Azaspiro derivative salt

Abstract

The present invention relates to novel salts of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione. More particularly, the invention relates to benzenesulfonic acid salt (BSA-salt). The invention also relates to processes for the preparation of the salts, compositions containing the salts, and uses of the salts.

Description

AZASPIRO DERIVATIVE SALT　The present invention relates to novel salts of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione　 which may be called Compound A through the present specification. More particularly, the invention relates to benzenesulfonic acid salt (BSA-salt). The invention also relates to processes for the preparation of the salts, compositions containing the salts, and uses of the salts.　Transient receptor potential (TRP) channels are one of the largest groups of ion channels, and they are divided into 6 sub-families (TRPV, TRPM, TRPA, TRPC, TRPP and TRPML). TRP channels are cation-selective channels that are activated by a variety of physical (e.g. temperature, osmolarity, mechanical) and chemical stimuli. Transient Receptor Potential Melastatin 8 (TRPM8) is a member of TRP channel family. The receptor was cloned in 2002 (NPL 1; and NPL 2) and it was found to be sensitive to cold temperature and menthol, and therefore named as cold menthol receptor-1 (CMR-1). TRPM8 can sense temperature changes in the range of both innocuous cold (15-28oC) and noxious cold (<15oC) as well as by chemical agents such as menthol and icilin.　TRPM8 is located on primary nociceptive neurons including A-delta and C-fibers and is also modulated by inflammation-mediated second messenger signals (NPL 3; and NPL 4). The localization of TRPM8 on both A-delta and C-fibers may provide a basis for abnormal cold sensitivity in pathologic conditions wherein these neurons are altered, resulting in pain, often of a burning nature (NPL 5; NPL 6; NPL 7; NPL 8; and NPL 9). Gauchan, P., et al. reported that the expression of TRPM8 in the primary afferents was increased in oxaliplatin-induced cold allodynia model in mice (NPL 10). Oxaliplatin, a third-generation platinum-based chemotherapy drug, induces serious sensory neurotoxicity in patients, which is aggravated by exposure to cold. Recently, Glenmark group reported that the small molecular TRPM8 antagonists produced a dose-dependent inhibition of nocifensive paw licking in oxaliplatin-induced cold allodynia in mice (NPL 11).　8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (Compound A) is disclosed in WO2015 / 136947 (PL1) as a TRPM8 antagonist, which is useful in the treatment or alleviation of disease conditions mediated by TRPM8 receptor antagonistic activity; in particular TRPM8 receptor antagonistic activity, such as wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, including wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, pain including chronic pain, neuropathic pain including cold allodynia and diabetic neuropathy, postoperative pain, osteoarthritis pain, rheumatoid arthritic pain, cancer pain; neuralgia; neuropathies; algesia; dentin hypersensitivity; nerve injury; migraine; cluster and tension headaches; ischaemia; irritable bowel syndrome; Raynaud's syndrome; neurodegeneration; fibromyalgia; stroke; itch; psychiatric disorders including anxiety and depression, anxiety including other stress-related disorders; inflammatory disorders including asthma, chronic obstructive pulmonary, airways disease including COPD (chronic obstructive pulmonary disease), pulmonary hypertension; urological diseases or disorders including detrusor overactivity or overactive bladder, urinary incontinence, neurogenic detrusor overactivity or detrusor hyperreflexia, idiopathic detrusor overactivity or detrusor instability, benign prostatic hyperplasia, and lower urinary tract symptoms; vasomotor symptoms; and combinations thereof.　A generic disclosure of pharmaceutically acceptable salts of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione of the instant application is disclosed, and the free base of the compound of the present invention is disclosed in PL 1.　Thus any salts of the compound have been neither practically described nor synthesized in prior art.　It has been found that BSA-salt of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione shown below, can be isolated as a crystalline form which has advantageous properties such as ease of making a formulation, high solubility, good stability, and high exposure.{PL 1} WO2015 / 136947{NPL 1} McKemy, D.D., et al., Nature 416, 52-58, 2002{NPL 2} Peier, A.D., Cell 108, 705-715, 2002{NPL 3} Abe, J., et al., Neurosci Lett, 397(1-2), 140-144, 2006{NPL 4} Premkumar, L.S., et al., J. Neurosci, 25(49), 11322-11329, 2005{NPL 5} Kobayashi, K., et al., J Comp Neurol, 493(4), 596-606, 2005{NPL 6} Roza, C, et al., Pain, 120(1-2), 24-35, 2006{NPL 7} Xing, H., et al., J Neurophysiol, 95(2), 1221-30, 2006{NPL 8} European Journal of Pharmacology, 716, Issues 1-3, 61-76, 2013{NPL 9} PAIN, 152, Issue 10, 2211-2223, 2011{NPL 10} Gauchan, P., et al., Neurosci Lett, 458, 93-95, 2009{NPL 11} Sachin, S. Chaudhari, et al., Bioorg. Med. Chem, 21, 6542-6553, 2013　As well-known by skilled in the art, it has been a desirable goal to find or to prepare a salt form in drug development from the various viewpoints including formulation and manufacturing of the drug. This is the most widely used approach to increase solubility of weakly acidic or basic NCEs (new chemical entities). (see e.g. Wadke, D. A. et al., Pharmaceutical Dosage Forms: Tablets, Vol. 1, 1989, pp 1-73). The advantages of a salt are typically driven by the counter ion and selection of counter-ion is based on many parameters such as solubility, hygroscopicity and stability of the physical form. In spite of the numerous advantages associated with salt forms, developing a stable salt is not always feasible. In many cases, increased dissolution rate is difficult to achieve because of the reconversion of salts into their respective acid or base forms.　