treating pain and / or simultaneously preventing the risk of dependence on tramadol" is defined as treating a patient suffering from pain and improving symptoms by preventing (or reducing) the development of dependence on tramadol upon administration of a therapeutically effective amount of the cocrystal. In this context, "preventing (or reducing)" is understood to mean lowering the risk of developing dependence when using the cocrystal compared to the risk when using tramadol alone or in combination with celecoxib to achieve at least the same pain treatment effect.

[0035] In a further aspect D), the present application also relates to a co-crystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain in patients who are or are at risk of becoming dependent on tramadol.

[0036] The application therefore also relates in this aspect D) to a method for treating pain in a patient who is or is at risk of becoming dependent on tramadol, comprising administering to the subject a therapeutically effective amount of a cocrystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof. The application therefore also relates in this aspect D) to a method for treating pain in a patient who is dependent on tramadol, comprising administering to the subject a therapeutically effective amount of a cocrystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof, or to a method for treating pain in a patient who is at risk of becoming dependent on tramadol, comprising administering to the subject a therapeutically effective amount of a cocrystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof.

[0037] In this application, "treating pain in a patient who is or is at risk of becoming dependent on tramadol" is defined as treating a patient who is suffering from pain and who is (or is at risk of becoming dependent on) tramadol by administering a therapeutically effective amount of the cocrystal to improve the symptoms. According to the WHO, dependence is defined as the repeated use of a drug despite the awareness and experience of adverse effects. Therefore, this effect and implication can also be understood to mean that the risk of developing (or worsening / severing) dependence when using the cocrystal is reduced compared to the risk when using tramadol alone or a combination of tramadol and celecoxib with at least the same pain treatment effect.

[0038] In a further aspect E), the present application also relates to a co-crystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain and preventing, delaying, reducing or halting dependence on tramadol.

[0039] The present application therefore also relates in this aspect E) to a method for treating pain and preventing, delaying, reducing or halting dependence on tramadol, the method comprising administering to a subject a therapeutically effective amount of a co-crystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof.

[0040] In this application, "inhibiting, delaying, reducing, or halting dependence on tramadol" is defined as treating a patient suffering from pain to improve their symptoms while simultaneously inhibiting, delaying, reducing, or halting (potential) dependence (or delaying or reducing the risk of potential dependence) by administering a therapeutically effective amount of a cocrystal. In this context, inhibiting, delaying, reducing, or halting is understood as lessening (or lowering, reducing, or delaying the risk of dependence) when using the cocrystal compared to when tramadol is used alone or in combination with celecoxib to provide at least the same level of pain treatment efficacy.

[0041] In a further aspect F), the present application also relates to a co-crystal of (rac)-tramadol HCl with celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain and reducing the incidence of dependence on tramadol.

[0042] The present application therefore also relates in this aspect F to a method for treating pain and reducing the incidence of dependence on tramadol, the method comprising administering to a subject a therapeutically effective amount of a co-crystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof.

[0043] In this application, "reducing the incidence of dependence on tramadol" is defined as treating a patient suffering from pain by administering a therapeutically effective amount of the cocrystal, thereby improving symptoms and simultaneously reducing the incidence of dependence on tramadol. In this context, reducing the incidence of dependence is understood to mean that the risk (or likelihood) of developing dependence when using the cocrystal is reduced compared to the risk / incidence when tramadol is used alone or in combination with celecoxib to achieve at least the same level of pain treatment efficacy.

[0044] In a further aspect G), the present application also relates to a co-crystal of (rac)-tramadol HCl with celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain and reducing the likelihood that this treatment will result in dependence on tramadol.

[0045] The present application therefore also relates in this aspect G) to a method for treating pain and reducing the likelihood that this treatment will result in dependence on tramadol, the method comprising administering to a subject a therapeutically effective amount of a co-crystal of (rac)-tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof.

[0046] In this application, "reducing the likelihood that a treatment will result in dependence on tramadol" is defined as treating a patient suffering from pain by administering a therapeutically effective amount of a cocrystal to alleviate symptoms while simultaneously reducing the likelihood that such treatment will result in dependence on tramadol. In this context, reducing the likelihood is understood to mean that the risk of developing dependence when using the cocrystal is reduced compared to the risk when using tramadol alone or in combination with celecoxib to achieve at least the same level of pain treatment effectiveness.

