Preparation method of lipoic acid particles and method for preparing lipoic acid particles into tablets and capsules

Abstract

The invention discloses a preparation method of lipoic acid particles and a method for preparing the lipoic acid particles into tablets and capsules, and relates to the technical field of production and preparation of medicines and health-care products. The preparation method comprises the following steps: carrying out fluidized bed top spraying granulation on a lipoic acid raw material, and then carrying out fluidized bed bottom spraying coating to obtain the lipoic acid granules. The obtained lipoic acid particles are subjected to the steps of total mixing, tabletting and the like, and the lipoic acid tablets can be prepared. The obtained lipoic acid particles are subjected to the steps of total mixing, filling and the like, and the lipoic acid hard capsule can be prepared. The prepared lipoic acid particles have the advantages of being low in peculiar smell, resistant to sticking, good in compressibility and the like. The prepared lipoic acid tablets and lipoic acid capsules have the advantages of high drug loading capacity, low peculiar smell, low production difficulty, better content stability, better dissolution stability and better disintegration time limit stability.

Description

Technical Field

[0001] The invention relates to the technical field of medicine and health product production and preparation, in particular to a method for preparing lipoic acid particles and a method for preparing the lipoic acid particles into tablets and capsules. Background Art

[0002] Lipoic acid, molecular formula is C8H 14 O2S2 is an organic compound with a pungent odor and light yellow crystals. Lipoic acid can act as a coenzyme to participate in the acyl transfer in the metabolism of substances in the body, and can eliminate free radicals that accelerate aging and cause disease. It was first isolated from pig liver by Reed et al. in the United States in 1950. In the 1970s, Germany approved it as a drug for the treatment of hepatitis. In the 1990s, it was approved for the treatment of type 2 diabetes. In 1997, the US FDA approved lipoic acid as a health product. After being absorbed by the intestines, lipoic acid enters the cells in the body. It has certain application value in promoting sugar metabolism, improving nervous system function, strengthening liver function, and anti-oxidation.

[0003] At present, the main dosage forms of lipoic acid on the market are injection, capsules and tablets. Lipoic acid is rapidly absorbed orally, and from the perspective of industrial production, convenience of use and compliance, tablets and capsules are superior to injections, and have great market potential. However, the melting point of lipoic acid is between 60 and 62°C, and it is easy to polymerize and oxidize at high temperatures, and it has a pungent odor. In the application process of tablets and capsules, there are often problems such as sticking, reduced content of active ingredients, and the presence of odor.

[0004] CN102579395A disclosed on July 18, 2012 discloses a lipoic acid capsule and its preparation process and use. The capsule contains a solid dispersion, which is composed of lipoic acid and a carrier material, and the carrier material is selected from poloxamer. The invention improves the in vitro dissolution rate of the lipoic acid preparation. However, the lipoic acid loading of the lipoic acid capsule obtained by the invention is 50% to 75%, which is relatively low.

[0005] CN103655495A disclosed on March 26, 2014 discloses a lipoic acid tablet with less types and dosage of auxiliary materials and a preparation method thereof, wherein the auxiliary material tablet is first pressed, and then the sieved lipoic acid is sprayed layer by layer on the auxiliary material tablet by a spray gun, and the lipoic acid tablet is obtained after drying. However, the method has many process steps, the overall layering spraying process is time-consuming, and the maximum lipoic acid loading is only 80%.

[0006] A method for preparing a stable thioctic acid tablet in CN115252569B disclosed on January 31, 2023, is to first dry granulate the thioctic acid raw material, then wet granulate it, and finally obtain thioctic acid tablets after steps such as total mixing, tableting, and coating. The thioctic acid tablets obtained by this invention have good in vitro dissolution curves, dissolution stability, and drug stability. However, the thioctic acid granules obtained by wet granulation still have some thioctic acid exposed in the outer layer of the granules, and more lubricants are required to solve the problem of sticking during tableting, and the granules still have a certain odor, and a higher coating weight gain is required to solve the odor problem. The drug loading of the thioctic acid tablets obtained by this invention does not exceed 75%.

