Crystals of dihydrosphingomyelin and method for producing the same, and pharmaceutical composition

Abstract

To provide crystals of dihydrosphingomyelin with a reduced water content, and a production method that enables the production of the crystals of dihydrosphingomyelin with a reduced water content.SOLUTION: The present invention provides a crystal of dihydrosphingomyelin represented by the following formula (1), having peaks at diffraction angles (2θ)=3.3±0.2°, 4.9±0.2°, 6.6±0.2°, 10.0±0.2°, 13.4±0.2°, 16.8±0.2°, 18.5±0.2°, 20.2±0.2°, 21.9±0.2°, and 23.7±0.2° in powder X-ray diffraction.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a dihydrosphingomyelin crystal, a method for producing the same, and a pharmaceutical composition. [Background technology]

[0002] Dihydrosphingomyelin (hereinafter, also referred to as "DHSM"), a sphingophospholipid, is a type of lipid present in the body and is known to have various physiological activities. It is also known as a lipid constituting liposome compositions and pharmaceutical compositions (see, for example, Patent Document 1).

[0003] Examples of the production of DHSM have been disclosed (see, for example, Patent Document 2 and Non-Patent Document 1). However, the properties of the crystals have not been investigated. In addition, the DHSM crystals obtained when producing DHSM by the method described in Non-Patent Document 1 may contain a high content of unnecessary components such as water, which is undesirable as a material for use in pharmaceuticals.

[0004] Therefore, it is desirable to develop DHSM crystals having a reduced water content and a method for producing such crystals. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2018 / 181963 [Patent Document 2] Special Publication No. 2016-511281 [Non-patent literature]

[0006] [Non-Patent Document 1] Rina Fujiwara and 3 others, "Development of a synthesis method for dihydrosphingomyelin and its application to nucleic acid delivery", Poster presentation at the 143rd Annual Meeting of the Pharmaceutical Society of Japan, 26P1-pm2-024 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a dihydrosphingomyelin crystal having a reduced water content, and a production method capable of producing the dihydrosphingomyelin crystal having a reduced water content. [Means for solving the problem]

[0008] As a result of intensive research by the present inventors to achieve a solution to the above-mentioned problems, they have found that the above-mentioned object can be achieved by a dihydrosphingomyelin crystal having a specific structure and a specific peak in powder X-ray diffraction, and a method for producing the dihydrosphingomyelin crystal, and have thus completed the present invention.

[0009] That is, the present invention relates to the following dihydrosphingomyelin crystals, a production method thereof, and a pharmaceutical composition. 1. A crystal of dihydrosphingomyelin represented by the following formula (1): [ka] In powder X-ray diffraction, it has peaks at diffraction angles (2θ) = 3.3 ± 0.2 °, 4.9 ± 0.2 °, 6.6 ± 0.2 °, 10.0 ± 0.2 °, 13.4 ± 0.2 °, 16.8 ± 0.2 °, 18.5 ± 0.2 °, 20.2 ± 0.2 °, 21.9 ± 0.2 °, and 23.7 ± 0.2 °. A dihydrosphingomyelin crystal characterized by the above-mentioned. 2. Represented by the following formula (1): [ka] 1. A method for producing a crystal of dihydrosphingomyelin having peaks at diffraction angles (2θ) of 3.3±0.2°, 4.9±0.2°, 6.6±0.2°, 10.0±0.2°, 13.4±0.2°, 16.8±0.2°, 18.5±0.2°, 20.2±0.2°, 21.9±0.2°, and 23.7±0.2° in powder X-ray diffraction, comprising: The method includes a step of crystallizing dihydrosphingomyelin from a mixed solvent containing an organic solvent and water. A method for producing crystals of dihydrosphingomyelin, comprising: 3. The method according to item 2, wherein the content of the water in the mixed solvent is 0.01 to 3.00% by mass, with the mixed solvent being 100% by mass. 4. The method according to item 2 or 3, wherein the organic solvent is a mixed organic solvent of an aprotic solvent and an alcohol. 5. The method according to item 4, wherein the alcohol is methanol. 6. The method according to item 4 or 5, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran and cyclohexanone. 7. A pharmaceutical composition comprising the dihydrosphingomyelin crystal according to item 1. Effect of the Invention