[0047] As used herein, a "cocrystal" is defined as a crystalline substance at room temperature (20-25°C, preferably 20°C) consisting of two or more compounds, at least two of which are bound by weak interactions, with at least one of the compounds being a cocrystallite. Weak interactions are defined as interactions that are neither ionic nor covalent, but include, for example, hydrogen bonds, van der Waals forces, and π-π interactions. A tramadol solvent that does not further contain cocrystallites is not a cocrystal in the present invention. However, a cocrystal may contain one or more solvent molecules within the crystal lattice. For clarity, it is important to emphasize the difference between a crystalline salt and a cocrystal. An active pharmaceutical ingredient (API) that is bound to another compound to form a salt by an ionic bond can be considered a "compound" in the present invention, but cannot be considered two compounds in itself.

[0048] The correct use of the term cocrystal is currently being debated in the scientific literature (see, for example, Desiraju, Cryst.Eng.Comm., 2003, 5(82), 466-467 and Dunitz, Cryst.Eng.Comm., 2003, 5(91), 506). A recent article by Zawarotko (Zwarotko, Crystal Growth & Design, Vol. 7, No. 1, 2007, 4-9) provides a definition of cocrystal that is consistent with the above definition and is also the definition of the "cocrystal" used in the present invention. According to this article, "a cocrystal is a complex crystal that is solid under ambient conditions when all components are in pure form. These components consist of target molecules or ions and molecular cocrystallites, which coexist at the molecular level in the same crystal lattice."

[0049] In a preferred embodiment according to all aspects A) to G), the present application also relates to a co-crystal according to the invention, in which the molar ratio of (rac)-tramadol HCl to celecoxib is 1:1.

[0050] E-58425 is a novel cocrystal of tramadol HCl and celecoxib in a 1:1 molecular ratio. An example can be found in WO 2011 / 044962. The overall profile of E-58425, an oral formulation with two related active ingredients for pain treatment, suggests a unique and useful role in the management of moderate to severe pain.

[0051] Cocrystal E-58425 is formulated for oral administration and contains a cocrystal of racemic tramadol hydrochloride and celecoxib as the drug.

[0052] In a preferred embodiment of all aspects A) to G), the present application also provides for the use of (or a method of treatment using) a cocrystal according to the present invention comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein the cocrystal is and a method of treatment using the same, characterized in that the powder X-ray diffraction pattern has at least one peak [2θ] selected from peaks [2θ] at 2.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2, and 37.2 [°].

[0053] The 2θ values ​​are calculated from the copper radiation (CuK α1 The powder X-ray diffraction pattern was obtained using a method similar to that of E-58425 (1.54060 Å). The exact same method for determining this powder X-ray diffraction pattern (which corresponds to the powder X-ray diffraction pattern of E-58425) can be found in the examples and figures of WO 2011 / 044962.

[0054] In another preferred embodiment of all aspects A) to G), the present application also provides the use of (or a method of treatment using) a cocrystal according to the invention comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein said cocrystal is ·14.1 and 22.7[°], ·14.1 and 19.0[°], ·14.1 and 16.8[°], 16.8 and 22.7°, 16.8 and 19.0°, and ·19.0 and 22.7[°], The 2θ value is determined by copper radiation (CuK α1 The powder X-ray diffraction pattern was obtained using a method similar to that of E-58425 (1.54060 Å). The exact same method for determining this powder X-ray diffraction pattern (which corresponds to the powder X-ray diffraction pattern of E-58425) can be found in the examples and figures of WO 2011 / 044962.

[0055] In another preferred embodiment of all aspects A) to G), the present application also provides the use of (or a method of treatment using) a cocrystal according to the invention comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein said cocrystal is ·14.1, 16.8 and 22.7[°], ·14.1, 19.0 and 22.7[°], ·14.1, 16.8 and 19.0[°], and 16.8, 19.0 and 22.7 [°]. The 2θ value is determined by the copper radiation (CuK α1 The powder X-ray diffraction pattern was obtained using a method similar to that of E-58425 (1.54060 Å). The exact same method for determining this powder X-ray diffraction pattern (which corresponds to the powder X-ray diffraction pattern of E-58425) can be found in the examples and figures of WO 2011 / 044962.

[0056] In another preferred embodiment of all aspects A) to G), the present application also relates to the use of (or a method of treatment using) a cocrystal according to the invention comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, characterized in that said cocrystal exhibits a powder X-ray diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0, and 22.7 [°]. In a further preferred embodiment of this embodiment, said cocrystal exhibits additional peaks [2θ] at 7.1, 19.9, and 20.5 [°], and in an even more preferred embodiment of this embodiment, said cocrystal exhibits additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4, and 26.1 [°].

