Continuous production method of lipoic acid tablets

Abstract

The invention relates to the technical field of production of pharmaceutic adjuvants, in particular to a continuous production method of lipoic acid tablets, which sequentially comprises the following steps: crushing a lipoic acid raw material, and premixing the crushed lipoic acid raw material with a composite antioxidant compounded by vitamin E succinate and ascorbyl palmitate and an anti-agglomeration agent; the pretreated mixture and auxiliary materials are subjected to wet granulation and gradient heating drying to obtain particles, and a filling agent in the auxiliary materials is ascorbic acid modified microcrystalline cellulose; mixing the particles with a lubricant, and pressing the mixture into plain tablets by a tablet press with real-time feedback control; coating the uncoated tablet with a coating solution containing an antioxidant and an opacifying agent, and finally packaging and placing an oxygen absorbent in the uncoated tablet. The technical problem that lipoic acid is extremely easy to oxidize is solved through the multi-level synergistic anti-oxidation design from raw material pretreatment, modified auxiliary material addition for granulation, tabletting to external coating and packaging, the stability, content uniformity and production continuity of the product are improved, and the long-term effectiveness of the medicine is ensured.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical excipient production, in particular to a continuous production method of lipoic acid tablets. BACKGROUND

[0002] As an active ingredient with antioxidant and metabolic improvement functions, lipoic acid is widely used in the clinical treatment of diabetic peripheral neuropathy and oxidative stress-related diseases. The market demand is large and the requirement for product oxidative stability is extremely strict. However, in the existing production technology of lipoic acid tablets, due to the inherent characteristics of the raw material and the traditional batch production mode, the oxidation problem has become a core bottleneck affecting the product quality, shelf life and clinical application value, which has not been effectively solved.

[0003] The disulfide bond (-S-S-) in the molecular structure of lipoic acid is highly sensitive to oxygen and temperature, which is the core inducement of oxidative degradation. In the traditional production process, the mixing, granulation, tabletting, coating and other links are operated in stages and intermittently. The material is exposed to air for several hours, and oxygen and lipoic acid are in full contact, which easily leads to the breakage of disulfide bond and the generation of oxidation impurities. More importantly, the drying stage often uses constant temperature process, which is far beyond the stable threshold of lipoic acid. High temperature will accelerate the molecular thermal motion, increase the oxidation degradation rate, and finally lead to the deviation of lipoic acid content in the tablet, which does not meet the drug quality standard. Some batches even need to be scrapped in whole due to the excessive oxidation impurities.

[0004] Therefore, in the existing production technology of lipoic acid tablets, the production process oxidative degradation caused by the sensitivity of the disulfide bond of the raw material, and the storage period oxidation problem caused by the lack of targeted anti-oxidation protection of the preparation have become the key obstacles to the stable industrial production and safe clinical application of lipoic acid tablets. Therefore, it is urgent to develop a continuous production method that can inhibit oxidation from production to storage to ensure the content stability of lipoic acid tablets, prolong the shelf life and meet the clinical drug demand. SUMMARY

[0005] In view of the shortcomings of the prior art, the present application provides a continuous production method of lipoic acid tablets, which sequentially passes through the steps of crushing premixing, wet granulation, tabletting and coating. The lipoic acid is crushed and premixed with a composite antioxidant and an anti-agglomerating agent; the modified microcrystalline cellulose is used as a filler for granulation, and gradient temperature drying is performed; the compound lubricant is added for tabletting and the quality is controlled in real time; and the coating liquid containing an antioxidant and a light shielding agent is intermittently sprayed for coating, so as to solve the problems of easy oxidation, sticking and poor quality in batch production of lipoic acid.

