An epalrestat co-compound, a preparation method thereof, and a pharmaceutical preparation containing the same

Abstract

The present invention relates to the field of pharmaceutical preparations and discloses an epalrestat co-compound, a preparation method thereof, and a pharmaceutical preparation containing the same. The preparation method comprises dissolving epalrestat and veratraldehyde in a mixed solution of tetrahydrofuran and acetone, and drying the mixture to obtain the product. Hydrogen bonds are formed between veratraldehyde and epalrestat, thereby significantly improving solubility; at the same time, stability is enhanced, and the source of veratraldehyde is clear and safe. Therefore, the epalrestat co-compound prepared using the method of the present invention has the advantages of high solubility, strong stability, and good safety.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an epalrestat co-compound, a preparation method thereof, and a pharmaceutical preparation containing the same. Background Art

[0002] Epalrestat is a novel aldose reductase inhibitor developed by Ono Pharmaceuticals of Japan. It was first marketed in Japan in 1992 for the treatment of diabetic complications such as neuropathy, corneal epitheliopathy, retinopathy, and microangiopathy. Epalrestat can be used to treat or prevent a variety of diseases, and its therapeutic activity in various diseases has been demonstrated in clinical literature. Although epalrestat's therapeutic efficacy has received extensive research and attention, its solid-state form is crucial for its pharmacological properties. Epalrestat is poorly water-soluble and classified as a poorly soluble drug, classified as Class II under the BCS (Biopharmaceutical Classification System). Its particle size is crucial for its in vivo efficacy. Furthermore, epalrestat is highly sensitive to light and heat during storage. The active ingredient in epalrestat has a Z / E configuration, which is easily isomerized under light or in solution to form inactive substances with Z / Z, E / E, and E / Z configurations, resulting in poor stability.

[0003] To address the above issues, patent WO2010011926A2 discloses an epalrestat betaine cocrystal, patent CN102216281B discloses an epalrestat dihydrocholine cocrystal, and patent CN103951634B discloses an epalrestat 1-methyl-4-hydroxypiperidine cocrystal. After forming a cocrystal, epalrestat exhibits improved water solubility, but the improvement in water solubility of the three cocrystals is not significant. Patent CN115925650B discloses an epalrestat 4,4'-bipyridine cocrystal. Although its water solubility is significantly improved compared to the previous three cocrystals, 4,4'-bipyridine is a highly toxic compound, which limits its use in the pharmaceutical field. Therefore, it is crucial to develop an epalrestat cocrystal with high solubility, strong stability, and good safety. Summary of the Invention

[0004] The present invention addresses the problems of poor solubility and stability of epalrestat in the prior art. By trying different substances, the present invention surprisingly discovered that, among the selected substances, veratraldehyde has a significant protective effect on epalrestat. Therefore, the present invention provides an epalrestat co-compound, a preparation method thereof, and a pharmaceutical preparation containing the same. The epalrestat co-compound prepared by the preparation method of the present invention not only has significantly improved solubility, but also has a low degree of isomerization, good stability, and good safety.

[0005] To achieve the above technical objectives, the present invention provides a method for preparing a co-existing product of epalrestat, comprising dissolving epalrestat and veratraldehyde in a mixed solution of tetrahydrofuran and acetone, and drying the solution to obtain the co-existing product.

[0006] The mass ratio of epalrestat to veratraldehyde is 50:0.5-2.0, preferably 50:1.5.

[0007] The mass ratio of tetrahydrofuran to acetone in the mixed solution is 20-30:15-35; preferably 20-25:21-30; more preferably 20.9:25.5.

[0008] The mass ratio of epalrestat to the mixed solution is 50:30-80.

[0009] The drying method is selected from one or more of atmospheric pressure drying, spray drying and freeze drying.

[0010] The drying method is spray drying, with an inlet air temperature of 110-130°C and an air volume of 0.65-0.75 cm 3 / min, liquid supply frequency is 15-25Hz, and atomization pressure is 0.004-0.006MPa.

[0011] Preferably, the starting spraying temperature is 105-115°C, and the material temperature is controlled at 65±5°C.

[0012] The present invention also provides an epalrestat co-administered compound.

[0013] The present invention also provides a pharmaceutical preparation comprising an epalrestat co-compound.