[0057] The 2θ values ​​are calculated from the copper radiation (CuK α1 The powder X-ray diffraction pattern was obtained using a method similar to that of E-58425 (1.54060 Å). The exact same method for determining this powder X-ray diffraction pattern (which corresponds to the powder X-ray diffraction pattern of E-58425) can be found in the examples and figures of WO 2011 / 044962.

[0058] In another preferred embodiment of all aspects A) to G), the present application also provides for the use of (or a method of treatment using) a cocrystal according to the present invention comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein the cocrystal is selected from the group consisting of: 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3 , 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2, and 37.2 [°]. The 2θ values ​​are determined by copper radiation (CuK α1The powder X-ray diffraction pattern was obtained using a method similar to that of E-58425 (1.54060 Å). The exact same method for determining this powder X-ray diffraction pattern (which corresponds to the powder X-ray diffraction pattern of E-58425) can be found in the examples and figures of WO 2011 / 044962.

[0059] In another preferred embodiment of all aspects A) to G), the present application also provides for the use of (or a method of treatment using) a cocrystal according to the present invention comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein the cocrystal has the following molecular weights: 3481.6(m), 3133.5(m), 2923.0(m), 2667.7(m), 1596.0(m). , 1472.4(m), 1458.0(m), 1335.1(m), 1288.7(m), 1271.8(m), 1168.7(s), 1237.3(m), 1168.7( s), 1122.6(s), 1100.9(m), 1042.2(m), 976.8(m), 844.6(m), 820.1(m), 786.5(m), 625.9(m)cm -1 The present invention relates to a use (or a method of treatment using the same) characterized in that the Fourier transform infrared pattern exhibits an absorption band at 1000 nm. The exact same method for determining this Fourier transform infrared pattern (which corresponds to the Fourier transform infrared pattern of E-58425) can be found in the examples and drawings of WO 2011 / 044962.

[0060] In another preferred embodiment of all aspects A) to G), the present application also relates to the use of (or a method of treatment using) a cocrystal according to the invention comprising (rac)-tramadol HCl and celecoxib in a 1:1 molecular ratio, said cocrystal having the following dimensions:

number

[0061] In another preferred embodiment of all aspects A) to G), the present application also relates to the use of (or a method of treatment using) a cocrystal according to the present invention comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, characterized in that the cocrystal has a sharp endothermic peak with an onset at 164° C., corresponding to its melting point. The exact same method for determining the onset of the sharp endothermic peak corresponding to the melting point of the cocrystal (which corresponds to the onset of the sharp endothermic peak corresponding to the melting point of E-58425) can be found in the examples and drawings of WO 2011 / 044962.

[0062] In another preferred embodiment according to all aspects A) to G), the present application also relates to the use of a cocrystal according to the invention for (or a method of treatment using) treating acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain associated with central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy, as well as osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica.

[0063] In another preferred embodiment of all aspects A) to G), the present application also relates to the use of a cocrystal according to the invention for (or a method of treatment using) treating moderate to severe acute and chronic pain, moderate to severe acute pain, moderate acute pain, severe acute pain, moderate to severe chronic pain, moderate chronic pain, or severe chronic pain.

[0064] "Pain" is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with or described in terms of actual or potential tissue damage" (IASP, Classification of chronic pain, 2nd ed., IASP Press (2002), 210). Pain is always subjective, but its causes or syndromes can be classified. One classification naming subtypes of pain would be to divide general pain syndromes into acute and chronic pain subtypes, or - by pain intensity - into mild, moderate and severe pain. In other definitions, general pain syndromes are also divided into "nociceptive" (caused by activation of nociceptors), "neuropathic" (caused by damage or dysfunction of the nervous system) and pain related to central sensitization (central pain syndromes).

[0065] According to the International Association for the Study of Pain (IASP), "allodynia" is defined as "pain elicited by stimuli that are not normally painful" (IASP, Classification of chronic pain, 2nd ed., IASP Press (2002), 210). Allodynic symptoms are most likely to be associated with neuropathic pain, but this is not necessarily the case, as allodynia is more regionally widespread than neuropathic pain, and there are allodynic symptoms that are not related to neuropathic pain.

[0066] The International Association for the Study of Pain (IASP) further distinguishes between "allodynia," "hyperalgesia," and "dysodynia" as follows (IASP, Classification of chronic pain, 2nd ed., IASP Press (2002), 210): [Table A] According to the IASP, "neuropathy" is defined as "a functional disorder or primary lesion of the nervous system" (IASP, Classification of chronic pain, 2nd ed., IASP Press (2002), 210). Neuropathic pain can be of central or peripheral origin.