[0010] The dihydrosphingomyelin crystal of the present invention has a reduced water content. Furthermore, according to the method for producing a dihydrosphingomyelin crystal of the present invention, a dihydrosphingomyelin crystal with a reduced water content can be produced. [Brief description of the drawings]

[0011] [Figure 1] FIG. 2 is a diagram showing an XRD chart of the DHSM crystal produced in Example 1. [Diagram 2] FIG. 13 is a diagram showing an XRD chart of the DHSM crystal produced in Example 7. [Diagram 3] FIG. 2 is a diagram showing an XRD chart of the DHSM crystal produced in Comparative Example 1. [Figure 4] FIG. 2 is a diagram showing measurement charts of differential thermal analysis (DTA) and thermogravimetry (TG) of the DHSM crystal produced in Example 1. [Diagram 5] FIG. 1 shows differential thermal analysis (DTA) and thermogravimetry (TG) measurement charts of the DHSM crystal produced in Example 7. [Figure 6] FIG. 2 is a diagram showing measurement charts of differential thermal analysis (DTA) and thermogravimetry (TG) of the DHSM crystal produced in Comparative Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] 1. Sphingophospholipid precursors The dihydrosphingomyelin crystal of the present invention (hereinafter, may be simply referred to as "the crystal of the present invention" or "the crystal") is a crystal of dihydrosphingomyelin represented by the following formula (1): [ka] The dihydrosphingomyelin crystal of the present invention is a novel crystal having a structure represented by the above formula (1) and a structure having a specific peak in powder X-ray diffraction. The dihydrosphingomyelin crystal having such a structure has a reduced water content and can be usefully used in fields where a dihydrosphingomyelin crystal having such properties is required.

[0013] The crystal of the present invention may have a peak at least at the specific diffraction angle, and may have a peak at other diffraction angles. Examples of the diffraction angles having such a peak include diffraction angles (2θ)=15.1±0.2°, 25.5±0.2°, 27.0±0.2°, and 28.8±0.2°. The crystal of the present invention preferably has a peak at diffraction angles (2θ)=15.1±0.2°, 25.5±0.2°, 27.0±0.2°, and 28.8±0.2°. By having a peak at the above diffraction angles, the water content of the crystal of the present invention is further suppressed.

[0014] In this specification, the peak of the diffraction angle (2θ) of the crystal is measured using a powder X-ray diffractometer (Mini flex, manufactured by Rigaku Corporation) under the following conditions. Wavelength 1.54050Å (CuKα), output 30kV, 15mA Measurement angle 3.00~50.00(°), sampling width 0.01, scan speed 2.00° / min

[0015] The crystal of the present invention preferably has a peak at a specific temperature in differential thermal analysis (DTA). Examples of specific temperatures having a peak in such differential thermal analysis include temperatures of 133±2°C, 141±2°C, and 153±2°C. The crystal of the present invention may have a peak at any of 133±2°C, 141±2°C, and 153±2°C, or may have peaks at 133±2°C or 141±2°C and 153±2°C. When the crystal of the present invention has a peak in differential thermal analysis at the above temperature, the water content of the crystal of the present invention is further suppressed.

[0016] In this specification, the differential thermal analysis peak of a crystal is measured using a measuring device (Thermo Plus series differential TG-DTA TG8120 manufactured by Rigaku Corporation) under measurement conditions in which the temperature is raised from room temperature to 200° C. at a rate of 5.0° C. / h.

[0017] The crystal of the present invention may have a temperature at which the weight starts to decrease in thermogravimetry (TG) of 200°C or less, or 150°C or less. When the upper limit of the temperature is within the above range, the water content of the crystal of the present invention is further suppressed. The lower limit of the temperature is not particularly limited, and may be about 145°C.

