An epalrestat solid dispersion and a pharmaceutical preparation, a preparation method and application thereof

Abstract

An ipriflavone solid dispersion contains ipriflavone and a carrier material; the carrier material includes MOF-74(Mg); the specific surface area of the carrier material is greater than or equal to 500 m 2 / g; the mass ratio of ipriflavone and the carrier material is less than 9:1; the present application also includes a preparation method of the ipriflavone solid dispersion, a pharmaceutical preparation of the ipriflavone solid dispersion and a preparation method. The present application significantly improves the solubility of ipriflavone by using MOF-74(Mg) to adsorb drugs with high porosity; MOF-74(Mg) can also inhibit the crystallization of amorphous drugs, so that the drugs can maintain amorphous state during storage and transportation, and have excellent stability; by using the water instability of MOF-74(Mg), the contact condition of the poorly soluble drug with the release medium is improved, and the situation that part of the drug cannot be released in the later stage is avoided.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to an ipriflavone dispersion and its pharmaceutical preparation, preparation method and application. BACKGROUND

[0002] Improving the solubility of poorly soluble drugs to improve bioavailability is still a difficulty and hotspot in formulation development. Common solubilization methods include amorphous solid dispersion, co-crystallization technology, and co-solvent solubilization method. Although these solubilization technologies can improve the solubility of poorly soluble drugs to some extent, they still have different defects, mainly involving drug chemical stability and crystal inhibition physical stability. Therefore, new methods for improving drug solubility still need to be developed.

[0003] Ipriavone tablets (KINEDAK) were developed by Ono Pharmaceutical in 1992. The chemical name is 5-[(1Z, 2E)-2-methyl-3-phenyl-2-propenyl]-4-oxo-2-thioxo-3-thiazolidine acetic acid, which is an aldose reductase (AR) inhibitor used for the treatment of diabetic neuropathy. Ipriflavone has poor solubility in water and belongs to BCS II class drugs (low solubility and high permeability). Improving the solubility of ipriflavone can improve its bioavailability, improve patient compliance, achieve 1-day administration, and has great clinical significance in the field of diabetes treatment. In addition, ipriflavone is unstable under light or in solution and tends to form dimers, making it more difficult to solubilize.

[0004] A common defect of some sustained-release preparations is that as the amount of drug in the preparation gradually decreases, the release rate of the drug often decreases synchronously. This phenomenon is particularly pronounced in poorly soluble drugs - their release behavior is significantly delayed in the later stage, and even approaches complete stagnation, making some drugs unable to be effectively released, or causing drug burst release over time. This incomplete release not only causes significant waste of drugs and increases the cost of medication for patients, but more importantly, it makes the actual dose lower than the designed dose, which may lead to reduced efficacy, prolonged treatment period, and even drug safety issues. SUMMARY

[0005] The technical problem to be solved by the present application is to overcome the above-mentioned defects existing in the prior art, and to provide a solid dispersion capable of improving the solubility of ipriflavone, as well as its pharmaceutical preparation, preparation method and application.

[0006] The technical solution adopted by the present application to solve the technical problem is as follows: a solid dispersion of ipriflavone, containing ipriflavone and a carrier material; the carrier material includes MOF-74(Mg);

[0007] The specific surface area of the carrier material is ≥500m 2 / g;

[0008] The mass ratio of the epalrestat and the carrier material is less than 9:1;

[0009] The MOF-74(Mg) is composed of magnesium ions and 2,5-dihydroxyterephthalic acid ligands, wherein the molar ratio of the magnesium ions to the ligands is 1.5-4:1; and the pore size of the MOF-74(Mg) is 1.0-1.5 nm.

[0010] Preferably, the MOF-74(Mg) is obtained by uniformly mixing 2,5-dihydroxyterephthalic acid and a soluble magnesium salt in a solvent, and reacting at 100-150°C for 10-36 h.

[0011] Based on the same inventive concept, the present application also provides a pharmaceutical preparation of the epalrestat solid dispersion, which is a double-layer osmotic pump tablet comprising a drug-containing layer and a booster layer; the drug-containing layer and the booster layer are provided with a semi-permeable membrane coating layer; a drug release pore is provided on the semi-permeable membrane coating layer on one side of the drug-containing layer; and the drug-containing layer contains the epalrestat solid dispersion.

[0012] Preferably, the drug-containing layer comprises the epalrestat solid dispersion, a suspending agent, a binder, and a lubricant.

[0013] Preferably, the booster layer comprises an expanding agent, an osmotic pressure promoter, a binder, a lubricant, and a bleaching aid.

[0014] Preferably, the semi-permeable membrane coating layer comprises a semi-permeable membrane material and a pore-forming agent.

[0015] Preferably, the semi-permeable membrane coating layer accounts for 10-15% of the total mass of the double-layer osmotic pump tablet.

[0016] Preferably, the drug-containing layer further comprises a filler.

[0017] More preferably, the suspending agent of the drug-containing layer comprises low molecular weight PEO; and the molecular weight (Mv) of the low molecular weight PEO is 100000-300000.

[0018] More preferably, the filler of the drug-containing layer comprises one or more than two of lactose, microcrystalline cellulose, mannitol, and starch.

[0019] More preferably, the binder of the drug-containing layer comprises one or two of hydroxypropyl cellulose and povidone.

[0020] More preferably, the lubricant of the drug-containing layer comprises one or more than two of magnesium stearate, silicon dioxide, and sodium stearyl fumarate.

[0021] More preferably, the swelling agent of the boost layer comprises one or more of high molecular weight PEO, hydroxypropyl methyl cellulose, water-swellable cellulose; the molecular weight (Mv) of the high molecular weight PEO is 4000000-7000000.

