A lipoic acid pharmaceutical composition and a method for preparing the same

Abstract

The application discloses a lipoic acid pharmaceutical composition and a preparation method thereof. The pharmaceutical composition is in the form of wet granules, and comprises lipoic acid, hydroxypropyl cellulose and an ethanol aqueous solution. The ethanol aqueous solution of the hydroxypropyl cellulose is added into a mixture containing the lipoic acid to prepare the wet granules by a wet granulation method, and the concentration of the ethanol aqueous solution is controlled to be 20-60%, so that the problems of sticking and cracking in the tabletting process are avoided, and the process is feasible. Moreover, the dosage of the ethanol aqueous solution of the hydroxypropyl cellulose is only 15-30% of the mass of the lipoic acid, the problem of difficult drying of the granules caused by excessive wetting is avoided, and the industrial production is facilitated.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of lipoic acid preparation, and particularly relates to a lipoic acid pharmaceutical composition and a preparation method thereof. BACKGROUND

[0002] Lipoic acid, also known as alpha-lipoic acid, is an eight-carbon fatty acid with water-soluble and fat-soluble dual properties. Lipoic acid can effectively eliminate oxygen free radicals, chelate metal ions and regenerate other antioxidants in the body, and is a powerful multifunctional oxidative stress inhibitor. The ADA (American Diabetes Association) guidelines and the EASD (European Association for the Study of Diabetes) guidelines consistently regard lipoic acid as a first-line drug for preventing and treating diabetic neuropathy; the Chinese Medical Doctor Association Expert Consensus on Diabetic Peripheral Neuropathy recommends lipoic acid for the treatment of diabetic neuropathy. Based on abundant evidence-based medical evidence, lipoic acid has gradually become a mainstream treatment for diabetic neuropathy.

[0003] At present, lipoic acid preparations on the market worldwide include tablets, injections, soft capsules and the like. The original research factory of lipoic acid tablets is MEDA pharmaceutical in Germany, and the product name is Thioctacid, with specifications of 0.2g and 0.6g. The drug instruction discloses that the auxiliary materials thereof include hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate and coating materials (hydroxypropyl methyl cellulose, polyethylene glycol 6000, talc, titanium dioxide, quinoline yellow, aluminum lake, indigo carmine, aluminum salt).

[0004] However, the development of lipoic acid tablets has technical difficulties: the melting point of lipoic acid is about 60℃, and when the content of lipoic acid in the tablet material is greater than 45%, the tabletting process is prone to problems such as sticking, cracking and the like; increasing the amount of auxiliary materials to dilute the content of the main drug can overcome the tabletting problem, but will lead to an increase in tablet weight and tablet diameter, and difficulty in swallowing for patients. Therefore, it is necessary to develop a lipoic acid tablet and a preparation method thereof, which can increase the content of the main drug while overcoming the tabletting problem.

[0005] The original research preparation patent US5376382A solves the above-mentioned problems of main drug content and tabletting by adding a large amount of water or binder solution (more than 30% of the mass of the main drug) to wet granulation. Embodiments 3 and 4 disclose a preparation method of lipoic acid tablets: a mixture of lipoic acid and hydroxypropyl cellulose is wet granulated with water in an amount of 60% of the mass of lipoic acid, the granules are dried, and then mixed with magnesium stearate to obtain tablets with a lipoic acid content of 300mg / 331mg tablet weight, and smooth tablet surface without cracks. However, the preparation method of the lipoic acid tablets has the problem of difficulty in drying the excessively wet granules, which is not conducive to industrial production.

[0006] Document 1 (Ni Hualili. Experimental study on lipoic acid tablets [D]. Shandong University, 2013.) solves the above-mentioned problems of main drug content and tabletting by optimizing the type and amount of lubricant. "2.5 Best prescription and process verification" discloses a lipoic acid tablet: lipoic acid 300 g / tablet, microcrystalline cellulose 100 g / tablet, sodium carboxymethyl starch 50 g / tablet, 3% PVP ethanol solution 140-160 g / tablet, micro-silica gel 15 g / tablet, and magnesium stearate 5 g / tablet. However, the type and amount of lubricant have limited effect on improving the tabletting problem, and a large amount of diluent and other excipients are still needed, resulting in a lipoic acid content of less than 60% in the obtained tablet, and the main drug content has not been significantly improved.

