Fingolimod medicinal salt, method of manufacture, pharmaceutical composition containing the same, and use

Abstract

The present invention provides a medicinal salt of fingolimod, a preparation method thereof, a pharmaceutical composition containing the same, and use thereof. The medicinal salt of fingolimod is a salt formed from a free base of fingolimod and an organic acid having 6 or more carbon atoms. The solubility and stability of the medicinal salt of fingolimod are both relatively good, and the market prospects are good. [Formula 1] JPEG2024521882000025.jpg30169

Description

Technical Field

[0001] The present invention claims the priority of the prior application filed with the China National Intellectual Property Administration on May 31, 2021, with the patent application number 202110601645.0 and the invention title "Pharmaceutical salt of fingolimod, preparation method, pharmaceutical composition comprising the same and use". The full text of the above prior application is incorporated into the present application by reference.

[0002] The present invention relates to a pharmaceutical salt of fingolimod, a preparation method, a pharmaceutical composition comprising the same and use thereof.

Background Art

[0003] Multiple sclerosis (MS) is an autoimmune disease mainly characterized by inflammatory demyelinating lesions of central nervous system proteins, which has serious adverse effects on the activity, intelligence and even mental state of patients. Currently, the incidence rate of MS worldwide is increasing year by year, the number of patients exceeds 2.5 million, the morbidity rate of women is higher than that of men, and affected individuals include adolescents and children.

[0004] Fingolimod is a compound with relatively strong immunosuppressive activity that was first isolated from the fungus *Isaria sinclairii* and its related cordyceps, and is a sphingosine 1-phosphate (S1PR) receptor modulator. Fingolimod hydrochloride (the structural formula is shown in Formula II) is obtained through structural modification and is named FTY 720.

[0005]

Chemical Formula

[0006] Fingolimod hydrochloride capsules developed by Novartis are the world's first oral preparation (capsule) for treating MS, and also the first drug for treating pediatric MS, and have remarkable therapeutic effect in reducing the recurrence rate of MS patients.

[0007] The inventors, in their research process, found that because fingolimod hydrochloride has high water solubility, the release rate of its oral dosage form is too fast, requiring frequent administration to maintain blood drug concentration, resulting in poor patient medication compliance. Patent document WO2010055028A2 describes several crystalline forms of fingolimod hydrochloride. These crystalline forms undergo crystal transformation due to temperature changes, resulting in poor stability of the fingolimod hydrochloride crystalline form. Changes in crystalline form affect aspects such as dissolution rate and bioavailability, which is detrimental to the processability and stability of the formulation.

[0008] Therefore, finding a medicinal salt form of fingolimod that has low solubility, is suitable for sustained-release administration, is highly stable, has good clinical efficacy, and is suitable for commercialization is a technical problem that urgently needs to be solved. [Overview of the Initiative]

[0009] The present invention provides a salt of fingolimod represented by formula I.

[0010] [ka]

[0011] Of these, X is an organic acid with 6 or more carbon atoms, or an ester containing a hydroxyl group, and n is 0.5 to 2.0. Preferably, the salt is a medicinal salt.

[0012] According to embodiments of the present invention, the organic acid having 6 or more carbon atoms may be selected from organic acids with carbon atoms of C6 to C30, for example, organic acids with carbon atoms of C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, and C30.

[0013] According to embodiments of the present invention, X is caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, decanoic acid, sebacic acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, cetyl acid (i.e., palmitic acid or hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, heneicosanoic acid One or more selected from docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic acid (melisinic acid), glyceric acid, lignic acid, embonic acid (i.e., pamoic acid), 1-hydroxy-2-naphthoic acid, and naphthenic acid derivatives (the above naphthenic acid derivatives include, but are not limited to, naphthenic acid esters).

[0014] According to embodiments of the present invention, X is one or more selected from embonic acid, 1-hydroxy-2-naphthoic acid, lauric acid, cetyl acid, sebacic acid, undecanoic acid, and heptanoic acid.

[0015] According to embodiments of the present invention, n is 0.5, 1.0, or 2.0.

[0016] According to embodiments of the present invention, the salt of fingolimod may be fingolimod monopamoate (i.e., n=1.0, also called fingolimod monoembonate), fingolimod hemipamoate (i.e., n=0.5, also called fingolimod hemiembonate), fingolimod 1-hydroxy-2-naphthoate, fingolimod laurate, fingolimod cetylate, fingolimod sebacinate, fingolimod undecanoate, or fingolimod heptaneate.

[0017] According to embodiments of the present invention, the salt of fingolimod may be in the form of a single-phase crystal, amorphous, or mixed crystal.

[0018] According to an embodiment of the present invention, the above-mentioned single-phase crystal refers to a structure in which a large number of microscopic material units (atoms, ions, molecules, etc.) are arranged in a certain regular order, and includes crystalline forms of non-solvates (e.g., anhydrates) and solvates (e.g., hydrates) of fingolimod salt.

[0019] According to an embodiment of the present invention, the above term "mixed crystal" refers to a solid comprising different crystalline forms of the same compound and / or other solid molecular forms, for example, two or more crystalline forms and / or amorphous forms of the above-mentioned fingolimod salt.

[0020] According to an embodiment of the present invention, the above-mentioned fingolimod salt comprises a solvate formed from the above-mentioned fingolimod salt and a solvent. For example, the above-mentioned solvate includes hydrates of fingolimod salt and solvates formed from fingolimod salt and an organic solvent. Preferably, the "organic solvent" described in the above "solvate formed from fingolimod salt and an organic solvent" includes, but is not limited to, one or more of ethanol, acetone, and dimethyl sulfoxide.

[0021] The present invention further provides a method for preparing a fingolimod salt, comprising the step of subjecting fingolimod free base to a neutralization reaction with the above X (i.e., an organic acid having 6 or more carbon atoms) to obtain the above fingolimod salt.

[0022] According to an embodiment of the present invention, the above method for preparing a fingolimod salt may be carried out in a solvent or under solvent-free conditions.

[0023] The present invention further provides another method for preparing a fingolimod salt, comprising the steps of dissolving fingolimod free base in an inorganic acid to form a solution, dissolving the above X (i.e., an organic acid having 6 or more carbon atoms) in an inorganic base to form a solution, and then mixing the two solutions to obtain the above fingolimod salt.

[0024] According to an embodiment of the present invention, in the above two preparation methods, the organic acid having 6 or more carbon atoms may be a C6 to C30 organic acid.

[0025] According to an embodiment of the present invention, in the above two production methods, X is selected from the group consisting of one or more of caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, decanoic acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic acid (melissic acid), glyceric acid, lignoceric acid, embonic acid (pamoic acid), 1-hydroxy-2-naphthoic acid, and naphthenic acid derivatives (the naphthenic acid derivatives include, but are not limited to, naphthenic acid esters), but are not limited thereto.

[0026] According to an embodiment of the present invention, the above-mentioned embonic acid is also called pamoic acid, and its CAS registration number is 130-85-8.

[0027] The present invention further provides a crystalline form of a salt of fingolimod, which is, for example, a crystalline form of fingolimod embonate, or a crystalline form of 1-hydroxy-2-naphthoate of fingolimod.

[0028] According to an embodiment of the present invention, the crystalline form of fingolimod embonate is crystalline form B of fingolimod embonate, and the X-ray powder diffraction pattern of the crystalline form B of fingolimod embonate has characteristic peaks at positions where 2θ values are 3.3°±0.2°, 17.1°±0.2°, 21.8°±0.2°, etc.

[0029] Furthermore, the X-ray powder diffraction pattern of the crystalline form B of fingolimod embonate has characteristic peaks at positions where 2θ values are 3.3°±0.2°, 17.1°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 21.8°±0.2°, 23.4°±0.2°, etc.

[0030] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form B exhibits characteristic peaks at 2θ values ​​of 3.3°±0.2°, 17.1±0.2°, 17.7°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 20.6°±0.2°, 21.8°±0.2°, 23.4°±0.2°, etc.