[0007] CN118512408A disclosed on August 20, 2024 discloses a thioctic acid tablet and a preparation method thereof, wherein thioctic acid raw materials are dry mixed with fillers, a prepared adhesive solution is added for wet granulation, a lubricant is added after drying, the whole granules are granulated, the total mixing is followed by tableting, and coating is obtained. The invention solves the problem of easy sticking of tablets by using an adhesive with excellent film-forming properties, controlling the drying temperature and drying time at the same time, ensuring that the thioctic acid particles are wrapped by the adhesive solution, and avoiding direct contact between the raw materials and the tablet press. However, the invention involves the commonality of wet granulation, and the active ingredients cannot be completely wrapped by the slurry after wet granulation. Some functional materials are still exposed to the outer layer of the particles, which can easily lead to sticking problems, and more lubricants are required to solve the sticking problem during tableting. The drug loading of the thioctic acid tablets obtained by the invention does not exceed 80%.

[0008] The above existing thioctic acid tablets and thioctic acid capsules adopt solid dispersion method, wet granulation or first dry granulation and then wet granulation to process thioctic acid, to achieve the purpose of anti-sticking, mitigating peculiar smell, improving the dissolution stability of active ingredient content.But the solid dispersion method has complicated process, higher production loss, high auxiliary material dosage, and low drug loading of active ingredient in the obtained finished product.The complicated process of wet granulation after dry granulation, and some thioctic acid is still exposed in the outer layer after wet granulation, and the thioctic acid granules obtained by wet granulation process mainly reduce the specific surface area of ​​active ingredient, and some thioctic acid is still exposed in the outer layer, which easily causes the sticking phenomenon in tableting or filling process, and still has peculiar smell. Summary of the invention

[0009] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing thioctic acid granules, which has simple process, high production efficiency, low production loss, and the obtained thioctic acid granules are anti-sticking, low in odor, and good in compressibility. The present invention also provides the application direction of the thioctic acid granules, and the obtained thioctic acid tablets and thioctic acid capsules have high drug loading, low in odor, low in production difficulty, good in content stability, dissolution stability, and disintegration time stability.

[0010] The technical solution adopted by the present invention to solve the technical problem is: a method for preparing lipoic acid particles, comprising the following steps:

[0011] (1) passing the formulated amount of lipoic acid through a 30-mesh sieve;

[0012] (2) Put the sieved lipoic acid into the fluidized bed, use the fluidized bed top spray module to perform granulation operation, add binder, and the air volume is 30-80m 3 / h, air inlet temperature 40~60℃, material temperature 20~50℃, spraying speed 20~50r / min, atomization pressure 0.1~0.3MPa, the obtained particles are passed through a 20-mesh sieve;

[0013] (3) The sieved particles are placed in a fluidized bed and coated using a fluidized bed bottom spray module to spray the coating material with an air volume of 30 to 80 m 3 / h, air inlet temperature 40-60°C, material temperature 20-50°C, spraying speed 5-25r / min, atomization pressure 0.1-0.3MPa, the obtained particles are sieved through a 20-mesh sieve to obtain thioctic acid particles.

[0014] Furthermore, the percentage of each component of the zinc sulfate granules in the total formula weight is: 85% to 92% of lipoic acid, 1% to 3% of binder, and 7% to 12% of coating material.

[0015] Furthermore, the adhesive is one or more of maltodextrin, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, povidone, and gum arabic.

[0016] Furthermore, the coating material is one or more of maltodextrin, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, and gum arabic.

[0017] The method for preparing the prepared lipoic acid granules into lipoic acid tablets comprises the following steps:

[0018] (1) Total mixing: add 1 / 2 of the formula amount of lipoic acid granules, filler, disintegrant, and 1 / 2 of the formula amount of lipoic acid granules in order, mix for 20 minutes, and then add lubricant and mix for 5 minutes;

[0019] (2) Tableting: Use oval punching tablets with a size of T16 mm*8.5 mm, control the tablet weight to 690 mg / tab±5%, and hardness to 190 N±20 N;

[0020] Wherein, the filler is one or more of microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, corn starch, cyclodextrin, and rice flour;

[0021] The disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and hydroxypropyl cellulose;

[0022] The lubricant is one or more of magnesium stearate, stearic acid and talc.