[0007] Patent CN 113181129 A solves the above-mentioned problems of main drug content and tabletting by combining wet granulation with dry granulation of the secondary granulation process. Example 3 discloses a preparation method of lipoic acid tablets: a mixture of lipoic acid, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose is wet granulated with an appropriate amount of 50% ethanol solution, the granules are dried, then mixed with low-substituted hydroxypropyl cellulose and magnesium stearate, dry granulated, and the total mixture of magnesium stearate is added and tabletted to obtain tablets with a lipoic acid content of 600 mg / 800 mg tablet weight and no sticking during tabletting. However, the preparation method of the lipoic acid tablet has the disadvantage of complex granulation process, which is not conducive to industrial production.

[0008] In summary, a lipoic acid pharmaceutical composition and its preparation method are provided, which solves the problems of main drug content and tabletting, avoids the problems of multiple granulation and difficult granule drying, and is suitable for industrial production, and improves the stability of the preparation quality of the composition product, which is a technical problem that has not been solved in the art. SUMMARY

[0009] The first technical problem to be solved by the present application is to provide a lipoic acid pharmaceutical composition and its preparation method, which improves the main drug content while overcoming the tabletting problem by using an ethanol aqueous solution of hydroxypropyl cellulose as a binder for wet granulation, and avoids the problems of multiple granulation and difficult granule drying, which is conducive to industrial production.

[0010] Due to the particularity of lipoic acid material, when using a binder for wet granulation, although the effect of a specific type of binder on solving the sticking problem during tabletting is investigated, the inventors have further found that after solving the sticking problem during tabletting, the selection of the type of binder also has different effects on the dissolution stability of the preparation (especially the long-term stability of the preparation), which is not conducive to the quality control of the preparation during industrial production.

[0011] Therefore, the second technical problem to be solved by the present application is to ensure accelerated 6-month dissolution stability by optimizing the selection of a specific hydroxypropyl cellulose type and a suitable amount, based on the solution of the problems of tablet sticking or cracking, etc., so as to be beneficial to the long-term stability of the quality of the lipoic acid pharmaceutical composition.

[0012] The technical problem of the present application is solved by the following technical scheme:

[0013] In one aspect, the present application provides a lipoic acid pharmaceutical composition, the form of the pharmaceutical composition is wet granules, which comprises lipoic acid, hydroxypropyl cellulose and an ethanol aqueous solution.

[0014] Preferably, the hydroxypropyl cellulose and the ethanol aqueous solution are (0.15-0.3):1 (w / w) to lipoic acid.

[0015] Preferably, the concentration of the ethanol aqueous solution is 20-60wt%.

[0016] More preferably, the concentration of the ethanol aqueous solution is 30-45wt%.

[0017] Preferably, the hydroxypropyl cellulose is low-viscosity hydroxypropyl cellulose, including but not limited to one or more of hydroxypropyl cellulose ELF, hydroxypropyl cellulose EXF, and hydroxypropyl cellulose LXF.

[0018] More preferably, the hydroxypropyl cellulose is hydroxypropyl cellulose ELF.

[0019] Preferably, the hydroxypropyl cellulose is (0.01-0.1):1 (w / w) to lipoic acid.

[0020] More preferably, the hydroxypropyl cellulose is (0.015-0.05):1 (w / w) to lipoic acid.

[0021] More preferably, the mass fraction of the hydroxypropyl cellulose to lipoic acid is 1.5%, or 3.33%, or 5%.

[0022] Preferably, it further comprises internal pharmaceutically acceptable adjuvants, including but not limited to diluents and disintegrants.