[0006] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0007] In the first aspect, the present application provides a continuous production method of lipoic acid tablets, which comprises the following steps:

[0008] Step 1. The lipoic acid raw material is crushed by a continuous crusher, and then is premixed with a composite antioxidant and an anti-agglomeration agent in a total mixer to obtain a pretreated mixture; the composite antioxidant is obtained by compounding vitamin E succinate and ascorbic acid palmitate;

[0009] Step 2. The pretreated mixture and excipients are put into a fluidized bed granulator, and are first dry-mixed, then are granulated by spraying a binder solution, and then are dried by gradient heating, to obtain granules after sieving; the excipients include a filler and a disintegrant; the filler is modified microcrystalline cellulose, which is prepared by reacting microcrystalline cellulose with ascorbic acid;

[0010] Step 3. The granules are mixed with a compounded lubricant to obtain total-mixed granules; the total-mixed granules are put into a tablet press to obtain tablets;

[0011] Step 4. The tablets are put into a coating pan, and are coated by using a coating liquid in an intermittent spraying mode, to obtain lipoic acid tablets after coating is completed; the coating liquid contains an antioxidant and a light shielding agent.

[0012] In the present application, the lipoic acid molecule contains a sulfhydryl group (-SH), which is easily oxidized to a disulfide bond (-S-S-) by oxygen and light, resulting in a decrease in activity. First, the composite antioxidant added in the pretreated mixture stage releases hydrogen atoms (H·) from the phenolic hydroxyl group (-OH) of vitamin E succinate, which combines with the free radicals (·OOH, ·OH) generated by the oxidation of lipoic acid; the enediol structure (-C(OH)=C(OH)-) of ascorbic acid palmitate can reduce the oxidized vitamin E free radical to regenerate its antioxidant activity, forming a cyclic antioxidant, thereby maintaining the antioxidant activity of lipoic acid for a longer time in the pretreated mixture stage and reducing the oxidation threshold in the granulation stage. Second, the modified microcrystalline cellulose grafts ascorbic acid onto the cellulose skeleton by covalent bonding, which provides uniform antioxidant active sites in the granule interior on the one hand, and slowly releases H·, continuously captures oxygen free radicals in the granule interior during granulation and tablet pressing, and avoids the accelerated oxidation of lipoic acid due to frictional heat on the other hand. Third, the antioxidant in the coating liquid is dispersed in the intermolecular space of the film-forming agent, which reacts with oxygen to form stable phenolic oxygen free radicals, thereby reducing oxygen permeation; the light shielding agent titanium dioxide scatters / absorbs ultraviolet light to avoid photo-induced electron transition of lipoic acid molecules.

[0013] Preferably, the particle size of the thioctic acid raw material after pulverization in step 1 is 80-150 mesh; the amount of the composite antioxidant added is 0.3-0.5% of the mass of the thioctic acid raw material; the mass ratio of vitamin E succinate to ascorbate palmitate is 1:(1-3); the anti-agglomeration agent includes any one of nano-sized silica, micronized silica gel and talc, and the amount of the anti-agglomeration agent added is 0.2% to 0.3% of the mass of the thioctic acid raw material.

[0014] Preferably, in step 1, the continuous pulverizer has a pulverizing speed of 1500-2000 rpm and a pulverizing time of 50-90 s; the pulverizing chamber of the continuous pulverizer uses a water-cooled jacket to control the material temperature to ≤25℃; and the total mixer has a speed of 12-18 rpm and a time of 6-10 min.

[0015] Preferably, in step 2, the adhesive solution comprises an aqueous solution of hydroxypropyl methylcellulose (HPMC), an aqueous solution of polyvinylpyrrolidone (PVP K30), and an aqueous solution of pregelatinized starch; the concentration of the adhesive solution is 5%-8%; the mass ratio of the adhesive solution to the pretreated mixture is (0.2-0.35):1; the mass ratio of the filler to the pretreated mixture is (0.48-0.65):1; the disintegrant comprises either croscarmellose sodium or carboxymethyl starch sodium; the mass ratio of the disintegrant to the pretreated mixture is (0.07-0.10):1; and the mass ratio of microcrystalline cellulose to ascorbic acid is 100:(2-3).

[0016] Preferably, in step 2, the stirring speed of the dry mixing process is 100-300 rpm and the time is 5-15 min; the shearing speed of the granulation process is 100-150 rpm and the time is 5-8 min; the gradient temperature drying includes a first stage drying and a second stage drying; the first stage drying temperature is 35-38℃ and the time is 10-12 min, and the second stage drying temperature is 40-42℃ and the time is 8-10 min.