According to the line, great efforts have been made to find or prepare a salt form of Compound A which was disclosed in 2015 (WO2015 / 136947, PL 1), but no pharmaceutically suitable salt forms of the said compound have been identified yet.　As disclosed in the working example of the present invention, Compound A (8.27 g, 19.96 mmol) is suspended in acetone (500 mL) at room temperature and to which benzenesulfonic acid (anhydrous, 98% purity, 3.22 g, 19.96 mmol) in acetone (10 mL) is added. The mixture is stirred at 40oC overnight, then gradually cooled down to room temperature. Resulting precipitates are collected by filtration, and dried in vacuo to give the Compound A BSA-salt.　Various salts including, HCl-salt, HBr-salt, sulfuric acid salt, methanesulfonic acid salt, ethanesulfonic acid salt, p-toluenesulfonic acid salt, 1,2-ethane disulfonic acid salt, (+)-(1S)-camphor-10-sulfonic acid salt, napthalene-2-sulfonic acid salt, naphthalene-1,5-disulfonic acid salt, and oxalic acid salt other than the BSA-salt are prepared in the following manner. Namely a solid of the said Compound A is dissolved or suspended in an appropriate solvent which includes acetone, acetonitrile, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, methanol, methylethyl ketone, 2-propanol, N-methylpyrrolidone, tert-butylmethyl ether or tetrahydrofuran at 30oC to 70oC and to which a solution of the counterion source in an appropriate solvent which includes methanol, ethanol, 2- propanol, 1,4-dioxane, acetone, tetrahydrofuran and / or water is added. The mixture is stirred at room temperature to reflux temperature of the solvent, preferably at 40oC to 70oC, for 3 min to 72 hours, then gradually cooled down to room temperature. Resulting precipitates are collected by filtration, washed with an appropriate solvent which includes ethanol, ethyl acetate, acetonitrile, tetrahydrofuran or acetone, and dried in vacuo to give the corresponding salt.　In addition, once the seed of the salt is obtained, where applicable, the same salt can generally be easily obtained in a small scale synthesis. On large scale synthesis, temperature control is essential for preparing a pharmaceutically suitable salt.　It is an object of this invention to provide pharmaceutically suitable salt of Compound A, which can be easily, economically and reproducibly prepared for use in a pharmaceutical formulation having consistent performance characteristics, which are excellent in for example solubility, solubility rate, stability and non-hygroscopicity. Also it is an object of this invention to provide processes for the preparation of compositions containing such salt and to provide uses of such salt.　The Compound A with pyridazine moiety of weak basicity is preferred strong acids as counterion. The four acids of HCl, sulfuric acid, methanesulfonic acid, and benzenesulfonic acid (BSA) are selected from strong acids. Further, the solvent is also important factor for salt screening. The acetone, acetonitrile, and 1,4-dioxane are selected from solubility screening of Compound A. These combination of acids with solvents are performed, and the each salt form of Compound A is isolated. Then, each salt form is evaluated by stability, solubility, and reproducibility, and the Compound A BSA-salt is finally found.　Thus, the invention provides:[1] 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate.[2] The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in [1], which is characterized by NMR pattern obtained by measurement using DMSO-d6which includes main peaks at delta: 9.29 (d, 1H), 9.06 (br.s, 1H), 8.23 (d, 2H), 7.87 (d, 2H), 7.64-7.54 (m, 2H), 7.38-7.25 (m, 3H), 5.07 (s, 2H), 2.42 (s, 3H), 2.28-1.77 (m, 8H), wherein each peak has a margin of error of + / - 0.05 (ppm).[3] 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I, which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 16.8, 20.5 and 25.5 (°), wherein each peak has a margin of error of + / - 0.2 (°).[4] The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I as described in [3], which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 16.8, 18.2, 20.5, 25.5 and 28.5 (°), wherein each peak has a margin of error of + / - 0.2 (°).[5] The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I as described in [3] or [4], which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 16.8, 17.0, 18.2, 20.5, 22.8, 24.5, 25.2, 25.5, 27.1, 28.5, 29.4 and 32.7 (°), wherein each peak has a margin of error of + / - 0.2 (°).[6] The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I as described in any one of [3] to [5], which is further characterized by differential scanning calorimetry (DSC) in which it exhibits an endothermic event at 255.5oC (onset), wherein the temperature has a margin of error of + / - 2oC.[7] 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form II, which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 8.0, 15.6, 15.8, 17.5, 18.4 and 19.7 (°), wherein each peak has a margin of error of + / - 0.2 (°).[8] A pharmaceutical composition including 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of [1] to [7], together with one or more pharmaceutically acceptable excipients.[9] 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of [1] to [8] for use as a medicament.