[0022] More preferably, the osmotic pressure promoter of the boost layer comprises one or more of sodium bicarbonate, sodium carbonate, sodium chloride, potassium chloride, mannitol, sodium sulfate, potassium sulfate.

[0023] More preferably, the adhesive of the boost layer comprises one or more of hydroxypropyl cellulose, povidone.

[0024] More preferably, the lubricant of the boost layer comprises one or more of magnesium stearate, silicon dioxide, sodium stearyl fumarate.

[0025] More preferably, the floatation aid of the boost layer comprises one or more of calcium silicate, mesoporous silicon dioxide.

[0026] More preferably, the semi-permeable membrane material comprises one or more of cellulose acetate, ethyl cellulose, polyvinyl chloride, EUDRAGIT series materials.

[0027] More preferably, the porogen comprises one or more of polyethylene glycol, hydroxypropyl methyl cellulose, polyvinyl alcohol.

[0028] Based on the same inventive concept, the present application also provides a preparation method of the pharmaceutical preparation of the solid dispersion of epalrestat, comprising: mixing raw materials of the drug-containing layer to obtain total mixed powder of the drug-containing layer; mixing raw materials of the boost layer to prepare boost layer granules; compressing the total mixed powder of the drug-containing layer and the boost layer granules into a bilayer tablet to obtain a tablet core; the hardness of the tablet core is 100-200N; coating the tablet core with a solution prepared from raw materials of a semi-permeable membrane coating layer; and after drying, punching holes on the surface of the drug-containing layer with a diameter of 0.5mm-0.8mm.

[0029] Based on the same inventive concept, the present application also provides a preparation method of the solid dispersion of epalrestat, comprising: adding a carrier material to a solvent in which epalrestat is dissolved, uniformly dispersing, and then preparing the solid dispersion of epalrestat by spray drying.

[0030] Preferably, the solvent is one or more of N, N-dimethylformamide, tetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, dichloromethane.

[0031] Preferably, the solvent further contains a solubilizing agent; the solubilizing agent is one or more of Tween 80, polyethylene glycol, poloxamer.

[0032] Preferably, the ratio of the solvent to the amount of use of the epalrestat is 5 mL-300 mL:1 g.

[0033] Preferably, the ratio of the solvent to the amount of use of the solubilizer is 1 L:0.5 g-5 g.

[0034] Preferably, the inlet air temperature of the spray drying is 80-120 DEG C, the inlet liquid amount is 1-5 mL / min, the atomization pressure is 0.1-0.5 MPa, and the material temperature is 50-80 DEG C.

[0035] Based on the same inventive concept, the present application also provides the application of one or more of the solid dispersion of epalrestat, the pharmaceutical preparation of the solid dispersion of epalrestat, the pharmaceutical preparation of the solid dispersion of epalrestat prepared by the preparation method of the solid dispersion of epalrestat, and the solid dispersion of epalrestat prepared by the preparation method of the solid dispersion of epalrestat in the treatment of diabetic neuropathy.

[0036] The present application has the following beneficial effects:

[0037] (1) The present application adsorbs drugs in MOF-74(Mg) with high porosity, so that the drugs cannot be arranged in order according to the crystal structure, but in amorphous state, thereby significantly improving the solubility of epalrestat; MOF-74(Mg) can also inhibit the crystallization of amorphous drugs, so that the drugs can maintain amorphous state during storage and transportation, and have excellent stability.

[0038] (2) The MOF-74(Mg) used is easy to hydrolyze in water, and the MOF-74(Mg) loaded with drugs can hydrolyze and decompose itself while releasing drugs in the release medium; as the drug release proceeds, the contact condition of the poorly soluble drug with the release medium is improved synchronously, avoiding the situation that part of the drug cannot be released in the later stage, and also playing a role in promoting release.

[0039] In addition to the objects, features and advantages described above, the present application has other objects, features and advantages. The present application will be further described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0040] The accompanying drawings, which form a part of this application, are included to provide a further understanding of the application, illustrate preferred embodiments of the present application, and assist in the explanation of the present application. In the drawings:

[0041] Figure 1 is the in-vitro average cumulative release curve of some samples in Example 1, Comparative Examples 1-2 in a pH 6.8 phosphate medium;

[0042] Figure 2 is the XRD pattern of some samples in Example 1, Comparative Examples 1-2 of the present application;

[0043] Figure 3 is the in-vitro average cumulative release curve of some double-layer osmotic pump tablets in Example 2, Comparative Example 3 of the present application in pH 6.8 medium. DETAILED DESCRIPTION

[0044] In order to make the purpose, scheme and beneficial technology of the present application more clear, the present application is further described in detail below in combination with examples and drawings. It should be pointed out that the examples described in the present specification are only for explaining the present application, and are not intended to limit the present application.

[0045] For the sake of simplicity, only some numerical ranges are explicitly disclosed herein. However, any lower limit can be combined with any upper limit to form a range not explicitly recited; and any lower limit can be combined with other lower limits to form a range not explicitly recited, as can any upper limit with any other upper limit to form a range not explicitly recited. Furthermore, although not explicitly recited, every point or individual value within a range is to be included as if explicitly recited. Thus, every point or individual value can be combined as if it were its own lower or upper limit with any other point or individual value or with other lower or upper limits to form a range not explicitly recited.

[0046] In the description herein, it should be noted that, unless otherwise specified, "above", "below" are inclusive of the number, and the meaning of "multiple" in "one or more" is two or more, and the meaning of "multiple" in "one or more" is two or more.

[0047] In the present specification, the meaning of API is: active pharmaceutical ingredient.