[0017] Preferably, in step 3, the compound lubricant is obtained by compounding magnesium stearate and polyethylene glycol-4000; the magnesium stearate and polyethylene glycol-4000 are in a mass ratio of 1:(1-3), and the mass ratio of the particles to the compound lubricant is 100:(0.8-1.0).

[0018] Preferably, in step 4, the antioxidant includes any one of tert-butyl-p-hydroxyanisole (BHA) and tert-butyl-hydroxytoluene (BHT); the opacifier includes any one of titanium dioxide, talc, and iron oxide pigments; the mass of the coating solution is 2%-5% of the mass of the uncoated film; and the mass ratio of the opacifier to the antioxidant is (8-20):1.

[0019] Preferably, in step 4, the intermittent spraying mode working time is 5-15s, and the interval time is 10-30s.

[0020] Compared with the prior art, the application has the beneficial effects that:

[0021] The application provides a continuous production method of lipoic acid tablets. In the application, the lipoic acid molecule contains a sulfhydryl group (-SH) and is easily oxidized into a disulfide bond (-S-S-) by oxygen and light, resulting in a decrease in activity. First, the composite antioxidant added in the pretreatment mixing stage releases hydrogen atoms (H·) from the phenolic hydroxyl group (-OH) of vitamin E succinate, which combines with the free radicals (·OOH, ·OH) generated by the oxidation of lipoic acid; the enediol structure (-C(OH)=C(OH)-) of ascorbic acid palmitate can reduce the oxidized vitamin E free radical to regenerate its antioxidant activity, forming a cyclic antioxidant, thereby maintaining the antioxidant activity of lipoic acid for a longer time in the pretreatment mixing stage and reducing the oxidation threshold in the granulation stage. Second, the modified microcrystalline cellulose grafts ascorbic acid onto the cellulose skeleton through covalent bonding. On the one hand, the enediol structure of ascorbic acid provides uniform antioxidant active sites inside the granules, which can slowly release H· to continuously capture oxygen free radicals inside the granules during the granulation and tablet pressing process, thereby avoiding the accelerated oxidation of lipoic acid due to frictional heat. On the other hand, the residual antioxidant activity in the pressed tablets can protect lipoic acid during the interval between coating operations, thereby avoiding short-term oxidation during the intermittent spraying waiting process. Finally, the antioxidants in the coating liquid are dispersed in the intermolecular gaps of the film-forming agent, which preferentially reacts with oxygen to form stable phenolic oxygen free radicals, thereby reducing oxygen permeation. The ultraviolet light scattering / absorbing agent titanium dioxide avoids the photo-induced electron transition of lipoic acid molecules, thereby improving the antioxidant efficiency of the lipoic acid tablet production process and the product quality stability and storage shelf life. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 It is a flowchart of a continuous production method of lipoic acid tablets.

[0023] Figure 2 It is a graph of the change in lipoic acid content over time in the accelerated stability test of the lipoic acid tablets of Examples 1-3 and Comparative Examples 1-3. DETAILED DESCRIPTION

[0024] In order to make the technical problems, technical solutions and beneficial effects of the application clearer, the application will be further described in detail below in conjunction with the examples. However, this should not be understood as limiting the scope of the application to the following examples. Without departing from the method idea of the application, all other examples obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the application.

[0025] The terminology used in this application is for the purpose of describing particular embodiments only and is not intended to be limiting of this application.

[0026] As used in this application, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0027] In addition, if the terms "first", "second", "third", "fourth" and the like are used in the present application, these terms are used to describe various embodiments, and do not imply or suggest any relative importance.

[0028] The raw material sources of the modified microcrystalline cellulose used in the present embodiment are as follows:

[0029] Microcrystalline cellulose: Jiangxi Yipu Pharmaceutical Co., Ltd., model SH-101;

[0030] Ascorbic acid: Yida Pharmaceutical Group, pharmaceutical grade 100 mesh fine powder.

[0031] The following will be combined with different embodiments to specifically describe a continuous production method of lipoic acid tablets provided by the present application.