[0023] The method for preparing the prepared lipoic acid granules into lipoic acid capsules comprises the following steps:

[0024] (1) Total mixing: Mix the formulated amount of lipoic acid granules, disintegrant, and lubricant for 10 minutes;

[0025] (2) Hard capsule filling: Use 00#23.0mm metering disk for filling, and control the capsule weight to 560mg / cap±5%;

[0026] Wherein, the disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxypropyl cellulose, and corn starch;

[0027] The lubricant is one or more of magnesium stearate, stearic acid and talc.

[0028] The method for preparing lipoic acid granules and the method for preparing the lipoic acid granules into tablets and capsules of the present invention have the following beneficial effects:

[0029] 1. The present invention provides a thioctic acid granule, which has good fluidity, less fine powder, narrow particle size distribution range, high yield, anti-sticking, slight special odor of thioctic acid, and good compressibility;

[0030] 2. The present invention provides a method for preparing lipoic acid granules, which has simple process, high production efficiency and low production loss;

[0031] 3. The present invention provides an application direction of thioctic acid particles, and the obtained thioctic acid tablets and thioctic acid hard capsules have high drug loading, low odor, low production difficulty, good content stability, dissolution stability and disintegration time stability. DETAILED DESCRIPTION

[0032] The present invention is now further described in detail with reference to the examples, but it does not mean that the present invention is limited thereto. The values ​​in the examples are any specific numerical values ​​within the scope of the present invention, which are all feasible.

[0033] Example 1: Preparation of lipoic acid granules by implementing the scheme of the present invention

[0034] The formulation of this embodiment includes the components shown in Table 1:

[0035] Material Name Dosage(g) Proportion (%) Lipoic Acid 1000.000 90.909 Hydroxypropyl methylcellulose (15CP) (binder) 20.000 1.818 Povidone (PVP-K30) (coating material) 80.000 7.273 total 1100.000 100.000

[0036] Table 1

[0037] The preparation method is as follows:

[0038] (1) passing the formulated amount of lipoic acid through a 30-mesh sieve;

[0039] (2) The sieved lipoic acid is put into a fluidized bed, and granulation is performed using a fluidized bed top spray module, and hydroxypropyl methylcellulose (15CP) is added as a binder, wherein the beating ratio of the binder is hydroxypropyl methylcellulose: water = 3:97. Granulation process parameters: air volume 70m 3 / h, air inlet temperature 52℃, material temperature 35~23℃, spraying speed 40r / min, atomization pressure 0.16MPa, the obtained particles pass through a 20-mesh sieve;

[0040] (3) The sieved particles are placed in a fluidized bed and coated using a fluidized bed bottom spray module, spraying polyvinylpyrrolidone (PVP-K30) as a coating material, wherein the slurry ratio of the coating material is polyvinylpyrrolidone: water = 5:95. Coating process parameters: air volume 65m 3 / h, inlet air temperature 50°C, material temperature 35-30°C, spraying speed 12r / min, atomization pressure 0.2MPa, the obtained particles passed through a 20-mesh sieve to obtain thioctic acid particles.

[0041] The obtained lipoic acid particle detection data are shown in Table 2:

[0042]

[0043] Table 2

[0044] The obtained particles have good fluidity, less fine powder, narrow particle size distribution range, high yield, and slight special odor of lipoic acid, but significantly lighter than that of the raw material.