[0010] A use of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of [1] to [7], or a pharmaceutical composition as described in [8], in the preparation of a medicament for the curative, palliative or prophylactic treatment of disease conditions mediated by TRPM8 receptor antagonistic activity.

[0011] A method of treating disease conditions mediated by TRPM8 receptor antagonistic activity, which comprises administering an effective amount of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of [1] to [7], or a pharmaceutical composition as described in [8], to an animal, including a human, in need of such treatment.

[0012] A process for preparing 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of [1] to [7], comprising the step of exposing 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione in an organic solvent with benzenesulfonic acid in an organic solvent.

[0013] A process for preparing 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I as described in any one of [1] to [6], comprising the step of converting the benzenesulfonate Form II described in [7] to the benzenesulfonate Form I.　As mentioned above, it is an object of the present invention to find or prepare a salt form in drug development from the various viewpoints including formulation and manufacturing of the drug. It has now been surprisingly found that this object has been achieved by the present invention, which provides salt forms of Compound A known as the BSA-salt, HCl-salt, sulfuric acid salt, and methanesulfonic acid salt. 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione may be abbreviated as the said Compound A throughout the specification.　Compound A is disclosed in WO2015 / 136947 (PL 1). BSA-salt of Compound A in the present invention has an excellent and unexpected advantage over the free forms disclosed in the prior art.　In addition, in terms of solubility, the Compound A BSA-salt of the present invention has an excellent and unexpected advantage over the free forms of the compound disclosed in the prior art.　As mentioned above, the Compound A BSA-salt has a good solubility and rapid solubility comparing with the free forms disclosed in the prior art, and particularly, the Compound A BSA-salt is 5.3 and 44.6 times higher than free forms disclosed in the prior art in rapid solubility test of two different methods. Therefore, Compound A BSA-salt is superior to absorption and suitable for drug development.　As mentioned above, the Compound A BSA-salt has a good PK profile in animals. In the comparison with 30 mg / kg, Cmaxand AUClastof Compound A BSA-salt demonstrate 1.7 and 1.4 times higher than that of the free forms of Compound A, respectively. Further, in the case of 100 mg / kg, Cmaxand AUClastof Compound A BSA-salt improve significantly 6.4 and 2.4 times higher than that of the free forms of Compound A, respectively. Therefore, Compound A BSA-salt is suitable for drug development.　The Compound A BSA-salt of the present invention is found to be applicable for a large scale synthesis. They have acceptable solid-state properties for solid-dosage form development.Figure 1 shows the NMR pattern of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione.Figure 2 shows the NMR pattern of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt.Figure 3 shows the PXRD pattern of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt (Form I).Figure 4 shows the DSC pattern of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt (Form I).Figure 5 shows the PXRD pattern of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt (Form II).Figure 6 shows the PXRD pattern of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione Free-form (Free- Form I).Figure 7 shows the DSC pattern of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5] decane-2,4-dione Free-form (Free- Form I).Figure 8 shows the solubility study of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5] decane-2,4-dione Free-form (Free- Form I) and 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt (Form I).Figure 9 shows the photostability study of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5] decane-2,4-dione BSA-salt (Amorphous) and 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt (Form I).Figure 10 shows the PXRD pattern of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5] decane-2,4-dione BSA-salt (Amorphous).　8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt (Form I), which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta 16.8, 17.0, 18.2, 20.5, 22.8, 24.5, 25.2, 25.5, 27.1, 28.5, 29.4 and 32.7 (o), wherein each peak has a margin of error of + / - 0.2 (o).　8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5] decane-2,4-dione BSA-salt (Form I) as described above, which is further characterized by differential scanning calorimetry (DSC) in which it exhibits an endothermic event at 255.5oC (onset), wherein the temperature has a margin of error of + / - 2oC.　In one embodiment of the present invention, there is provided a pharmaceutical composition including 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione salt form of the present invention, together with one or more pharmaceutically acceptable excipients.　As a further aspect of the invention, there is provided 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione salt form of the present invention for use as a medicament.　As a yet further aspect of the invention, there is provided the use of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione salt form of the present invention in the manufacture of a medicament for the treatment of any diseases which are mediated by TRPM8 receptor antagonistic activity, particularly for the curative, prophylactic or palliative treatment of inflammatory, pain and urological diseases or disorders, including wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, pain including chronic pain, neuropathic pain including cold allodynia and diabetic neuropathy, postoperative pain, osteoarthritis pain, rheumatoid arthritic pain, cancer pain; neuralgia; neuropathies; algesia; dentin hypersensitivity; nerve injury; migraine; cluster and tension headaches; ischaemia; irritable bowel syndrome; Raynaud's syndrome; neurodegeneration; fibromyalgia; stroke; itch; psychiatric disorders including anxiety and depression, anxiety including other stress-related disorders; inflammatory disorders including asthma, chronic obstructive pulmonary, airways disease including COPD, pulmonary hypertension; urological diseases or disorders including detrusor overactivity or overactive bladder, urinary incontinence, neurogenic detrusor overactivity or detrusor hyperreflexia, idiopathic detrusor overactivity or detrusor instability, benign prostatic hyperplasia, and lower urinary tract symptoms; vasomotor symptoms; and combinations thereof.　As an alternative aspect, there is provided a method for the treatment of any diseases which are mediated by TRPM8 receptor antagonistic activity, particularly for the curative, prophylactic or palliative treatment of inflammatory, pain and urological diseases or disorders, including wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, pain including chronic pain, neuropathic pain including cold allodynia and diabetic neuropathy, postoperative pain, osteoarthritis pain, rheumatoid arthritic pain, cancer pain; neuralgia; neuropathies; algesia; dentin hypersensitivity; nerve injury; migraine; cluster and tension headaches; ischaemia; irritable bowel syndrome; Raynaud's syndrome; neurodegeneration; fibromyalgia; stroke; itch; psychiatric disorders including anxiety and depression, anxiety including other stress-related disorders; inflammatory disorders including asthma, chronic obstructive pulmonary, airways disease including COPD, pulmonary hypertension; urological diseases or disorders including detrusor overactivity or overactive bladder, urinary incontinence, neurogenic detrusor overactivity or detrusor hyperreflexia, idiopathic detrusor overactivity or detrusor instability, benign prostatic hyperplasia, and lower urinary tract symptoms; vasomotor symptoms; and combinations thereof, including administration of a therapeutically effective amount of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione salt form of the present invention to an animal, including a human, in need of such treatment.　