[0032] Embodiment 1

[0033] As shown in the following table, the present embodiment provides a continuous production method of lipoic acid tablets, which includes the following steps: Figure 1 Step 1. The lipoic acid raw material is crushed by a continuous crusher at a speed of 1500 rpm for 50 s, and the material temperature is controlled to be ≤25°C by a water-cooled jacket, so that the particle size of the crushed lipoic acid reaches 80 mesh. Then the lipoic acid raw material is put into a total mixer together with a composite antioxidant and nano-sized silicon dioxide, and mixed at a speed of 12 rpm for 6 min, wherein the composite antioxidant is compounded by vitamin E succinate and ascorbyl palmitate at a mass ratio of 1:1, and the addition amount is 0.3% of the mass of the lipoic acid raw material, and the addition amount of nano-sized silicon dioxide is 0.2% of the mass of the lipoic acid raw material, and finally a pretreated mixture is obtained.

[0034]

[0035] ​Step 2. The pretreated mixture, modified microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose are fed into a fluidized bed granulator. The modified microcrystalline cellulose is prepared by reacting microcrystalline cellulose with ascorbic acid at 50°C and a mass ratio of 100:2 at 200 rpm for 2 hours, with the mass ratio of modified microcrystalline cellulose to the pretreated mixture being 0.48:1 and the mass ratio of cross-linked sodium carboxymethyl cellulose to the pretreated mixture being 0.07:1. Dry mixing is performed first, with a stirring speed of 100 rpm for 15 minutes. Then, a 5% hydroxypropyl methylcellulose (HPMC) aqueous solution is sprayed in for granulation, with a mass ratio of 5% to the pretreated mixture being 0.2:1. The granulation process is carried out at a shear speed of 100 rpm for 5 minutes. After granulation, gradient temperature drying is performed, including a first stage drying at 35°C for 10 minutes and a second stage drying at 40°C for 8 minutes. After drying, the granules are obtained by sieving.

[0036] Step 3. Add the granules to a compound lubricant made of magnesium stearate and polyethylene glycol-4000 in a mass ratio of 1:1 and mix to obtain a total mixed granule, wherein the mass ratio of the total mixed granule to the compound lubricant is 100:0.8; put the total mixed granule into a tablet press and compress to obtain a plain tablet;

[0037] Step 4. Place the uncoated tablets into a coating pan and coat them with coating solution using an intermittent spray mode. The working time of the intermittent spray mode is 5 seconds and the interval is 10 seconds. The mass of the coating solution is 2% of the mass of the uncoated tablets, and the coating solution is titanium dioxide and tert-butyl-p-hydroxyanisole (BHA) in a mass ratio of 8:1. After coating is completed and the tablets pass the test, they are packaged and a composite oxygen absorber is placed in the packaging before being put into storage.

[0038] Example 2

[0039] like Figure 1 As shown, this embodiment provides a continuous production method for thioctic acid tablets, including the following steps:

[0040] Step 1. The lipoic acid raw material is pulverized in a continuous pulverizer at a speed of 1800 rpm for 70 seconds. The material temperature in the pulverizing chamber is controlled to be ≤25℃ by a water-cooled jacket, so that the particle size of the pulverized lipoic acid reaches 100 mesh. Then, the lipoic acid raw material, composite antioxidant, and micronized silica gel are put into a mixer and mixed at a speed of 16 rpm for 8 minutes. The composite antioxidant is composed of vitamin E succinate and ascorbate palmitate in a mass ratio of 1:2, and its addition amount is 0.4% of the mass of the lipoic acid raw material. The micronized silica gel is added at a mass of 0.2% of the mass of the lipoic acid raw material. Finally, a pretreated mixture is obtained.