[0023] More preferably, the diluents include but are not limited to one or more of microcrystalline cellulose, starch, lactose, and calcium phosphate.

[0024] More preferably, the disintegrants include but are not limited to one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and polyvinylpyrrolidone.

[0025] More preferably, the other pharmaceutically acceptable adjuvants are (0-0.25):1 (w / w) to lipoic acid.

[0026] The kind and amount of the internal pharmaceutically acceptable excipient do not have significant influence on the tabletting of lipoic acid. The appropriate internal excipient can improve the color difference of lipoic acid, but the increase of the amount of the excipient cannot solve the content problem of lipoic acid. The person skilled in the art can know that the amount of the excipient should be reduced as much as possible on the basis of solving the technical problem, and therefore the kind and amount of the internal pharmaceutically acceptable excipient can be adjusted appropriately.

[0027] Preferably, the following components are included by weight parts:

[0028] lipoic acid 600 parts by weight

[0029] hydroxypropyl cellulose 6-30 parts by weight

[0030] ethanol aqueous solution 90-150 parts by mass.

[0031] More preferably, the following components are included by weight parts:

[0032]

[0033] Most preferably, the following components are included by weight parts:

[0034]

[0035] A preparation method of a lipoic acid pharmaceutical composition includes adding an ethanol aqueous solution of hydroxypropyl cellulose to a mixture containing lipoic acid to wet granulation.

[0036] A preparation method of a lipoic acid pharmaceutical composition includes the following steps:

[0037] a) mixing lipoic acid or lipoic acid and internal pharmaceutically acceptable excipients uniformly;

[0038] b) wet granulation by adding an ethanol aqueous solution of hydroxypropyl cellulose;

[0039] c) wet granulation.

[0040] Preferably, the mixing in step a) uses a wet granulator.

[0041] More preferably, the stirring speed of the wet granulator in step a) is 150-300 rpm, and the cutter speed is 900-1500 rpm.

[0042] Preferably, the wet granulation in step b) uses a wet granulator.

[0043] More preferably, the stirring speed of the wet granulator in step b) is 150-300 rpm, and the cutter speed is 900-1500 rpm.

[0044] Preferably, the ethanol aqueous solution of step b) is added in a reverse flow or a spray flow.

[0045] Preferably, the wet granulation of step b) has a liquid adding time of 2-5 min and a granulation time of 2-5 min.

[0046] Preferably, the wet granulation of step c) uses a swing granulator.

[0047] More preferably, the wet granulation of step c) uses a screen mesh of 16-24 mesh.

[0048] The skilled in the art can adjust the process equipment and the range of process parameters according to the phenomenon of the wet granulation process to achieve the purpose of preparing wet granules.

[0049] In another aspect, the present application provides a lipoic acid pharmaceutical composition in the form of a tablet, comprising the above wet granules and additional pharmaceutically acceptable excipients, wherein the ethanol aqueous solution is removed during the production process.

[0050] Preferably, the additional pharmaceutically acceptable excipients include, but are not limited to, one or more of diluents, disintegrants, lubricants, film-coating premixes.

[0051] More preferably, the diluents include, but are not limited to, one or more of microcrystalline cellulose, starch, lactose, calcium phosphate.

[0052] More preferably, the disintegrants include, but are not limited to, one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, polyvinyl pyrrolidone.

[0053] More preferably, the lubricants include, but are not limited to, one or more of magnesium stearate, micro-powder silica, talc.

[0054] More preferably, the other pharmaceutically acceptable excipients: lipoic acid is (0.05-0.25): 1 (w / w).

[0055] The type and amount of additional pharmaceutically acceptable excipients do not significantly affect the tabletting of lipoic acid, and it is common knowledge in the art to appropriately add lubricants and other excipients, but the increase in the amount of excipients is not suitable for solving the problem of lipoic acid content. The skilled in the art can know that on the basis of solving technical problems, the amount of excipients should be minimized, therefore, the type and amount of additional pharmaceutically acceptable excipients can be appropriately adjusted.

