Compounds for treating or preventing pain, inflammation and / or autoimmunity

Abstract

The present invention relates to a polymorph of (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide or a synonymous polymorph of N-[2-(4-hydroxy-phenyl)-(2-hydroxy-propoxymethyl)-ethyl]-3-phenyl-propionamide, and to the treatment or prevention of pain, inflammation and / or autoimmunity, and provides a method for treating or preventing pain, inflammation and / or autoimmunity in humans and / or non-human animals, as well as use of the polymorph in the preparation of a medicament for treating or preventing pain (preferably nociceptive or neuropathic pain), inflammation and / or autoimmunity in humans and / or non-human animals.

Description

[0001] The present invention relates to a polymorph of (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide or a synonymous polymorph of N-[2-(4-hydroxy-phenyl)-1-(2-hydroxy-propyloxymethyl)-ethyl]-3-phenyl-propylamide, and to the treatment or prevention of pain, inflammation and / or autoimmunity, and provides a method for treating or preventing pain, inflammation and / or autoimmunity in humans and / or non-human animals, as well as the use of the polymorph in the preparation of a medicament for treating or preventing pain (preferably nociceptive or neuropathic pain), inflammation and / or autoimmunity in humans and / or non-human animals. Background Art

[0002] The compound 2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide has been disclosed in US 7,754,771 and its use in treating or preventing pain and inflammation has been described in WO 2009 / 1099850, WO 2011 / 030105, US 2011 / 0086910 and WO 2013 / 084238. Previous disclosures of this compound have been directed to racemates containing all four enantiomers and diastereomers, namely (S,S), (S,R), (R,R) and (R,S). WO 2013 / 084238 mentions that racemates containing the S enantiomer at the chiral position adjacent to the amide exhibit particularly advantageous properties.

[0003] Pain is a multifaceted or multidimensional experiential response to a variety of stimuli. 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."

[0004] Pain in animals is usually the result of nociception, which is activity in the nervous system caused by stimulation of nociceptors. Neuropathic pain differs from nociceptive pain in that it involves damage to the nerves that causes the sensation of pain. In central pain, the pain is produced in the brain by some form of damage. Occasionally, pain can be psychogenic, i.e. caused by a mental illness.

[0005] Pain can be acute or chronic. Acute pain is usually caused by soft tissue injury, infection and / or inflammation, among other reasons. Acute pain serves to warn you after an injury or malfunction. Chronic pain may have no apparent cause or may be caused by an ongoing disease or imbalance. Chronic pain is defined as a painful condition; it may vary in origin, duration, intensity and specific symptoms.

[0006] The experience of physiological pain can be grouped according to the source and the associated nociceptors. Cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin and, due to the high concentration of nerve endings, produce well-defined localized pain of short duration. Examples of injuries that cause cutaneous pain include: paper cuts, minor cuts, minor (first degree) burns, and lacerations. Somatic pain originates from ligaments, tendons, bones, blood vessels, and nerves. It is detected by nociceptors in the body. The lack of pain receptors in these areas produces dull, poor localized pain that lasts longer than cutaneous pain; examples include sprains and fractures. Myofascial pain is usually caused by trigger points in muscles, tendons, and fascia and may be localized or referred pain. Visceral pain originates from the internal organs or organs of the body. Visceral nociceptors are located in organs and cavities of the human body. The greater lack of nociceptors in these areas produces pain that is generally more painful and lasts longer than somatic pain. Visceral pain is particularly difficult to localize, and several injuries to visceral tissue manifest as "referred" pain, in which the sensation is localized to an area completely unrelated to the site of injury. Phantom limb pain, a type of referred pain, refers to the sensation of pain coming from a limb that has been lost or from a limb that a person is no longer receiving physical signals from. Neuropathic pain can result from damage or disease to the nerve tissue itself. This can disrupt the ability of sensory nerves to transmit correct information to the thalamus, so that the brain can interpret stimuli as painful even when the pain has no obvious psychological cause.

[0007] Acute pain is generally treated with both drugs or appropriate techniques to eliminate the cause and drugs or appropriate techniques to control the pain sensation (usually analgesics).

[0008] Analgesics are divided into three categories: opioid (narcotic) analgesics, non-opioid analgesics, and adjunctive analgesics. Opioid analgesics are powerful analgesics chemically related to morphine. However, opioids have many side effects that are more likely to occur in patients with certain conditions: kidney failure, liver disease, chronic obstructive pulmonary disease (COPD), dementia or other brain conditions. Drowsiness, constipation, nausea, vomiting, and itching are common after starting opioids. In addition to morphine, opioid analgesics known at the time of this writing include: codeine, fentanyl, hydrocodone, hydromorphone, levorphan, pethidine, methadone, oxycodone, oxymorphone, pentazocine, and propoxyphene.

[0009] As of this writing, a variety of non-opioid analgesics are also available. They are generally effective for mild to moderate pain. Most non-opioid analgesics are classified as non-steroidal anti-inflammatory drugs (NSAIDs). An example of an analgesic that is not an NSAID is acetaminophen, more commonly known as paracetamol. Acetaminophen has essentially no anti-inflammatory properties.

[0010] NSAIDs are used to treat mild to moderate pain and can be used in combination with opioids to treat moderate to severe pain. NSAIDs not only relieve pain, but also reduce the inflammation that often accompanies and worsens pain. Although widely used, NSAIDs can also have side effects, sometimes serious ones, including digestive problems, bleeding problems, problems with fluid retention, and an increased risk of heart and blood vessel disease. Current NSAIDs include: aspirin, ibuprofen, ketoprofen, naproxen, cyclooxygenase-2 (cox-2) inhibitors such as celecoxib, choline magnesium trisalicylate, diflunisal, salsalate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, oxaprozin, piroxicam, sulindac, and tolmetin.

[0011] Adjunctive analgesics include: antidepressants such as imipramine, amitriptyline, bupropion, desipramine, fluoxetine, and venlafaxine; anticonvulsants (such as carbamazepine, gabapentin, and pregabalin); and oral and topical local anesthetics.

[0012] In the treatment of chronic pain, the "three-step analgesia ladder" developed by the World Health Organization is often used. For mild pain, acetaminophen, aspirin or other NSAIDs can be used. For mild to moderate pain, weak opioids (such as codeine and dihydrocodeine) can be used in combination with acetaminophen, aspirin or other NSAIDs. In cases of moderate to severe pain, strong opioids (such as morphine, diacetylmorphine or fentanyl, hydromorphone, methadone, oxycodone or benzocaine) can be combined with acetaminophen, aspirin or other NSAIDs.