[0031] Furthermore, the X-ray powder diffraction patterns of the above fingolimod embonate crystal form B show 2θ values ​​of 3.3°±0.2°, 7.1°±0.2°, 9.8°±0.2°, 11.2°±0.2°, 11.8°±0.2°, 12.6°±0.2°, 13.5°±0.2°, 14.3°±0.2°, 14.7°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 16.7°±0.2°, and 17.1°± Absorption peaks are found at 0.2°, 17.7°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.6°±0.2°, 20.0°±0.2°, 20.6°±0.2°, 21.8°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 23.8°±0.2°, 25.2°±0.2°, 26.5°±0.2°, 27.5°±0.2°, 30.1°±0.2°, etc.

[0032] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embondate crystal form B is basically as shown in Figure 1.

[0033] According to one embodiment of the present invention, the fingolimod emponate crystalline form B has the X-ray powder diffraction pattern shown in Table 1.

[0034] According to embodiments of the present invention, the thermogravimetric spectrum of the fingolimodoemponic acid crystal form B is basically as shown in Figure 2.

[0035] According to embodiments of the present invention, the nuclear magnetic spectrum of the fingolimodoemponic acid crystal form B is basically as shown in Figure 3.

[0036] According to an embodiment of the present invention, in the above fingolimod embonic acid crystal form B, the molar ratio of fingolimod to embonic acid is 1:0.5.

[0037] According to embodiments of the present invention, the above-mentioned fingolimod embondate crystalline form B is a hydrate.

[0038] According to embodiments of the present invention, the method for producing the above fingolimod embondate crystal form B is as follows: Embonic acid is mixed with solvent 1 to obtain an embonic acid solution, fingolimod hydrochloride is mixed with solvent 2, the embonic acid solution is added to this, and the mixture is stirred to react and obtain the fingolimod embonate crystalline form B. The solvent 1 mentioned above is an alkaline solution, for example, an inorganic alkaline solution, preferably an aqueous potassium hydroxide solution. The solvent 2 mentioned above is water, methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, or a mixture of at least two of the above solvents, and is preferably water.

[0039] According to an embodiment of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form A.

[0040] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embonate crystal form A has characteristic peaks at 2θ values ​​of 3.2°±0.2°, 19.3°±0.2°, 20.4°±0.2°, etc.

[0041] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form A exhibits characteristic peaks at 2θ values ​​of 3.2°±0.2°, 9.6°±0.2°, 12.5°±0.2°, 18.5°±0.2°, 19.3°±0.2°, and 20.4°±0.2°.

[0042] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form A exhibits characteristic peaks at 2θ values ​​of 3.2°±0.2°, 9.6°±0.2°, 12.5°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.4°±0.2°, and 24.3°±0.2°.

[0043] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form A exhibits characteristic peaks at 2θ values ​​such as 3.2°±0.2°, 9.2°±0.2°, 9.6°±0.2°, 10.8°±0.2°, 11.6°±0.2°, 12.5°±0.2°, 13.1°±0.2°, 14.8°±0.2°, 15.1°±0.2°, 16.3°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.4°±0.2°, 21.6°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 24.3°±0.2°, and 25.2°±0.2°.

[0044] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embondate crystal form A is basically as shown in Figure 4.

[0045] According to one embodiment of the present invention, the fingolimod emponate crystal form A has the X-ray powder diffraction pattern shown in Table 2.

[0046] According to an embodiment of the present invention, the differential scanning calorimetry spectrum of the fingolimod embonate crystal form A is basically as shown in Figure 5. In one embodiment, the fingolimod embonate crystal form A has two endothermic peaks and one heat dissipation peak, for example, the peak temperatures of the endothermic peaks are 128±5°C and 180±5°C, and for example, the peak temperature of the heat dissipation peak is 153±5°C.

[0047] According to embodiments of the present invention, the thermogravimetric spectrum of the fingolimod embondate crystal form A is basically as shown in Figure 6.

[0048] According to embodiments of the present invention, the fingolimod embondate crystalline form A is an anhydrous or tunnel hydrate.

[0049] According to embodiments of the present invention, the nuclear magnetic spectrum of the fingolimod embondate crystal form A is basically as shown in Figure 7.

[0050] According to an embodiment of the present invention, in the above fingolimod embonic acid crystal form A, the molar ratio of fingolimod to embonic acid is 1:0.5.

[0051] According to embodiments of the present invention, the method for producing the above-mentioned fingolimod embondate crystal form A is as follows: Fingolimod embondate crystalline form B is dried to obtain fingolimod embondate crystalline form A. Preferably, the drying temperature is 25-50°C, for example, 30°C or 40°C. Preferably, the drying is performed under vacuum.

[0052] According to an embodiment of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form I.

[0053] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned fingolimod embonate crystal form I has characteristic peaks at 2θ values ​​such as 3.0°±0.2°, 8.9°±0.2°, and 19.9°±0.2°.

[0054] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form I exhibits characteristic peaks at 2θ values ​​such as 3.0°±0.2°, 3.3°±0.2°, 5.6°±0.2°, 5.9°±0.2°, 6.9°±0.2°, 8.9°±0.2°, 9.8°±0.2°, 15.0°±0.2°, 16.2°±0.2°, 18.0°±0.2°, 18.8°±0.2°, 19.1°±0.2°, 19.6°±0.2°, 19.9°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 25.2°±0.2°.

[0055] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embondate crystal form I is basically as shown in Figure 8.

[0056] According to one embodiment of the present invention, the fingolimod emponate crystal form I has the X-ray powder diffraction pattern shown in Table 3.

[0057] According to embodiments of the present invention, the method for producing the above fingolimod embondate crystalline form I is as follows: The above embonic acid is mixed with solvent 1 to obtain an embonic acid solution. Fingolimod hydrochloride is mixed with solvent 2, the above embonic acid solution is added to it, the mixture is stirred and reacted, filtered and dried to obtain the above fingolimod embonic acid crystalline form I. The solvent 1 mentioned above is an alkaline solution, for example, an inorganic alkaline solution, preferably an aqueous potassium hydroxide solution. The solvent 2 mentioned above is water, methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, or a mixture of at least two of the above solvents, and is preferably water.

[0058] According to embodiments of the present invention, the drying time is 2 to 7 days, preferably 2 days.

[0059] According to an embodiment of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form J.

[0060] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned fingolimod embonate crystal form J has characteristic peaks at 2θ values ​​of 3.2°±0.2°, 5.3°±0.2°, 10.1°±0.2°, 10.8°±0.2°, 18.1°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 21.7°±0.2°, etc.

[0061] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form J exhibits characteristic peaks at 2θ values ​​such as 3.2°±0.2°, 5.3°±0.2°, 6.3°±0.2°, 9.5°±0.2°, 10.1°±0.2°, 10.8°±0.2°, 13.5°±0.2°, 17.0°±0.2°, 17.8°±0.2°, 18.1°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 21.7°±0.2°, 22.0°±0.2°, 24.5°±0.2°, and 25.5°±0.2°.

[0062] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embondate crystal form J is basically as shown in Figure 9.

[0063] According to one embodiment of the present invention, the fingolimod emponate crystalline form J has the X-ray powder diffraction pattern shown in Table 4.

[0064] According to embodiments of the present invention, the method for producing the above-mentioned fingolimod embondate crystalline form J is as follows: Fingolimodene vonate crystal form I is left to dry at room temperature to obtain fingolimodene vonate crystal form J.

[0065] According to an embodiment of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form C.

[0066] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embonate crystalline form C has characteristic peaks at 2θ values ​​of 3.2°±0.2°, 6.4°±0.2°, 19.8°±0.2°, etc.

[0067] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form C exhibits characteristic peaks at 2θ values ​​of 3.2°±0.2°, 6.4°±0.2°, 9.6°±0.2°, 15.1°±0.2°, 19.8°±0.2°, and 20.4°±0.2°.

[0068] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form C exhibits characteristic peaks at 2θ values ​​of 3.2°±0.2°, 6.4°±0.2°, 9.6°±0.2°, 13.6°±0.2°, 15.1°±0.2°, 15.6°±0.2°, 19.8°±0.2°, 20.4°±0.2°, etc.