[0056] Preferably, the components include the following in parts by weight:

[0057]

[0058] wherein the ethanol aqueous solution is removed during the production process.

[0059] More preferably, by weight parts, the following components are included:

[0060]

[0061] Most preferably, by weight parts, the following components are included:

[0062]

[0063] Wherein, the water is removed during the production process.

[0064] More preferably, by weight parts, the following components are also included:

[0065] Film coating premix 24 parts by weight

[0066] Water 135 parts by weight

[0067] Wherein, the water is removed during the production process.

[0068] A method for preparing a lipoic acid pharmaceutical composition in the form of a tablet, comprising the following steps:

[0069] Drying the wet granules obtained by wet granulation, sizing, mixing with additional pharmaceutically acceptable excipients, tabletting, and coating.

[0070] Preferably, the drying is performed using a fluidized bed dryer.

[0071] More preferably, the drying is controlled by setting the inlet air temperature to 40-45℃.

[0072] Preferably, the sizing is performed using a swing granulator.

[0073] More preferably, the sizing is performed using a screen mesh size of 14-24 mesh.

[0074] Preferably, the coating process is controlled by setting the material temperature to below 45℃.

[0075] The skilled person can adjust the process equipment and process parameter ranges as appropriate based on the phenomena observed during the drying, tabletting, and coating processes, in order to achieve the goal of preparing lipoic acid tablets.

[0076] Compared to the prior art, the lipoic acid pharmaceutical composition of the present application has the following beneficial effects:

[0077] 1、The lipoic acid pharmaceutical composition of the present application is wet granulated with ethanol aqueous solution of hydroxypropyl cellulose as a binder, and the concentration of the ethanol aqueous solution is controlled to be 20-60%, preferably 30-45%, so that the tabletting process avoids the problems of sticking and cracking, and has process feasibility; moreover, the amount of the ethanol aqueous solution of hydroxypropyl cellulose is only 15-30% of the mass of lipoic acid, which avoids the problem of difficult drying of the granules caused by excessive wetting in US5376382A, and is beneficial to industrial production.

[0078] 2、The lipoic acid pharmaceutical composition of the present application preferably uses ELF as the type of the binder hydroxypropyl cellulose, and the amount of the binder is preferably 1.5-5% of the mass of lipoic acid, which has superior dissolution stability effect, and after being placed under accelerated conditions (40℃, 75% RH) for 6 months, the 45min dissolution is >75%, which meets the enterprise internal control requirements of product quality; other low-viscosity hydroxypropyl celluloses, such as hydroxypropyl cellulose EXF and hydroxypropyl cellulose LXF, do not have dissolution stability, and the dissolution is significantly reduced during the accelerated condition placing process. DETAILED DESCRIPTION

[0079] The following are specific embodiments of the present application, which further describe the technical solutions of the present application, but the protection scope of the present application is not limited to these embodiments. Any changes or equivalent replacements without departing from the concept of the present application are protected within the protection scope of the present application.

[0080] The reagents and instruments used in the embodiments are all conventional reagents and instruments in the art, and can be purchased through conventional channels. The following are only illustrative.

[0081] Reagents:

[0082] Lipoic acid (type: pharmaceutical grade, manufacturer: Suzhou Fuji Lei)

[0083] Hydroxypropyl cellulose (type: ELF, manufacturer: Asia Lan)

[0084] Hydroxypropyl cellulose (type: LXF, manufacturer: Asia Lan)

[0085] Low-substituted hydroxypropyl cellulose (type: SH-LH22, manufacturer: Anhui Shanhe)

[0086] Magnesium stearate (type: SH-YM-M, manufacturer: Anhui Shanhe)

[0087] Film coating premix (type: gastroresistant, Shanghai Kalikang)

[0088] Instruments:

[0089] Wet granulator (type: GM-150E, manufacturer: Zhejiang Xiaolun)