[0041] Step 2. The pretreated mixture, modified microcrystalline cellulose, and croscarmellose sodium are fed into a fluidized bed granulator. The modified microcrystalline cellulose is prepared by reacting microcrystalline cellulose with ascorbic acid at 55°C and a mass ratio of 100:2.5 at 250 rpm for 2.5 hours. The mass ratio of modified microcrystalline cellulose to the pretreated mixture is 0.52:1, and the mass ratio of croscarmellose sodium to the pretreated mixture is 0.08:1. Dry mixing is performed first, with the mixing speed at 200 rpm. Mix for 10 minutes at a stirring speed, then spray in a 7% polyvinylpyrrolidone (PVPK30) aqueous solution for granulation, with a mass ratio of 0.25:1 to the pretreated mixture. The granulation process is carried out at a shear speed of 120 rpm for 6 minutes. After granulation, gradient temperature drying is performed, which includes a first stage drying and a second stage drying. The first stage drying temperature is 36℃ for 11 minutes, and the second stage drying temperature is 41℃ for 9 minutes. After drying, the granules are obtained by sieving.

[0042] Step 3. Add the granules to a compound lubricant made of magnesium stearate and polyethylene glycol-4000 in a mass ratio of 1:2 and mix to obtain a total mixed granule, wherein the mass ratio of the total mixed granule to the compound lubricant is 100:0.9; put the total mixed granule into a tablet press and compress to obtain a tablet.

[0043] Step 4. Place the uncoated tablets into the coating pan and coat them with the coating solution using an intermittent spray mode. The working time of the intermittent spray mode is 10 seconds and the interval is 20 seconds. The mass of the coating solution is 3% of the mass of the uncoated tablets, and the coating solution is iron oxide pigment and tert-butyl-p-hydroxyanisole (BHA) with a mass ratio of 16:1. After the coating is completed and the tablets pass the test, they are packaged and a compound oxygen absorber is placed in the packaging before being put into storage.

[0044] Example 3

[0045] like Figure 1 As shown, this embodiment provides a continuous production method for thioctic acid tablets, including the following steps:

[0046] Step 1. The lipoic acid raw material is pulverized in a continuous pulverizer at a speed of 2000 rpm for 90 seconds. The material temperature in the pulverizing chamber is controlled to be ≤25℃ by a water-cooled jacket, so that the particle size of the pulverized lipoic acid reaches 150 mesh. Then, the lipoic acid raw material, compound antioxidant, and talc are put into a general mixer and mixed at a speed of 18 rpm for 10 minutes. The compound antioxidant is composed of vitamin E succinate and ascorbate palmitate in a mass ratio of 1:3, and its addition amount is 0.5% of the mass of the lipoic acid raw material. The talc addition amount is 0.3% of the mass of the lipoic acid raw material. Finally, a pretreated mixture is obtained.

[0047] Step 2. The pretreated mixture, modified microcrystalline cellulose and sodium carboxymethyl starch are put into the fluidized bed granulator. The modified microcrystalline cellulose is prepared by stirring the microcrystalline cellulose and ascorbic acid at 60℃ for 3h at a mass ratio of 100:3 and a stirring speed of 300rpm. The mass ratio of the modified microcrystalline cellulose to the pretreated mixture is 0.65:1, and the mass ratio of the sodium carboxymethyl starch to the pretreated mixture is 0.10:1. First, dry mixing is performed at a stirring speed of 300rpm for 15min, and then pre-gelatinized starch solution with a concentration of 8% is sprayed for granulation. The mass ratio of the pre-gelatinized starch solution to the pretreated mixture is 0.35:1, and the granulation process is performed at a shearing speed of 150rpm for 8min. After granulation, gradient temperature drying is performed, which includes first stage drying at a temperature of 38℃ for 12min and second stage drying at a temperature of 42℃ for 10min. After drying, sieving is performed to obtain granules.

[0048] Step 3. The granules are mixed with a compounded lubricant prepared by compounding magnesium stearate and polyethylene glycol-4000 at a mass ratio of 1:3 to obtain total mixed granules. The mass ratio of the total mixed granules to the compounded lubricant is 100:1. The total mixed granules are put into a tablet press to obtain tablets.

[0049] Step 4. The tablets are put into a coating pan and coated with a coating liquid in an intermittent spraying mode. The working time of the intermittent spraying mode is 15s, the interval time is 30s, the mass of the coating liquid is 5% of the mass of the tablets, and the coating liquid is talc and tert-butylhydroxytoluene (BHT) at a mass ratio of 20:1. After coating, the tablets are detected to be qualified, packaged, and placed in the warehouse with a composite oxygen absorber.