[0013] For neuropathic pain, currently available therapies have only low to moderate efficacy, and many patients do not experience significant pain relief. For the millions of people suffering from neuropathic pain, as well as other types of pain, the lack of adequate pain relief represents a huge unmet medical need, which the present invention addresses. Summary of the invention

[0014] The present invention relates to polymorphs of (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide, and to the treatment or prevention of pain, inflammation and / or autoimmunity, and provides a method for treating or preventing pain, inflammation and / or autoimmunity in humans and / or non-human animals, and the use of the polymorphs in the preparation of drugs for treating or preventing pain (preferably nociceptive or neuropathic pain), inflammation and / or autoimmunity in humans and / or non-human animals. More specifically, the compound used in the present invention is a compound having the following chemical formula:

[0015]

[0016] It is the (S,S) isomer of 2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide.

[0017] The present invention relates to polymorphs of the compound. The polymorphs of the compound are used in the present invention. The polymorph, hereinafter also referred to as polymorph 2, can be characterized by methods such as X-ray, DSC and / or Raman spectroscopy.

[0018] As discussed later, it was surprisingly found that polymorph 2 is less hygroscopic, more stable and more bioavailable than other crystalline forms such as polymorph 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 : X-ray powder diffraction pattern of polymorph 2;

[0020] Figure 2 : SEM image of polymorph 2;

[0021] Figure 3 : Raman spectrum of polymorph 2 measured on a Bruker RFS 100 / S at 1064 nm;

[0022] Figure 4 : TGA / DTA data of polymorph 2;

[0023] Figure 5 : Analytical data table of polymorph 1;

[0024] Figure 6 : Analytical data table of polymorph 2;

[0025] Figure 7 : Pre-dose body weight, and calculated doses of Form 1 (141232) and Form 2 (COEN4-091-M) of NRD135S.E1 after oral administration of Form 1 (141232) and Form 2 (COEN4-091-M) of NRD135S.E1 to male beagle dogs at a target dose level of 60 mg / kg;

[0026] Figure 8 : Actual blood sampling time after oral administration of Form 1 (141232) and Form 2 (COEN4-091-M) of NRD135S.E1 at the target dose level of 60 mg / kg in week 2;

[0027] Fig. 9 : Mean and individual plasma concentrations of NRD135S.E1 after oral administration of Form 1 (141232) and Form 2 (COEN4-091-M) of NRD135S.E1 at a target dose level of 60 mg / kg;

[0028] Fig.10 : Mean and individual pharmacokinetic parameters of Form 1 (141232) and Form 2 (COEN4-091-M) of NRD135S.E1 in plasma of male beagle dogs following oral administration at a nominal dose of 60 mg / kg in week 1;

[0029] Fig.11 : Mean and individual pharmacokinetic parameters of Form 1 (141232) and Form 2 (COEN4-091-M) of NRD135S.E1 in plasma of male beagle dogs after oral administration at a nominal dose of 60 mg / kg in week 2;

[0030] Fig.12 : Mean plasma concentrations of Form 1 (141232) and Form 2 (COEN4-091-M) of NRD135S.E1 in male beagle dogs following oral administration at a nominal dose of 60 mg / kg;

[0031] Fig.13 : Individual plasma concentrations of Form 1 (141232) of NRD135S.E1 in male beagle dogs after oral administration at a nominal dose of 60 mg / kg (sequence 1-1 old);

[0032] Fig.14 : Individual plasma concentrations of Form 2 (COEN4-091-M) of NRD135S.E1 in male beagle dogs after oral administration at a nominal dose of 60 mg / kg (Sequence 2-1 New);

[0033] Fig.15 : Individual plasma concentrations of Form 2 (COEN4-091-M) of NRD135S.E1 in male beagle dogs after oral administration at a nominal dose of 60 mg / kg (Sequence 1-2 new);

[0034] Fig.16 : Individual plasma concentrations of Form 1 (141232) of NRD135S.E1 in male beagle dogs after oral administration at a nominal dose of 60 mg / kg (Sequence 2-2 old);

[0035] Fig.17 :(S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide 1 H-NMR spectrum. DETAILED DESCRIPTION

[0036] The present invention relates to a polymorph of a specific compound, and to the treatment or prevention of pain, inflammation and / or autoimmunity, and provides a method for treating or preventing pain, inflammation and / or autoimmunity in humans and / or non-human animals, and the use of the polymorph in the preparation of a medicament for treating or preventing pain (preferably nociceptive or neuropathic pain), inflammation and / or autoimmunity in humans and / or non-human animals. More specifically, the compound used in the present invention is a compound having the following chemical formula:

[0037]

[0038] The compound ((S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide), including its enantiomers and diastereomers, can be prepared as described in WO 2013 / 084238 (which is incorporated herein by reference, particularly Examples 1 and 2 thereof).

[0039] The (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide used in the present invention is an enantiomer that is preferably substantially free of other stereoisomeric forms of the compound. A representative substantially pure enantiomer contains greater than 90 wt% of one enantiomer of the compound and less than 10 wt% of another stereoisomeric form of the compound; preferably greater than 95 wt% of one enantiomer of the compound and less than 5 wt% of another stereoisomeric form of the compound; even further preferably greater than 98 wt% of one enantiomer of the compound and less than 2 wt% of another stereoisomeric form of the compound. The term "other stereoisomeric forms" generally refers to the (S,R), (R,S) and (R,R) enantiomers or diastereomeric forms of the compound 2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide. The substantially pure (S,S)-enantiomer is able to activate BLK and LynA tyrosine kinases, while having no or substantially no effect on the activity of LynB tyrosine kinase.

[0040] The polymorph of the compound is used in the present invention. The polymorph, also referred to hereinafter as polymorph 2, can be characterized by methods such as X-ray, DSC and / or Raman spectroscopy.

[0041] The inventors surprisingly found that polymorph 2 is less hygroscopic and more stable than other crystalline forms (such as polymorph 1 discussed later). In addition, it was surprisingly found that polymorph 2 has better bioavailability than polymorph 1. This is particularly surprising in view of its higher stability. Thermal analysis of polymorph 2 shows an onset melting point at 104.5°C and a melting point peak at 107.2°C. Melting enthalpy ΔH 熔化 It is about 121 J / g.