[0090] Fluidized bed granulator (Model: FBG-150E, Manufacturer: Zhejiang Xiaolun)

[0091] High efficiency tablet press (Model: GZP-26, Manufacturer: Beijing Xinlongli)

[0092] High efficiency coating machine (Model: BGB-75FD, Manufacturer: Zhejiang Xiaolun)

[0093] Example 1

[0094] A lipoic acid tablet, the prescription composition is shown in the following table:

[0095]

[0096] A lipoic acid tablet preparation method, comprising the following steps:

[0097] (1) Granulation: add the prescription amount of lipoic acid and low-substituted hydroxypropyl cellulose (internal addition) into a wet granulator, set the stirring speed to 150-300 rpm, and the cutter speed to 900-1500 rpm, mix uniformly; add the prescription amount of hydroxypropyl cellulose ethanol solution by pouring, control the liquid addition time to 2-3 min, and continue granulating for 2-3 min; use a swing granulator (20 mesh screen) for wet granulation.

[0098] (2) Drying: fluidized bed drying, control the inlet air temperature to 40-45℃, and make the material drying loss ≤1.5%; use a swing granulator (16 mesh screen) for dry granulation.

[0099] (3) Total mixing: add the prescription amount of low-substituted hydroxypropyl cellulose (external addition) and magnesium stearate, and mix at 12 rpm for 5 min.

[0100] (4) Tablet pressing: control the weight difference to ±5%, the average weight to ±3%, and the average main pressure to 10-23 KN.

[0101] (5) Coating: prepare a coating solution with a solid content of 15% for coating, control the inlet air temperature to 40-60℃, the inlet air flow to 1200-2000 m 3 / h, the atomizing air pressure to 0.2-0.4 MPa, the fan pressure to 0.2-0.4 MPa, the peristaltic pump speed to 10-40 rpm, and maintain the product temperature to 33-38℃ during the coating process.

[0102] Examples 2-5

[0103] On the basis of Example 1, investigate the effects of the amount of adhesive hydroxypropyl cellulose (Example 2, Example 3) and the proportion of adhesive mixed solvents (Example 4, Example 5) on the tablet pressing process feasibility and dissolution stability.

[0104] A lipoic acid tablet, the prescription composition is shown in the following table:

[0105]

[0106] A preparation method of lipoic acid tablets, same as example 1.

[0107] Example 6

[0108] On the basis of example 1, the effects of adhesive hydroxypropyl cellulose type: ELF (example 1), LXF (example 6) on the feasibility of tabletting process and dissolution stability were investigated.

[0109] A lipoic acid tablet, the prescription composition is different from example 1 in that the type of hydroxypropyl cellulose is replaced by LXF.

[0110] A preparation method of lipoic acid tablets, same as example 1.

[0111] Example 7

[0112] On the basis of example 1, the effects of granulation process adhesive hydroxypropyl cellulose addition method: solution form (example 1) or dry powder form (example 7) on the feasibility of tabletting process and dissolution stability were investigated.

[0113] The difference from example 1 is that a preparation method of lipoic acid tablets, (1) granulation: add the prescription amount of lipoic acid, low-substituted hydroxypropyl cellulose (internal addition) and hydroxypropyl cellulose into the wet granulator, set the stirring speed to 150-300 rpm, the cutter speed to 900-1500 rpm, and mix uniformly; add the prescription amount of ethanol aqueous solution by pouring, control the liquid addition time to 2-3 min, and continue granulating for 2-3 min; use the swing granulator (20 mesh screen) for wet granulation.

[0114] Example 8 lipoic acid tablets and intermediate property detection

[0115] The properties of lipoic acid tablets and intermediates in examples 1-7 above were detected, and the detection items included dry granule powder properties, particle size distribution, tabletting phenomenon, and tablet dissolution curve.

[0116] The detection process is as follows:

[0117] Powder properties: determined by reference bulk density and tap density determination method (Chinese Pharmacopoeia 2020 edition four general rules 0993).