[0045] Example 2: Preparation of lipoic acid granules by implementing the scheme of the present invention

[0046] The formulation of this embodiment includes the components shown in Table 3:

[0047] Material Name Dosage(g) Proportion (%) Lipoic Acid 1000.000 90.090 Gum Arabic (adhesive) 30.000 2.703 Gum Arabic (coating material) 80.000 7.207 total 1110.000 100.000

[0048] Table 3

[0049] The preparation method is as follows:

[0050] (1) passing the formulated amount of lipoic acid through a 30-mesh sieve;

[0051] (2) The sieved lipoic acid is put into a fluidized bed, and granulation is performed using a fluidized bed top spray module, and gum arabic is added as a binder, wherein the beating ratio of the binder is gum arabic: water = 20:80. Granulation process parameters: air volume 70m 3 / h, air inlet temperature 52℃, material temperature 35~23℃, spraying speed 40r / min, atomization pressure 0.16MPa, the obtained particles pass through a 20-mesh sieve;

[0052] (3) The sieved particles are placed in a fluidized bed and coated using a fluidized bed bottom spray module, spraying gum arabic as a coating material, wherein the slurry ratio of the coating material is gum arabic: water = 10:90. Coating process parameters: air volume 65m 3 / h, inlet air temperature 50°C, material temperature 35-30°C, spraying speed 15r / min, atomization pressure 0.2MPa, the obtained particles passed through a 20-mesh sieve to obtain thioctic acid particles.

[0053] The obtained lipoic acid particle detection data are shown in Table 4:

[0054]

[0055] Table 4

[0056] The obtained particles have good fluidity, a small amount of fine powder, a narrow particle size distribution range, and the special odor of lipoic acid is extremely slight and significantly lighter than that of the raw material.

[0057] Example 3: Preparation of lipoic acid tablets by implementing the scheme of the present invention

[0058] The formulation of this embodiment includes the components shown in Table 5:

[0059]

[0060] Table 5

[0061] The preparation method is as follows:

[0062] (1) Total mixing: Mix 1 / 2 of the formula amount of lipoic acid granules, microcrystalline cellulose, crospovidone, and 1 / 2 of the formula amount of lipoic acid granules for 20 minutes, then add magnesium stearate and mix for 5 minutes;

[0063] (2) Tablet pressing: Use oval punching tablets with a size of T16 mm*8.5 mm, and control the tablet weight to 690 mg / tab±5% and the hardness to 190 N±20 N.

[0064] The obtained thioctic acid tablets have smooth surfaces, no sticking phenomenon during tableting, good compressibility, and extremely slight thioctic acid odor.

[0065] Example 4: Preparation of lipoic acid capsules by implementing the scheme of the present invention

[0066] The formulation of this embodiment includes the components shown in Table 6:

[0067]

[0068] Table 6

[0069] The preparation method is as follows:

[0070] (1) Total mixing: Mix the formulated amount of lipoic acid granules, cross-linked sodium carboxymethyl cellulose, and magnesium stearate for 10 minutes;

[0071] (2) Hard capsule filling: Use 00#23.0mm metering disk for filling and control the capsule weight to 560mg / cap±5%.

[0072] The obtained lipoic acid hard capsules have uniform appearance, no powder inclusion at the locking position, no sticking phenomenon during the filling process, and no lipoic acid smell.

[0073] Comparative Example 1: Preparation of lipoic acid granules using wet granulation

[0074] This comparative example formulation includes the components shown in Table 7:

[0075] Material Name Dosage(g) Proportion (%) Lipoic Acid 610.000 76.100 Low substituted hydroxypropyl cellulose LH-22 152.000 19.000 Highly substituted hydroxypropyl cellulose EF 19.000 2.400 Magnesium Stearate 20.000 2.500 total 801.000 100.000

[0076] Table 7

[0077] The preparation method is as follows:

[0078] (1) Wet granulation: 20% hydroxypropyl cellulose EF was prepared with purified water as a binder solution, and the formulated amount of lipoic acid and 80% of the formulated amount of low-substituted hydroxypropyl cellulose were mixed and put into a wet granulator. Stirring was started, the speed was set to 20 Hz, and stirring was performed for 5 minutes. Then, shearing was started at 35 Hz, and stirring and shearing were performed for 8 minutes to obtain lipoic acid granules.