[0018] In this specification, the thermogravimetry (TG) of the crystal is measured using a measuring device (Thermo Plus series differential TG-DTA TG8120 manufactured by Rigaku Corporation) under the measurement conditions of heating from room temperature to 200° C. at a rate of 5.0° C. / h.

[0019] The water content of the crystal of the present invention is preferably less than 2.0% by mass, with the crystal being taken as 100% by mass. The lower the water content of the crystal, the more preferable it is, and for example, the upper limit may be 0.3% by mass or less, 0.1% by mass or less, 0.05% by mass or less, 0.03% by mass or less, 0.01% by mass or less, or 0.05% by mass or less. By having the water content within the above range, the crystal of dihydrosphingomyelin having the above characteristics can be usefully used in fields where such characteristics are required. The lower limit of the water content of the crystal is not particularly limited, and may be, for example, 0% by mass, with the crystal being taken as 100% by mass.

[0020] In this specification, the content of water of crystallization is the content measured by the Karl Fischer method.

[0021] 2. Method for producing dihydrosphingomyelin crystals The method for producing a crystal of dihydrosphingomyelin of the present invention is represented by the following formula (1): [ka] A method for producing a crystal of dihydrosphingomyelin having peaks at diffraction angles (2θ) of 3.3±0.2°, 4.9±0.2°, 6.6±0.2°, 10.0±0.2°, 13.4±0.2°, 16.8±0.2°, 18.5±0.2°, 20.2±0.2°, 21.9±0.2°, and 23.7±0.2° in powder X-ray diffraction, the method comprising a step of crystallizing dihydrosphingomyelin in a mixed solvent containing an organic solvent and water. The production method of the present invention comprises a step of crystallizing dihydrosphingomyelin in a mixed solvent containing an organic solvent and water, and thereby the produced dihydrosphingomyelin crystal can have a specific structure having peaks at the above diffraction angles (2θ), and the water content of the crystal having such a specific structure is suppressed. In particular, the production method of the present invention can achieve the unexpected effect of suppressing the water content of the produced crystals to a low content by intentionally mixing water with the organic solvent during crystallization. The crystals produced by the production method of the present invention can be usefully used in fields requiring dihydrosphingomyelin crystals having the characteristic of a low water content.

[0022] In the step of the production method of the present invention, a mixed solvent containing an organic solvent and water is used. The mixed solvent may contain other solvents other than these, but it is preferable to use a mixed solvent consisting of only an organic solvent and water.

[0023] The water content in the mixed solvent is preferably 0.01 to 3.00 mass%, more preferably 0.05 to 2.00 mass%, further preferably 0.10 to 1.50 mass%, particularly preferably 0.15 to 1.00 mass%, and most preferably 0.20 to 0.50 mass%, based on 100 mass% of the mixed solvent. By keeping the water content in the mixed solvent within the above range, the water content of the produced crystals can be further suppressed.

[0024] The organic solvent is not particularly limited, and any known organic solvent used in the production of dihydrosphingomyelin crystals can be used, including aprotic solvents, alcohol solvents, and the like.

[0025] Examples of the aprotic solvent include ethers, ketones, carboxylates, amides, hydrocarbons, halogenated hydrocarbons, etc. Among these, ethers and ketones are preferably used.

[0026] Examples of ethers include diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 4-methyltetrahydropyran, 1,4-dioxane, cyclopentyl methyl ether, t-butyl methyl ether, etc. Among these, tetrahydrofuran and 2-methyltetrahydrofuran are preferably used.

[0027] Examples of ketones include acetone, butanone, pentanone, hexanone, etc. Among these, specifically, cyclohexanone is preferably used.

[0028] The alcohol solvent is not particularly limited, and any known alcohol solvent that is commonly used as an organic solvent can be used.