[0118] Particle size distribution: determined by reference particle size and particle size distribution determination method (Chinese Pharmacopoeia 2020 edition four general rules 0982).

[0119] Tablet sticking phenomenon: observe the tabletting process phenomenon, refer to the weight difference determination method (Chinese Pharmacopoeia 2020 edition four general rules 0101) and the friability test method (Chinese Pharmacopoeia 2020 edition four general rules 0923).

[0120] Tablet dissolution: refer to the dissolution determination method (Chinese Pharmacopoeia 2020 edition four general rules 0931 second method), with water 900ml as the dissolution medium, the rotation speed is 75 revolutions per minute.

[0121] The test results are as follows:

[0122]

[0123] The test results show that:

[0124] ① The wet granulation of the binder hydroxypropyl cellulose affects the tabletting: hydroxypropyl cellulose is added in the form of dry powder (Example 7), and the subsequent tabletting process appears sticking problem; added in the form of solution (Example 1), which can avoid the sticking problem in the tabletting process.

[0125] ② The concentration of the binder hydroxypropyl cellulose ethanol aqueous solution affects the tabletting: when the concentration of the ethanol aqueous solution is 11wt% (Example 4), the subsequent tabletting process appears sticking problem; the concentration is 20-60%, especially 34 (Example 5)-45% (Example 2), which can avoid the sticking problem in the tabletting process; when the concentration is higher than 60%, the tablet cracking phenomenon is easy to appear.

[0126] ③ The type of the binder hydroxypropyl cellulose affects the dissolution stability: the type of hydroxypropyl cellulose is LXF (Example 6), the dissolution rate significantly decreases after 6 months of acceleration, and the dissolution rate at 45min is less than 75% (the dissolution rate at 45min is 66.2% after 3 months of acceleration); the type is ELF (Example 2), the dissolution rate has no significant change after 6 months of acceleration, and the dissolution rate at 45min is still more than 75%, which has superior dissolution stability.

[0127] ④ The amount of the binder hydroxypropyl cellulose affects the dissolution stability: when the amount of hydroxypropyl cellulose is 9 parts by weight (i.e. 1.5% of the mass of thioctic acid, Example 2)-30 parts by weight (i.e. 5% of the mass of thioctic acid, Example 3), the dissolution rate has no significant change after 6 months of acceleration, and the dissolution rate at 45min is still more than 75%, which has superior dissolution stability.

[0128] In addition, the inventors found that when the amount of hydroxypropyl cellulose is further increased, for example, from 5% to 10% of the mass of thioctic acid, the dissolution rate decreases to less than 75%, which affects the dissolution stability, and cannot meet the enterprise's internal control requirements of product quality.

[0129] In summary, the present application uses the ethanol aqueous solution of hydroxypropyl cellulose as the binder solution to perform the wet granulation, and controls the concentration of the ethanol aqueous solution to be 20-60%, so that the problems of sticking and cracking in the subsequent tabletting process can be avoided, and the process is feasible.

[0130] Further, the present application preferably uses the ELF type of hydroxypropyl cellulose, and preferably uses the hydroxypropyl cellulose in an amount of 1.5-5% of the mass of lipoic acid, so that the effect of accelerating the dissolution stability of 6-month 45min dissolution rate>75% can be achieved.

Claims

1. A lipoic acid pharmaceutical composition in the form of a wet granulate, characterized in that, The pharmaceutical composition comprises lipoic acid, low viscosity hydroxypropyl cellulose and ethanol solution, wherein: The mass ratio of the low viscosity hydroxypropyl cellulose and ethanol solution to lipoic acid is (0.15-0.3):

1. The concentration of the ethanol solution is 30-45 wt%. In the preparation, the ethanol solution of the low viscosity hydroxypropyl cellulose is added to the mixture containing lipoic acid for wet granulation.

2. The lipoic acid pharmaceutical composition of claim 1, wherein, The low viscosity hydroxypropyl cellulose is selected from one or more of hydroxypropyl cellulose ELF, hydroxypropyl cellulose EXF and hydroxypropyl cellulose LXF.