[0050] Comparative Example 1

[0051] A continuous production method of lipoic acid tablets, which is different from Example 1 in that vitamin E succinate is added in step 1.

[0052] Comparative Example 2

[0053] A continuous production method of lipoic acid tablets, which is different from Example 1 in that ordinary microcrystalline cellulose (without ascorbic acid modification) is used as the filler in step 2.

[0054] Comparative Example 3

[0055] A continuous production method of lipoic acid tablets, which is different from Example 1 in that only titanium dioxide is added in step 4.

[0056] Performance test:

[0057] 1. Accelerated stability test: The finished coated tablets (including packaging and composite oxygen absorbent) of Examples 1-3 and Comparative Examples 1-2 were placed in an environment of 40°C ± 2°C and 75% ± 5% relative humidity, and the lipoic acid content (mg / tablet) was determined at 0, 1, 2, 3, and 6 months.

[0058] 2. Dissolution test: Ten tablets each of the tablets of Examples 1-3 and Comparative Examples 1-2 were taken, and the lipoic acid content (HPLC method) of each tablet was determined separately, and the A+2.2S value (A is the mean deviation, and S is the standard deviation) was calculated. The paddle method (50 rpm) was used, and the cumulative dissolution rate at 30 min and 60 min was determined in a pH 6.8 phosphate buffer.

[0059] 3. Physical stability test: The average hardness of ten tablets each of the tablets of Examples 1-3 and Comparative Examples 1-2 was determined using a tablet hardness tester. Another 6.5 g of tablets (or 20 tablets, whichever is greater) were placed in the rotating drum of a friability tester, and the rotation speed was set to 25 rpm. After 100 rotations, the tablets were taken out, the surface powder was removed, and the weight was determined. The weight loss rate was calculated, and the tablets were checked for cracking and breaking.

[0060] The performance test data are analyzed as follows:

[0061] Table 1. Accelerated stability test data

[0062] Group 0 month content (mg / tablet) 1 month content (mg / tablet) 2 month content (mg / tablet) 3 month content (mg / tablet) 6 month content (mg / tablet) 6 month content retention rate (%) Example 1 100.0 98.2 96.5 94.8 92.1 92.1 Example 2 100.2 98.5 97.1 95.6 93.5 93.3 Example 3 100.1 98.8 97.5 96.2 94.7 94.6 Comparative Example 1 100.3 96.1 93.2 90.5 84.6 84.3 Comparative Example 2 100.4 97.3 94.8 92.1 87.5 87.2 Comparative Example 3 100.0 97.0 94.5 92.0 89.5 89.5

[0063] From Table 1 and Figure 2 It can be seen from the accelerated stability test data at 40°C ± 2°C and 75% ± 5% relative humidity that the stability of the lipoic acid tablets of Examples 1-3 is better than that of Comparative Examples 1-2. The content retention rate after 6 months is 92.1%-94.6%. The retention rate of Comparative Example 1, which uses only vitamin E succinate as an antioxidant, is only 84.3% after 6 months, and the content decreases to 90.5% after 3 months. The retention rate of Comparative Example 2, which uses ordinary microcrystalline cellulose as a filler, is only 87.2% after 6 months. The content retention rate of Comparative Example 3 is 89.5% after 6 months, which is lower than that of Example 1 (92.1%) but higher than that of Comparative Examples 1 and 2. The vitamin E succinate-ascorbic acid palmitate composite antioxidant used in the examples can form a cyclic antioxidant mechanism through the hydrogen-donating phenolic hydroxyl group and the enediol structure regeneration, continuously inhibiting the oxidation of the lipoic acid sulfhydryl group (-SH) from the pretreatment stage. At the same time, the ascorbic acid-modified microcrystalline cellulose can slowly release hydrogen atoms to supplement the antioxidant activity during granulation, tabletting, and storage, greatly delaying the oxidative degradation. Comparative Example 1 lacks the ability of antioxidant regeneration, and Comparative Example 2 lacks the antioxidant assistance of ordinary microcrystalline cellulose, so they cannot effectively block the oxidation path of lipoic acid, resulting in rapid content decay.