[0048] The embodiment of the present application provides a solid dispersion of eptastigmine, which contains eptastigmine and a carrier material; the carrier material comprises MOF-74(Mg);

[0049] The specific surface area of the carrier material is greater than or equal to 500 m 2 / g;

[0050] The mass ratio of eptastigmine and the carrier material is less than 9:1;

[0051] The MOF-74(Mg) is composed of magnesium ions and 2,5-dihydroxy terephthalic acid ligands, wherein the molar ratio of magnesium ions to ligands is 1.5-4:1; the pore size of the MOF-74(Mg) is 1.0-1.5 nm.

[0052] Among the magnesium ions and 2,5-dihydroxyterephthalic acid ligands constituting MOF-74(Mg), magnesium is an essential element for the human body, and 2,5-dihydroxyterephthalic acid has an LD50 exceeding 1 g / kg, indicating a high safe oral dose. Both the metal ions and ligands of MOF-74(Mg) exhibit good biocompatibility. Tests have shown that MOF-74(Mg) can achieve a drug loading capacity of over 60%, and the drug is adsorbed within the pores of MOFs, preventing it from arranging in an ordered crystalline structure and instead presenting an amorphous state, significantly improving the solubility of epalrestat.

[0053] In an embodiment of the present invention, MOF-74(Mg) is obtained by uniformly mixing 2,5-dihydroxyterephthalic acid and a soluble magnesium salt in a solvent and reacting at 100°C to 150°C for 10 to 36 hours.

[0054] In some embodiments of the present invention, 2,5-dihydroxyterephthalic acid is mixed with a soluble magnesium salt in a DMF-ethanol-water solution.

[0055] In some embodiments of the present invention, the specific surface area of ​​the carrier material is ≥1000 m². 2 / g.

[0056] In some embodiments of the present invention, the mass ratio of epalrestat to carrier material is 0.65 to 4:1.

[0057] The present invention also provides a pharmaceutical formulation of the epalrestat solid dispersion, which is a double-layer osmotic pump tablet comprising a drug-containing layer and a booster layer; a semi-permeable membrane coating layer is provided outside the drug-containing layer and the booster layer; a drug release pore is provided on the semi-permeable membrane coating layer on one side of the drug-containing layer; the drug-containing layer contains epalrestat solid dispersion.

[0058] The bilayer osmotic pump tablets of epalrestat solid dispersion prepared using MOF-74(Mg) as a carrier exhibit good biocompatibility and excellent sustained-release effect, effectively prolonging the time it takes for the drug to reach its maximum plasma concentration in vivo. C max ) time ( T max This improves bioavailability and provides a new approach to achieving once-daily dosing.

[0059] In embodiments of the present invention, the drug-containing layer includes epalrestat solid dispersion, suspending agent, binder, and lubricant.

[0060] In embodiments of the present invention, the booster layer includes an expanding agent, an osmotic pressure promoter, an adhesive, a lubricant, and a bleaching agent.

[0061] The auxiliary layer of the double-layer osmotic pump tablet is added with a floating agent, so that the preparation can float on the surface of the medium immediately during dissolution, and the auxiliary layer is always upward during the release detection process, the drug-containing layer is always downward to release the drug continuously, food interference is avoided, the release degree reaches 100% within 24 hours, and good sustained-release effect is achieved.

[0062] In the embodiments of the present application, the semi-permeable membrane coating layer comprises a semi-permeable membrane material and a pore-forming agent.

[0063] In the embodiments of the present application, the semi-permeable membrane coating layer accounts for 10% to 15% of the total mass of the double-layer osmotic pump tablet.

[0064] In some embodiments of the present application, the drug-containing layer further comprises a filler.

[0065] In some embodiments of the present application, the suspending agent of the drug-containing layer comprises low-molecular-weight PEO; the molecular weight (Mv) of the low-molecular-weight PEO is 100000 to 300000. PEO is the abbreviation of polyethylene oxide.

[0066] In some embodiments of the present application, the filler of the drug-containing layer comprises one or more of lactose, microcrystalline cellulose, mannitol and starch.

[0067] In some embodiments of the present application, the binder of the drug-containing layer comprises one or both of hydroxypropyl cellulose and povidone.

[0068] In some embodiments of the present application, the lubricant of the drug-containing layer comprises one or more of magnesium stearate, silicon dioxide and sodium stearyl fumarate.

[0069] In some embodiments of the present application, the swelling agent of the auxiliary layer comprises one or more of high-molecular-weight PEO, hydroxypropyl methyl cellulose and water-swellable cellulose. The molecular weight (Mv) of the high-molecular-weight PEO is 4000000 to 7000000.

[0070] In some embodiments of the present application, the osmotic pressure promoter of the auxiliary layer comprises one or more of sodium bicarbonate, sodium carbonate, sodium chloride, potassium chloride, mannitol, sodium sulfate and potassium sulfate.

[0071] In some embodiments of the present application, the binder of the auxiliary layer comprises one or both of hydroxypropyl cellulose and povidone.

[0072] In some embodiments of the present application, the lubricant of the auxiliary layer comprises one or more of magnesium stearate, silicon dioxide and sodium stearyl fumarate.

[0073] In some embodiments of the present application, the bleaching aid of the booster layer comprises one or both of calcium silicate and mesoporous silica. The double-layer osmotic pump tablet booster layer uses low-density material as a bleaching aid, which can immediately float in each medium, and by using the density difference between the booster layer and the drug-containing layer, the double-layer osmotic pump tablet can have the booster layer always facing upwards and the drug-containing layer always facing downwards in each medium, thereby avoiding the problem of the drug-containing layer facing the stomach in the human body and affecting drug release.