[0042] Thermal analysis for determining the melting point and melting enthalpy of the claimed polymorph can be performed by heating the sample at 25°C at a rate of 10°C / min, typically from 25°C to 300°C, using a TGA / DTA analyzer (e.g., Perkin-Elmer STA 600 TGA / DTA analyzer), during which the weight change and differential thermal analysis (DTA) signal are monitored, while the purge gas used is nitrogen at a flow rate of 20 cm 3 / min.

[0043] Scanning electron microscopy (SEM) showed that polymorph 2 had a regular rectangular block habit with particle sizes ranging from 2-10 μm in length and 2-5 μm in width. Particle size is usually expressed as D measured using laser diffraction. 50Volume median particle size.

[0044] Gravimetric vapor sorption (GVS) showed that polymorph 2 was only slightly hygroscopic, with a weight increase of 0.6% for 80% RH.

[0045] Polymorph 2 of the present invention can be isolated by slurrying in water and crystallizing from a 50 / 50 by weight mixture of methanol and water. It can also be prepared by rapidly cooling a solution in chloroform and isopropyl acetate.

[0046] The polymorph 2 of the present invention generally has an X-ray powder diffraction pattern (CuKα) comprising a peak at 19.0±0.2°2θ, more preferably at 19.0±0.1°2θ, and even more preferably at 19.0±0.05°2θ. More preferably, the polymorph has an X-ray powder diffraction pattern (CuKα) further comprising one or more peaks selected from the group consisting of peaks at 11.25±0.2°, 17.38±0.2°, 17.57±0.2°, 20.74±0.2°, 20.91±0.2°, 22.42±0.2°, and 23.30±0.2°2θ. Even more preferably, the other peaks are selected from 11.25±0.1°, 17.38±0.1°, 17.57±0.1°, 20.74±0.1°, 20.91±0.1°, 22.42±0.1° and 23.30±0.1° 2θ. Still more preferably, the peaks are selected from 11.25±0.05°, 17.38±0.05°, 17.57±0.05°, 20.74±0.05°, 20.91±0.05°, 22.42±0.05 and 23.30±0.05° 2θ. Preferably, the peak at 19.0±0.2°2θ, more preferably at 19.0±0.1°2θ, is the peak with the highest relative intensity in the X-ray powder diffraction pattern (CuKα) of Polymorph 2 (particularly in the range of 5 to 40°2θ).

[0047] Polymorph 2 preferably does not contain any peak within the range of 15±0.3°2θ and 16.5±0.2°2θ. More preferably, Polymorph 2 does not contain any peak within the range of 15±0.5°2θ and 16.5±0.3°2θ.

[0048] Even more preferably, the X-ray powder diffraction pattern (CuKα) of the polymorph 2 of the present invention is substantially as follows Figure 1 shown.

[0049] The melting point of polymorph 2 is generally in the range of about 105° C. to about 110° C. Further preferably, the melting point is in the range of about 106° C. to about 109° C., preferably in the range of about 107° C. to about 108° C.

[0050] In addition to the above, as described in the experimental data described herein, it was even more surprising to find that the bioavailability of Polymorph 2 of the present invention was exceptionally high, particularly higher than the bioavailability of Polymorph 1, in dog bioavailability testing.

[0051] In contrast, the properties of polymorph 1 show higher hygroscopicity and lower stability than polymorph 2 of the present invention.

[0052] That is, thermal analysis of polymorph 1 shows an onset melting point at 119.6°C and a melting point peak at 125.6°C. Melting enthalpy ΔH 熔化 It is about 19 J / g.

[0053] Simultaneous Thermal analysis (STA) data of polymorph 1 further indicated a small weight loss of slightly less than 1% between 90-115° C., followed by a single thermal event with melting onset at ˜119.5° C. Therefore, polymorph 1 may be a partial hydrate.

[0054] Scanning electron microscopy (SEM) showed that polymorph 1 had particles that were mostly irregular in shape with a width less than 10 μm.

[0055] Gravimetric Vapour Sorption (GVS) showed that polymorph 1 is hygroscopic, with a weight gain of -1.3% for 70% RH. However, rapid water uptake was followed by a weight gain of 5.6% between 70% RH and 80% RH, and a hysteresis (gap) between the adsorption and desorption cycles, suggesting a change in form. This different form appears to be more hygroscopic, with the second adsorption cycle showing a weight gain well above the satisfactory limit of 2% at only 40% RH.

[0056] Polymorph 1 can be prepared by recrystallization from various solvents such as methanol, ethanol, 2-propanol, acetonitrile, acetone, 1,4-dioxane and dimethylformamide.

[0057] Medical Uses

[0058] The present invention also relates to the use of polymorph 2 as a medicament, and to the use of polymorph 2 in treating or preventing a disease selected from pain, inflammation and autoimmunity. The disease is preferably pain.

[0059] In addition, the present invention includes a pharmaceutical composition for treating or preventing pain, inflammation and / or autoimmunity, wherein the composition comprises a pharmaceutically effective amount of polymorph 2, and optionally one or more pharmaceutically acceptable excipients. Additionally or alternatively, a pharmaceutical composition of the present invention is provided for treating or preventing inflammation.

[0060] The pharmaceutical composition is preferably formulated into a unit dosage form. The unit dosage form preferably contains 0.1 mg to about 500 mg of polymorph 2.

[0061] The polymorphs of the present invention can be used to treat or prevent acute or chronic pain. For example, the polymorphs can be used to treat nociceptive pain, such as cutaneous pain, somatic pain, myofascial pain, visceral pain, phantom limb pain or neuropathic pain. The polymorphs of the present invention can also be used to treat headaches or migraines. The polymorphs can be used alone or in combination with acetaminophen or another NSAID to treat mild chronic pain, or in combination with weak or strong opioids to treat moderate or severe pain.

[0062] The polymorphs of the present invention can also be used to treat or prevent neuropathic pain, and can be used in combination with one or more antidepressants or antiepileptic drugs (e.g., gabapentin or pregabalin). Therefore, according to another aspect of the present invention, there is provided a method for treating or preventing pain, inflammation and / or autoimmunity in a human or non-human animal patient, the method comprising administering a therapeutically effective amount of the polymorphs of the present invention to the patient in need. For human patients, the polymorphs in a pure, substantially pure or partially pure form as described in more detail below can be appropriately administered at a daily dose of 1.0 mg to 15 g. The polymorphs can be administered in an amount sufficient to achieve effective pain management under the supervision of a practicing physician. In some embodiments, the daily dose of the polymorphs can be titrated to determine this effective amount. The daily dose can contain about 5.0 mg to 1 g, typically about 5 mg to 500 mg. In some embodiments, the dose can contain 10 mg to 100 mg of the polymorphs per day. The polymorphs can be administered in a regimen of 1-4 times per day. The polymorphs may be administered parenterally, transdermally, intramuscularly, intravenously, intradermally, intranasally, subcutaneously, intraperitoneally, intraventricularly, intrathecally or rectally. Preferably, the polymorphs are administered orally. Optionally, the polymorphs of the present invention may be administered simultaneously, sequentially or separately with at least one opioid analgesic, antidepressant or antiepileptic. Alternatively, the polymorphs of the present invention may be administered simultaneously, sequentially or separately with one or more other NSAIDs or acetaminophen.