[0079] (2) Drying: Place the lipoic acid particles into a fluidized bed and use a top spray module with an air inlet temperature of 40°C and an air volume of 60 m 3 / h, dry for 2h, and control the moisture content of the material after drying to ≤2%.

[0080] (3) Total mixing: After mixing the formulated amount of lipoic acid granules and the remaining 20% ​​of the formulated amount of low-substituted hydroxypropyl cellulose for 20 minutes, magnesium stearate was added and mixed for 5 minutes.

[0081] (4) Tablet pressing: Use oval punching tablets with a size of T17 mm*9 mm, and control the tablet weight to 810 mg / tab±5% and the hardness to 210 N±20 N.

[0082] The obtained lipoic acid tablets have smooth surfaces, slight sticking phenomenon in the later stage of tableting, good compressibility, and a certain lipoic acid smell.

[0083] Comparative Example 2: Preparation of lipoic acid granules by dry granulation followed by wet granulation + fluidized bed granulation

[0084] This comparative example formulation includes the components shown in Table 8:

[0085] Material Name Dosage(g) Proportion (%) Lipoic Acid 600.000 74.900 Low substituted hydroxypropyl cellulose 157.000 19.600 Highly substituted hydroxypropyl cellulose 20.000 2.500 Magnesium Stearate 24.000 3.000 total 801.000 100.000

[0086] Table 8

[0087] The preparation method is as follows:

[0088] (1) Dry granulation: Weigh the prescribed amount of lipoic acid, 30% of the prescribed amount of low-substituted hydroxypropyl cellulose LH-22, and 50% of the prescribed amount of magnesium stearate, add them into a dry granulator, set the pressure to 2-3 MPa, the roller speed to 10 rpm, and the granulator speed to 70 rpm for granulation, and after granulation, use a 1.0 mm diameter sieve to sieve the granules to obtain dry granules;

[0089] (2) Wet mixing: Use purified water to prepare 20% hydroxypropyl cellulose EF as a binder solution; add dry granules and 50% of the prescription amount of low-substituted hydroxypropyl cellulose LH-22 into a wet granulator, start stirring, set the speed to 20 Hz and the shear to 40 Hz, mix for 8 minutes, and mix evenly;

[0090] (3) Fluidized bed granulation: preheat the fluidized bed, set the air inlet temperature to 45°C and the air inlet volume to 35Hz, add the premixed powder to the fluidized bed, turn on the heating when the temperature reaches 35°C, and start the liquid spraying (binder solution), and control the temperature at 40°C during the liquid spraying process; after the liquid spraying is completed, dry and control the moisture content to less than 2%; after drying, use a swing granulator equipped with a 1.2mm planing screen to granulate the granules to obtain wet granules;

[0091] (4) Total mixing: Mix the formulated amount of wet granulation and the remaining 20% ​​of low-substituted hydroxypropyl cellulose LH-22 for 20 minutes, then add magnesium stearate and mix for 5 minutes;

[0092] (5) Tablet pressing: Use oval punching tablets with a size of T17 mm*9 mm, and control the tablet weight to 810 mg / tab±5% and the hardness to 210 N±20 N.

[0093] The obtained lipoic acid tablets have smooth surfaces, slight sticking phenomenon in the later stage of tableting, good compressibility, and a certain lipoic acid smell.

[0094] Example 5: Accelerated stability test of Example 3, Example 4, Comparative Example 1 and Comparative Example 2

[0095]

[0096] Table 9

[0097] The accelerated stability test conditions are: temperature: 40±2℃, relative humidity: 75%±5%. Inspection period: 6 months. Product packaging: plastic bag + silica gel + aluminum foil bag + carton. Inspection items: lipoic acid content, lipoic acid solubility, disintegration time, odor.

[0098] According to USP <2040> The α-lipoic acid content was detected by HPLC; the disintegration time limit conditions for tablets were medium water with baffles, and the disintegration time limit conditions for hard capsules were medium 0.05 M acetic acid solution without baffles; the dissolution conditions for tablets were medium 900 mL water, 75 rpm, and paddle method, and the dissolution conditions for hard capsules were medium 900 mL water, 100 rpm, and basket method.