[0074] In some embodiments of the present application, the semi-permeable membrane material comprises one or more of cellulose acetate, ethyl cellulose, polyvinyl chloride, and EUDRAGIT series materials.

[0075] In some embodiments of the present application, the pore-forming agent comprises one or more of polyethylene glycol, hydroxypropyl methyl cellulose, and polyvinyl alcohol.

[0076] The embodiments of the present application also provide a preparation method of the pharmaceutical preparation of the epalrestat solid dispersion, comprising: mixing raw materials of the drug-containing layer to obtain total mixed powder of the drug-containing layer; mixing raw materials of the booster layer to prepare booster layer granules; compressing the total mixed powder of the drug-containing layer and the booster layer granules to obtain a tablet core; the tablet core has a hardness of 100-200 N; coating the tablet core with a solution prepared from raw materials of a semi-permeable membrane coating layer; and after drying, punching holes on the surface of the drug-containing layer, with a hole diameter of 0.5-0.8 mm.

[0077] In some embodiments of the present application, the preparation method of the booster layer granules comprises: mixing raw materials other than the binder and the lubricant, then adding a solution prepared from the binder to mix and granulate, and drying the wet granules to a moisture content of ≤2 wt%, and then adding the lubricant and mixing to obtain the booster layer granules.

[0078] In some embodiments of the present application, the tablet core has a diameter of 11-13 mm.

[0079] In some embodiments of the present application, the punching is performed by using a laser punching machine.

[0080] In some embodiments of the present application, a stomach-soluble coating film can be further coated on the surface of the obtained pharmaceutical preparation.

[0081] The embodiments of the present application also provide a preparation method of the epalrestat solid dispersion, comprising: adding a carrier material to a solvent in which epalrestat is dissolved, uniformly dispersing, and then preparing the epalrestat solid dispersion by spray drying.

[0082] In the embodiments of the present application, the solvent is one or more of N, N-dimethylformamide, tetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, and dichloromethane.

[0083] In the embodiments of the present application, the solvent further contains a solubilizer; the solubilizer is one or more than two of Tween 80, polyethylene glycol, poloxamer.

[0084] In the embodiments of the present application, the ratio of the solvent to the amount of use of epalrestat is 5 mL ~ 300 mL: 1 g. The solvent is finally removed by spray drying, and has little effect on the epalrestat solid dispersion, so the amount thereof can be selected in a large range.

[0085] In the embodiments of the present application, the ratio of the solvent to the amount of use of the solubilizer is 1 L: 0.5 g ~ 5 g.

[0086] In the embodiments of the present application, the inlet air temperature of the spray drying is 80 ℃ ~ 120 ℃, the inlet liquid amount is 1 mL / min ~ 5 mL / min, the atomization pressure is 0.1 MPa ~ 0.5 MPa, and the material temperature is 50 ℃ ~ 80 ℃.

[0087] The embodiments of the present application further provide one or more than two of the epalrestat solid dispersion, the pharmaceutical preparation of the epalrestat solid dispersion, the preparation method of the pharmaceutical preparation of the epalrestat solid dispersion, the pharmaceutical preparation of the epalrestat solid dispersion prepared by the preparation method of the epalrestat solid dispersion, and the application of the epalrestat solid dispersion prepared by the preparation method of the epalrestat solid dispersion in the treatment of diabetic neuropathy.

[0088] Embodiments

[0089] The following examples more specifically describe the present disclosure, which are merely illustrative and not restrictive, because various modifications and changes within the scope of the present disclosure will be apparent to those skilled in the art. Unless otherwise stated, all parts, percentages, and ratios reported in the following examples are by weight. Unless otherwise stated, all reagents used in the examples are available by conventional commercial sources or are synthesized according to conventional methods and are used directly without further purification. Unless otherwise stated, all instruments used in the examples are available by conventional commercial sources.

[0090] The MOFs described in each embodiment refer to MOF-74 (Mg) with a specific surface area greater than 1000 m 2 / g and a pore size of 1.0 ~ 1.5 nm. It is composed of magnesium ions and 2,5-dihydroxyterephthalic acid ligands. The preparation process is as follows:

[0091] To a solid mixture of 2,5-dihydroxyterephthalic acid (1 eq, purchased from Aldrich) and Mg(NO3)2·6H2O (3.3 eq, purchased from Aldrich), 50 mL of DMF-ethanol-water mixed solution (volume ratio of 15:1:1) was added. The suspension was stirred and mixed, then ultrasonic treatment was performed until a homogeneous solution was obtained. Subsequently, the solution was sealed and placed in an oven at 125°C for reaction. After 20 hours, the sample was removed, cooled to room temperature, and filtered to obtain the crude product. The crude product was washed with methanol and dried at 250°C under vacuum for more than 5 hours to remove the solvent, thereby obtaining a dark yellow microcrystalline porous material.

[0092] Drug loading test of MOF-74(Mg):

[0093] Epalrestat and MOF-74(Mg) were weighed according to a mass ratio of 4:1; epalrestat was dissolved in tetrahydrofuran, and MOF-74(Mg) was added and stirred for 24 hours. The supernatant was obtained by centrifugation, and epalrestat that was not loaded by MOF-74(Mg) remained in the supernatant. The epalrestat content in the supernatant was measured, and the difference in concentration from the case without MOFs was calculated to obtain the drug loading. The maximum drug loading of epalrestat loaded by MOF-74(Mg) was 1.75 (mg-epalrestat / mg-MOFs) or 63.6% (mg-epalrestat / total mass).