[0063] The polymorphs of the present invention can be used to treat or prevent autoimmunity, i.e., autoimmune diseases. In a preferred embodiment of the present invention, the autoimmune disease is celiac disease, type I diabetes, sarcoidosis, systemic lupus erythematosus (SLE), Sjögren's syndrome ( syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM), or multiple sclerosis (MS).

[0064] The present invention also relates to the use of the polymorphs of the present invention in the preparation of a medicament for treating or preventing pain, inflammation and / or autoimmunity. The medicament may be manufactured for co-administration with one or more of acetaminophen, another NSAID, an opioid, an antiepileptic or an antidepressant. In another embodiment, the present invention provides the use of the polymorphs of the present invention in the preparation of a medicament for treating or preventing inflammation.

[0065] Advantageously, the polymorphs described herein have been found to be effective for reducing or preventing inflammation. The polymorphs described herein have also been found to have no or substantially no (ie within acceptable limits) deleterious effects on the central nervous system.

[0066] In another aspect of the present invention, a pharmaceutical composition for treating or preventing pain, inflammation and / or autoimmunity is provided, the composition comprising a pharmaceutically effective amount of the polymorph of the present invention. The composition may further comprise one or more pharmaceutically acceptable excipients. In some embodiments, the composition may further comprise acetaminophen, one or more other NSAIDs, one or more weak or strong opioids, antidepressants or antiepileptics.

[0067] The pharmaceutical composition of the present invention can include the polymorph of the present invention in a pure, substantially pure or partially pure form. In some embodiments, the substantially pure form can include at least 95wt% of the polymorph, such as 96wt%, 97wt%, 98wt% or more than 99wt% of the polymorph.

[0068] The composition can be formulated as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, automatic syringes, suppositories, creams or gels. The composition can be suitable for oral, enteral, parenteral, intrathecal, intranasal, sublingual, rectal or topical administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.

[0069] To prepare solid dosage forms such as tablets, the polymorphs may be mixed with one or more pharmaceutical excipients, for example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, or other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a substantially uniform mixture of the polymorphs, such that the polymorphs are evenly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules.

[0070] The solid preformulation composition is then subdivided into unit dosage forms of the type described above, each containing 0.1 mg to about 500 mg of the polymorph of the invention. Advantageous unit dosage forms contain 1-500 mg, for example 1, 5, 10, 25, 50, 100, 300 or 500 mg of the polymorph of the invention.

[0071] When being mixed with tablet or pill, described tablet or pill can be coated or otherwise mixed to provide the dosage form with the advantage of long-acting effect.For example, described tablet or pill can comprise inner dosage and outer dosage component, and the latter exists with coating form relative to the former.These two components can be separated by the enteric layer for resisting the disintegration in the stomach, and allow the inner component to enter the duodenum intact or be delayed release.The various materials used in this enteric layer or coating are known, and these materials comprise the mixture of many polymeric acids and polymeric acids and materials such as shellac, cetyl alcohol and cellulose acetate.

[0072] Alternatively, the pharmaceutical composition of the present invention can be formulated into a liquid dosage form for oral administration or administration by injection; for example, an aqueous solution, a suitably flavored syrup, an aqueous suspension or an oil suspension or a flavored emulsion with an edible oil (e.g., cottonseed oil, sesame oil, coconut oil or peanut oil), and an elixir or similar pharmaceutical carrier. Suitable dispersants or suspending agents for aqueous suspensions include synthetic or natural gums, for example, tragacanth, gum arabic, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

[0073] In addition, the present invention also relates to a method for treating or preventing pain, inflammation and / or autoimmunity in a human or non-human animal patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of polymorph 2 or a pharmaceutical composition containing polymorph 2. In this method, polymorph 2 is administered at a daily dose of 0.1 mg to 15 g. Polymorph 2 is preferably administered orally.

[0074] Unless specifically stated otherwise, the following definitions apply throughout the specification.

[0075] For example, the "treatment" of a disorder or disease may result in a cessation of progression of the disorder or disease (e.g., no worsening of symptoms) or a delay in the progression of the disorder or disease (when the cessation of progression is only temporary). The "treatment" of a disorder or disease may also result in a partial response (e.g., symptom improvement) or a complete response (e.g., disappearance of symptoms) in a subject / patient with the disorder or disease. Therefore, the "treatment" of a disorder or disease may also refer to the improvement of the disorder or disease, for example, which may result in a cessation of progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It should be understood that the subject / patient may experience a wide range of responses to treatment (e.g., exemplary responses as described herein above). The treatment of a disorder or disease may include, in particular, curative treatment (e.g., changing the disease, preferably resulting in a complete response and ultimately resulting in a cure of the disorder or disease) and palliative treatment (including symptom relief).

[0076] The terms "prevent" or "prevent" a condition or disease as used herein are also well known in the art. For example, a patient / subject suspected of being susceptible to a condition or disease may particularly benefit from the prevention of the condition or disease. The subject / patient may have a susceptibility or a predisposition to the condition or disease, including but not limited to a genetic predisposition to the condition or disease. Such a predisposition to the condition may be determined by standard methods or analysis using, for example, genetic markers or phenotypic indicators. It should be understood that the condition or disease to be prevented according to the present invention has not yet been diagnosed in the patient / subject or cannot be diagnosed (e.g., the patient / subject does not have any clinical or pathological symptoms). Therefore, the term "prevent" or "prevention" includes the use of the polymorphs described in the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0077] The term "about" preferably refers to ±10% of the indicated numerical value, more preferably ±5% of the indicated numerical value, and especially the indicated exact numerical value. For example, the expression "about 100" preferably refers to 100±10% (i.e. 90 to 110), more preferably 100±5% (i.e. 95 to 105), and even more preferably a specific value of 100. If the term "about" is used in conjunction with the endpoints of a range, it preferably refers to a range from a lower endpoint that is 10% lower than its indicated numerical value to an upper endpoint that is +10% higher than its indicated numerical value, more preferably a range from a lower endpoint that is 5% lower than its indicated numerical value to an upper endpoint that is +5% higher than its indicated numerical value, and even more preferably a range defined by the exact numerical values ​​of the lower and upper endpoints. Therefore, the expression "about 10 to about 20" preferably refers to a range from 9 to 22, more preferably a range from 9.5 to 21, and even more preferably a range from 10 to 20. If the term "about" is used in conjunction with an end point of an open-ended range, it preferably refers to the corresponding range starting from 10% of the lower end point or from +10% of the upper end point, more preferably the corresponding range starting from 5% of the lower end point or from +5% of the upper end point, and even more preferably the open-ended range defined by the exact numerical values ​​of the corresponding end points. For example, the expression "at least about 10%" preferably means at least 9%, more preferably at least 9.5%, and even more preferably at least 10%.