[0064] Table 2 Dissolution test data

[0065]

[0066] From the dissolution test data in Table 2, it can be clearly seen that the lipoic acid tablets of Examples 1-3 exhibit excellent performance in content uniformity and dissolution efficiency, which is superior to the comparative examples. The core difference lies in the synergistic optimization of the excipient system and process of the examples.

[0067] In terms of content uniformity (A+2.2S), the values of Examples 1-3 are only 7.6-8.3, and Comparative Example 1 also reaches 8.5, which are much lower than 14.6 of Comparative Example 2. As ascorbic acid modified microcrystalline cellulose is used in the examples, its hydrophilic side chain can improve the mixing and dispersibility of lipoic acid raw materials and excipients, and combined with continuous dry mixing, it ensures the uniformity of drug content per tablet. While ordinary microcrystalline cellulose is used in Comparative Example 2, it has poor compatibility and uneven dispersion with lipoic acid, resulting in large content fluctuation.

[0068] In terms of dissolution rate, the 30min cumulative dissolution rate of Examples 1-3 reaches 80.1%-83.2%, and all exceeds 90% at 60min. Comparative Examples 1 and 3 are close to them, but Comparative Example 2 is only 68.3% and 81.2%. The reason is that the modified microcrystalline cellulose structure and gradient temperature drying in the examples are synergistic, which avoids the formation of hard core of particles, and the hydrophilicity of modified microcrystalline cellulose can accelerate the penetration of dissolution medium and promote the rapid release of lipoic acid. The ordinary microcrystalline cellulose in Comparative Example 2 tightly wraps the drug and the particles are easy to agglomerate, resulting in delayed dissolution.

[0069] Table 3 Physical stability test data

[0070]

[0071] As can be seen from Table 3, the lipoic acid tablets of Examples 1-3 are superior to Comparative Examples 1-3 in hardness and friability performance, which is due to the synergistic effect of ascorbic acid modified microcrystalline cellulose and the compound lubricant. In terms of hardness, the average hardness of the tablets of Examples 1-3 is 45.1-49.2 N, which is higher than 34.3 N of Comparative Example 2. After modification by ascorbic acid, the hydrophilic groups are introduced into the molecular chain of microcrystalline cellulose, which enhances the interparticle adhesion and makes the tablet structure more compact. The adhesion of the ordinary microcrystalline cellulose used in Comparative Example 2 is weak, and the tablet is prone to loose after compression, which greatly reduces the hardness. In terms of friability performance, the weight loss rate of Examples 1-3 is only 0.3%-0.5%, and there is no fracture or cracking, only a small amount of floating powder. The weight loss rate of Comparative Example 2 is 1.3%, and edge cracking also occurs. The average hardness (44.8 N) and the weight loss rate (0.4%) of the tablets of Comparative Example 3 and the appearance state are basically the same as those of Example 1, and there is no fracture or cracking phenomenon, which is superior to Comparative Example 2. Because the antioxidant (BHA) in the tablet coating liquid does not participate in the tablet forming process and does not change the microstructure of the tablet, it has no effect on hardness and friability. The compound lubricant (magnesium stearate and polyethylene glycol-4000) of the examples can reduce particle friction and further improve the stability of the tablet structure. The performance of Comparative Example 1 is close to that of the examples, which confirms that the type of antioxidant does not affect the physical properties and highlights the key value of the modified excipient design of the examples.

[0072] In summary, the lipoic acid tablets of Examples 1-3 exhibit comprehensive and significant performance advantages in accelerated stability, dissolution, and physical stability by virtue of the synergistic process of the vitamin E succinate, ascorbic acid palmitate compound antioxidant system, and ascorbic acid modified microcrystalline cellulose. The related properties of Comparative Examples are significantly degraded, which fully confirms the superiority of the production scheme of the examples.

[0073] The above results show and describe the basic principles and main features of the present application and the advantages of the present application.

[0074] Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the claimed present application. The scope of protection claimed by the present application is defined by the equivalents of the appended claims.