[0067] "Sciatica" or "sciatic neuritis" is defined herein as a group of symptoms involving pain resulting from irritation of the sciatic nerve or its root.

[0068] "Frozen shoulder" or "adhesive capsulitis" is defined herein as a condition in which the connective tissue surrounding the shoulder joint, or the shoulder capsule itself, becomes inflamed and stiff, causing chronic pain.

[0069] "Ankylosing spondylitis" or "Morbus Bechterew's disease" is a chronic inflammatory arthritis and autoimmune disease that primarily affects the joints of the spine and the sacroiliac joints of the pelvis, eventually leading to fusion of the spine.

[0070] "Pain associated with central sensitization" / "central pain syndrome" is defined herein as a neurological disorder caused by damage to or dysfunction of the central nervous system (CNS), including the brain, brainstem, and spinal cord. This syndrome may be caused by, among other things, stroke, multiple sclerosis, tumor, epilepsy, brain or spinal cord trauma, or Parkinson's disease.

[0071] "Nociceptive pain" is defined as the type of pain caused by activation of nociceptors. Nociceptive pain is divided into somatic and visceral pain. "Visceral pain" is pain that generally originates from organs, whereas "(severe) somatic pain" originates from ligaments, tendons, bones, blood vessels, fascia and muscles.

[0072] In another preferred embodiment according to all aspects A) to G), the present application also relates to the use of a cocrystal according to the present invention (or a method of treatment using the same), characterized in that a pharmaceutical composition contains the cocrystal and also contains at least one solubility-enhancing polymer, wherein the solubility-enhancing polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or selected from copovidone, povidone, cyclodextrin, polyethylene glycol, and lauroyl macrogol-32 glyceride EP, preferably the solubility-enhancing polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or copovidone or other hydrophilic polymers selected from povidone, and most preferably the solubility-enhancing polymer is copovidone.

[0073] Further details of this formulation / pharmaceutical composition (also referred to as E-58425) can be found in WO 2011 / 151080.

[0074] The invention is illustrated below by means of the following figures and examples, which are provided by way of illustration only and are not intended to limit the invention. [Brief explanation of the drawings]

[0075] [Figure 1] 1 shows the linear profiles of mean plasma concentrations of tramadol and O-desmethyltramadol following oral administration of cocrystal E-58425 (Treatment 1), Ultram® (Treatment 2), and Ultram® + Celebrex® (Treatment 4) to healthy male and female subjects. [Figure 2]Abuse Quotient (AQ) calculated from data obtained in a four-period crossover study of tramadol and its metabolite M1 obtained from cocrystals E-58425 (Treatment 1), Ultram® (Treatment 2), and Ultram® + Celebrex® (Treatment 4). For opioids, the Cmax / Tmax ratio is highly correlated with pharmacodynamic effect, with a higher Cmax / Tmax (faster and / or greater absorption) indicating greater abuse potential.

[0076] For cocrystal E-5842, the AQ of tramadol obtained in a four-period crossover study was (登録商標) What has been learned about Ultra (登録商標) and Celebrex (登録商標) These differences were statistically significant, suggesting a lower abuse potential for the cocrystals. (登録商標) Taken alone or with Celebrex (登録商標) No statistically significant difference was observed in the combination of

[0077] Pharmacokinetic parameter definitions C max Maximum plasma concentration T max Time of peak plasma concentration AQ Abuse Index HPLC High-Performance Liquid Chromatography MS / MS triple quadrupole mass spectrometry IS1 / ISTD1 Internal Standard (Tramadol-D6) IS2 / ISTD2 Internal Standard (O-Desmethyltramadol-D6) K2-EDTA Dipotassium Ethylenediaminetetraacetic Acid LOQ Lower limit of quantitation M1: O-desmethyltramadol SD standard deviation SE standard error CV Coefficient of Variation mg milligram mL milliliter ng nanogram [Example]

[0078] This study was a single-center, randomized, single-dose, open-label, four-period, four-sequence, crossover design in healthy male and female subjects. The following treatments were administered under fasting conditions: Treatment 1: 2 x 100 mg cocrystal E-58425 tablets administered alone Treatment 2: 2 × 50 mg tramadol HCl tablets (Ultram (登録商標) ) administered alone Treatment 3: 1 x 100 mg celecoxib capsule (Celebrex (登録商標) ) was administered alone (data not shown) Treatment 4: 2 x 50 mg tramadol tablets (Ultram (登録商標) ) and 1 x 100 mg celecoxib capsule (Celebrex (登録商標) ) taken at the same time

[0079] Thirty-six subjects received the product, with a washout period of 7 calendar days in each case.