[0078] The terms "optional", "optionally" and "may" mean that the indicated feature may be present but may also be absent. Whenever the terms "optional", "optionally" or "may" are used, the present invention specifically relates to both possibilities, i.e., the presence of the corresponding feature, or alternatively, the absence of the corresponding feature. For example, if it is indicated that a component of a composition is "optional", the present invention specifically relates to both possibilities, i.e., the presence of the corresponding component (included in the composition) or the absence of the corresponding component in the composition.

[0079] Unless expressly stated otherwise or contradictory by context, the term "comprising" (or "covering", "including", "containing", "including" or "containing") means "including, especially", i.e., "including, in addition to other optional elements, also ...". In addition, the term also includes the narrower meanings of "essentially consisting of" and "consisting of". For example, the term "A comprises B and C" has the meaning of "A especially contains B and C", where A may also contain other optional elements (e.g., "A contains B, C and D" would also be included), but the term also includes the meaning of "A essentially consists of B and C" and the meaning of "A consists of B and C" (i.e., no other components except B and C are included in A).

[0080] Any parameter referred to herein (for example, including any amount / concentration expressed as "mg / ml" or "% (v / v)", and any pH value) should preferably be determined under standard ambient temperature and pressure conditions, in particular at a temperature of 25°C (298.15K) and an absolute pressure of 1 atm (101.325 kPa).

[0081] It should be understood that the present invention is specifically directed to each and every combination of features and embodiments described herein, including any combination of typical and / or preferred features / embodiments.

[0082] In this specification, many documents including patent applications and scientific literature are cited. Although the disclosures of these documents are not considered relevant to the patentability of the present invention, their entire contents are incorporated herein by reference. More specifically, all cited documents are incorporated by reference to the same extent as follows: just as if each individual document was specifically and individually indicated to be incorporated by reference.

[0083] Example

[0084] The embodiments of the present invention are given purely for illustrative and non-limiting purposes.

[0085] Example 1 - (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide preparation

[0086] (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide was prepared as described in WO 2013 / 084238 and US 2011 / 0086910.

[0087] In the first step, 2g of methyl lactate is reacted with excess benzyl bromide to obtain 880mg (S)-benzyloxymethyl lactate. The reaction is carried out by slurrying sodium hydride in THF and cooling to about -15°C. Then, the reaction mixture is slowly warmed to room temperature and stirred for about 1-2 hours. The reaction is quenched with saturated ammonium chloride solution and extracted twice with MTBE, and then the solvent is removed on a rotary evaporator to obtain a crude oil. The crude product is purified by column chromatography to obtain pure (S)-2-benzyloxymethyl lactate. (R)-2-benzyloxymethyl lactate isomers are present only at 0.93%. The yield of this step can be improved by avoiding the presence of moisture in the reaction solution.

[0088] In the second step, 880 mg of (S)-2-benzyloxymethyl lactate obtained in step 1 was reduced with lithium aluminum hydride to obtain (S)-2-benzyloxypropanediol with a purity of 98.7% in a yield of 83.8%. A solution of pure (S)-2-benzyloxymethyl lactate in dichloromethane was stirred and the lithium aluminum hydride solution was slowly added to it at about 5°C. The reaction was monitored by TLC and quenched very carefully with USP-PW water. No racemization occurred in this step.

[0089] Then, in the third step, (S)-2-benzyloxypropanediol was reacted with methanesulfonyl chloride in dichloromethane in the presence of triethylamine to give the mesylate in 88% yield. The solution from step 2 was stirred in dichloromethane and methanesulfonyl chloride was added dropwise at <5°C. After the addition was complete, the progress of the reaction was monitored by TLC. The reaction was quenched with USP-PW water. After the layers were separated, the aqueous layer was stripped with dichloromethane. The dichloromethane layers were then combined and washed 3 times with USP-PW water to remove most of the methanesulfonic acid. No racemization occurred in this step.

[0090] In the fourth step, the mesylate (of step 3) is coupled with SO-benzyltyrosinol to form a double protected product in 22.7% yield with a purity of 97.4%. The reaction is carried out at room temperature using a combination of DMF as solvent and sodium hydride as a base. After stirring at room temperature for at least 12 hours, the reaction is complete.

[0091] In the fifth step, 340 mg of the product of step 4 was reduced by hydrogenation at 50° C. using dichloromethane as a solvent in the presence of a 10% palladium carbon catalyst and hydrochloric acid. The reaction was completed in about 4 hours without racemization, and the desired product was obtained in a yield of 84.3% and a purity of 98.9%. More specifically, the catalyst was removed by filtration, and the filtrate was then concentrated at 33° C. The resulting mixture of solid and oil was mixed with ethyl acetate. The resulting slurry was filtered, and the solid was washed with ethyl acetate and dried under vacuum at 40-45° C. to obtain the desired product.

[0092] Example 2 - Preparation of Polymorph 2

[0093] (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide (500 mg) was suspended in water (5 mL) and the resulting suspension was shaken and temperature cycled between 40°C and 25°C every 4 hours for 72 hours. Excess water was drained as far as practicable using a syringe and needle. Thereafter, the product was dried, first by evaporating the water at ambient temperature and then drying under vacuum at 50°C until constant weight was reached.

[0094] Methods for the analysis of polymorphs

[0095] X-ray powder diffraction (XRPD)

[0096] About 5 mg of sample was gently compressed on an XRPD zero background single bevel cut silica sample holder. The sample was then loaded into a Philips X-Pert MPD diffractometer and analyzed using the following experimental conditions.