[0094] Example 1

[0095] Epalrestat solid dispersion and a preparation method thereof:

[0096] The carrier material of the epalrestat solid dispersion of the present example was the MOF-74(Mg), and the mass ratio of epalrestat to the carrier material was 0.43-9:1. The specific ratio is shown in Table 1.

[0097] Table 1: Naming and ratio of each epalrestat solid dispersion of Example 1

[0098]

[0099] The preparation method of the epalrestat solid dispersion was:

[0100] (1) Ethanol solution containing 0.1 wt% Tween 80 was used to dissolve epalrestat, and then MOF-74(Mg) was added. The epalrestat was fully adsorbed by stirring for 12 hours to obtain an epalrestat-MOF-74(Mg) suspension;

[0101] (2) The epalrestat-MOF-74(Mg) suspension was used to prepare a solid dispersion (SD) by spray drying: the inlet temperature was set to 100-110°C, the liquid inlet amount was 3 mL / min, the atomization pressure was 0.15-0.3 MPa, and the material temperature was controlled at 65±5°C.

[0102] Comparative Example 1

[0103] Using the MOF-74(Mg) as the carrier material, the eptastigmine and the carrier material were weighed in a mass ratio of 1:1 (50% drug loading), mixed thoroughly to obtain the eptastigmine-MOF-74(Mg) physical blend (PM).

[0104] Comparative Example 2

[0105] The eptastigmine solid dispersions were prepared using povidone K30 as the carrier material; the mass ratio of eptastigmine to carrier material was 0.1-1:1, and the specific ratio is shown in Table 2.

[0106] Table 2: Naming and ratio of each eptastigmine solid dispersion in Comparative Example 2

[0107]

[0108] The specific operation steps for preparing the solid dispersion in this comparative example were consistent with those in Example 1.

[0109] In-vitro dissolution experiment of the solid dispersion:

[0110] To investigate the solubilization effect of MOF-74(Mg) on eptastigmine, the dissolution of pure API, the solid dispersions or mixtures of Example 1 and Comparative Examples 1-2 in pH 6.8 phosphate medium was determined, and the experimental results are shown in Table 3. Some representative samples were selected to draw the corresponding in-vitro average cumulative release curves, as shown in Figure 1 .

[0111] Table 3: Dissolution of pure API and each eptastigmine solid dispersion or mixture in phosphate medium

[0112]

[0113] Solid dispersion characterization and stability test:

[0114] XRD characterization was performed on pure API, MOF-74(Mg), PVP K30, 70% MOF-74(Mg) (SD) in Example 1, 80% MOF-74(Mg) (SD) in Example 1, 50% MOF-74(Mg) (PM) in Comparative Example 1, and 30% PVP K30 (SD) in Comparative Example 2, and the results are shown in Figure 2 .

[0115] The 30% MOF-74(Mg)(SD), 50% MOF-74(Mg)(SD), 70% MOF-74(Mg)(SD) in Example 1, 50% MOF-74(Mg)(PM) in Comparative Example 1, 10% PVP K30(SD) in Comparative Example 2 were subjected to light exposure experiment and accelerated test (40℃, 20%RH), and compared with pure API in terms of impurity and content change, and the results are shown in Table 4. The 70% MOF-74(Mg)(SD) after 6 months of accelerated test was also subjected to XRD characterization, and the results are shown in Figure 2 .

[0116] Table 4 Stability test results of etiformin solid dispersion

[0117]

[0118] It can be seen from Figure 2 that the 50% MOF-74(Mg)(PM) physical blend and 30% PVP K30(SD) have many characteristic peaks of pure API within 10°~35°, while the 70% MOF-74(Mg)(SD) and 80% MOF-74(Mg)(SD) do not have characteristic peaks of etiformin within 10°~35° or the peak intensity is greatly reduced, indicating that etiformin forms an amorphous state in MOFs, and the pore structure of MOFs inhibits the crystallization of etiformin in the solid dispersion.

[0119] After 12 days of light exposure and 6 months of acceleration, the impurities and content of the solid dispersion prepared using MOF-74(Mg) as the carrier do not change significantly, indicating that the light stability of the etiformin solid dispersion is good. The XRD pattern of the 70% MOF-74(Mg)(SD) solid dispersion after 6 months of acceleration does not change significantly, and there is no characteristic peak of etiformin, indicating that etiformin can exist in an amorphous form for a long time in the solid dispersion, and the stability is good. Using MOF-74(Mg) as the carrier of the solid dispersion can inhibit the crystallization of API during storage, so that API can exist in an amorphous state for a long time.

[0120] As can be seen from Table 3, MOF-74(Mg) as a carrier material of etiformin solid dispersion can significantly enhance the release rate of etiformin; while the effect is very small when only physically mixed.

[0121] It can be seen from the XRD pattern that the epalrestat in MOF-74(Mg)(SD) exists in an amorphous form, and MOF-74(Mg) prevents the epalrestat loaded therein from crystallizing, thereby improving the drug solubility and playing a role in promoting the drug release. In addition, MOF-74(Mg) is unstable in water, and the MOF-74(Mg) in MOF-74(Mg)(SD) is hydrolyzed and decomposed after contacting the medium, so that the epalrestat molecules can be quickly dissolved and released, showing a faster dissolution rate.

[0122] The epalrestat solid dispersion prepared by using the traditional polymer material PVP K30 as a carrier has a 12h release rate of 95% when the drug loading amount is 20%, and the release rate gradually decreases as the drug loading amount increases. MOF-74(Mg) also has a similar trend, but due to its high dissolution rate, when the drug loading amount reaches 70%, the 12h release rate can still reach more than 95%.