Claims

1. A method for the continuous production of lipoic acid tablets, characterized by, The application relates to a preparation method of lipoic acid tablets. Step 1: lipoic acid raw materials are crushed by a continuous crusher, and then are premixed with a composite antioxidant and an anti-agglomeration agent in a total mixer to obtain a pretreated mixture; the composite antioxidant is obtained by compounding vitamin E succinate and ascorbic acid palmitate; Step 2: the pretreated mixture and auxiliary materials are put into a fluidized bed granulator, are dry-mixed, are sprayed with a binder solution to be granulated, and then are subjected to gradient temperature drying, and are sieved to obtain granules; the auxiliary materials include a filler and a disintegrant; the filler is modified microcrystalline cellulose which is prepared by reacting microcrystalline cellulose with ascorbic acid; Step 3: the granules are mixed with a compounded lubricant to obtain total mixed granules; the total mixed granules are put into a tablet press to be pressed into tablets; Step 4: the tablets are put into a coating pot, are coated by using an intermittent spraying mode with a coating liquid, and are obtained after coating to be lipoic acid tablets; the coating liquid contains an antioxidant and a light shielding agent.

2. A method for the continuous production of lipoic acid tablets according to claim 1, characterized by, The particle size of the lipoic acid raw materials crushed in step 1 is 80-150 meshes; the addition amount of the composite antioxidant is 0.3%-0.5% of the mass of the lipoic acid raw materials; the mass ratio of the vitamin E succinate to the ascorbic acid palmitate is 1: (1-3); the anti-agglomeration agent includes any one of nano-sized silicon dioxide, micro-powder silica gel and talc powder, and the addition amount of the anti-agglomeration agent is 0.2%-0.3% of the mass of the lipoic acid raw materials.

3. The method of claim 1, wherein the lipoic acid tablet is produced continuously. In step 1, the crushing speed of the continuous crusher is 1500-2000 rpm, and the crushing time is 50-90 s; the rotating speed of the total mixer is 12-18 rpm, and the time is 6-10 min.

4. The continuous production process of lipoic acid tablets as claimed in claim 1, wherein, In step 2, the binder solution includes a hydroxypropyl methyl cellulose (HPMC) aqueous solution, a polyvinylpyrrolidone (PVP K30) aqueous solution and a pregelatinized starch aqueous solution; the concentration of the binder solution is 5%-8%; the mass ratio of the binder solution to the pretreated mixture is (0.2-0.35):1; the mass ratio of the filler to the pretreated mixture is (0.48-0.65):1; the disintegrant includes any one of crosslinked sodium carboxymethyl cellulose and sodium carboxymethyl starch; the mass ratio of the disintegrant to the pretreated mixture is (0.07-0.10):1; and the mass ratio of the microcrystalline cellulose to ascorbic acid is 100: (2-3).

5. The method of claim 1, wherein the lipoic acid tablet is produced continuously. In step 2, the stirring rotating speed in the dry-mixing process is 100-300 rpm, and the time is 5-15 min; the shearing rotating speed in the granulating process is 100-150 rpm, and the time is 5-8 min; the gradient temperature drying includes first-stage drying and second-stage drying; the first-stage drying temperature is 35-38 DEG C, and the time is 10-12 min; the second-stage drying temperature is 40-42 DEG C, and the time is 8-10 min.

6. The continuous production process of lipoic acid tablets as claimed in claim 1, wherein, In step 3, the compounded lubricant is obtained by compounding magnesium stearate and polyethylene glycol-4000; the mass ratio of the magnesium stearate to the polyethylene glycol-4000 is 1: (1-3), and the mass ratio of the granules to the compounded lubricant is 100:(0.8-1.0).

7. The method of claim 1, wherein the lipoic acid tablet is produced continuously. In step 4, the antioxidant includes any one of t-butyl hydroxy anisole (BHA) and t-butyl hydroxy toluene (BHT); the sunscreen includes any one of titanium dioxide, talc, and iron oxide colorant; the mass of the coating liquid is 2%-5% of the mass of the elemental tablet; and the mass ratio of the sunscreen to the antioxidant is (8-20):

1.

8. The continuous production process of lipoic acid tablets as claimed in claim 1, wherein, In step 4, the intermittent spraying mode working time is 5-15s, and the interval time is 10-30s.

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