[0097] Tube anode: copper

[0098] Generator tension: 40kV

[0099] Tube current: 40mA

[0100] Wavelength α1:

[0101] Wavelength α2:

[0102] Starting angle [2θ]: 5

[0103] End angle [2θ]: 50

[0104] Continuous Scan

[0105] Representative X-ray data were acquired in the range of 4-40° 2Θ at a slower scan speed.

[0106] Raman spectroscopy

[0107] Raman

[0108] Raman spectra were acquired on a Bruker RFS 100 / S using an excitation wavelength of 1064 nm. Samples for analysis were prepared by placing the material in a sample holder and placing it in the spectrometer.

[0109] Simultaneous Thermal Analysis (STA)

[0110] In this article, simultaneous thermal analysis (STA) refers to the simultaneous application of thermogravimetric analysis (TGA) and differential thermal analysis (DTA) to the same sample in a single instrument.

[0111] About 5 mg of sample was accurately weighed into a ceramic crucible and then placed in the chamber of a Perkin-Elmer STA 600 TGA / DTA analyzer at ambient temperature (25°C). The sample was then heated at a rate of 10°C / min, typically from 25°C to 300°C, during which the weight change and DTA signal were monitored. The purge gas used was nitrogen at a flow rate of 20 cm 3 / min

[0112] Differential Scanning Calorimetry (DSC)

[0113] DSC was investigated with a Netzsch-DSC 204F1 Phoenix. Approximately 5-6 mg of sample was placed in the DSC pan. The analysis was carried out in a sealed aluminum pan with a small hole. Under a nitrogen atmosphere, the sample was heated from 25°C to 125°C at a rate of 10 K / min.

[0114] Scanning electron microscopy (SEM)

[0115] Scanning electron microscopy was performed using a Tescan Vega 3 scanning electron microscope operated at 15 KV and a slight tilt of 15°.

[0116] Prior to analysis, samples were prepared by adhering them to the SEM stub using double-sided carbon-impregnated adhesive tabs supplied by Agar Scientific.

[0117] The prepared sample stage was then coated with 15 nm of gold using a Quorum Q150ES sputter coater.

[0118] Gravimetric Vapor Sorption (GVS)

[0119] Approximately 10 mg of sample was placed in a wire mesh vapor sorption balance and loaded onto an "IgaSorp" vapor sorption balance (Hiden Analytical Instruments). The sample was then dried in an environment maintained at 0% humidity until no further weight change was recorded. The sample was then subjected to a gradient curve from 0-90% RH in increments of 10% RH, with the sample held at each step until equilibrium was reached (99% of the steps were completed). Once equilibrium was reached, the % RH within the device was raised to the next step and the equilibrium procedure was repeated. After the adsorption cycle was complete, the sample was then dried using the same procedure. The weight change during the adsorption / desorption cycle was then monitored to determine the hygroscopicity of the sample.

[0120] Polymorph analysis results

[0121] The obtained XRPD is as follows Figure 1 A list of the observed peaks is provided below.

[0122] Table 1

[0123]

[0124]

[0125] The molecular weight of (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide was measured before and after crystallization to obtain polymorph 2. 1 H-NMR spectrum. These hydrogen spectra, if consistent with each other, indicate that no chemical conversion has occurred.

[0126] STA data showed no weight loss, indicating that the sample was not hydrated or solvated. DTA thermogram (see Figure 4 ) shows a sharp melting with an onset at about 104.5 °C.

[0127] Scanning electron microscopy (SEM) (see Figure 2 ) showed that this crystal form has a regular rectangular blocky habit with particle sizes ranging from 2-10 μm in length and 2-5 μm in width.

[0128] GVS showed that the sample was only slightly hygroscopic, with a weight increase of 0.6% for 80% RH, indicating that Form 2 is less hygroscopic than Form 1. There was a sharp weight loss at 90% RH for both cycles, which may be the result of further crystallization of the amorphous content. This resulted in an overall weight loss of ~1% at the end of both sorption / desorption cycles, but XRPD showed no change in polymorph.

[0129] Example 3 - Bioavailability of Polymorphs 1 and 2

[0130] This study was designed to obtain plasma samples to compare the bioavailability and pharmacokinetics of two different polymorphs 1 and 2 after single oral dose administration to six dogs. A crossover design was used for three dogs treated with sequence 1 (polymorph 1 followed by polymorph 2) and three dogs treated with sequence 2 (polymorph 2 followed by polymorph 1) with a washout period of one week between treatments.

[0131] The concentration-time curves after treatment with both polymorphs were characterized by rapid absorption, a peak concentration, and a sharp decline in concentration; at 4 hours and beyond, a second hump in the curves suggested enterohepatic recirculation.

[0132] The drug exposure, maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) measurements appeared to be higher after administration of polymorph 2 compared to polymorph 1. The least squares (LS) geometric mean estimate of AUC (0-∞) (corrected to a 60.0 mg dose) was 13170 h.ng / mL for polymorph 1 and 20064 h.ng / mL for polymorph 2 (p=0.0016). The corresponding C maxThe values ​​(corrected for a 60.0 mg dose) were 4986 ng / mL (polymorph 1) and 11088 ng / mL (polymorph 2), respectively (p=0.0009). Therefore, the geometric mean ratio of AUC measurements (polymorph 2 / polymorph 1) was 1.52 (90% CI: 1.35, 1.71), and the geometric mean ratio of Cmax measurements (polymorph 2 / polymorph 1) was 2.22 (90% CI: 1.84; 2.70). If the individual parameters were not corrected for dose differences, or if the AUC values ​​that were not extrapolated were analyzed, the results and conclusions obtained from the analysis were also different. These differences between the polymorphs indicate that polymorph 2 has a higher usability.

[0133] Polymorph 1 was provided by Quay Pharmaceuticals as a white powder and was stored at room temperature in the testing facility. A copy of the analytical data sheet for NRD 135S.E1 Form 1 is available at Figure 5 shown.

[0134] Polymorph 2 was prepared as described above. A copy of the analytical data sheet for NRD 135S.E1 Form 2 is provided as Figure 6 shown.

[0135] Each polymorph was prepared as a suspension in sterile water in a vehicle of 0.5% w / v HPMC K15M / 0.5% w / v Tween 80.