[0123] Example 2

[0124] The drug preparation of the epalrestat solid dispersion of this example is a double-layer osmotic pump tablet, and the composition is shown in Formulation 2-1 to Formulation 2-11 in Tables 5, 6 and 7, wherein the epalrestat solid dispersion uses 50% MOF-74(Mg)(SD), 60% MOF-74(Mg)(SD), 70% MOF-74(Mg)(SD) and 80% MOF-74(Mg)(SD); and acetone and water are used as solvents to prepare a coating solution during preparation of the semi-permeable membrane coating layer. Formulations 2-1 to 2-8 and 2-11 have a specification of 150mg, and Formulations 2-9 to 2-10 have a specification of 135mg.

[0125] Formulation 2-1: drug-containing layer 461.5mg, boost layer 381mg, semi-permeable membrane coating layer 110mg, total 952.5mg; coating accounts for 11.55% of the total mass.

[0126] Formulation 2-2: drug-containing layer 384.8mg, boost layer 381mg, semi-permeable membrane coating layer 100mg, total 865.8mg; coating accounts for 11.55% of the total mass.

[0127] Formulation 2-3: drug-containing layer 329.49mg, boost layer 381mg, semi-permeable membrane coating layer 93mg, total 803.49mg; coating accounts for 11.57% of the total mass.

[0128] Formulation 2-4: drug-containing layer 288.6mg, boost layer 381mg, semi-permeable membrane coating layer 87mg, total 756.6mg; coating accounts for 11.50% of the total mass.

[0129] Table 5 Pharmaceutical preparation composition of the epalrestat solid dispersion of Example 2: prescription 2-1 to prescription 2-4

[0130]

[0131] Prescription 2-5: drug-containing layer 329.49 mg, boost layer 381 mg, semi-permeable membrane coating layer 93 mg, total 803.49 mg; coating accounts for 11.57% of the total mass.

[0132] Prescription 2-6: drug-containing layer 329.49 mg, boost layer 430.5 mg, semi-permeable membrane coating layer 99 mg, total 858.99 mg; coating accounts for 11.53% of the total mass.

[0133] Prescription 2-7: drug-containing layer 384.8 mg, boost layer 381 mg, semi-permeable membrane coating layer 100 mg, total 865.8 mg; coating accounts for 11.55% of the total mass.

[0134] Prescription 2-8: drug-containing layer 384.8 mg, boost layer 430.5 mg, semi-permeable membrane coating layer 106 mg, total 921.3 mg; coating accounts for 11.51% of the total mass.

[0135] Table 6 Pharmaceutical preparation composition of the epalrestat solid dispersion of Example 2: prescription 2-5 to prescription 2-8

[0136]

[0137] Prescription 2-9: drug-containing layer 296.86 mg, boost layer 430.5 mg, semi-permeable membrane coating layer 95 mg, total 822.36 mg; coating accounts for 11.55% of the total mass.

[0138] Prescription 2-10: drug-containing layer 296.86 mg, boost layer 381 mg, semi-permeable membrane coating layer 88 mg, total 765.86 mg; coating accounts for 11.49% of the total mass.

[0139] Prescription 2-11: drug-containing layer 329.49 mg, boost layer 360.5 mg, semi-permeable membrane coating layer 99 mg, total 788.99 mg; coating accounts for 12.55% of the total mass.

[0140] The preparation method of the pharmaceutical preparation of the epalrestat solid dispersion of the present embodiment comprises: preparing boost layer granules and drug-containing layer total mixed powder respectively, tabletting, coating and punching, and the specific preparation process is as follows:

[0141] Preparation of drug-containing layer total mixed powder: uniformly mix the raw materials of the drug-containing layer to obtain the drug-containing layer total mixed powder.

[0142] Preparation of the booster layer granules: the raw materials except the binder and lubricant were mixed uniformly, then 5% HPC EXF ethanol solution was added to make soft material, the wet granules were sieved through a 60 mesh sieve, fluidized bed drying was performed until the moisture content was less than or equal to 2 wt%, and then the lubricant (magnesium stearate) was added and mixed uniformly to obtain the booster layer granules.

[0143] Tabletting: the total mixed powder of the drug-containing layer and the booster layer granules were compressed into double-layer tablets according to the prescription ratio, the tablet core hardness was 100-200 N, and the tablet core size was 12 mm.

[0144] Coating and perforation: the semi-permeable membrane coating solution was prepared according to the prescription, and then the tablet core was coated, dried at 40°C for 24 h, and then perforated on the surface of the drug-containing layer side of the tablet core using a laser perforator, with a hole diameter of 0.5-0.8 mm.

[0145] The obtained pharmaceutical preparation can be further coated with a gastric-soluble coating film.

[0146] Table 7 Pharmaceutical preparation composition of the epalrestat solid dispersion of Example 2 and the formulation of Comparative Example 3

[0147]

[0148] Comparative Example 3

[0149] The epalrestat pharmaceutical preparation of the present comparative example is a double-layer osmotic pump tablet, and the composition is shown in Table 7. Acetone and water were used as solvents to prepare the coating solution of the semi-permeable membrane coating layer. The specification is 150 mg.

[0150] The formulation of Comparative Example 3: the drug-containing layer is 265.2 mg, the booster layer is 381 mg, the semi-permeable membrane coating layer is 84 mg, and the total is 730.2 mg; the coating accounts for 11.50% of the total mass.

[0151] The preparation method of the pharmaceutical preparation of the present comparative example comprises: preparing the booster layer granules and the total mixed powder of the drug-containing layer, tabletting, coating and perforating, and the specific preparation process is as follows:

[0152] Preparation of the total mixed powder of the drug-containing layer: the raw materials of the drug-containing layer were mixed uniformly to obtain the total mixed powder of the drug-containing layer.