[0014] The technical solution of the present invention has the following beneficial effects:

[0015] (1) The present invention provides a method for preparing a co-existing compound of epalrestat, comprising dissolving epalrestat and veratraldehyde in a mixed solution of tetrahydrofuran and acetone, and drying the mixture to obtain the compound. Veratraldehyde and epalrestat can form hydrogen bonds, thereby significantly improving solubility; at the same time, stability is improved, and the source of veratraldehyde is clear and safe. Therefore, the co-existing compound of epalrestat prepared by the method of the present invention has the advantages of high solubility, strong stability, and good safety.

[0016] (2) The present invention provides a method for preparing a co-existing product of epalrestat, wherein the mass ratio of epalrestat to veratraldehyde is 50:0.5-2.0, preferably 50:1.5; the mass ratio of tetrahydrofuran to acetone in the mixed solution is 20-30:15-35, preferably 20-25:21-30, and more preferably 20.9:25.5; the solubility and stability of epalrestat are further improved by optimizing the method.

[0017] (3) The present invention provides a method for preparing a co-existing compound of epalrestat, wherein the drying method is spray drying, the inlet air temperature is 110-130°C, the air volume is 0.65-0.75cm3 / min, liquid supply frequency of 15-25Hz, atomization pressure of 0.004-0.006MPa, and further optimization of the method to start liquid spraying temperature of 105-115℃ and material temperature controlled at 65±5℃, which reduced the loss in the preparation process and improved the quality of epalrestat co-existing product.

[0018] (4) The present invention provides a method for preparing a co-existing compound of epalrestat and a pharmaceutical preparation. In the method, veratraldehyde, tetrahydrofuran and acetone are widely available and easily obtained, and the spray drying technology is mature, which has the advantages of easy availability of raw materials and simple preparation technology. The co-existing compound of epalrestat is prepared into a pharmaceutical preparation, such as tablets, granules, capsules, etc., which has improved solubility during use and good long-term storage stability, thereby improving the clinical medication effect and can be widely used in clinical practice. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0020] Figure 1 This is a graph showing the particle size of the epalrestat co-polymer prepared in Example 6 of Experimental Example 3 of the present invention. DETAILED DESCRIPTION

[0021] The following examples are provided for a better understanding of the present invention and are not intended to limit the best mode of implementation. They do not limit the content and scope of protection of the present invention. Any product identical or similar to the present invention obtained by anyone under the guidance of the present invention or by combining the features of the present invention with other prior arts shall fall within the scope of protection of the present invention.

[0022] If specific experimental procedures or conditions are not specified in the examples, the procedures or conditions may be performed according to conventional experimental procedures or conditions described in literature in the field. Reagents or instruments used without manufacturer indication are commercially available. The epalrestat raw material used in the following examples and comparative examples was purchased from Zhejiang Haixiang Chuannan Pharmaceutical Co., Ltd. under batch number P-585-CN20130302.

[0023] Examples 1-4

[0024] Examples 1-4 provide a series of epalrestat co-compounds. The formula of the epalrestat co-compounds provided in each example is shown in Table 1. The preparation method is as follows:

[0025] Under light-proof conditions, epalrestat and veratraldehyde were dissolved in a mixed solution of tetrahydrofuran and acetone according to Table 1 below, and the mixed solution was spray-dried. The inlet air temperature of the spray dryer was set to 120°C and the air volume was 0.7 cm 3 / min, the liquid supply frequency is 20 Hz and the atomization pressure is 0.005 MPa. When the inlet air temperature rises to 110°C, the liquid spraying begins. The material temperature is controlled at 65°C throughout the process. After the liquid spraying is completed, the solid is collected to obtain the epalrestat co-existing product.

[0026] Table 1 Epalrestat co-administered compound formulation (g)

[0027] composition Example 1 Example 2 Example 3 Example 4 Epalrestat 50 50 50 50 Veratraldehyde 0.5 1.5 0.80 2.0 Tetrahydrofuran 25.5 25.5 25.5 25.5 acetone 20.9 20.9 20.9 20.9

[0028] Examples 5-6

[0029] Examples 5-6 provide a series of epalrestat co-compounds. The formula of the epalrestat co-compounds provided in each example is shown in Table 2. The preparation method is the same as that of Examples 1-4.

[0030] Table 2 Epalrestat co-administered compound formulation (g)

[0031] composition Example 5 Example 6 Epalrestat 50 50 Veratraldehyde 1.5 1.5 Tetrahydrofuran 22.8 20.9 acetone 22.7 25.5

[0032] Comparative Examples 1-4

[0033] Comparative Examples 1-4 provide a series of epalrestat co-polymers. The formulas of the epalrestat co-polymers provided in each comparative example are shown in Table 3. The preparation methods are basically the same as those of Examples 1-4, except that in Comparative Example 1, the "mixed solution of tetrahydrofuran and acetone" is replaced with "tetrahydrofuran"; in Comparative Example 2, the "mixed solution of tetrahydrofuran and acetone" is replaced with "acetone"; and in Comparative Examples 3-4, the "mixed solution of tetrahydrofuran and acetone" is replaced with "a mixed solution of ethanol and methanol".