[0029] The alcohol solvent may be an alcohol having 1 to 10 carbon atoms. The number of carbon atoms in the alcohol is preferably 1 to 5, more preferably 1 to 3, and even more preferably 1 to 2. Specifically, methanol and ethanol are preferably used as such an alcohol, and methanol is more preferably used.

[0030] As the organic solvent, it is more preferable to use a mixed organic solvent of an aprotic solvent and an alcohol solvent.

[0031] The organic solvents may be used alone or in combination of two or more.

[0032] In the mixed organic solvent, the volume ratio of the aprotic solvent to the alcohol (aprotic solvent:alcohol) is preferably 80:20 to 99:1, more preferably 85:15 to 97:3, and still more preferably 90:10 to 95:5.

[0033] The content of the organic solvent in the mixed solvent is preferably 97.00 to 99.99% by mass, more preferably 98.00 to 99.95% by mass, still more preferably 99.00 to 99.90% by mass, particularly preferably 99.50 to 99.85% by mass, and most preferably 99.60 to 99.80% by mass, based on 100% by mass of the mixed solvent. By having the content of the organic solvent in the mixed solvent within the above range, the water content of the produced crystals is further suppressed.

[0034] The production method of the present invention includes a step of crystallizing dihydrosphingomyelin in the above-mentioned mixed solvent. In the above-mentioned step, the crystallization method is not particularly limited as long as the above-mentioned mixed solvent is used, and an example of the method includes dissolving dihydrosphingomyelin, which is a raw material, in the mixed solvent to prepare a solution, and removing the mixed solvent from the solution.

[0035] The form of dihydrosphingomyelin used as the raw material in the production method of the present invention is not particularly limited as long as it is dihydrosphingomyelin, and dihydrosphingomyelin obtained by a known production method can be used. As such dihydrosphingomyelin, a crude product obtained by a known production method and containing dihydrosphingomyelin in an amorphous state, a crystalline state, a suspension state, a solution state, or the like can be used as it is.

[0036] The dihydrosphingomyelin that is the raw material used in the production method of the present invention may also be dihydrosphingomyelin prepared by recrystallizing a crude product containing dihydrosphingomyelin in an amorphous state, crystalline state, suspension state, solution state, or the like obtained by a known production method in a pretreatment step described below.

[0037] Specifically, as shown in the following scheme, the production method of the present invention includes a method for producing crystals, which includes (1) step 1 of mixing dihydrosphingomyelin, which is a raw material, with a mixed solvent and dissolving it by heating to prepare a solution, (2) step 2 of cooling the solution prepared in step 1 to prepare a suspension, and (3) step 3 of filtering and drying the solid from the suspension prepared in step 2. Each step of the production method will be described below.

[0038] [ka]

[0039] (Process 1) Step 1 is a step of preparing a solution by mixing dihydrosphingomyelin, which is a raw material, with a mixed solvent and dissolving it by heating. The conditions of the raw material dihydrosphingomyelin, the mixed solvent, and the mixing ratio thereof are as described above.

[0040] In step 1, the mixing ratio of the raw material dihydrosphingomyelin to the mixed solvent is preferably 3 to 10 mL, more preferably 3 to 4 mL, per 100 mg of the raw material dihydrosphingomyelin. By having the mixing ratio within the above range, the raw material dihydrosphingomyelin can be sufficiently dissolved in the mixed solvent, which makes it easier to prepare a suspension in step 2 described below.

[0041] The heating temperature in step 1 is not particularly limited as long as the starting dihydrosphingomyelin is dissolved in the solvent. The heating temperature in step 1 is preferably 10° C. or higher, more preferably 20° C. or higher, even more preferably 30° C. or higher, and particularly preferably 40° C. or higher. The heating temperature in step 1 is preferably 120° C. or lower, more preferably 110° C. or lower, and even more preferably 100° C. or lower.