[0069] Furthermore, the X-ray powder diffraction patterns of the above fingolimod emponate crystal form C show 2θ values ​​of 3.2°±0.2°, 5.4°±0.2°, 6.4°±0.2°, 9.6°±0.2°, 12.8°±0.2°, 13.6°±0.2°, 14.3°±0.2°, 15.1°±0.2°, 15.6°±0.2°, 16.7°±0.2°, and 17. It exhibits characteristic peaks at angles such as 0.3°±0.2°, 17.7°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.4°±0.2°, 22.7°±0.2°, 23.1°±0.2°, 23.5°±0.2°, 25.9°±0.2°, and 29.2°±0.2°.

[0070] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embondate crystal form C is basically as shown in Figure 10.

[0071] According to one embodiment of the present invention, the fingolimod emponate crystalline form C has the X-ray powder diffraction pattern shown in Table 5.

[0072] According to embodiments of the present invention, the method for producing the above fingolimod embondate crystalline form C is as follows: The fingolimod embondate crystalline form J is suspended in solvent 3 and crystallized by stirring to obtain the above fingolimod embondate crystalline form C. The solvent 3 above is a mixed solvent of n-heptane and ethyl acetate. Preferably, the temperature of the above-mentioned stirring crystallization is 50-80°C, for example, 60°C. Preferably, the time for the above stirring crystallization is 2 to 10 days, for example, 7 days. Preferably, the above manufacturing method further includes separating the material after stirring and crystallization, and drying the separated solid to obtain the fingolimod embondate crystalline form C.

[0073] According to an embodiment of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form D.

[0074] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embondate crystal form D has characteristic peaks at 2θ values ​​of 3.3°±0.2°, 10.1°±0.2°, 20.3°±0.2°, etc.

[0075] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form D exhibits characteristic peaks at 2θ values ​​of 3.3°±0.2°, 6.7°±0.2°, 10.1°±0.2°, 16.9°±0.2°, 18.8°±0.2°, and 20.3°±0.2°.

[0076] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form D exhibits characteristic peaks at 2θ values ​​of 3.3°±0.2°, 6.7°±0.2°, 7.2°±0.2°, 10.1°±0.2°, 16.9°±0.2°, 18.8°±0.2°, 20.3°±0.2°, and 23.8°±0.2°.

[0077] Furthermore, the X-ray powder diffraction patterns of the above fingolimod embonate crystal form D show 2θ values ​​of 3.3°±0.2°, 5.0±0.2°, 6.7°±0.2°, 7.3°±0.2°, 8.9°±0.2°, 10.1°±0.2°, 10.5°±0.2°, 13.1°±0.2°, 13.5°±0.2°, 13.8°±0.2°, and 15.5°±0. It exhibits characteristic peaks at angles such as 2°, 16.2°±0.2°, 16.9°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 20.3°±0.2°, 22.2°±0.2°, 23.8°±0.2°, 25.7°±0.2°, 27.4°±0.2°, and 29.1°±0.2°.

[0078] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embondate crystal form D is basically as shown in Figure 11.

[0079] According to one embodiment of the present invention, the fingolimod emponate crystal form D has the X-ray powder diffraction pattern shown in Table 6.

[0080] According to embodiments of the present invention, the method for producing the above-mentioned fingolimod emponate crystalline form D is as follows: Fingolimod embondate crystalline form B is dissolved in a good solvent 1 and subjected to volatilization and crystallization to obtain the above-mentioned fingolimod embondate crystalline form D.

[0081] The above good solvent 1 is a mixed solvent of ethanol and water. Preferably, the temperature for the volatile crystallization is room temperature.

[0082] According to an embodiment of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form E.

[0083] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned fingolimod embonate crystal form E has characteristic peaks at 2θ values ​​of 3.3°±0.2°, 17.3°±0.2°, 19.0°±0.2°, etc.

[0084] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form E exhibits characteristic peaks at 2θ values ​​of 3.3°±0.2°, 9.8°±0.2°, 17.3°±0.2°, 17.7°±0.2°, 19.0°±0.2°, and 21.8°±0.2°.

[0085] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form E exhibits characteristic peaks at 2θ values ​​of 3.3°±0.2°, 9.8°±0.2°, 17.3°±0.2°, 17.7°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 20.0°±0.2°, and 21.8°±0.2°.

[0086] Furthermore, according to embodiments of the present invention, the X-ray powder diffraction patterns of the above fingolimod embonate crystal form E are as follows: 2θ values ​​of 3.3°±0.2°, 7.3°±0.2°, 7.5°±0.2°, 8.6°±0.2°, 8.9°±0.2°, 9.1°±0.2°, 9.8°±0.2°, 10.1°±0.2°, 10.5°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 16 It exhibits characteristic peaks at angles such as 0.4°±0.2°, 17.1°±0.2°, 17.3°±0.2°, 17.7°±0.2°, 18.2°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 20.0°±0.2°, 21.2°±0.2°, 21.8°±0.2°, 22.8°±0.2°, 23.2°±0.2°, 23.9°±0.2°, and 24.3°±0.2°.

[0087] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embondate crystal form E is basically as shown in Figure 12.

[0088] According to one embodiment of the present invention, the fingolimod emponate crystal form E has the X-ray powder diffraction pattern shown in Table 7.

[0089] According to embodiments of the present invention, the method for producing the above fingolimod embondate crystal form E is as follows: Fingolimod embondate crystal form B is dissolved in a good solvent 2 and subjected to volatilization and crystallization to obtain the above-mentioned fingolimod embondate crystal form E.

[0090] The above good solvent 2 is dioxane. Preferably, the temperature for the volatile crystallization is 50 to 80°C, for example, 60°C.

[0091] According to embodiments of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form F.

[0092] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned fingolimod emponate crystal form F has characteristic peaks at 2θ values ​​of 3.7°±0.2°, 18.0°±0.2°, 21.9°±0.2°, etc.

[0093] Furthermore, the X-ray powder diffraction pattern of the above-mentioned fingolimod embonate crystal form F exhibits characteristic peaks at 2θ values ​​such as 3.7°±0.2°, 9.2°±0.2°, 16.4°±0.2°, 17.0°±0.2°, 18.0°±0.2°, 19.7°±0.2°, 20.1°±0.2°, and 21.9°±0.2°.

[0094] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form F exhibits characteristic peaks at 2θ values ​​such as 3.7°±0.2°, 8.0±0.2°, 9.2°±0.2°, 11.3°±0.2°, 16.4°±0.2°, 17.0°±0.2°, 18.0°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 20.1°±0.2°, and 21.9°±0.2°.

[0095] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embondate crystal form F is basically as shown in Figure 13.

[0096] According to one embodiment of the present invention, the fingolimod emponate crystalline form F has the X-ray powder diffraction pattern shown in Table 8.

[0097] According to embodiments of the present invention, the method for producing the above-mentioned fingolimod emponate crystalline form F is as follows: The fingolimod embondate crystal form B is prepared as a slurry in solvent 3, and crystallized by stirring to obtain the above fingolimod embondate crystal form F. The solvent 3 mentioned above is n-heptane, isopropyl acetate, or a mixture thereof.

[0098] Preferably, the temperature for the stirring crystallization is 50 to 80°C, for example, 60°C.

[0099] According to an embodiment of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form G.

[0100] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned fingolimod embondate crystal form G has characteristic peaks at 2θ values ​​of 3.6°±0.2°, 7.2°±0.2°, 19.9°±0.2°, etc.

[0101] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form G exhibits characteristic peaks at 2θ values ​​of 3.6°±0.2°, 7.2°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 19.9°±0.2°, 21.8°±0.2°, 22.6°±0.2°, and 25.1°±0.2°.

[0102] Furthermore, according to embodiments of the present invention, the X-ray powder diffraction patterns of the above fingolimod embonate crystal form G are as follows: 2θ values ​​of 3.6°±0.2°, 7.2°±0.2°, 9.0±0.2°, 9.5°±0.2°, 10.0°±0.2°, 11.2°±0.2°, 11.6°±0.2°, 11.8°±0.2°, 12.1°±0.2°, 13.1°±0.2°, 13.5°±0.2°, 15.1°±0.2°, 17.0°± It exhibits characteristic peaks at angles such as 0.2°, 18.1°±0.2°, 18.4°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.5°±0.2°, 20.9°±0.2°, 21.8°±0.2°, 22.6°±0.2°, 23.2°±0.2°, 23.9°±0.2°, 24.7°±0.2°, 25.1°±0.2°, 27.6°±0.2°, and 28.1°±0.2°.