[0034] Table 3 Epalrestat co-administered compound formulation (g)

[0035] composition Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Epalrestat 50 50 50 50 Veratraldehyde 1.5 1.5 1.5 1.5 Tetrahydrofuran 45.5 - - - acetone - 45.5 - - ethanol - - 25.5 20.9 Methanol - - 20.9 25.5

[0036] Comparative Examples 5-8

[0037] Comparative Examples 5-8 provide a series of epalrestat co-polymers. The formulas of the epalrestat co-polymers provided in each comparative example are shown in Table 4. The preparation methods are basically the same as those of Examples 1-4, with the only difference being that in comparative example 5, "veratraldehyde" is replaced with "polyvinyl pyrrolidone"; in comparative example 6, "veratraldehyde" is replaced with "vanillin"; in comparative example 7, "veratraldehyde" is replaced with "hydroxypropyl methylcellulose"; and in comparative example 8, "veratraldehyde" is replaced with "cyclodextrin".

[0038] Table 4 Epalrestat co-administered compound formula (g)

[0039] composition Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Epalrestat 50 50 50 50 Polyvinylpyrrolidone 1.5 - - - Vanillin - 1.5 - - Hydroxypropyl methylcellulose - - 1.5 - Cyclodextrin - - - 1.5 Tetrahydrofuran 25.5 25.5 25.5 25.5 acetone 20.9 20.9 20.9 20.9

[0040] Comparative Example 9

[0041] This comparative example provides an epalrestat co-polymer, the formula of which is shown in Table 5. The preparation method is as follows: Under light-shielding conditions, epalrestat and veratraldehyde are taken according to Table 5 below, mixed and added into the hopper of a hot melt extruder, and the hot melt temperature is set to 220°C and the extrusion speed is set to 20 rpm / min for hot melt extrusion. The obtained strip extrudate is ground and sieved to obtain the epalrestat co-polymer.

[0042] Table 5 Epalrestat co-administered compound formula (g)

[0043] composition Comparative Example 9 Epalrestat 50 Veratraldehyde 1.5

[0044] Experimental Example 1

[0045] This experimental example investigates the changes in related substances of the epalrestat raw material and the epalrestat co-existing products prepared in Examples 1-6 and Comparative Examples 1-9 after being placed under light irradiation (lx4500) for 0 day and 10 days.

[0046] Test method for related substances: High performance liquid chromatography was used, the chromatographic column was ACQUITY HSS T3, 1.8μm, 2.1*50mm, the mobile phase was 0.02mol / L dimethyl hydrogen phosphate solution-acetonitrile (5:1), the flow rate was 0.4mL / min, the column temperature was 30℃, the sample temperature was 8℃, the detection wavelength was 280nm, and the injection volume was 0.2mL.

[0047] Sample preparation method: Dissolve the sample in N,N-dimethylformamide and filter it through 0.22 μm nylon into a 10 mL brown injection bottle.

[0048] The measurement results are shown in Table 6 below.

[0049] Table 6 Changes in related substances of epalrestat coadministered substances

[0050]

[0051] Note: Isomer 3 is a Z / Z isomer; zz1 is an E / E isomer; zz2 is an E / Z isomer.

[0052] As shown in Table 6, compared with Comparative Examples 1-9 and the epalrestat raw material, the contents of related substances in Examples 1-6 at 0 days and 10 days were lower, and the range of change from 0 days to 10 days was also smaller, indicating that the epalrestat co-existing products of Examples 1-6 had a lower degree of isomerization under light conditions and were more stable.

[0053] Experimental Example 2

[0054] This experimental example investigates the solubility of epalrestat co-deposits. The method is as follows: 10 mg each of the epalrestat co-deposits of Example 6, the epalrestat co-deposits of Comparative Example 7, the epalrestat raw material, and the epalrestat dihydrocholine co-crystal, epalrestat betaine co-crystal, epalrestat 1-methyl-4-hydroxypiperidine co-crystal, and epalrestat 4,4'-bipyridine co-crystal prepared according to the prior art were placed in different 250 mL stoppered conical flasks, 100 mL of water was added to each flask, and ultrasonication was performed for 30 minutes (protecting from light during the ultrasonication process). After the ultrasonication, the filtrate was allowed to cool to room temperature, filtered, and the filtrate was taken as the test solution.