The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5] decane-2,4-dione salt form of the present invention is useful for the general treatment of disease conditions mediated by TRPM8 receptor antagonistic activity.　The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione salt form of the present invention can also be useful for the treatment of a disorder or condition selected from the group consisting of inflammatory, pain and urological diseases or disorders, including wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, pain including chronic pain, neuropathic pain including cold allodynia and diabetic neuropathy, postoperative pain, osteoarthritis pain, rheumatoid arthritic pain, cancer pain, neuralgia; neuropathies; algesia; dentin hypersensitivity; nerve injury; migraine; cluster and tension headaches; ischaemia; irritable bowel syndrome; Raynaud's syndrome; neurodegeneration; fibromyalgia; stroke; itch; psychiatric disorders including anxiety and depression, anxiety including other stress-related disorders; inflammatory disorders including asthma, chronic obstructive pulmonary, airways disease including COPD, pulmonary hypertension; urological diseases or disorders including detrusor overactivity or overactive bladder, urinary incontinence, neurogenic detrusor overactivity or detrusor hyperreflexia, idiopathic detrusor overactivity or detrusor instability, benign prostatic hyperplasia, and lower urinary tract symptoms; vasomotor symptoms; and combinations thereof.　In another embodiment of the present invention, there is provided 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione Free-form (Free Form I), which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 16.8, 17.7, 18.3, 19.1, 20.0, 21.4, 24.8 and 27.0 (°), wherein each peak has a margin of error of + / - 0.2 (°).　In another embodiment of the present invention, there is provided 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione Free-form (Free Form I), which is further characterized by differential scanning calorimetry (DSC) in which it exhibits an endothermic event at 257oC (onset), wherein the temperature has a margin of error of + / - 2oC.　Synthetic routes for the preparation of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione Free-form are described in WO2015 / 136947 (PL 1).　8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt can be prepared by exposing the compound A with benzenesulfonic acid.　Depending on the concentration of the compound, the reducing rate of temperature at the crystallization is generally lower than 70oC / hour at the concentration of about 0.1 mg / mL to about 200 mg / mL. Preferably lower than 50oC / hour, more preferably lower than 20oC / hour, and most preferably lower than 5oC / hour can be applied for the crystallization.　Preferable solvent for the salt preparation includes acetone, acetonitrile, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, methanol, methylethyl ketone, 2-propanol, tert-butylmethyl ether, or tetrahydrofuran, and more preferably acetone, acetonitrile and 1,4-dioxane.　The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione salt form of the present invention can be administered alone or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.　Thus, as a further aspect of the present invention, there is provided a pharmaceutical composition including 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione salt form and one or more suitable excipients. The composition is suitable for the treatment of disease conditions mediated by TRPM8 receptor antagonistic activity.　The term "salt form(s)", as used herein, includes HCl-salt, HBr-salt, BSA-salt, sulfuric acid salt, methanesulfonic acid salt, ethanesulfonic acid salt, p-toluenesulfonic acid salt, 1,2-ethane disulfonic acid salt, (+)-(1S)-camphor-10-sulfonic acid salt, napthalene-2-sulfonic acid salt, naphthalene-1,5-disulfonic acid salt, and oxalic acid salt.　For the avoidance of doubt, the term 'organic solvent' is used herein, but not limited to, water; acetonitrile; alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tert-butylmethyl ether, dioxane, and tetrahydrofuran; hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ketones such as acetone and methylethylketone; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Preferably examples of solvents which can be mixed with one or more solvents selected from: water; acetonitrile; alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tert-butylmethyl ether, dioxane, and tetrahydrofuran; hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ketones such as acetone and methylethylketone; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide.　The term 'solvent' is used herein, but not limited to, water; acetonitrile; alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tert-butylmethyl ether, dioxane, and tetrahydrofuran; hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ketones such as acetone and methylethylketone; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Preferably examples of solvents which can be mixed with one or more solvents selected from: water; acetonitrile; alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tert-butylmethyl ether, dioxane, and tetrahydrofuran; hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ketones such as acetone and methylethylketone; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide.　Weight purity of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione form of the present invention is not limited, but preferably an essentially pure salt form can be used for specific embodiments in this invention.　References herein to "treatment" include references to curative, palliative and prophylactic treatment.　The term "animal," as used herein, includes a mammalian subject or a non-mammalian subject. Examples of suitable mammalian subject may include, without limit, human, rodents, companion animals, livestock, and primates. Suitable rodents may include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals may include, but are not limited to, cats, dogs, rabbits, and ferrets. Suitable livestock may include, but are not limited to, horses, goats, sheep, swine, cattle, llamas, and alpacas. Suitable primates may include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys. Examples of suitable non-mammalian subject may include, without limit, birds, reptiles, amphibians, and fish. Non-limiting examples of birds include chickens, turkeys, ducks, and geese. The preferred mammalian subject is a human.　For non-human animal administration, the term 'pharmaceutical' as used herein may be replaced by 'veterinary.'　Pharmaceutical compositions suitable for the delivery of salt form of the invention and methods for the preparation will be readily apparent to those skilled in the art. Such compositions and methods for the preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).ORAL ADMINISTRATION　Salt form of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and / or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.　Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches.　Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid taken from a sachet etc.　Salt form of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Wermuth, C.G. and Stahl, P.H. (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, pp19-39 and 83-116, Wiley-Verlag Helvetica Acta, (2002).　For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant comprises from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.　Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.　Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may be contained from 0.2 weight % to 5 weight % of the tablet, and glidants may be contained from 0.2 weight % to 1 weight % of the tablet.　Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.　Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.　Exemplary tablets contain up to about 80 % drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.　Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.　