[0103] According to embodiments of the present invention, the X-ray powder diffraction pattern of the fingolimod embondate crystal form G is basically as shown in Figure 14.

[0104] According to one embodiment of the present invention, the fingolimod emponate crystalline form G has the X-ray powder diffraction pattern shown in Table 9.

[0105] According to embodiments of the present invention, the method for producing the above fingolimod embondate crystalline form G is as follows: The fingolimod embondate crystal form B is prepared as a slurry in solvent 5, and crystallized by stirring to obtain the above fingolimod embondate crystal form G. The solvent 5 mentioned above is a mixed solvent of N,N-dimethylformamide and water.

[0106] According to embodiments of the present invention, the temperature of the stirring crystallization is 50 to 80°C, for example, 60°C.

[0107] According to embodiments of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form H.

[0108] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned fingolimod emponate crystalline form H has characteristic peaks at 2θ values ​​of 3.3°±0.2°, 10.1°±0.2°, 17.2°±0.2°, etc.

[0109] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystalline form H exhibits characteristic peaks at 2θ values ​​of 3.3°±0.2°, 6.7°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 17.2°±0.2°, 20.3°±0.2°, 20.6°±0.2°, etc.

[0110] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystalline form H exhibits characteristic peaks at 2θ values ​​such as 3.3°±0.2°, 5.0°±0.2°, 6.7°±0.2°, 7.3°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 17.2°±0.2°, 18.8°±0.2°, 20.3°±0.2°, 20.6°±0.2°, 21.8°±0.2°, 22.2°±0.2°, 23.7°±0.2°, and 27.7°±0.2°.

[0111] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above fingolimod embondate crystalline form H is basically as shown in Figure 15.

[0112] According to one embodiment of the present invention, the fingolimod emponate crystalline form H has the X-ray powder diffraction pattern shown in Table 10.

[0113] According to embodiments of the present invention, the method for producing the above-mentioned fingolimod embondate crystalline form H is as follows: The fingolimod embondate crystalline form B is dissolved in a good solvent 3, a poor solvent is gradually added, and crystallization is performed by stirring to obtain the above fingolimod embondate crystalline form H.

[0114] The above good solvent 3 is one or more of ethanol, isopropanol, dioxane, and dimethyl sulfoxide, and is preferably ethanol. The poor solvent mentioned above is water.

[0115] According to embodiments of the present invention, the crystalline form of the fingolimod embondate is fingolimod embondate crystalline form K.

[0116] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned fingolimod embonate crystal form K has characteristic peaks at 2θ values ​​of 3.4°±0.2°, 6.7°±0.2°, 7.3°±0.2°, 10.2°±0.2°, 10.5°±0.2°, 17.0°±0.2°, 18.9°±0.2°, 20.4°±0.2°, etc.

[0117] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embonate crystal form K exhibits characteristic peaks at 2θ values ​​such as 3.4°±0.2°, 6.7°±0.2°, 7.3±0.2°, 10.2°±0.2°, 10.5°±0.2°, 13.1°±0.2°, 13.8°±0.2°, 16.3°±0.2°, 17.0°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 18.2°±0.2°, 18.9°±0.2°, and 20.4°±0.2°.

[0118] Furthermore, the X-ray powder diffraction pattern of the above fingolimod embondate crystal form K is basically as shown in Figure 16.

[0119] According to one embodiment of the present invention, the fingolimod emponate crystalline form K has the X-ray powder diffraction pattern shown in Table 11.

[0120] According to embodiments of the present invention, the method for producing the above fingolimod embondate crystalline form K is as follows: The fingolimod free base is dissolved in solvent 6, embonic acid is added, and the mixture is stirred and reacted to obtain the above fingolimod embonate crystalline form K. The solvent 6 is an alkyl acetate, for example, the alkyl group is a C1-C5 alkyl group, and for example, the solvent 6 is one or more of ethyl acetate, isopropyl acetate, and n-butyl acetate, preferably n-butyl acetate.

[0121] According to embodiments of the present invention, the crystalline form of the above-mentioned fingolimod 1-hydroxy-2-naphthoate is fingolimod 1-hydroxy-2-naphthoate crystalline form 1.

[0122] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above fingolimod 1-hydroxy-2-naphthoate crystalline form 1 has characteristic peaks at 2θ values ​​such as 3.2°±0.2°, 12.9°±0.2°, and 19.4°±0.2°.

[0123] Furthermore, the X-ray powder diffraction pattern of the above fingolimod 1-hydroxy-2-naphthoate crystalline form 1 exhibits characteristic peaks at 2θ values ​​of 3.2°±0.2°, 9.6°±0.2°, 12.9°±0.2°, 16.1°±0.2°, 19.4°±0.2°, and 25.9°±0.2°.

[0124] Furthermore, the X-ray powder diffraction pattern of the above fingolimod 1-hydroxy-2-naphthoate crystalline form 1 exhibits characteristic peaks at 2θ values ​​such as 3.2°±0.2°, 9.6°±0.2°, 12.9°±0.2°, 16.1°±0.2°, 19.4°±0.2°, 25.9°±0.2°, 29.3°±0.2°, and 36.0°±0.2°.

[0125] Furthermore, the X-ray powder diffraction patterns of the above fingolimod 1-hydroxy-2-naphthoate crystalline form 1 show 2θ values ​​of 3.2°±0.2°, 6.4°±0.2°, 9.6°±0.2°, 12.9°±0.2°, 13.9°±0.2°, 14.4°±0.2°, 15.7°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 17.4°±0.2°, and 18.3°± Absorption peaks are found at 0.2°, 19.4°±0.2°, 20.0°±0.2°, 21.0°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 25.1°±0.2°, 25.9°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 32.6°±0.2°, 36.0°±0.2°, etc.

[0126] According to embodiments of the present invention, the X-ray powder diffraction pattern of the above fingolimod 1-hydroxy-2-naphthoethate crystalline form 1 is basically as shown in Figure 17.

[0127] According to one embodiment of the present invention, the fingolimod 1-hydroxy-2-naphthoate crystalline form 1 has the X-ray powder diffraction pattern shown in Table 12.

[0128] According to embodiments of the present invention, the differential scanning calorimetry spectrum of the fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is basically as shown in Figure 18, and in one embodiment, the fingolimod 1-hydroxy-2-naphthoate crystalline form 1 has endothermic peaks at 125°C and 144°C.

[0129] According to embodiments of the present invention, the thermogravimetric spectrum of the fingolimod 1-hydroxy-2-naphthoic acid crystal form 1 is basically as shown in Figure 19. In one embodiment, the fingolimod 1-hydroxy-2-naphthoic acid crystal form 1 does not lose weight up to 120±5℃.

[0130] According to embodiments of the present invention, the above fingolimod 1-hydroxy-2-naphthoic acid crystalline form 1 is an anhydrous.

[0131] According to embodiments of the present invention, the nuclear magnetic spectrum of the above fingolimod 1-hydroxy-2-naphthoic acid crystal form 1 is basically as shown in Figure 20.

[0132] According to embodiments of the present invention, in the above fingolimod 1-hydroxy-2-naphthoic acid crystal form 1, the molar ratio of fingolimod to 1-hydroxy-2-naphthoic acid is 1:1.

[0133] According to embodiments of the present invention, the method for producing the above-mentioned fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is as follows: Fingolimod and 1-hydroxy-2-naphthoic acid are each dissolved in solvent 7, stirred, and reacted to obtain the above fingolimod 1-hydroxy-2-naphthoate crystalline form 1. The solvent 7 is an alkyl acetate, for example, the alkyl group is a C1-C5 alkyl group, preferably the solvent 7 is one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate, preferably ethyl acetate. Preferably, the temperature of the stirring reaction is 25 to 80°C, more preferably 40 to 60°C, and even more preferably 60°C.

[0134] Preferably, the stirring reaction described above refers to adding the fingolimod solution dropwise to the 1-hydroxy-2-naphthoic acid solution, or adding the 1-hydroxy-2-naphthoic acid solution dropwise to the fingolimod solution.

[0135] The present invention further provides pharmaceutical compositions comprising a salt and / or crystalline form of the above-mentioned fingolimod, and pharmaceutically acceptable adjuvants.