[0042] The reaction time in step 1 is preferably 10 minutes or more, more preferably 30 minutes or more, and preferably 24 hours or less, more preferably 12 hours or less, and even more preferably 6 hours or less.

[0043] In step 1 described above, the raw material dihydrosphingomyelin is mixed with a mixed solvent and dissolved by heating to prepare a solution.

[0044] (Process 2) Step 2 is a step of preparing a suspension by cooling the solution prepared in step 1. By cooling the solution prepared in step 1, dihydrosphingomyelin in the solution is precipitated, and a suspension is prepared.

[0045] The cooling temperature in step 2 is preferably −20 to 50° C., more preferably 5 to 30° C. When the cooling temperature is within the above range, dihydrosphingomyelin in the solution precipitates more uniformly and more sufficiently.

[0046] The cooling rate in step 2 is preferably 1 to 15° C. / h, more preferably 3 to 6° C. / h. When the cooling rate is within the above range, dihydrosphingomyelin in the solution precipitates more uniformly and more sufficiently.

[0047] In step 2, the use of seed crystals in preparing the suspension makes it easier to prepare the suspension, but the suspension can also be prepared without using seed crystals.

[0048] In the above-described step 2, the solution prepared in step 1 is cooled, and a suspension is prepared.

[0049] (Step 3) Step 3 is a step of filtering and drying the solid from the suspension prepared in step 2. By filtering and drying the solid from the suspension prepared in step 2, crystals of dihydrosphingomyelin are produced.

[0050] In step 3, the method for filtering the solid from the suspension is not particularly limited, and the solid can be filtered by a conventionally known filtering method. Examples of such filtering methods include filtering through a filter medium.

[0051] The method for drying the filtered solid is not particularly limited, and the solid can be dried by a conventionally known method, such as a method of leaving the solid in a dryer or a method of ventilating the solid.

[0052] The drying temperature for drying the solid is preferably 5 to 50° C., more preferably 20 to 40° C. By keeping the drying temperature within the above range, it is possible to obtain crystals with a sufficiently reduced water content while suppressing damage to the produced crystals.

[0053] The drying time for drying the solid is preferably 1 to 48 hours, more preferably 2 to 24 hours. By keeping the drying time within the above range, it is possible to obtain crystals with a sufficiently reduced water content while suppressing damage to the produced crystals.

[0054] By the above-described step 3, the solid is filtered out from the suspension prepared in step 2, and the crystals of the present invention can be produced.

[0055] (Pretreatment process) The production method of the present invention may include a step of preparing a raw material dihydrosphingomyelin by recrystallizing a crude product containing dihydrosphingomyelin in an amorphous state, a crystalline state, a suspension state, a solution state, or the like obtained by a known production method, prior to the above step 1. The raw material dihydrosphingomyelin prepared in the pretreatment step can be suitably used as the raw material dihydrosphingomyelin in step 1 of the present invention.

[0056] Specifically, as shown in the following scheme, the pretreatment step includes: (i) step i of mixing a crude product containing dihydrosphingomyelin with a mixed solvent and dissolving the mixture by heating to prepare a pretreatment composition solution; (ii) step ii of cooling the pretreatment composition solution prepared in step i to prepare a pretreatment suspension; and (iii) step iii of filtering out and drying a solid from the pretreatment suspension prepared in step ii.

[0057] [ka]

[0058] In the above pretreatment step, in step i, the crude product is mixed with a mixed solvent and dissolved by heating to prepare a pretreatment composition solution. The mixed solvent may be any of those mentioned above, but water is not used in the pretreatment step.

[0059] In step i, the rest is the same as in step 1 above.

[0060] Moreover, steps ii and iii in the pretreatment step are the same as steps 2 and 3 described above.

[0061] 3. Pharmaceutical Compositions The pharmaceutical composition of the present invention is a pharmaceutical composition containing the above-mentioned dihydrosphingomyelin crystals.