The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).　Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a salt form in accordance with the invention, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.　Salt forms of the invention may be water-soluble or insoluble depending upon circumstances or conditions. A water-soluble compound typically may be contained from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may be contained in a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, salt forms of the invention may be in the form of multiparticulate beads.　The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range of 0.01 to 99 weight %, more typically in the range of 30 to 80 weight %.　Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.　Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper.　This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.　Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.　Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al. (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298.PARENTERAL ADMINISTRATION　The salt form of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.　Parenteral formulations are typically aqueous solutions which may contain excipients such as carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.　The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.　Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus the salt form of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres.TOPICAL ADMINISTRATION　The salt form of the invention may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955- 958, by Finnin and Morgan (October 1999).　Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject (trade mark), Bioject (trade mark), etc.) injection. Topical administration may also be achieved using a patch, such as a transdermal iontophoretic patch.　Formulations for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.　The salt form of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.　The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of a salt form in accordance with the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.　Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.　Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.　A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 microg to 100 mg of the compound A of the invention per actuation and the actuation volume may vary from 1 micro L to 500 micro L. A typical formulation may comprise a salt form in accordance with the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.　Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled / intranasal administration.　Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using, for example, PLGA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.　In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 microg to 100 mg of the Compound A. The overall daily dose will typically be in the range of 1 microg to 500 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.RECTAL / INTRAVAGINAL ADMINISTRATION　Salt form of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.　Formulations of the invention for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.OCULAR / AURAL ADMINISTRATION　Salt form of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gellan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.　Formulations including the salt of the invention for ocular / aural administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.OTHER TECHNOLOGIES　Salt form of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.　Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Publication Nos. WO 91 / 11172, WO 94 / 02518, WO 98 / 55148 and Evrard, B., et al., Journal of Controlled Release 96 (3), pp. 403-410, 2004.DOSAGE　For treating or preventing the disease conditions mediated by TRPM8 receptor antagonistic activity such as inflammatory, pain, and urological diseases, a suitable dosage level of salt form of this invention is about 0.05 to 3000 mg per day, preferably about 1 to 1000 mg per day, and more preferably about 10 to 500 mg per day of the active Compound A. The compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, a dosage outside these limits may be used.　These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.　Salt form of the present invention (Compound A Salt form) may also optionally be combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly for the treatment of disease conditions mediated by TRPM8 receptor antagonistic activity. For example, the salt form of the present invention, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:　- an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;　- a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;　- a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, thiamylal or thiopental;　- a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;　- an H1 antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;　- a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;　- a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;　- an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-methoxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex (registered trademark), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl}-3,4-dihydro-2(1H)-quinolinone;　- an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;　- a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;　- an anticonvulsant, e.g. carbamazepine, lamotrigine, topiramate or valproate;　- a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6,13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869, aprepitant), lanepitant, dapitant, 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenylpiperidine (2S,3S) or fezolinetant;　- a muscarinic antagonist, e.g. oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium;　- a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;　- a coal-tar analgesic, in particular paracetamol;　- a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion (registered trademark) or sarizotan;　- a vanilloid receptor agonist (e.g. resiniferatoxin) or antagonist (e.g. capsazepine);　- a transient receptor potential cation channel subtype (V1, V2, V3, V4, M2, M3, M7, A1) agonist or antagonist;　- a beta-adrenergic such as propranolol;　- a local anaesthetic such as mexiletine;　- a corticosteroid such as dexamethasone;　- a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;　- a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);　- a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;　-Tramadol (registered trademark);　- a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;　- an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (3-(aminomethyl)-bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, , (3S,5R)-3-amino-5-methyloctanoic　acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-((1H-tetrazol-5-yl)methyl)cycloheptyl]methylamine, (3S,4S)-(1-(aminomethyl)-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;　- a cannabinoid;　- a metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;　- a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;　- a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropron metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan (registered trademark)), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;　- a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;　- an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyldisulfide;　- an acetylcholinesterase inhibitor such as donepezil;　- a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;　- a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870,　- a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);　- a sodium channel blocker, such as lidocaine;　- a calcium channel blocker, such as ziconotide, zonisamide, mibefradil;　- a 5-HT3 antagonist, such as ondansetron;　- a calcitonin gene related peptide (CGRP) antagonist;　- a bradykinin (BK1 and BK2) antagonist;　- a voltage gated sodium dependent channel blocker (Nav1.3, Nav1.7, Nav1.8);　- a voltage dependent calcium channel blocker (N-type, T-type);　- a P2X (ion channel type ATP receptor) antagonist;　- an acid-sensing ion channel (ASIC1a, ASIC3) antagonist;　- an angiotensin AT2 antagonist;　- a chemokine CCR2B receptor antagonist;　- a cathepsin (B, S, K) inhibitor;　- a sigma1 receptor agonist or antagonist;　- a calcium / magnesium;　- a goshajinkigan;　and the pharmaceutically acceptable salts and solvates thereof.　