[0099] As shown in Table 9, the lipoic acid content stability of Examples 3 and 4 is better, slightly better than that of Comparative Examples 1 and 2, that is, the content stability of the lipoic acid granules obtained by fluidized bed top spray granulation + bottom spray coating after tableting or filling is better than that of wet granulation.

[0100] As shown in Table 9, the dissolution rate stability of Examples 3 and 4 is better, slightly better than that of Comparative Examples 1 and 2, that is, the dissolution stability of the lipoic acid granules obtained by fluidized bed top spray granulation + bottom spray coating after tableting or filling is better than that of wet granulation.

[0101] It can be seen from Table 9 that the disintegration time stability of Examples 3 and 4 is good, that is, the lipoic acid granules obtained by fluidized bed top spray granulation + bottom spray coating have no adverse effect on the disintegration time stability of the finished product.

[0102] The present invention has been described according to the preferred embodiments. It should be understood that the foregoing description and embodiments are merely for the purpose of illustrating the invention. Without departing from the spirit and scope of the present invention, those skilled in the art may devise various alternatives and improvements of the present invention, which should all be understood to be within the scope of protection of the present invention.

Claims

1. A method for preparing thioctic acid granules, characterized in that: The following steps are involved: (1) passing the formulated amount of lipoic acid through a 30-mesh sieve; (2) Put the sieved lipoic acid into the fluidized bed, use the fluidized bed top spray module to perform granulation operation, add binder, and the air volume is 30-80m 3 / h, air inlet temperature 40~60℃, material temperature 20~50℃, spraying speed 20~50r / min, atomization pressure 0.1~0.3MPa, the obtained particles are passed through a 20-mesh sieve; (3) The sieved particles are placed in a fluidized bed and coated using a fluidized bed bottom spray module to spray the coating material with an air volume of 30 to 80 m 3 / h, air inlet temperature 40-60°C, material temperature 20-50°C, spraying speed 5-25r / min, atomization pressure 0.1-0.3MPa, the obtained particles are sieved through a 20-mesh sieve to obtain thioctic acid particles.

2. The method for preparing lipoic acid granules according to claim 1, wherein: The percentage of each component of the zinc sulfate granules in the total formula weight is: 85% to 92% of lipoic acid, 1% to 3% of adhesive, and 7% to 12% of coating material.

3. The preparation method of a thioctic acid granule according to claim 2, characterized in that: The adhesive is one or more of maltodextrin, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, povidone and gum arabic.

4. The method for preparing lipoic acid granules according to claim 2, wherein: The coating material is one or more of maltodextrin, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol and gum arabic.

5. The method for preparing the thioctic acid granules according to claim 1 into thioctic acid tablets is characterized in that: The following steps are involved: (1) Total mixing: add 1 / 2 of the formula amount of lipoic acid granules, filler, disintegrant, and 1 / 2 of the formula amount of lipoic acid granules in order, mix for 20 minutes, and then add lubricant and mix for 5 minutes; (2) Tableting: Use oval punching tablets with a size of T16 mm*8.5 mm, control the tablet weight to 690 mg / tab±5%, and hardness to 190 N±20 N; Wherein, the filler is one or more of microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, corn starch, cyclodextrin, and rice flour; The disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and hydroxypropyl cellulose; The lubricant is one or more of magnesium stearate, stearic acid and talc.

6. A method for preparing lipoic acid capsules from the lipoic acid granules according to claim 1, characterized in that: The following steps are involved: (1) Total mixing: Mix the formulated amount of lipoic acid granules, disintegrant, and lubricant for 10 minutes; (2) Hard capsule filling: Use 00#23.0mm metering disk for filling, and control the capsule weight to 560mg / cap±5%; Wherein, the disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxypropyl cellulose, and corn starch; The lubricant is one or more of magnesium stearate, stearic acid and talc.

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