[0080] [Table 1] Sample handling Separate blood samples were obtained for analysis of tramadol / M1 metabolites and for analysis of celecoxib (data not shown). Blood samples for quantification of tramadol and M1 metabolites (Treatment 1, Treatment 2, and Treatment 4) were collected before drug administration and at 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, and 48 hours after drug administration in K2-EDTA vacutainers. As soon as possible after collection, blood was centrifuged at 1500 g for approximately 10 minutes at a nominal temperature of 4°C. The resulting plasma was aliquoted into duplicate polypropylene culture tubes. Each tube was labeled to identify the drug being assayed and assigned a code number that did not reveal the identity of the formulation. Samples were frozen face up and kept at a nominal temperature of −20°C in a hospital freezer before being shipped on dry ice to the bioanalytical facility for assay.

[0081] Measurement method Human plasma test samples were analyzed for tramadol and the M1 metabolite (O-desmethyltramadol) and for celecoxib (data not shown) using two different validated bioanalytical methods by HPLC with MS / MS detection.

[0082] Sample preparation involved liquid-liquid extraction of tramadol and O-desmethyltramadol from 0.100 mL of human plasma, with tramadol-D6 and O-desmethyltramadol-D6 used as internal standards. The compounds were identified and quantified using Hilic HPLC with MS / MS detection within a theoretical concentration range of 2.00 ng / mL to 800.00 ng / mL for tramadol and 0.500 ng / mL to 200.00 ng / mL for O-desmethyltramadol. Concentrations for tramadol and O-desmethyltramadol were calculated from peak area ratios and weighted (1 / x). 2 ) Linear (y=mx+b) least squares regression analysis was used to determine the linearity of the calibration curve.

[0083] Pharmacokinetic analysis Pharmacokinetic parameters were estimated from the individual plasma concentration-time profiles for each subject. The main absorption and kinetic parameters were obtained using non-compartmental methods under the assumption of a log-linear terminal phase. Peak plasma concentration C max and time of peak plasma concentration T max was obtained directly from the test data. The area under the curve (AUC; data not shown) was estimated using the trapezoidal rule, and the coefficient of determination (T 1 / 2 The terminal phase was estimated by maximizing .times. ... The following formula

number

[0084] result [Table 2.1]

[0085] Subjects 17, 32, and 34 withdrew consent and were excluded from the study.

[0086] [Table 2.2]

[0087] Subjects 17, 32, and 34 withdrew consent and were excluded from the study.

[0088] [Table 2.3]

[0089] Subjects 17, 32, and 34 withdrew consent and were excluded from the study.

[0090] [Table 3]

[0091] Embodiments: E1) A co-crystal of (rac) tramadol HCl and celecoxib, or a pharmaceutically acceptable derivative thereof, for treating pain while reducing the abuse liability of tramadol. E2) The cocrystal for use according to embodiment E1), wherein the molar ratio of (rac)-tramadol HCl to celecoxib is 1:1. E3) A co-crystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein the co-crystal has the following molecular weights: 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.0, 23.2, 23.4, 23.6, 23.8, 24.0, 24.2, 24.4, 24.6, 24.8, 25.0, 25.2, 25.6, 25.8, 26.0, 26.2, 26.4, 26.6, 26.8, 27.0, 27.2, 27.4, 27.6, 28.0, 28.2, 28.4, 28.6, 28.8, 29.0, 30.0, 30.2 ... and a powder X-ray diffraction pattern having at least one peak [2θ] selected from 3.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2, and 37.2 [°], wherein the 2θ values ​​are those of copper radiation (CuK α1 1.54060 Å). E4) The co-crystal is ·14.1 and 22.7[°], ·14.1 and 19.0[°], ·14.1 and 16.8[°], 16.8 and 22.7°, 16.8 and 19.0°, or ·19.0 and 22.7[°], The powder X-ray diffraction pattern has peaks [2θ] of 0.01 to 0.01, the 2θ values ​​being determined by copper radiation (CuK α11.54060 Å). E5) The co-crystal is ·14.1, 16.8 and 22.7[°], ·14.1, 19.0 and 22.7[°], 14.1, 16.8 and 19.0°, or · 16.8, 19.0 and 22.7[°], The powder X-ray diffraction pattern has peaks [2θ] of 0.01 to 0.01, the 2θ values ​​being determined by copper radiation (CuK α1 1.54060 Å). E6) The cocrystal exhibits a powder X-ray diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7 [°], the 2θ values ​​being determined by copper radiation (CuK α1 1.54060 Å). E7) The co-crystal for use according to embodiment E6), wherein the co-crystal exhibits additional peaks [2θ] at 7.1, 19.9 and 20.5 [°]. E8) The co-crystal for use according to embodiment E7), characterized in that the co-crystal exhibits further peaks at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1 [°]. E9) A co-crystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein the co-crystal has the following molecular weights: 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6,