3. The lipoic acid pharmaceutical composition of claim 1, wherein, The mass ratio of the low viscosity hydroxypropyl cellulose to lipoic acid is (0.01-0.1):

1.

4. The lipoic acid pharmaceutical composition of claim 1, wherein, The low viscosity hydroxypropyl cellulose accounts for 1.5%, 3.33% or 5% of the mass of lipoic acid.

5. The lipoic acid pharmaceutical composition according to any one of claims 1 to 4, wherein The pharmaceutical composition further comprises internal pharmaceutically acceptable excipients, which include diluents and disintegrants.

6. The lipoic acid pharmaceutical composition of claim 5, wherein, The diluents are selected from one or more of microcrystalline cellulose, starch, lactose and calcium phosphate. The disintegrants are selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and polyvinylpyrrolidone.

7. A lipoic acid pharmaceutical composition in the form of wet granules, characterized in that, The pharmaceutical composition comprises lipoic acid, low viscosity hydroxypropyl cellulose and ethanol solution, wherein: The mass ratio of the low viscosity hydroxypropyl cellulose and ethanol solution to lipoic acid is (0.15-0.3):

1. The concentration of the ethanol solution is 30-45 wt%. The low viscosity hydroxypropyl cellulose is selected from one or more of hydroxypropyl cellulose ELF. In the preparation, the ethanol solution of the low viscosity hydroxypropyl cellulose is added to the mixture containing lipoic acid for wet granulation.

8. The lipoic acid pharmaceutical composition of claim 7, wherein, The mass ratio of the low viscosity hydroxypropyl cellulose to lipoic acid is (0.015-0.05):

1.

9. The lipoic acid pharmaceutical composition of claim 7, wherein, The low viscosity hydroxypropyl cellulose accounts for 1.5%, 3.33% or 5% of the mass of lipoic acid.

10. The lipoic acid pharmaceutical composition according to any one of claims 7-9, wherein, The pharmaceutical composition further comprises internal pharmaceutically acceptable excipients, which include diluents and disintegrants.

11. The lipoic acid pharmaceutical composition of claim 10, wherein, The diluents are selected from one or more of microcrystalline cellulose, starch, lactose and calcium phosphate. The disintegrants are selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and polyvinylpyrrolidone.

12. A lipoic acid pharmaceutical composition in the form of a wet granulate, characterized in that, The pharmaceutical composition comprises lipoic acid, low viscosity hydroxypropyl cellulose and ethanol solution, wherein: The mass ratio of the low viscosity hydroxypropyl cellulose and ethanol solution to lipoic acid is (0.15-0.3):

1.

13. The lipoic acid pharmaceutical composition of claim 12, wherein, The concentration of the ethanol solution is 30-45 wt%. The low viscosity hydroxypropyl cellulose is selected from one or more of hydroxypropyl cellulose ELF. In the preparation, the ethanol solution of the low viscosity hydroxypropyl cellulose is added to the mixture containing lipoic acid for wet granulation. The mass ratio of the low viscosity hydroxypropyl cellulose to lipoic acid is (0.015-0.05):

1. The low viscosity hydroxypropyl cellulose accounts for 1.5%, 3.33% or 5% of the mass of lipoic acid. The pharmaceutical composition further comprises internal pharmaceutically acceptable excipients, which include diluents and disintegrants. The diluents are selected from one or more of microcrystalline cellulose, starch, lactose and calcium phosphate. The disintegrants are selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and polyvinylpyrrolidone. The pharmaceutical composition comprises lipoic acid, low viscosity hydroxypropyl cellulose and ethanol solution, wherein: The mass ratio of the low viscosity hydroxypropyl cellulose and ethanol solution to lipoic acid is (0.15-0.3):