Such combinations offer significant advantages, including synergistic activity, in therapy.COMBINATION DRUG and KIT　One embodiment of the present invention is a combination of salt form of the present invention, and a drug for inflammatory, pain and urological diseases, which is different from salt form of the present invention. A "combination" according to the invention may be present as a "fix combination" or as a "kit of parts combination". A "fix combination" is defined as a combination wherein the (i) at least one drug for inflammatory, pain and urological diseases, which is different from salt form of the present invention, and (ii) salt form of the present invention are present in one unit. A "kit of parts combination" is defined as a combination wherein the (i) at least one drug for inflammatory, pain and urological diseases, which is different from salt form of the present invention, and (ii) salt form of the present invention are present in more than one unit. The components of the "kit of parts combination" may be administered simultaneously, sequentially or separately. The molar ratio of the drug for inflammatory, pain and urological diseases, which is different from salt form of the present invention, to salt form used according to the invention is within the range of from 1:100 to 100:1, such as from 1:50 to 50:1 or from 1:20 to 20:1 or from 1:10 to 10:1. The two drugs may be administered separately in the same ratio.　The present invention extends to a combination comprising 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione salt form and one or more therapeutic agents, such as those listed above, for simultaneous, separate or sequential use in the curative, prophylactic or palliative treatment of disease conditions mediated by TRPM8 receptor antagonistic activity.EXAMPLES　The following examples are for reference only.ANALYSISNuclear Magnetic Resonance (NMR)　NMR data is determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 400 MHz (JEOL JMTC-400 / 54 / SS spectrometer) using deuterated dimethylsulfoxide (99.9 % D) as solvent, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, etc.Powder X-Ray Diffraction (PXRD)　The PXRD analyses are performed using a Rigaku RINT-TTR or MiniFlex600 X-ray powder diffractometer using Cu-K-alpha radiation. The samples can also be measured under the high / low temperature condition by using the attachment of the variant-temperature sample holder. The instrument is equipped with a fine focus X-ray tube. The tube voltage and amperage are set to 50 kV and 300 mA, or 40 kV and 15 mA, respectively. Diffracted radiation is detected by a NaI scintillation detector. A theta-two theta continuous scan at 4 (o) / min (step size 0.02 (o)) from 3 to 40 °2-theta is used. A silicon standard is analyzed to check the machine alignment. Data are collected and analyzed using Rigaku X-ray system. Samples are prepared for analysis by placing them in an aluminum sample holder that is horizontally rotated at 60 rpm during data acquisition.　As another device, PXRD analysis was carried out on a PANalytical X’Pert Pro X-ray Diffractometer, scanning the samples between 2 and 40 2-theta. Material was loaded into a 96-well plate with kapton (trademark) film as the base. The samples were then loaded into the plate holder of a PANalytical X’Pert Pro X-ray Diffractometer running in transmission mode and analyzed.FT-IR Spectroscopy　Infrared spectra are acquired on Fourier Transform Infrared Spectrophotometer (FT-IR), a Shimadzu IRPrestige-21, equipped with air cooled high energy ceramic light source, Germanium-coated on potassium bromide (KBr) beamsplitter, a high sensitivity pyroelectric detector (DLATGS) and DRS-8000 diffuse reflectance accessory. Each spectrum represents 40 co-added scans collected at a spectral resolution of 4 cm-1. A small amount of the sample is put on the plate (6 mm in diameter and 1.5 mm in depth) of the auto-sampler. A background data set is acquired with a blank sample plate. Reported values are rounded and should therefore be considered approximate.Differential scanning calorimetry (DSC)　DSC analysis is performed using Mettler Toledo DSC822. The sample is placed into an aluminum DSC pan and the weight is accurately recorded. The pan is covered with a lid with a pinhole and then crimped. Each sample is heated under a nitrogen purge at a rate of 5oC / min, up to a final temperature of 220-290oC. Indium metal is used as the calibration standard. Reported values are rounded and should therefore be considered approximate.Hygroscopicity study by dynamic vapor sorption analysis (DVS)　Hygroscopicity study is performed using Surface Measurement Systems DVS-1. The sample is placed on a microbalance in the instrument and the weight change during the sorption at 25oC is monitored. One of the programs consists of a sorption scan from 0 to 95 % relative humidity (RH) at 5 %RH increments and the sample is allowed to equilibrate for 360 minutes or until equilibration had been attained at each step.High Performance Liquid Chromatography (HPLC) measurement　HPLC data are obtained by Waters HPLC system with PDA detector using the following conditions;Column: XBridge C8 (3.5 microm, 3.0 x 150 mm),Eluent: acetonitrile / 10 mM ammonium acetate = 25 / 75,Detection: UV at 215 nm,Flow rate: 0.5 mL / min, andColumn temperature: 40oC.　Data processing is performed with Empower 2 software supplied from Waters Corporation.Thermogravimetry / differential thermal analysis (TG / DTA)　TG / DTA is performed using Seiko 6200R system. The sample is placed into an aluminum TG / DTA pan. Each sample is heated under a nitrogen purge at a rate of 5oC / min, up to a final temperature of 300oC. Indium metal is used as the calibration standard. Reported values are rounded and should therefore be considered approximate.Thermogravimetric analysis (TGA)　TGA is performed using Mettler Toledo TGA 2. The sample is placed into an aluminum pan. Each sample is heated under a nitrogen purge at a rate of 5oC / min, up to a final temperature of 300oC. Isatherm metal is used as the calibration standard. Reported values are rounded and should therefore be considered approximate.　Room temperature means 15 to 35oC, but not limited to that as long as the purpose is achieved.　Chemical symbols have their usual meanings throughout the specification; M (mole(s) per liter), L (liter(s)), mL (milliliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles).　For other studies, the crystalline forms of the invention can be distinguished by polarized light microscopy (PLM), scanning electron microscopy (SEM), hot stage optical microscopy, electron crystallography, single crystal X-ray diffractometry, quantitative analysis, particle size analysis (PSA) (e.g. particle size, particle size distribution (PSD), and particle shape), specific surface area (SSA) analysis, surface energy analysis (e.g. inverse gas chromatography or IGC), by dissolution studies, or a combination of these techniques.EXAMPLE 1[Preparation of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione Free-form (Free-Form I)]　8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (44.29 g) prepared according to example 6-14 of WO2015 / 136947 (PL 1) is diluted with methanol (500 mL) and the suspension solution is heated at 85oC for 3 hours, then 12 hours at room temperature. The mixture is stirred at 5oC for 30 minutes and the precipitated solid is filtered and the collected solid is washed with chilled methanol (ca. 0-5oC, 100 mL). The collected solid is dried over at room temperature under vacuum pump for 2 hours. Then, the solid is transferred to 200 mL beaker and dried with a vacuum pump in desiccator (inner temperature: 55oC) for total 4 hours to give Compound A Free-form (Free-Form I, 42.38 g, 98% yield).1H-NMR (400 MHz, DMSO-d6): delta 9.13 (d, J = 5.5 Hz, 1H), 9.03 (br.s, 1H), 8.20 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 7.9 Hz, 2H), 7.70 (d, J = 6.1 Hz, 1H), 5.05 (s, 2H), 2.35 (s, 3H), 2.26-1.80 (m, 8H). (Fig. 1)m.p. (DSC onset): 257oC.The temperature has a margin of error of + / - 2oC. (Fig. 7)Crystallinity by PXRD: Crystal : Main peaks at 2-theta: 16.8, 17.7, 18.3, 19.1, 20.0, 21.4, 24.8 and 27.0 (o). Each peak has a margin of error of + / - 0.2. (Fig. 6)EXAMPLE 2[Salt Screening]1)　Approximately, the free derivative (15 mg) is suspended in 1 mL of each screening solvent (acetone, acetonitrile, and 1,4-dioxane).2)　1 equivalent of benzenesulfonic acid is dissolved in 100 microL solvent before addition to the free derivative slurry.3)　ca.18 mM stock solutions are prepared from concentrated liquid acids (aqueous hydrochloride acid, sulfuric acid, and neat methanesulfonic acid), and 200 microL thereof (corresponds to 1 equivalent) add to the free derivative.4)　The free derivative / counterion / solvent mixtures are temperature cycled between room temperature and 40oC in 4 hours cycles for 72 hours. Samples are agitated during temperature cycling by shaking.