[0153] Preparation of the booster layer granules: the raw materials except the binder and lubricant were mixed uniformly, then 5% HPC EXF ethanol solution was added to make soft material, the wet granules were sieved through a 60 mesh sieve, fluidized bed drying was performed until the moisture content was less than or equal to 2 wt%, and then the lubricant (magnesium stearate) was added and mixed uniformly to obtain the booster layer granules.

[0154] Tabletting: the total mixed powder of the drug-containing layer and the booster layer granules were compressed into double-layer tablets according to the prescription ratio, the tablet core hardness was 100-200 N, and the tablet core size was 12 mm.

[0155] Coating and punching: coat the tablet core with the semi-permeable membrane coating solution prepared according to the prescription, dry at 40°C for 24 h, and then punch holes on the surface of the tablet core containing the drug layer with a laser punching machine, with a hole diameter of 0.5-0.8 mm.

[0156] The obtained drug preparation can be further coated with a gastric-soluble coating film.

[0157] Release curve detection:

[0158] Take the double-layer osmotic pump tablets obtained in Example 2 and Comparative Example 3 without the gastric-soluble coating film, and detect the release curve. According to the first method of Chinese Pharmacopoeia 2020 edition, part IV, general test 0931, use pH 6.8 medium, rotate at 100 rpm, and take samples at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h for detection of the release degree. The results are shown in Table 8. Among them, the prescription 2-11 does not add a floating aid to the booster layer, and after being put into the dissolution cup, the direction of the drug-containing layer is indefinite, and the repeatability of in vitro release is poor, so the results are not included in Table 8. Some representative samples are selected to draw the in vitro average cumulative release curve of the double-layer osmotic pump tablets, as shown in Figure 3 .

[0159] Table 8 Release degree of the double-layer osmotic pump tablets obtained in Example 2 and Comparative Example 3

[0160]

[0161] The double-layer osmotic pump tablets of prescriptions 2-1 to 2-10 and Comparative Example 3 add calcium silicate as a floating aid to the booster layer, and can immediately float on the surface of the medium after being put into the dissolution medium, and the booster layer is always on top during the release detection.

[0162] Compared with Comparative Example 3, prescriptions 2-1 to 2-3 and 2-8 can all achieve complete release (>99%) within 12 hours and remain stable within 24 hours. Prescription 2-8 has a weak gel structure of the drug-containing layer and a large amount of swelling agent in the booster layer, so the boosting ability is strong, and the release rate is the fastest. Prescription 2-7 has a large gel strength of the drug-containing layer, and the release is the slowest. The release of the solid dispersion in prescription 2-4 does not reach 100%, so it is difficult to release completely after being prepared into a double-layer osmotic pump tablet. Prescriptions 2-6, 2-9, and 2-10 do not use sodium bicarbonate as a gas-forming osmotic pressure enhancer, so the release starts relatively slowly, but the release can reach more than 90% after 16 hours.

[0163] Example 2 uses multiple formulations to prepare double-layer osmotic pump tablets, and the results show that by adjusting the prescription ratio, sustained and stable drug release can be achieved, and the release characteristics are close to zero order.

[0164] Example 3

[0165] The pharmacokinetics of the double-layer osmotic pump tablets of Formulation 2-6 and Formulation 2-9 of Example 2 were evaluated, and the control preparation was a 50 mg epalrestat tablet (trade name: KINEDAK) of the original Japanese manufacturer. ® Three groups (3 beagles each) of beagles were orally administered with the control preparation, the osmotic pump tablet of Formulation 2-6 (150 mg), and the osmotic pump tablet of Formulation 2-9 (135 mg), respectively.

[0166] The control preparation was administered once every 8 h, one tablet each time, for a total of 3 times. Blood samples were taken at 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h after the first administration, 0 h before the second administration (8 h after the first administration), 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h after the second administration, 0 h before the third administration (8 h after the second administration), 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, and 8 h (24 h after the first administration) after the third administration to determine the blood drug concentration of each beagle. The osmotic pump tablets of Formulation 2-6 and Formulation 2-9 were administered once, one tablet each time, and blood samples were taken at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, 20 h, 22 h, and 24 h after administration to determine the blood drug concentration of each beagle. The washout period for each preparation was 7 days. The average blood drug concentration of each group of beagles was calculated based on the above data, and the results are shown in Table 9.

[0167] The experimental results show that, compared with the ordinary tablet, the osmotic pump tablets of Formulation 2-6 and Formulation 2-9 both have sustained-release effects and can achieve the purpose of once-daily administration. Compared with the ordinary tablet, the blood drug concentration of the beagles administered with the osmotic pump tablet of Formulation 2-6 (150 mg) AUC was significantly higher than that of the beagles administered with the ordinary tablet 3 times per day AUC , and the blood drug concentration of the beagles administered with the osmotic pump tablet of Formulation 2-9 (135 mg) AUC was comparable to that of the beagles administered with the ordinary tablet 3 times per day AUC , indicating that the bioavailability was improved by improving the solubility of epalrestat in the embodiments of the present application.

[0168] Table 9 Pharmacokinetic evaluation results of the double-layer osmotic pump tablets of Formulation 2-6 and Formulation 2-9 of Example 2

[0169]

[0170] The above merely provides the preferred embodiments of the present application, and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the principles and technical scope of the present application shall fall into the scope of the present application.