[0136] In the present invention, the pharmaceutical composition includes, but is not limited to, tablets, capsules, solutions, suspensions, (long-acting) injections, and semi-solid formulations. Its purpose is to facilitate the administration of compounds (i.e., active ingredients) to living organisms such as humans or other mammals, and it is preferably an injection, and more preferably a long-acting injection.

[0137] According to embodiments of the present invention, the concentration of the salt and / or crystalline form of the salt of fingolimod is 15 mg / mL or more.

[0138] In the present invention, the above-mentioned pharmaceutically acceptable adjutant includes one or more physiologically or pharmaceutically acceptable carriers, diluents, mediators, and / or excipients.

[0139] According to embodiments of the present invention, the above-mentioned pharmaceutically acceptable adjutant may further be one or more selected from suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers, and surfactants.

[0140] According to embodiments of the present invention, the concentration range of the suspending agent is 0 to 75 mg / mL, preferably 10 mg / mL to 75 mg / mL, for example 30 mg / mL, 40 mg / mL, 50 mg / mL, or 75 mg / mL.

[0141] According to embodiments of the present invention, the suspending agent is one or more selected from carboxymethylcellulose sodium, methylcellulose, polyethylene glycol 4000, and polyvinylpyrrolidone, and is preferably polyethylene glycol 4000.

[0142] According to embodiments of the present invention, the concentration range of the wetting agent is 1 mg / mL to 10 mg / mL, preferably 1 mg / mL to 5 mg / mL, for example 1 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, or 5.0 mg / mL, preferably 1 mg / mL.

[0143] According to embodiments of the present invention, the wetting agent is one or more selected from Tween20, Tween80, and poloxamer188, and is preferably poloxamer188.

[0144] According to embodiments of the present invention, the buffering agent is one or more selected from phosphoric acid, phosphate, guanoic acid, sodium guanoic acid, hydrochloric acid, and sodium hydroxide.

[0145] According to embodiments of the present invention, the solvent is water, for example, water for injection.

[0146] As an example, the above pharmaceutical composition is (a) Fingolimod 1-hydroxy-2-naphthoate or its crystalline form, for example, fingolimod 1-hydroxy-2-naphthoate crystalline form 1, (b) Polyethylene glycol 4000, (c) Poloxamer, (d) Disodium hydrogen phosphate, (e) Sodium dihydrogen phosphate, (f) may include water for injection, Furthermore, the above pharmaceutical composition may optionally contain sodium hydroxide or hydrochloric acid.

[0147] The present invention further, (1) A step of dissolving the wetting agent, buffering agent and suspending agent in a solvent, (2) Add an appropriate amount of solvent to the fingolimod solid particles after sieving, thoroughly wet them, and disperse them. (3) A manufacturing method comprising the step of adjusting the volume to a target volume with a solvent to obtain a suspension, The present invention provides a method for producing the above-mentioned pharmaceutical composition, wherein the solvent is water, for example, water for injection.

[0148] According to embodiments of the present invention, the fingolimod solid particles may be selected from fingolimod, a pharmaceutically acceptable salt of fingolimod, or a crystalline form of the salt thereof.

[0149] According to embodiments of the present invention, the fingolimod solid particles include, but are not limited to, fingolimod emponate or its crystalline form, or fingolimod 1-hydroxy-2-naphthoate or its crystalline form.

[0150] According to embodiments of the present invention, in step (1), the wetting agent, buffering agent, and suspending agent may be sequentially dissolved in a solvent, for example, in water for injection.

[0151] According to embodiments of the present invention, in step (2), the fingolimod solid particles may be sieved, for example, through a 400-mesh sieve.

[0152] The present invention further provides the use of the above-mentioned fingolimod medicinal salt in the manufacture of drugs for the treatment and / or prevention of multiple sclerosis.

[0153] The present invention further provides a method for treating and / or preventing multiple sclerosis, comprising administering the above-mentioned pharmaceutical composition or drug to an applicant.

[0154] The present invention further provides the use of the above-mentioned pharmaceutical composition in the manufacture of drugs for treating and / or preventing multiple sclerosis.

[0155] Unless otherwise specified, the following terms used in the specification and claims of this invention have the meanings set forth below: In the present invention, the terms “pharmaceutically acceptable,” “carrier,” “diluent,” “mediator,” or “excipient” refer to one (or more) substances that can be contained together with a specific drug (active ingredient) to form a pharmaceutical composition, and which may be solid or liquid. The solid carriers include, but are not limited to, starch, calcium sulfate dihydrate, gypsum powder, talc powder, lactose, sucrose, mica, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. The liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, aqueous saline solutions, and water. The carriers or diluents may also include art-known delayed or time-release materials, such as glyceryl monostearate or glyceryl distearate, alone or together with wax, ethylcellulose, hydroxypropyl methylcellulose, methyl methacrylate, etc.

[0156] According to embodiments of the present invention, the term "solvate" above refers to a molecular complex comprising a drug and one or more solvent molecules (e.g., ethanol) in a stoichiometric or non-stoichiometric manner. When the solvent is tightly bound to the drug, the resulting complex has a clearly defined stoichiometry regardless of humidity. However, when the solvent is weakly bound to the drug, the solvent content depends on humidity and dry conditions, as is the case with channel solvates and hygroscopic compounds. In such cases, the complex is usually non-stoichiometric.

[0157] According to embodiments of the present invention, the term "hydrate" above refers to a drug and a solvate containing stoichiometric or non-stoichiometric water. The term "relative humidity" refers to the ratio of the amount of water vapor at a given temperature to the maximum amount of water vapor that can be maintained at that temperature and pressure, and is expressed as a percentage.

[0158] By arbitrarily combining the above preferred conditions without deviating from common sense in the field, each preferred example of the present invention can be obtained.

[0159] The reagents and raw materials used in this invention are all commercially available.

[0160] In this invention, the above-mentioned room temperature refers to an ambient temperature of 10 to 35°C.

[0161] Beneficial effects of the present invention: The solubility and stability of the fingolimod medicinal salt of the present invention are both relatively good, and the prospects for commercialization are favorable. This overcomes the shortcomings of conventional fingolimod hydrochloride, such as insufficient water solubility and stability.

[0162] The composition containing the fingolimod medicinal salt of the present invention has good stability, safety, and a long drug sustained release cycle. [Brief explanation of the drawing]

[0163] [Figure 1] This is the XRPD pattern of fingolimod emponate crystal form B obtained in Example 1. [Figure 2] This is the TGA pattern of fingolimod emponate crystal form B obtained in Example 1. [Figure 3] This is the 1H-NMR pattern of fingolimod emponate crystal form B obtained in Example 1. [Figure 4] This is the XRPD pattern of fingolimod emponate crystal form A obtained in Example 3. [Figure 5] This is the DSC pattern of fingolimod emponate crystal form A obtained in Example 3. [Figure 6] This is the TGA pattern of fingolimod emponate crystal form A obtained in Example 3. [Figure 7] This is the 1H-NMR pattern of fingolimod emponate crystal form A obtained in Example 3. [Figure 8]This is the XRPD pattern of fingolimod emponate crystal form I obtained in Example 4. [Figure 9] This is the XRPD pattern of fingolimod emponate crystal form J obtained in Example 5. [Figure 10] This is the XRPD pattern of fingolimod emponate crystal form C obtained in Example 6. [Figure 11] This is the XRPD pattern of fingolimod emponate crystal form D obtained in Example 7. [Figure 12] This is the XRPD pattern of fingolimod emponate crystal form E obtained in Example 8. [Figure 13] This is the XRPD pattern of fingolimod emponate crystal form F obtained in Example 9. [Figure 14] This is the XRPD pattern of fingolimod emponate crystal form G obtained in Example 10. [Figure 15] This is the XRPD pattern of fingolimod emponate crystalline form H obtained in Example 11. [Figure 16] This is the XRPD pattern of fingolimod emponate crystal form K obtained in Example 13. [Figure 17] This is the XRPD pattern of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 obtained in Example 14. [Figure 18] This is the DSC pattern of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 obtained in Example 14. [Figure 19] This is the TGA pattern of fingolimod 1-hydroxy-2-naphthoate crystal form 1 obtained in Example 14. [Figure 20] This is the 1H-NMR pattern of fingolimod 1-hydroxy-2-naphthoate crystal form 1 obtained in Example 14. [Figure 21] This figure shows the relationship between the average blood drug concentration and time for the oral formulation sample of Example 21. [Figure 22] This figure shows the relationship between the average blood drug concentration and time for the suspension formulation sample of Example 21. [Modes for carrying out the invention]

[0164] The technical aspects of the present invention will be described in more detail below, in accordance with specific embodiments. It should be understood that the following embodiments are merely illustrative and interpretable to illustrate the present invention, and should not be interpreted as limiting the scope of the claims. Any technology realized based on the above-described aspects of the present invention falls within the scope of the claims according to the present invention.