[0033] represents a powder X-ray diffraction pattern having peaks [2θ] at 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2 [°], said 2θ values ​​being determined by copper radiation (CuK α1 1.54060 Å). E10) A co-crystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molecular ratio, wherein the co-crystal has the following peaks: 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (m), 1237.3 (m), 1168.7 (m), 1122.6 (m), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m), 625.9 (m) cm -1 4. A co-crystal for use according to any one of embodiments E1) to E9), characterized in that it exhibits a Fourier transform infrared pattern having an absorption band at E11) A co-crystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molecular ratio, said co-crystal having the following dimensions:

number

number

number

number

number

number

number

Claims

1. A pharmaceutical composition comprising a co-crystal of (rac)-tramadol HCl and celecoxib for use in treating pain in patients who are dependent on tramadol while reducing the abuse liability of tramadol.

2. 2. The pharmaceutical composition of claim 1, wherein the molar ratio of (rac)-tramadol HCl to celecoxib is 1:

1.

3. A co-crystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein the co-crystal has the following molecular weights: 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23. and the powder X-ray diffraction pattern has at least one peak [2θ] selected from the group consisting of 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2, and 37.2 [°], wherein the value of 2θ is the value of copper radiation (CuK α１ 3. The pharmaceutical composition according to claim 1 or 2, characterized in that it is obtained using a fluorine-containing fluoride (H2O 2 , 1.54060 Å).

4. The co-crystal exhibits a powder X-ray diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7 [°], the 2θ values ​​being determined by copper radiation (CuK α１ 4. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is obtained using a fluorine-containing fluoride (fluorine-containing fluoride) having a fluorine-containing fluoride content of 1.54060 Å.

5. The pharmaceutical composition of claim 4, characterized in that the co-crystal exhibits additional peaks [2θ] at 7.1, 19.9 and 20.5 [°].

6. 6. The pharmaceutical composition of claim 5, wherein the co-crystal exhibits additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1 [°].

7. A co-crystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molar ratio, wherein the co-crystal has the following molecular weights: 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, and 37.2 [°], wherein the values ​​of 2θ are determined by copper radiation (CuK). α１ 7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is obtained using a fluorine-containing fluoride (fluorine-containing fluoride) having a fluorine-containing fluoride content of 1.54060 Å.

8. A co-crystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molecular ratio, wherein the co-crystal has a molecular weight of 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m), 625.9 (m) cm －１ 8. The pharmaceutical composition according to claim 1, which exhibits a Fourier transform infrared pattern having an absorption band at

9. A co-crystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molecular ratio, said co-crystal having the following dimensions: [Equation 1] 9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has an orthorhombic unit cell having the formula:

10. 10. The pharmaceutical composition according to any one of claims 1 to 9, which is a cocrystal comprising (rac)-tramadol HCl and celecoxib in a 1:1 molecular ratio, wherein the cocrystal exhibits a sharp endothermic peak with an onset at 164°C, corresponding to the melting point.

11. A pharmaceutical composition according to any one of claims 1 to 10 for use in the treatment of acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain associated with central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy, and osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica.

12. A pharmaceutical composition described in any one of claims 1 to 11, characterized in that the pain is moderate to severe acute and chronic pain, moderate to severe acute pain, moderate acute pain, severe acute pain, moderate to severe chronic pain, moderate chronic pain, or severe chronic pain.

13. at least one solubility-enhancing polymer; the solubility-enhancing polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or selected from copovidone, povidone, cyclodextrin, polyethylene glycol, and lauroyl macrogol-32 glyceride EP; Preferably, the solubility-enhancing polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophilic polymer selected from copovidone or povidone; Most preferably, the pharmaceutical composition according to any one of claims 1 to 12, characterized in that the solubility-enhancing polymer is copovidone.

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