[0062] The content of dihydrosphingomyelin crystals in the pharmaceutical composition is not particularly limited and may be appropriately adjusted depending on the application of the pharmaceutical composition. For example, the content is preferably 10 to 95% by mass, more preferably 35 to 75% by mass.

[0063] The above dihydrosphingomyelin crystals can be usefully used as pharmaceutical compositions such as lipid particle formulations, etc. The pharmaceutical composition of the present invention containing the above dihydrosphingomyelin crystals is excellent in blood retention, migration to target sites, etc., and can exert sufficient effects as a pharmaceutical composition. EXAMPLES

[0064] Examples of the present invention will be described below, but the present invention is not limited to the following examples.

[0065] Example 1 Based on the following scheme, a crude product containing dihydrosphingomyelin in an amorphous state was subjected to a pretreatment step to recrystallize, thereby preparing the starting material DHSM.

[0066] [ka]

[0067] Using the raw material DHSM prepared as described above, dihydrosphingomyelin crystals were produced according to the steps shown in the following scheme.

[0068] [ka]

[0069] The production of the crystals in Example 1 will now be specifically described.

[0070] The raw material DHSM (90 mg) was mixed with a tetrahydrofuran (THF) / methanol (MeOH) mixture (volume ratio 94 / 6, 3.0 mL) and water (10 μL), and dissolved by raising the external temperature to 65° C. The resulting solution was cooled to 6° C. at a rate of 5° C. / h while stirring. The solid was filtered from the resulting suspension and dried to produce DHSM (80 mg).

[0071] Example 2 The raw material DHSM (90 mg) was mixed with a tetrahydrofuran (THF) / methanol (MeOH) mixture (volume ratio 94 / 6, 3.0 mL) and water (30 μL), and dissolved by raising the external temperature to 65° C. The resulting solution was cooled to 5° C. at a rate of 6° C. / h while stirring. The solid was filtered from the resulting suspension and dried to produce DHSM (75 mg).

[0072] Example 3 The raw material DHSM (90 mg) was mixed with a THF / ethanol (EtOH) mixture (volume ratio 84 / 16, 3.4 mL) and water (10 μL), and dissolved by raising the external temperature to 70° C. The resulting solution was cooled to 5° C. at a rate of 6° C. / h while stirring. The solid was filtered from the resulting suspension and dried to produce DHSM (61 mg).

[0073] Example 4 The raw material DHSM (90 mg) was mixed with a mixture of 2-methyltetrahydrofuran (2-MeTHF) / methanol (MeOH) (volume ratio 94 / 6, 3.0 mL) and water (10 μL), and dissolved by raising the external temperature to 65° C. The resulting solution was cooled to 5° C. at a rate of 6° C. / h while stirring. The solid was filtered from the resulting suspension and dried to produce DHSM (69 mg).

[0074] Example 5 The raw material DHSM (90 mg) was mixed with a cyclohexanone / MeOH mixture (volume ratio 94 / 6, 3.0 mL) and water (10 μL), and dissolved by raising the external temperature to 95° C. The resulting solution was cooled to 5° C. at a rate of 6° C. / h while stirring. The solid was filtered from the resulting suspension and dried to produce DHSM (85 mg).

[0075] Example 6 The raw material DHSM (90 mg) was mixed with a cyclohexanone / EtOH mixture (volume ratio 91 / 9, 3.2 mL) and water (10 μL), and dissolved by raising the external temperature to 95° C. The resulting solution was cooled to 5° C. at a rate of 6° C. / h while stirring. The solid was filtered from the resulting suspension and dried to produce DHSM (48 mg).

[0076] Example 7 The raw material DHSM (90 mg) was mixed with a tetrahydrofuran (THF) / methanol (MeOH) mixture (volume ratio 94 / 6, 3.0 mL) and water (10 μL), and dissolved by raising the external temperature to 65° C. The resulting solution was cooled to 5° C. at a rate of 6° C. / h while stirring. The solid was filtered from the resulting suspension and dried to produce DHSM (79 mg).