[0165] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be manufactured by known methods.

[0166] Characteristics and measurements described in the following examples: Nuclear magnetic resonance ( 1 The basic compounds of each example were measured using 1H-NMR, and the measurement parameters are as follows: 1 The 1H-NMR measurements were performed using a Bruker Advance III 500M nuclear magnetic resonance spectrometer, with a measurement frequency of 400 MHz and deuterated DMSO as the solvent.

[0167] X-ray powder diffractometer (XRPD) XRPD measurements were performed using a Bruker D8 Advance X-ray powder diffractometer with a circular, zero-background single-crystal silicon sample stage. The scanning parameters were as follows: voltage 40 kV, current 40 mA, scanning range 3° to 45°, scanning step 0.02°, and scanning mode continuous scanning.

[0168] Differential Scanning Calorimetry (DSC) DSC measurements were performed in a sealed pan apparatus of model Q2000 from TA Instruments. Samples (approximately 1-2 mg) were weighed in an aluminum pan, transferred to the instrument, and measured. The measurement parameters were as follows. The instrument was equilibrated at 30°C and heated at a rate of 10°C / min. The experimental atmosphere was nitrogen gas.

[0169] Thermogravimetric analysis (TGA) TGA measurements were performed using a TA Instruments Q2000 instrument. Samples (approximately 2-5 mg) were weighed in a platinum pan, transferred to the instrument, and measured. The measurement parameters were as follows. The instrument was heated at a rate of 10°C / min, and the experimental atmosphere was nitrogen gas.

[0170] Method for detecting related substances using HPLC

[0171] [Table 1]

[0172] Example 1: Preparation of fingolimod emponate crystalline form B Step 1: Take 292 mg of potassium hydroxide and add 5 mL of water to obtain a potassium hydroxide solution.

[0173] Step 2: Take 78 mg of embonic acid, add 1 mL of water, stir and disperse, add 0.4 mL of potassium hydroxide solution, stir, filter to obtain an embonic acid solution.

[0174] Step 3: Take 68 mg of fingolimod hydrochloride, add 1 mL of water, stir, and clarify. Add 0.6 mL of the embonic acid solution obtained in Step 2, stir, and react. Add 7 mL of water to replenish, stir for 30 minutes, add 0.2 mL of the embonic acid solution obtained in Step 2, and react for another 30 minutes. Filter to obtain fingolimod embonate, which was detected as fingolimod embonate crystal form B by XRPD.

[0175] The XRPD pattern of fingolimod emponate crystal form B is shown in Figure 1. The XRPD analysis of fingolimod emponate crystal form B is shown in Table 1: [Table 2] The TGA pattern of fingolimod emponate crystal form B is shown in Figure 2. fingolimod emponate crystalline form B 1 The H-NMR pattern is shown in Figure 3. 1 ¹H-NMR (400 MHz, DMSO-d6):δ 8.21-8.16 (t, 2H), 7.83 (s, 3H), 7.62 (d, 2H), 7.10 (m, 5H), 6.99 (m, 1H), 5.46 (s, 2H), 4.67 (s, 1H), 3.55 (s, 4H), 2.56 (m, 2H), 1.79 (m, 2H), 1.52 (m, 2H), 1.24 (d, 10H), 0.86-0.83 (t, 3H), indicating that the molar ratio of fingolimod free base to embonic acid is approximately 1:0.5.

[0176] Example 2: Preparation of fingolimod emponate crystalline form B Step 1: Take 5.84 g of potassium hydroxide and add 100 mL of water to obtain a potassium hydroxide solution.

[0177] Step 2: Take 15.6 g of embonic acid, add 200 mL of water, stir and disperse, add 80 mL of potassium hydroxide solution, stir, filter to obtain an embonic acid solution.

[0178] Step 3: Take 13.6 g of fingolimod hydrochloride, add 200 mL of water, stir, and clarify. Add 120 mL of the embonic acid solution obtained in Step 2, stir, and react. Add 1400 mL of water, stir for 30 minutes, add 40 mL of the embonic acid solution obtained in Step 2, and react for another 30 minutes. Filter to obtain fingolimod embonate, which was detected as fingolimod embonate crystalline form B by XRPD.

[0179] Example 3: Preparation of fingolimod emponate crystalline form A 10 g of fingolimod emponate crystalline form B, produced in Example 2, was taken and vacuum-dried overnight at 40°C to obtain fingolimod emponate crystalline form A.

[0180] The XRPD pattern of fingolimod emponate crystal form A is shown in Figure 4. The XRPD analysis of fingolimod emponate crystal form A is shown in Table 2. [Table 3] The DSC pattern of fingolimod emponate crystalline form A is shown in Figure 5. The TGA pattern of fingolimod emponate crystal form A is shown in Figure 6. The 1H-NMR pattern of fingolimod embonate crystal form A is shown in Figure 7, indicating that the molar ratio of free fingolimod base to embonate is approximately 1:0.5.

[0181] Example 4: Preparation of fingolimod emponate crystalline form I: Step 1: Weigh 1192.23 mg of potassium hydroxide, add 20 mL of water, and dissolve to obtain an aqueous potassium hydroxide solution with a concentration of approximately 1.062 mmol / mL.

[0182] Step 2: Weigh 3124 mg of embonate, add 20 mL of water, stir to disperse, add 16.725 mL of potassium hydroxide aqueous solution, stir for 1 hour, filter to obtain potassium embonate solution.

[0183] Step 3: Preparation of fingolimod hydrochloride solution: Weigh 2721 mg of fingolimod hydrochloride, add 60 mL of water, stir, clarify, filter, and take the filtrate.

[0184] Step 4: Under stirring conditions, 20.990 mL of potassium embonate solution was slowly added to the fingolimod hydrochloride solution, stirred overnight at room temperature, collected by suction filtration, and vacuum-dried at 35°C for 2 days to obtain hemiembonate, which was detected as fingolimod embonate crystalline form I by XRPD.

[0185] The XRPD pattern of fingolimod emponate crystal form I is shown in Figure 8.

[0186] The XRPD analysis of fingolimod emponate crystal form I is shown in Table 3. [Table 4]

[0187] Example 5: Preparation of fingolimod emponate crystalline form J A sample of fingolimod emponate crystalline form I, prepared in Example 4, was taken and left to dry at room temperature for 10 days to obtain fingolimod emponate crystalline form J.

[0188] The XRPD pattern of fingolimod emponate crystal form J is shown in Figure 9.

[0189] The XRPD analysis of fingolimod emponate crystal form J is shown in Table 4. [Table 5]

[0190] Example 6: Preparation of fingolimod emponate crystalline form C 210 mg of the fingolimod emponate crystalline form J sample prepared in Example 5 was taken, 3.5 mL of n-heptane and 3.5 mL of ethyl acetate were added, the mixture was stirred at 60°C for 7 days, centrifuged, and vacuum-dried at 40°C for 4 hours to obtain fingolimod emponate crystalline form C.

[0191] The XRPD pattern of fingolimod emponate crystal form C is shown in Figure 10.

[0192] The XRPD analysis of fingolimod emponate crystal form C is shown in Table 5. [Table 6]

[0193] Example 7: Preparation of fingolimod emponate crystalline form D 25 mg of the fingolimod emponate crystalline form B sample prepared in Example 3 was taken, 0.3 mL of ethanol and 0.1 mL of water were added, and the mixture was evaporated at room temperature to obtain fingolimod emponate crystalline form D.

[0194] The XRPD pattern of fingolimod emponate crystal form D is shown in Figure 11.

[0195] The XRPD analysis of fingolimod emponate crystal form D is shown in Table 6.