● Solid material is obtained from every combination on free derivative / counterion / solvent.●　Solids are isolated by filtration and centrifugation in an estimated yield of 65-90%.●　Samples are allowed to dry at ambient condition for ca. 4 hours.●　The solids are analyzed by PXRD, PLM, and DSC.　In according to salt screening, 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione BSA-salt is obtained the same form-crystal (Form I) from acetone and acetonitrile and the different form-crystal (Form II) from 1,4-dioxane. The Form II is changed to Form I in stability test (storage at 45oC / 75% relative humidity and stored in a desiccator above saturated NaCl solution, 7 days). On the other hand, the Form I is stable in the same condition.　8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate (Form II):Crystallinity by PXRD: Crystal: Main peaks at 2-Theta: 8.0, 15.6, 15.8, 17.5, 18.4 and 19.7 (o). Each peak has a margin of error of + / - 0.2. (Fig. 5)EXAMPLE 3[Preparation of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate (Form I)]　To a stirred suspension of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (8.27 g, 19.96 mmol) in acetone (500 mL) is added a solution of benzenesulfonic acid (anhydrous, 98% purity, 3.22 g, 19.96 mmol) in acetone (10 mL) at room temperature. The mixture is stirred at 40oC for 15 hours. After the removal of oil bath, the mixture is stirred at room temperature for 1 hour and the precipitated solid is filtered and dried with a vacuum pump in desiccator (inner temperature: 55oC) for total 23 hours to give Compound A BSA-salt (Form I, 11.14 g, 98% yield).1H-NMR (270 MHz, DMSO-d6): delta 9.29 (d, J = 5.3 Hz, 1H), 9.06 (br.s, 1H), 8.23 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.64-7.54 (m, 2H), 7.38-7.25 (m, 3H), 5.07 (s, 2H), 2.42 (s, 3H), 2.28-1.77 (m, 8H). (A proton signal of PhSO3His not observed.) (Fig. 2)m.p. (DSC onset): 255.5oC.The temperature has a margin of error of + / - 2oC. (Fig. 4)Crystallinity by PXRD: Crystal : Main peaks at 2-theta: 16.8, 17.0, 18.2, 20.5, 22.8, 24.5, 25.2, 25.5, 27.1, 28.5, 29.4 and 32.7(o). Each peak has a margin of error of + / - 0.2. (Fig. 3)　The Compound A BSA-salt (Form I) can be prepared by the same procedure in acetonitrile instead of acetone.EXAMPLE 4[Preparation of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate (Amorphous)]　Compound A BSA-salt (200 mg) is dissolved in methanol (100 mL). The resulting solution is evaporated under reduced pressure at water bath and the residual oil-film is dried with a vacuum pump to give Compound A BSA-salt (Amorphous). Further, the collected amorphous solid is dried with a vacuum pump in desiccator (inner temperature: room temperature) for total 4 hours to give Compound A BSA-salt (Amorphous, 147.5 mg, 73.8% yield), which is showed halo pattern in PXRD. (Fig. 10)EXAMPLE 5[Solubility study]Solubility study (method 1):　The each Compound A Free-form and Compound A BSA-salt (Form I, 5 mg) is suspended in 5 mL buffer media (phosphate buffer pH 6.8) and stirred at ambient temperature. The supernatant aliquots of 200 microL are taken at the time point of 15 minutes. The each compound concentration is determined by HPLC.　As shown in Table 1, the solubility of Compound A BSA-salt (Form I) is 5.3 times higher than that of the Compound A Free-form.Solubility study (method 2):The dissolution tests of Compound A BSA-salt (Form I) and Compound A Free-form are performed using a μDISS in-situ UV monitoring system (Pion Inc., Billerica, USA). Each 0.8 mg (free-base equivalent value) of the sample (1.1 mg for BSA-salt, 0.8 mg for free-form) is added to 15 mL of pH 6.8 phosphate buffer stirred at 150 rpm at 37oC. The dissolved concentration is continuously monitored through fiber optic UV probes with a predefined time interval (Fig. 8).　As shown in Table 2, the solubility of Compound A BSA-salt (Form I) is 44.6 times higher than that of the Compound A Free-form at the point of 15 min.EXAMPLE 6[Pharmacokinetics (PK) study in Rats]In vivo pharmacokinetic study is carried out in rats.　Test article is administered once by oral gavage to male rats in fasted condition. The dose levels are set at 30 and 100 mg / kg as free base of Compound A and the dose volume is set at 10 mL / kg. The individual dose volume is calculated based on the body weight measured just before dosing. Appropriate amount of test article is accurately weighed, and is suspended in 0.5% (w / v) methylcellulose solution. The dosing formulations are administered by oral gavage with a disposable syringe attached to a gastric tube for rats. Serial blood samples are collected from jugular vein at 0.5, 1, 2, 4, 8, and 24 hours after dosing by heparinized syringe. The collected blood is immediately stored on ice, and then centrifuged (4000 x g, 5 minutes, 4oC) to obtain plasma.　Quantification of test article in plasma is conducted by an ultra high performance liquid chromatography / tandem-mass spectrometry (LC / MS / MS) method. And the pharmacokinetic parameters of test article are obtained directly from the observed data or calculated by a non-compartmental model analysis using the pharmacokinetic analysis software of Phoenix WinNonlin version 6.2 (Certara USA, Inc.).　In the comparison with 30 mg / kg, Cmaxand AUClastof the Compound A BSA-salt (Form I) demonstrate 1.7 and 1.4 times higher than those of the Compound A Free-form, respectively (Table 3). Furthermore, in the comparison with 100 mg / kg, Cmaxand AUClastof the Compound A BSA-salt (Form I) demonstrate 6.4 and 2.4 times higher than those of the Compound A Free-form, respectively.EXAMPLE 7[Hygroscopicity study]　In the hygroscopicity study by dynamic vapor sorption (DVS) analysis, the Compound A BSA-salt (Form I) shows good results (<1 %) against moisture gain under 40 %, 60%, 80 %, and 95 % relative humidity (RH) at 25oC.EXAMPLE 8[Stability study]　Solid-state stability study is performed using Nagano Science Constant temperature / humidity control chamber LH-20-11M, LH-21-11M, NST-80, LTL-200D3CJ-14, LTL-200A-14WCD or LTX-01. The sample is placed in the chamber and exposed under 25oC / 60 % RH, 40oC / 75 % RH and / or irradiated with a lamp. The crystalline form, thermal behavior, purity of the resultant sample after the exposure or irradiation are evaluated by PXRD, TG / DTA and / or DSC, HPLC, respectively.　The Compound A BSA-salt Form I is found to be stable.EXAMPLE 9[Photostability study]　Photostability test is performed according to Example 8. Each sample of Compound A BSA-salt (Form I) and Compound A BSA-salt (Amorphous) in an airtight vial is placed in Nagano Science LTL-200A-14WCD with D65 lamps and exposed to 4000 lux light at 25oC. The samples stored for 13, 26, 52 and 75 days under the condition are analyzed by HPLC.　In photostability tests of Compound A BSA-salt (Form I) and Compound A BSA-salt (Amorphous), Compound A BSA-salt (Form I) shows no more than 0.1% change from the initial sample during the storage period. On the other hand, Compound A BSA-salt (Amorphous) produces the degradation of 3% under conditions of 4000 lux for 75 days as shown in Figure 9. The Compound A BSA-salt (Form I) is found to be stable.