[0055] Epalrestat dihydrocholine cocrystal was prepared according to the method disclosed in CN102216281B; epalrestat betaine cocrystal was prepared according to the method disclosed in WO2010011926A2; epalrestat 1-methyl-4-hydroxypiperidine cocrystal was prepared according to the method disclosed in CN103951634B; epalrestat 4,4'-bipyridine cocrystal was prepared according to the method disclosed in CN115925650B.

[0056] Solubility determination method: High performance liquid chromatography was used, the chromatographic column was ACQUITY HSS T3, 1.8μm2.1*50mm, the mobile phase was 0.02mol / L dimethyl hydrogen phosphate solution-acetonitrile (5:1), the flow rate was 0.4mL / min, the column temperature was 30℃, the sample temperature was 8℃, the detection wavelength was 280nm, and the injection volume was 0.2mL.

[0057] Sample preparation method: Dissolve the sample in the mobile phase and filter it through 0.22 μm nylon into a 10 mL brown injection bottle.

[0058] The solubility test results are shown in Table 7 below.

[0059] Table 7 Solubility results

[0060] sample Solubility in aqueous medium (μg / mL) Epalrestat raw materials 6.71 Epalrestat co-polymer prepared in Example 6 435 Epalrestat co-existing product prepared in Comparative Example 7 330 Epalrestat dihydrocholine cocrystal 60 Epalrestat betaine cocrystal 45 Epalrestat 1-methyl-4-hydroxypiperidine cocrystal 50 Epalrestat 4,4'-bipyridine cocrystal 325

[0061] As shown in Table 7, the solubility of the epalrestat co-polymers prepared in Example 6 was greater than that of the other groups.

[0062] Experimental Example 3

[0063] This experimental example investigates particle size determination, and the epalrestat co-polymer of Example 6 and the epalrestat raw material were used for particle size determination.

[0064] Determination method: Particle size was measured by dry method using Malvern Mastersize 3000 laser particle size analyzer, with dispersion pressure of 2 Bar, light shielding of 0.1-15%, injection speed of 60%, funnel spacing (standard venturi tube) of 2.0 mm, and refractive index of 1.706.

[0065] The particle size determination results are shown in Table 8 and Figure 1 .

[0066] Table 8 Particle size results

[0067]

[0068] From Table 8 and Figure 1 It can be seen that the particle size of the co-existing product prepared in Example 6 is smaller than that of the epalrestat raw material, and the particle size distribution is more uniform, which is conducive to the therapeutic effect of epalrestat in vivo.

[0069] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A method for preparing an epalrestat co-existing compound, characterized in that: The method comprises dissolving epalrestat and veratraldehyde in a mixed solution of tetrahydrofuran and acetone, and drying the mixture to obtain the product; The mass ratio of epalrestat to veratraldehyde is 50:0.5-2.0; The mass ratio of tetrahydrofuran to acetone in the mixed solution is 20-30:15-35.

2. The method for preparing the epalrestat co-compound according to claim 1, wherein: The mass ratio of epalrestat to veratraldehyde is 50:1.

5.

3. The method for preparing the epalrestat co-compound according to claim 1, wherein: The mass ratio of tetrahydrofuran to acetone in the mixed solution is 20-25:21-30.

4. The method for preparing the epalrestat co-compound according to claim 1, wherein: The mass ratio of tetrahydrofuran to acetone in the mixed solution is 20.9:25.

5.

5. The method for preparing the epalrestat co-compound according to any one of claims 1 to 4, characterized in that: The mass ratio of epalrestat to the mixed solution is 50:30-80.

6. The method for preparing the epalrestat co-compound according to claim 1, wherein: The drying is selected from one or more of normal pressure drying, spray drying and freeze drying.

7. The method for preparing the epalrestat co-compound according to claim 6, wherein: The drying is spray drying, with an inlet air temperature of 110-130°C and an air volume of 0.65-0.75 cm 3 / min, liquid supply frequency is 15-25Hz, and atomization pressure is 0.004-0.006MPa.

8. The method for preparing the epalrestat co-compound according to claim 7, characterized in that: The starting spray temperature of the spray drying is 105-115°C, and the material temperature is controlled at 65±5°C.

9. An epalrestat co-compound obtained according to the preparation method according to any one of claims 1 to 8.

10. A pharmaceutical preparation, characterized in that Comprising the epalrestat co-administered substance according to claim 9.

Images