[0196] [Table 7]

[0197] Example 8: Preparation of fingolimod emponate crystalline form E 25 mg of the fingolimod emponate crystalline form B sample prepared in Example 3 was taken, 0.2 mL of 1,4-dioxane was added, and the mixture was evaporated at 60°C to obtain fingolimod emponate crystalline form E.

[0198] The XRPD pattern of fingolimod emponate crystal form E is shown in Figure 12.

[0199] The XRPD analysis of fingolimod emponate crystal form E is shown in Table 7.

[0200] [Table 8]

[0201] Example 9: Preparation of fingolimod emponate crystalline form F 30 mg of the fingolimod emponate crystalline form B sample prepared in Example 3 was taken, and 0.5 mL of n-heptane and 0.5 mL of isopropyl acetate were added to form a slurry, which was stirred at 60°C for 7 days to obtain fingolimod emponate crystalline form F.

[0202] The XRPD pattern of fingolimod emponate crystal form F is shown in Figure 13.

[0203] The XRPD analysis of fingolimod emponate crystal form F is shown in Table 8.

[0204] [Table 9]

[0205] Example 10: Preparation of fingolimod emponate crystalline form G 30 mg of the fingolimod emponate crystalline form B sample prepared in Example 3 was taken, and 0.1 mL of N,N-dimethylformamide and 1 mL of water were added to form a slurry. The slurry was stirred at 60°C for 7 days to obtain fingolimod emponate crystalline form G.

[0206] The XRPD pattern of fingolimod emponate crystal form G is shown in Figure 14.

[0207] The XRPD analysis of fingolimod emponate crystal form G is shown in Table 9.

[0208] [Table 10]

[0209] Example 11: Preparation of fingolimod emponate crystalline form H 100 mg of the fingolimod emponate crystalline form B sample prepared in Example 3 was taken, 0.5 mL of ethanol was added, the mixture was clarified, and 1 mL of water was slowly added. Crystallization was performed by stirring to obtain fingolimod emponate crystalline form H.

[0210] The XRPD pattern of fingolimod emponate crystalline form H is shown in Figure 15.

[0211] The XRPD analysis of fingolimod emponate crystalline form H is shown in Table 10.

[0212] [Table 11]

[0213] Example 12: Preparation of fingolimod free base 12.6 g of fingolimod hydrochloride was taken, 480 mL of water was added, the mixture was stirred, clarified, and aqueous ammonia was slowly added dropwise to adjust the pH to 9-10. The mixture was then stirred for 1 hour, filtered, and vacuum-dried at room temperature for 3 hours to obtain 11.1 g of free fingolimod base.

[0214] Example 13: Preparation of fingolimod emponate crystalline form K 1000 mg of the fingolimod free base prepared in Example 12 was added, 50 mL of n-butyl acetate was added, the mixture was stirred at 60°C and clarified, 530 mg of embonic acid was added, the mixture was stirred for 4 hours and reacted, the temperature was cooled to room temperature, the mixture was stirred overnight, the mixture was filtered and vacuum-dried overnight at 40°C to obtain fingolimod embonate crystalline form K.

[0215] The XRPD pattern of fingolimod emponate crystal form K is shown in Figure 16.

[0216] The XRPD analysis of fingolimod emponate crystalline form K is shown in Table 11.

[0217] [Table 12]

[0218] Example 14: Preparation of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 Step 1: Weigh 5500 mg of 1-hydroxy-2-naphthoic acid, add 75 mL of ethyl acetate, stir in a water bath at 60°C to dissolve, filter, and collect the filtrate.

[0219] Step 2: Take 7230 mg of the fingolimod free base from Example 12, add 250 mL of ethyl acetate, and dissolve in a water bath at 60°C.

[0220] Step 3: Under stirring conditions at 60°C, the 1-hydroxy-2-naphthoic acid solution was slowly added dropwise to the fingolimod solution, 17 mL of ethyl acetate was added, the mixture was washed, stirred overnight at room temperature, filtered, the filtered cake was washed with 85 mL of ethyl acetate, and the mixture was vacuum-dried overnight at 35°C to obtain fingolimod 1-hydroxy-2-naphthoate, which was detected as fingolimod 1-hydroxy-2-naphthoate crystalline form 1 by XRPD.

[0221] The XRPD pattern of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is shown in Figure 17. The XRPD analysis of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is shown in Table 12.

[0222] [Table 13] The DSC pattern of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is shown in Figure 18. The TGA pattern of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is shown in Figure 19. The 1H-NMR pattern of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is shown in Figure 20, indicating that fingolimod and 1-hydroxy-2-naphthoic acid form a salt in a 1:1 ratio.

[0223] Example 15: Formulation preparation of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 [Table 14] Manufacturing process: (1) Weigh out the formulation doses of poloxamer 188, sodium carboxymethylcellulose, polyethylene glycol 4000, disodium hydrogen phosphate, sodium dihydrogen phosphate, and approximately 60% of the total volume of water for injection shown in Table 13, and dissolve and disperse them by stirring. (2) Add fingolimod 1-hydroxy-2-naphthoate crystalline form 1, which has been sieved through a 400-mesh sieve, in the formulation dose shown in Table 13, and thoroughly wet and disperse it. (3) The volume was adjusted to 10 mL with sterile water for injection and mixed uniformly to obtain a suspension of fingolimod 1-hydroxy-2-naphthoate crystalline form 1.

[0224] When prescription samples obtained from prescriptions 1 to 3 were examined for needle permeability and sedimentation rate, it was found that the prescription sample obtained from prescription 2 had good needle permeability and sedimentation rate.

[0225] Example 16: Formulation preparation of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 As shown in Table 14, Formulations 4, 5, 6, 7 and 8 were obtained by adjusting the amount of polyethylene glycol 4000 in Formulation 3 of Example 15 to 200 mg, 300 mg, 400 mg, 500 mg and 600 mg, respectively, and manufacturing the formulations. Samples of Formulations 4 to 8 were taken and examined for needle permeability and sedimentation rate, and it was found that the obtained formulation samples had good needle permeability and sedimentation rate. Table 15

[0226] Example 17 Preparation of oral formulation sample of fingolimod hydrochloride 3.676 mg of fingolimod hydrochloride was taken, dissolved in water for injection, diluted, and adjusted to a constant volume of 100 mL to obtain an oral formulation sample of fingolimod hydrochloride.

[0227] Example 18 Preparation of formulation sample of fingolimod 1-hydroxy-2-naphthoate crystalline form 1 (1) 10 mg of poloxamer 188, 750 mg of polyethylene glycol 4000, 45 mg of disodium hydrogen phosphate, 9 mg of sodium dihydrogen phosphate and about 6 mL of water for injection were weighed, dissolved by stirring and dispersed, (2) 242.3 mg of fingolimod 1-hydroxy-2-naphthoate crystalline form 1, which had been passed through a 400-mesh sieve, was added, sufficiently wetted and dispersed, (3) The volume was adjusted to 10 mL with water for injection, and the mixture was shaken and mixed uniformly to obtain a suspension formulation sample of fingolimod 1-hydroxy-2-naphthoate crystalline form 1.

[0228] Example 19: Comparison of solid stability Fingolimod 1-hydroxy-2-naphthoate crystal form 1 prepared in Example 14, Fingolimod embonate crystal form A prepared in Example 3, and Fingolimod hydrochloride were each taken, left under conditions of high temperature (60°C), high humidity (25°C / 90%RH), accelerated (40°C / 75%RH), light illumination (1.2×10^6 Lux hr), and long-term (25°C / 60%RH), sampled on day 0, day 5 and day 10, and related substances were detected by HPLC.

[0229] The results of related substances are shown in Table 15, which indicate that Fingolimod 1-hydroxy-2-naphthoate crystal form 1 of the present invention is relatively stable, the total amount of related substances basically remains unchanged when left standing for 10 days under each condition, and Fingolimod embonate crystal form A is relatively stable under all other conditions except for a slight increase in impurities under light illumination conditions.