Claims

1. 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate.

2. The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in Claim 1, which is characterized by NMR pattern obtained by measurement using DMSO-d6which includes main peaks at delta: 9.29 (d, 1H), 9.06 (br.s, 1H), 8.23 (d, 2H), 7.87 (d, 2H), 7.64-7.54 (m, 2H), 7.38-7.25 (m, 3H), 5.07 (s, 2H), 2.42 (s, 3H), 2.28-1.77 (m, 8H), wherein each peak has a margin of error of + / - 0.05 (ppm).

3. 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I, which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 16.8, 20.5 and 25.5 (°), wherein each peak has a margin of error of + / - 0.2 (°).

4. The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I as described in Claim 3, which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 16.8, 18.2, 20.5, 25.5 and 28.5 (°), wherein each peak has a margin of error of + / - 0.2 (°).

5. The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I as described in Claim 3 or Claim 4, which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 16.8, 17.0, 18.2, 20.5, 22.8, 24.5, 25.2, 25.5, 27.1, 28.5, 29.4 and 32.7 (°), wherein each peak has a margin of error of + / - 0.2 (°).

6. The 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I as described in any one of Claim 3 to Claim 5, which is further characterized by differential scanning calorimetry (DSC) in which it exhibits an endothermic event at 255.5oC (onset), wherein the temperature has a margin of error of + / - 2oC.

7. 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form II, which is characterized by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with Cu-K-alpha radiation which includes main peaks at 2-theta: 8.0, 15.6, 15.8, 17.5, 18.4 and 19.7 (°), wherein each peak has a margin of error of + / - 0.2 (°).

8. A pharmaceutical composition including 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of Claim 1 to Claim 7, together with one or more pharmaceutically acceptable excipients.

9. 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of Claim 1 to Claim 8 for use as a medicament.

10. A use of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of Claim 1 to Claim 7, or a pharmaceutical composition as described in Claim 8, in the preparation of a medicament for the curative, palliative or prophylactic treatment of disease conditions mediated by TRPM8 receptor antagonistic activity.

11. A method of treating disease conditions mediated by TRPM8 receptor antagonistic activity, which comprises administering an effective amount of 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of Claim 1 to Claim 7, or a pharmaceutical composition as described in Claim 8, to an animal, including a human, in need of such treatment.

12. A process for preparing 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate as described in any one of Claim 1 to Claim 7, comprising the step of exposing 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione in an organic solvent with benzenesulfonic acid in an organic solvent.

13. A process for preparing 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione benzenesulfonate Form I as described in any one of Claim 1 to Claim 6, comprising the step of converting the benzenesulfonate Form II described in Claim 7 to the benzenesulfonate Form I.

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