[0136] Six male beagle dogs (tattoo numbers: 4986, 0964, 3611, 2380, 5002 and 1122, research animal numbers 001M, 002M, 003M, 004M, 005M and 006M, respectively) weighing 9.5-11.5 kg and aged 2-7 years at the time of dosing, currently part of the animal population (population number: 190431) were used for this study. The dogs were originally obtained from MarshallFarms USA (New York, USA) or Envigo RMS and were bred for scientific procedures. During the pre-experimental and study period, the animals were group-housed in cages appropriate for the species. Prior to acceptance for the study, the animals were examined by a veterinarian and found to be satisfactory. The holding and study areas had automatic control of the photoperiod and temperature. The photoperiod was 0700-1900 hours. The temperature and humidity ranges measured during the study were 17.0-21.8°C and 23.4-83.07%, respectively. All animals were weighed and body weights were recorded before each dose administration. Except for the fasting period from overnight before administration to 4 hours after administration, 200-300 g of standard laboratory diet of known preparation (SDS D3 (E) SQC) was allowed per day. Mains quality tap water was available ad libitum.

[0137] The formulation was always prepared on the morning of dosing. Each polymorph was prepared as a suspension in sterile water for injection at a concentration of 12 mg / mL in a vehicle of 0.5% w / v HPMC K15M / 0.5% w / v Tween 80. The required volume of vehicle was added to a suitable formulation container.

[0138] The volume of carrier required is calculated as follows:

[0139] V=(K×D)×1.25

[0140] in:

[0141] V = Final volume

[0142] K = kg of dose to be administered

[0143] D = administration volume (mL / kg)

[0144] 1.25 = Overdose

[0145] Weigh the test item accurately using the appropriate conversion factor and the following formula:

[0146] W=(C×V×100) / P

[0147] in:

[0148] W = Required weight (mg)

[0149] C = target formulation concentration (mg / mL, free base)

[0150] V = Final volume

[0151] P = Purity of free base (polymorph 1 = 98.1%, polymorph 2 = 98.7%)

[0152] Then, a small amount of the test item (under magnetic stirring) is added to the same container as the dose vehicle. Next, the formulation is placed under magnetic stirring for 15 minutes. The Ultraturrax homogenizer is used at an average speed for 15 minutes to obtain a uniform suspension. The formulation is then placed under magnetic stirring until a uniform suspension is obtained. The pH of the formulation is measured and the value is recorded. If the pH is below 3, it is adjusted to above level 3 by adding 1 M NaOH. After the formulation is completed, 3×100 μL dose aliquots are taken. The dose aliquots and any remaining formulation are stored at -80°C until shipping.

[0153] The following table shows a summary of each formulation:

[0154] Table 2

[0155]

[0156] Three male dogs in each group received a single oral dose of one polymorph at the target dose level of 60 mg / kg. After a 1-week washout period, three male dogs in each group received the other polymorph.

[0157] Animals were dosed according to the following table:

[0158] Table 3

[0159]

[0160] 1 Target value

[0161] For each group, whole blood samples (approximately 1.0 mL) were collected from the jugular vein into NaF / EDTA tubes at the following time points:

[0162] Before administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 25 hours after administration.

[0163] The times given above are target times and should be adhered to as closely as possible. The actual times of sample collection (and dosing) were recorded (Table 2) and used to assess pharmacokinetic parameters. Blood samples were placed on wet ice immediately after collection. Blood samples were centrifuged as quickly as possible (1500 g, 10 minutes at +4°C). The resulting plasma was divided into two aliquots (vial A: 100 μL plasma, vial B: remaining volume of plasma) and stored in appropriately labeled polypropylene tubes in a freezer to maintain a temperature of -80°C until shipment. All plasma samples, remaining dose preparations, and dose aliquots were stored in a freezer to maintain a temperature of -80°C until shipment.

[0164] Pharmacokinetic (PK) parameters were estimated using Phoenix Pharmacokinetics software using a non-compartmental approach consistent with the oral route of administration. All parameters were generated from individual concentrations of polymorphs 1 and 2 in plasma. Parameters were estimated using nominal sampling times relative to the start of each dose administration within the allowed deviation range (± 10%). Pre-dose samples below the limit of quantitation (0.5 ng / ml) were assumed to be 0 for PK analysis.

[0165] The area under the plasma concentration-time curve (AUC) for polymorphs 1 and 2 was calculated using the linear trapezoidal method with linear interpolation. The terminal elimination phase of each concentration-time curve was determined by visual inspection of the semi-logarithmic concentration-time plots. Due to irregularities in the curves caused by enterohepatic recycling of the drug in most cases, only the last two observed concentration values ​​could be used in this calculation. The slope of the terminal elimination phase was determined using log-linear regression of the unweighted concentration data. Parameters that depend on the determination of the terminal elimination phase are not reported (NR) if the determined coefficient is less than 0.800 and / or the AUC extrapolated to infinity represents more than 20% of the total area. The parameters described in Table 1 of the text are reported to 3 significant figures, with the exception of Tmax, which is reported as no more significant than the number required to interpret the time. Other parameters are automatically generated by Phoenix and are not required by the protocol but are retained in the original data.

[0166] Table 4

[0167]

[0168] The relative bioavailability of the polymorphs was statistically analyzed. The calculation was performed according to the FDA guidance document (Statistical Approaches to Establishing Bioequivalence) as follows:

[0169] AUC(0-∞), AUC(0-t), and Cmax values ​​with and without normalization for dose differences after natural logarithmic transformation were analyzed using linear mixed-effects model procedures including: sequence terms, subjects nested within sequences, periods, and treatment conditions (polymorphs). In addition, terminal elimination rate constants and their related half-lives, clearance (CL / F), and volume of distribution (V / F) were statistically compared using the same analytical approach. All statistical analyses used v9.4; the SAS code is provided in Appendix 3A and the output of the procedure is provided in Appendix 3B. Using the error variance obtained from the model, the least squares means of the differences between the new polymorph and the old polymorph and their 90% CIs were estimated. The point and interval estimates were back-transformed to give estimates of the ratios of the geometric means of the new polymorph relative to the old polymorph. For Tmax, the median difference between polymorphs 1 and 2 and their 90% CIs were calculated.

[0170] All oral administrations of polymorphs 1 and 2 were performed without incident. No adverse effects of oral administration were observed in animals at any dose. Details of body weight and dosing are as follows Figure 7All blood samples were collected at or close to the target sampling time (±6 minutes). The actual blood sampling time is shown in Figure 8 Data generated from plasma samples collected at the testing facility and subsequently shipped to the sponsor's representative for bioanalysis were used to generate pharmacokinetic parameters for Polymorphs 1 and 2. The results of the plasma analysis of the quality control samples provided assurance for the results reported for the sample studies performed.