Table 16

[0230] Example 20: Comparison of solubility Fingolimod 1-hydroxy-2-naphthoate crystal form 1 prepared in Example 14, Fingolimod embonate crystal form B prepared in Example 2, Fingolimod hydrochloride, and Fingolimod free base prepared in Example 12 were each taken, added separately to the corresponding media below, shaken at 37°C for 24 hours, filtered through a 0.45 μm aqueous phase filtration membrane, the filtrate was collected, and solubility was measured by high performance liquid chromatography. Among them, for the corresponding media: pH 3 and pH 5 are acetate buffer solutions, pH 7 and pH 9 are phosphate buffer solutions, and water is ultrapure water.

[0231] The results are shown in Table 16. Fingolimod free base and fingolimod hydrochloride showed relatively large differences in solubility in each medium. Furthermore, in high pH media, fingolimod hydrochloride dissociated to fingolimod free base. However, the solubility of fingolimod 1-hydroxy-2-naphthoate, embondate, and the crystalline forms of both produced by the present invention decreased significantly in water and under low pH conditions (pH 5 or less). The solubility of fingolimod 1-hydroxy-2-naphthoate in water was 5.46 μg / mL, which is equivalent to 1 / 4 to 1 / 5 (approximately 23 μg / mL) of fingolimod free base and 1 / 1000 to 1 / 2600 (approximately 14 μg / mL) of fingolimod hydrochloride. This corresponds to mg / mL, and is relatively low in all pH media. In other words, fingolimod 1-hydroxy-2-naphthoate, embondate, and the crystalline forms of both possess a sustained-release effect while simultaneously exhibiting considerable solubility in various pH media. The release rate can be minimally dependent on pH, thus avoiding the influence of pH environments in different areas of the body on the drug release rate, preventing burst release phenomena or excessive increases in blood drug concentration in local areas of the body, and reducing differences in drug release between individuals. This makes them suitable for long-acting formulations, reduces the number of administrations, improves patient medication compliance, and indicates a promising outlook for market commercialization. [Table 17]

[0232] Example 21: Comparison of Formulation Stability Three samples of the formulation prepared in Example 15 were taken and left under high temperature (60°C), accelerated incubation (40°C / 75%RH), and prolonged incubation (25°C / 60%RH) conditions. Samples were taken on day 0, day 5, and day 10 and detected by HPLC.

[0233] The results are shown in Table 17. The formulation samples produced according to the present invention were relatively stable under all conditions, and no significant changes were observed in the total amount of the relevant substances after being left for 10 days. [Table 18] The formulation sample produced in Example 18 exhibited similar stability to the formulation sample in Example 15.

[0234] Example 21: Pharmacokinetic experiment Six male SD rats were divided into two groups. One group received a single dose of 3 mg / kg of fingolimod 1-hydroxy-2-naphthoate crystalline form formulation sample (Example 18) via intramuscular injection, and plasma was collected at 0 h, 1 h, 3 h, 7 h, 24 h, 4 d, 7 d, 11 d, 15 d, 20 d, 25 d, 30 d, and 35 d after administration. The other group received a single dose of 0.1 mg / kg of fingolimod hydrochloride sample (Example 17) via forced oral administration, and plasma was collected at 5 min, 15 min, 30 min, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration. During the experiment, the animals in the intramuscular injection group had free access to food and water, while the animals in the forced oral administration group were fasted overnight before administration and resumed eating and drinking 4 hours after administration.

[0235] Plasma sample collection: Approximately 150 μL of blood was collected from the jugular vein (whole blood was centrifuged within 30 minutes to separate the plasma), placed in a test tube containing the anticoagulant EDTA-K2, and the processed plasma was stored in a -70°C refrigerator until use.

[0236] Plasma sample preparation: A 30 μL plasma sample was taken, 200 μL of internal standard solution (40 ng / mL Glipizide acetonitrile solution) was added, vortexed for 1 min, centrifuged at 5800 rpm at 4°C for 10 min, 100 μL of supernatant was taken and transferred to a new plate, and 5 μL of the solution was taken for LC-MS / MS analysis. The pharmacokinetic parameters of fingolimod in animal bodies are shown in Tables 18-19, and the drug-time curves are shown in Figures 21-22.

[0237] The results show that the oral fingolimod group reached peak blood drug concentration 12 hours after administration, maintained a blood drug concentration of 0.3 ng / mL or higher within 24 hours, and had a minimum reaction time (MRT) of only 12 hours. The fingolimod 1-hydroxy-2-naphthoate injection group reached peak blood concentration 3 hours after administration, reached a relatively stable blood concentration within 1 day, maintained a blood concentration of 0.3 ng / mL or higher for at least 15 days, and had an MRT of up to 12 days. This indicates that the formulation has a rapid onset of action and a long sustained drug release cycle, that Cmax does not increase proportionally with dose, and that there is a relatively large safety distance to toxic concentrations, indicating relatively high safety. [Table 19] [Table 20]

Claims

1. A drug comprising a salt of fingolimod having fingolimod 1-hydroxy-2-naphthoate crystalline form 1, used to avoid local burst release and / or excessive blood concentration increases, In the aforementioned fingolimod 1-hydroxy-2-naphthoate, the molar ratio of fingolimod to 1-hydroxy-2-naphthoic acid is 1:

1. The X-ray powder diffraction pattern of the fingolimod 1-hydroxy-2-naphthoate crystalline form 1 has characteristic peaks at 2θ values ​​of 3.2°±0.2°, 9.6°±0.2°, 12.9°±0.2°, 16.1°±0.2°, 19.4°±0.2°, and 25.9°±0.2°, wherein the drug.

2. The drug according to claim 1, wherein the X-ray powder diffraction pattern of the fingolimod 1-hydroxy-2-naphthoate crystalline form 1 has characteristic peaks at 2θ values ​​of 3.2°±0.2°, 9.6°±0.2°, 12.9°±0.2°, 16.1°±0.2°, 19.4°±0.2°, 25.9°±0.2°, 29.3°±0.2°, and 36.0°±0.2°.

3. The X-ray powder diffraction patterns of the aforementioned fingolimod 1-hydroxy-2-naphthoate crystalline form 1 show 2θ values ​​of 3.2°±0.2°, 6.4°±0.2°, 9.6°±0.2°, 12.9°±0.2°, 13.9°±0.2°, 14.4°±0.2°, 15.7°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 17.4°±0.2°, 18.3°±0.2°, 19.4°±0.2°, 20.0°±0.2°, 21.0°±0.2°, 21.6°±0.2°, and 22. The drug according to claim 1, having characteristic peaks at 4°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 25.1°±0.2°, 25.9°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 32.6°±0.2°, and 36.0°±0.2°.

4. The drug according to claim 1, wherein the X-ray powder diffraction pattern of the fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is as shown in Figure 17. [Figure 17]

5. The fingolimod 1-hydroxy-2-naphthoate crystalline form 1 has endothermic peaks at 125°C and 144°C; or The aforementioned fingolimod 1-hydroxy-2-naphthoate crystalline form 1 shows no weight loss up to 120±5℃. The drug according to claim 1.

6. The drug according to claim 1, wherein the fingolimod 1-hydroxy-2-naphthoate crystalline form 1 is an anhydrous form.

7. A method for producing a drug according to any one of claims 1 to 6, The process includes the steps of dissolving fingolimod and 1-hydroxy-2-naphthoic acid in solvent 7, stirring, and reacting them to obtain a salt of the fingolimod 1-hydroxy-2-naphthoate crystalline form 1, The solvent 7 is one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate. A method for producing the drug, wherein the stirring for the reaction is carried out at 40 to 60°C.

8. A pharmaceutical composition comprising a therapeutic or prophylactic effective amount of the drug described in any one of claims 1 to 6, and a pharmaceutically acceptable adjuvant.

9. The pharmaceutical composition is selected from tablets, capsules, solutions, suspensions, long-acting injections, and semi-solid formulations, and The aforementioned pharmaceutical composition, (a) The drug according to any one of claims 1 to 6, (b) Polyethylene glycol 4000, (c) Poloxamer, (d) Disodium hydrogen phosphate, (e) Sodium dihydrogen phosphate, and (f) Water for injection, and Optionally, the above pharmaceutical composition may contain sodium hydroxide or hydrochloric acid. The pharmaceutical composition according to claim 8.

10. Use of a drug according to any one of claims 1 to 6 in the manufacture of a drug for treating and / or preventing multiple sclerosis.

Images