1. The concentration of the ethanol solution is 30-45 wt%. The low viscosity hydroxypropyl cellulose is selected from one or more of hydroxypropyl cellulose ELF. In the preparation, the ethanol solution of the low viscosity hydroxypropyl cellulose is added to the mixture containing lipoic acid for wet granulation. The mass ratio of the low viscosity hydroxypropyl cellulose to lipoic acid is (0.015-0.05):

1. The low viscosity hydroxypropyl cellulose accounts for 1.5%, 3.33% or 5% of the mass of lipoic acid. The pharmaceutical composition further comprises internal pharmaceutically acceptable excipients, which include diluents and disintegrants. The diluents are selected from one or more of microcrystalline cellulose, starch, lactose and calcium phosphate. The disintegrants are selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and polyvinylpyrrolidone.

14. The lipoic acid pharmaceutical composition of claim 13, wherein, 600 parts by weight of lipoic acid, 9-30 parts by weight of low viscosity hydroxypropyl cellulose, 90-111 parts by weight of low-substituted hydroxypropyl cellulose, and 135 parts by weight of an aqueous ethanol solution.

15. The method of preparing a lipoic acid pharmaceutical composition according to any one of claims 1 to 14, wherein The method comprises the following steps: a) mixing lipoic acid or lipoic acid and pharmaceutically acceptable excipients uniformly; b) wet granulation by adding an aqueous ethanol solution of low viscosity hydroxypropyl cellulose; c) wet granulation.

16. The method of claim 15, wherein the lipoic acid pharmaceutical composition is prepared by, The aqueous ethanol solution of low viscosity hydroxypropyl cellulose is added in a reverse flow or spray flow manner.

17. A lipoic acid pharmaceutical composition in the form of a tablet, wherein the pharmaceutical composition is characterized in that, The wet granules and pharmaceutically acceptable excipients according to any one of claims 1-4 or 7-9, wherein the aqueous ethanol solution is removed in the production process.

18. The lipoic acid pharmaceutical composition of claim 17, wherein, The pharmaceutically acceptable excipients include one or more of diluents, disintegrants, lubricants, and film-coating premixes.

19. The lipoic acid pharmaceutical composition of claim 18, wherein, The diluents are selected from one or more of microcrystalline cellulose, starch, lactose, and calcium phosphate; the disintegrants are selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and polyvinylpyrrolidone; and the lubricants are selected from one or more of magnesium stearate, micro-powder silica, and talc.

20. The lipoic acid pharmaceutical composition of claim 17, in the form of a tablet, wherein, 600 parts by weight of lipoic acid, 6-30 parts by weight of low viscosity hydroxypropyl cellulose, 50-120 parts by weight of low-substituted hydroxypropyl cellulose added internally, 30-100 parts by weight of low-substituted hydroxypropyl cellulose added externally, 8-32 parts by weight of magnesium stearate, and 90-150 parts by weight of an aqueous ethanol solution.

21. The lipoic acid pharmaceutical composition of claim 20, wherein, 600 parts by weight of lipoic acid, 9-30 parts by weight of low viscosity hydroxypropyl cellulose, 90-111 parts by weight of low-substituted hydroxypropyl cellulose, and 135 parts by weight of an aqueous ethanol solution.

22. The lipoic acid pharmaceutical composition of claim 21, wherein, 600 parts by weight of lipoic acid, 9-30 parts by weight of low viscosity hydroxypropyl cellulose, 90-111 parts by weight of low-substituted hydroxypropyl cellulose, and 135 parts by weight of an aqueous ethanol solution.

23. The method of preparing a lipoic acid pharmaceutical composition according to any one of claims 17 to 22, wherein The method comprises the following steps: The wet granules obtained by wet granulation are dried, granulated, mixed with pharmaceutically acceptable excipients, tableted, and coated.

24. The method of claim 23, wherein the lipoic acid pharmaceutical composition is prepared by, The drying is controlled to have an inlet air temperature of 40-45°C, the granulation is controlled to have a screen mesh size of 14-24 meshes, and the coating process is controlled to have a material temperature lower than 45°C.

Images