[0171] The individual plasma concentration results of Forms 1 and 2 are as follows Fig. 9 shown.

[0172] The average and individual pharmacokinetic parameters of Forms 1 and 2 are shown in Fig.10 and Fig.11 The average concentration-time curves of Forms 1 and 2 after oral administration are shown in Fig.12 The individual concentration-time curves of Forms 1 and 2 are shown in Figure 13-16 shown.

[0173] After thawing of the aliquots reserved from the dosing formulation and each individual final dosing suspension, a homogeneous suspension could no longer be obtained and no valid concentration results could be obtained from them.

[0174] The overall pattern of the concentration-time curves between the two polymorphs is similar. After administration of either polymorph, the absorption of NRD135S.E1 is rapid. In many cases, the peak plasma concentration has been reached at or before the first sampling time point (0.25 hours), and Tmax will not be longer than 0.5h in any case. Subsequently, the concentration drops rapidly, reaching the first trough concentration at about 4 hours, which is at most 1 / 10 of the concentration initially reached. After this time point - consistent with the dog's re-access to food - the concentration rises again to form a second (low) peak, and then drops again. The secondary concentration increase suggests enterohepatic recirculation of the drug, and has been previously noted in rats (e.g., see study 12NVMDP1R1), dogs (see study VPT1468) and humans (see study NRD135S.E1.101). The irregularity of the concentration decline prevents accurate estimation of the elimination half-life. However, in the same animals, these terminal declines were generally very similar for both polymorphs, supporting an estimated mean half-life of approximately 3-4 hours for NRD135S.E1. Because the extrapolated portion of AUC(0-∞) was small (no more than 6%), AUC(0-∞) and hence the disposition parameters CL / F and V / F could still be reliably estimated. Both measured exposures to the drug appeared to be higher after administration of polymorph 2 than after administration of polymorph 1. The least squares (LS) geometric mean estimate of AUC(0-∞) (corrected to a 60.0 mg dose) was 13170 h.ng / mL for polymorph 1 (141232) and 20064 h.ng / mL for polymorph 2 (COEN4-91-M). The corresponding C max The values ​​(corrected for a 60.0 mg dose) were 4986 ng / mL (polymorph 1) and 11088 ng / mL (polymorph 2), respectively. These differences between the polymorphs indicate a higher usefulness of NRD135S.E1 when polymorph 2 is given. Polymorph 2 is thermodynamically more stable than polymorph 1, and such a result was not expected.

[0175] The results of the statistical analysis are given in Table 6. The new polymorph (polymorph 2) was found to have higher exposure than the old polymorph (polymorph 1). The least squares geometric mean estimates of AUC for the new polymorph were extrapolated to infinity (corrected for dose)<AUCINF_obs_D> The difference was statistically significant (p = 0.0016). The difference in maximum concentration was even higher, with the point estimate of the Cmax value (corrected for dose differences) being 2.22 times higher for the new polymorph than for the old polymorph (90% CI: 1.84; 2.70). The results and conclusions from the analysis did not differ if the individual parameters were not corrected for dose differences, or if the AUC values ​​were analyzed without extrapolation.

[0176] Although the extent of absorption was clearly different, there was no difference in the rate of absorption between the two polymorphs as judged by the time required to reach maximum concentration (Tmax). There were no differences in the elimination rate constants or observed half-lives following administration of the two polymorphs.

[0177] The concentration-time curves of NRD135S.E1 after administration of both polymorphs were characterized by rapid absorption, a peak concentration, and a sharp drop in concentration; at 4 hours and later, a second hump in the curve suggested enterohepatic recirculation.

[0178] Drug exposure measures, maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) appeared higher after administration of polymorph 2 compared to polymorph 1. The geometric mean ratio of AUC measurements obtained (polymorph 2 / polymorph 1) was 1.52 (90% CI: 1.35, 1.71), and the geometric mean ratio of Cmax measurements obtained (polymorph 2 / polymorph 1) was 2.22 (90% CI: 1.84; 2.70). The results and conclusions obtained from the analysis were not different if the individual parameters were not corrected for dose differences or if the AUC values ​​were analyzed without extrapolation. These differences between the polymorphs suggest a higher usability of NRD135S.E1 when polymorph 2 is given.

[0179] Although the extent of absorption was clearly different, there was no difference in the absorption rate between the two polymorphs as judged by the time required to reach maximum concentration (Tmax), and there were no differences in the elimination rate constants or observed half-lives following administration of the two polymorphs.

[0180] A relevant but statistically insignificant effect of sequence on Cmax was observed for the ratio of sequence 1 to sequence 2, estimated at 1.38 (90% CI: 1.06; 1.79). This effect on sequence reduces the precision with which the exposure difference between the two polymorphs can be estimated.

Claims

1. A polymorph of a compound having the formula: ， in, The melting point of the polymorph is in the range of 105°C to 110°C; wherein the X-ray powder diffraction pattern obtained using Cu Kα radiation comprises peaks at 19.0±0.2°2θ, 11.25±0.2°2θ, 17.38±0.2°2θ, 17.57±0.2°2θ, 20.74±0.2°2θ, 20.91±0.2°2θ, 22.42±0.2°2θ and 23.30±0.2°2θ.

2. The polymorph according to claim 1, wherein The melting point of the polymorph is 106°C to 109°C.

3. The polymorph according to claim 2, wherein: The melting point of the polymorph is 107°C to 108°C.

4. The polymorph according to claim 1, wherein The melting enthalpy of the polymorphs is in the range of 100 J / g to 140 J / g.

5. The polymorph according to claim 4, wherein The melting enthalpy of the polymorph is in the range of 110 J / g to 130 J / g.

6. The polymorph according to claim 5, wherein The melting enthalpy of the polymorph is in the range of 115 J / g to 125 J / g.

7. Use of the polymorph according to any one of claims 1 to 6 in the preparation of a medicament for treating or preventing pain.

8. Use of the polymorph according to any one of claims 1 to 6 in the preparation of a medicament for treating or preventing inflammation and / or autoimmunity.

9. A pharmaceutical composition for treating or preventing pain, inflammation and / or autoimmunity, the pharmaceutical composition comprising a pharmaceutically effective amount of one or more polymorphs according to any one of claims 1 to 6, and one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 9, wherein The pharmaceutical composition is formulated in unit dosage form.

11. The pharmaceutical composition according to claim 10, wherein The unit dosage form contains 0.1 mg to 500 mg of one or more of the polymorphs.

12. The pharmaceutical composition according to any one of claims 9 to 11, which is administered orally.

Images