[0077] Comparative Example 1 The raw material DHSM (90 mg) was mixed with a THF / methanol mixture (volume ratio 94 / 6, 3.0 mL) and dissolved by raising the external temperature to 65° C. The resulting solution was cooled to 5° C. at a rate of 5° C. / h while stirring. The solid was filtered from the resulting suspension and dried to produce DHSM (86 mg).

[0078] (Evaluation method) The following evaluations were carried out for the examples and comparative examples.

[0079] <Test Example 1> Powder X-ray diffraction analysis The peak diffraction angles (2θ) of the crystals of DHSM produced in the Examples and Comparative Examples were measured using a powder X-ray diffractometer (Mini flex, manufactured by Rigaku Corporation) under the following conditions. Measurement conditions: Wavelength 1.54050 Å (CuKα), output 30 kV, 15 mA, measurement angle 3.00 to 50.00 (°), sampling width 0.01, scan speed 2.00° / min

[0080] The peaks of the charts of each Example and Comparative Example are shown in Table 1. Also, Figs. 1 and 2 show XRD charts of the DHSM crystals produced in Example 1 and Example 7, and Fig. 3 shows the XRD chart of the DHSM crystal produced in Comparative Example 1.

[0081] <Test Example 2> Differential thermal analysis (DTA) and thermogravimetry (TG) The DTA and TG of the DHSM crystals produced in the Examples and Comparative Examples were measured under the following measurement conditions using a measuring device (Thermo Plus Series Differential TG-DTA TG8120, manufactured by Rigaku Corporation). Measurement conditions: The temperature was increased from room temperature to 200°C at a rate of 5.0°C / h.

[0082] Table 2 shows the DTA peaks and TG weight changes for each Example and Comparative Example. Figures 4 and 5 show the DTA and TG measurement charts for the DHSM crystals produced in Example 1 and Example 7, and Figure 6 shows the DTA and TG measurement charts for the DHSM crystal produced in Comparative Example 1.

[0083] <Test Example 3> Measurement of water content The water content of the crystals of DHSM produced in each Example and Comparative Example was measured by the Karl Fischer method. The results are shown in Table 3.

[0084] [Table 1]

[0085] [Table 2]

[0086] [Table 3]

Claims

1. A crystal of dihydrosphingomyelin represented by the following formula (1): 【Chemistry 1】 In powder X-ray diffraction, it has peaks at diffraction angles (2θ) = 3.3 ± 0.2 °, 4.9 ± 0.2 °, 6.6 ± 0.2 °, 10.0 ± 0.2 °, 13.4 ± 0.2 °, 16.8 ± 0.2 °, 18.5 ± 0.2 °, 20.2 ± 0.2 °, 21.9 ± 0.2 °, and 23.7 ± 0.2 °. A dihydrosphingomyelin crystal characterized by the above-mentioned.

2. Represented by the following formula (1): 【Chemistry 2】 1. A method for producing a crystal of dihydrosphingomyelin having peaks at diffraction angles (2θ) of 3.3±0.2°, 4.9±0.2°, 6.6±0.2°, 10.0±0.2°, 13.4±0.2°, 16.8±0.2°, 18.5±0.2°, 20.2±0.2°, 21.9±0.2°, and 23.7±0.2° in powder X-ray diffraction, comprising: The method includes a step of crystallizing dihydrosphingomyelin from a mixed solvent containing an organic solvent and water. A method for producing crystals of dihydrosphingomyelin, comprising:

3. The method according to claim 2, wherein the content of the water in the mixed solvent is 0.01 to 3.00 mass % relative to 100 mass % of the mixed solvent.

4. The method according to claim 2 , wherein the organic solvent is a mixed organic solvent of an aprotic solvent and an alcohol.

5. The method according to claim 4 , wherein the alcohol is methanol.

6. The method according to claim 4, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran and cyclohexanone.

7. A pharmaceutical composition comprising the crystal of dihydrosphingomyelin according to claim 1.

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