Claims

1. An epalrestat solid dispersion, characterized by, A pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and an effective amount of an epalrestat or a pharmaceutically acceptable salt thereof; wherein the effective amount of the epalrestat or the pharmaceutically acceptable salt thereof is less than 100 mg per day. 2 / g; The mass ratio of the epalrestat and the carrier material is 0.43-4:1; The MOF-74(Mg) is composed of magnesium ions and 2,5-dihydroxyterephthalic acid ligands, wherein the molar ratio of the magnesium ions to the ligands is 1.5-4:1; and the pore size of the MOF-74(Mg) is 1.0-1.5 nm.

2. The solid dispersion of epalrestat according to claim 1, wherein The MOF-74(Mg) is obtained by uniformly mixing 2,5-dihydroxyterephthalic acid and a soluble magnesium salt in a solvent and reacting at 100-150°C for 10-36 h.

3. A pharmaceutical preparation comprising the solid dispersion of epalrestat according to claim 1 or 2, characterized in that, The drug preparation is a double-layer osmotic pump tablet comprising a drug-containing layer and a boost layer; the drug-containing layer and the boost layer are coated with a semi-permeable membrane coating layer; a drug release hole is provided on the semi-permeable membrane coating layer on one side of the drug-containing layer; and the drug-containing layer contains a solid dispersion of epalrestat.

4. The drug preparation of the solid dispersion of epalrestat according to claim 3, characterized in that: The drug-containing layer comprises a solid dispersion of epalrestat, a suspending agent, a binder, and a lubricant; The boost layer comprises a swelling agent, an osmotic pressure promoter, a binder, a lubricant, and a bleaching aid; The semi-permeable membrane coating layer comprises a semi-permeable membrane material and a pore-forming agent.

5. The drug preparation of the solid dispersion of epalrestat according to claim 3, characterized in that: The semi-permeable membrane coating layer accounts for 10-15% of the total mass of the double-layer osmotic pump tablet; The drug-containing layer further comprises a filler.

6. The drug preparation of the solid dispersion of epalrestat according to claim 4, characterized in that: The suspending agent of the drug-containing layer comprises low molecular weight PEO; and the molecular weight of the low molecular weight PEO is 100000-300000; The binder of the drug-containing layer comprises one or both of hydroxypropyl cellulose and povidone; The lubricant of the drug-containing layer comprises one or more than two of magnesium stearate, silicon dioxide, and sodium stearyl fumarate; The swelling agent of the boost layer comprises one or both of high molecular weight PEO and water-swellable cellulose; and the molecular weight of the high molecular weight PEO is 4000000-7000000; The osmotic pressure promoter of the boost layer comprises one or more than two of sodium bicarbonate, sodium carbonate, sodium chloride, potassium chloride, mannitol, sodium sulfate, and potassium sulfate; The binder of the boost layer comprises one or both of hydroxypropyl cellulose and povidone; The lubricant of the boost layer comprises one or more than two of magnesium stearate, silicon dioxide, and sodium stearyl fumarate; The bleaching aid of the boost layer comprises one or both of calcium silicate and mesoporous silicon dioxide; The semi-permeable membrane material comprises one or more than two of cellulose acetate, ethyl cellulose, polyvinyl chloride, and EUDRAGIT series materials; The pore-forming agent comprises one or more than two of polyethylene glycol, hydroxypropyl methyl cellulose, and polyvinyl alcohol.

7. The pharmaceutical preparation of the eptastatin solid dispersion according to claim 5, characterized by: The filler of the drug-containing layer comprises one or more than two of lactose, microcrystalline cellulose, mannitol, and starch.

8. The pharmaceutical preparation of the eptastatin solid dispersion according to claim 6, characterized by: The water-swellable cellulose comprises hydroxypropyl methyl cellulose.

9. A process for preparing a pharmaceutical preparation of the eptastatin solid dispersion according to any one of claims 3 to 8, wherein Comprise: Mixing the raw materials of the drug-containing layer to obtain total mixed powder of the drug-containing layer; mixing the raw materials of the boosting layer to obtain boosting layer granules; compressing the total mixed powder of the drug-containing layer and the boosting layer granules to obtain a tablet core; the hardness of the tablet core is 100-200 N; coating the tablet core with a semipermeable membrane coating solution; after drying, punching holes on the surface of the drug-containing layer, the hole diameter is 0.5-0.8 mm.

10. The method for preparing the epalrestat solid dispersion as described in claim 1 or 2, characterized in that, The method comprises: adding a carrier material to a solvent in which the eptifibatide is dissolved, uniformly dispersing, and then preparing the eptifibatide solid dispersion by spray drying.

11. The method for preparing the eptifibatide solid dispersion according to claim 10, characterized in that: the solvent is one or more of N, N-dimethylformamide, tetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, dichloromethane; the solvent further contains a solubilizer; the solubilizer is one or more of Tween 80, polyethylene glycol, poloxamer; the ratio of the solvent to the eptifibatide is 5-300 mL: 1 g; the ratio of the solvent to the solubilizer is 1 L: 0.5-5 g; the inlet air temperature of the spray drying is 80-120 DEG C, the inlet liquid amount is 1-5 mL / min, the atomization pressure is 0.1-0.5 MPa, and the material temperature is 50-80 DEG C.

12. The use of one or more of the eptifibatide solid dispersion according to claim 1 or 2, the pharmaceutical preparation of the eptifibatide solid dispersion according to any one of claims 3-8, the eptifibatide solid dispersion prepared by the method for preparing the pharmaceutical preparation of the eptifibatide solid dispersion according to claim 9, or the eptifibatide solid dispersion prepared by the method for preparing the eptifibatide solid dispersion according to any one of claims 10-11 in the preparation of a drug for treating diabetic neuropathy.

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