A kind of lipoic acid tablet and preparation method thereof

Abstract

The invention belongs to the technical field of drug production and preparation, and discloses a thioctic acid tablet and a preparation method thereof. The thioctic acid tablet of the invention contains thioctic acid and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is a disintegrant, magnesium aluminum silicate, microcrystalline cellulose, a binder, a wetting agent and a lubricant, wherein the lubricant is a combination of silicon dioxide, sodium stearyl fumarate and polyethylene glycol, and the thioctic acid tablet solves the problem of easy sticking of thioctic acid tablets by adding magnesium aluminum silicate, microcrystalline cellulose and a specific disintegrant, lubricant and the like, and the obtained tablet has high stability.

Description

Technical Field

[0001] The invention relates to the technical field of drug production and preparation, and in particular to a thioctic acid tablet and a preparation method thereof. Background Art

[0002] The molecular formula of lipoic acid is C8H 14 O2S2, chemically known as (±)-5-[3-(1,2-dithiolane)]-pentanoic acid, is a coenzyme factor for the oxidative decarboxylation reaction of α-ketoglutaric acid in the pyruvate and tricarboxylic acid cycles. It can participate in the acyl transfer in the metabolism of substances in the body as a coenzyme and can eliminate free radicals that accelerate aging and cause disease. After being absorbed by the intestines, lipoic acid enters cells in the body. It has both fat-soluble and water-soluble properties and can be transported to most tissues of the body to exert its effects.

[0003] However, lipoic acid is extremely sensitive to heat and light, and is naturally hygroscopic with a low melting point (about 60°C). When lipoic acid is developed as an API into solid pharmaceutical dosage forms such as tablets, during production and storage, lipoic acid preparations are unstable and prone to produce impurities, which not only reduce the efficacy of lipoic acid preparations, but also increase the toxicity of lipoic acid preparations in the body to a certain extent, affecting the safety of the drug.

[0004] Chinese patent application CN103099793A discloses a tablet, claiming to solve the current technical problem of sticking and punching in the direct compression process of tablets for drugs with large viscosity and poor fluidity (such as lipoic acid), and the tablet can effectively overcome the sticking and punching problem in the tablet compression process by selecting each component and making a reasonable proportion, and the various indicators of the tablets finally prepared meet the requirements of the pharmacopoeia. The patent application repeatedly emphasizes that magnesium stearate with fine particle size is the key to solving the problem, but the inventor of Chinese patent application CN105267164A found that magnesium stearate would affect the stability of lipoic acid tablets, and provided a lipoic acid tablet without magnesium stearate, but the disadvantage is that the API content in the tablet is only 30% at most, the number of tablets taken by patients is high, and the medication compliance is poor.

[0005] Chinese patent application CN111557920A discloses a tablet containing lipoic acid and a preparation method thereof. The tablet prepared by the method of the patent application has a high content of lipoic acid as an active ingredient, not less than 70%, rapid dissolution, a smooth tablet core surface, no color spots, no signs of sticking, high bioavailability, and a fast disintegration rate, which solves the problem of low melting point of lipoic acid and easy sticking of tablets. However, in the preparation process of the application, the active ingredient, filler, and adhesive must be evenly mixed, and then an ethanol solution of a release agent must be added to make a soft material, and then granulation must be performed. After the obtained wet granules are dried, they are mixed with a disintegrant, a glidant, and a lubricant, and tableting is performed. The method is relatively complicated.

[0006] Based on the above reasons, there is a need for a formulation formula that can overcome the low melting point of lipoic acid, easy sticking of tablets, thermal instability, and high API content, as well as a simple and feasible preparation method. Summary of the invention

[0007] The purpose of the present invention is to overcome the shortcomings of the above-mentioned background technology, and to provide a thioctic acid tablet and a preparation method thereof. The thioctic acid tablet of the present invention solves the problem that thioctic acid tablets are easy to stick to the punch by adding magnesium aluminum silicate, microcrystalline cellulose and a specific disintegrant, a lubricant, etc., and the obtained tablet has high stability.

[0008] To achieve the purpose of the present invention, the lipoic acid tablet of the present invention comprises lipoic acid and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is a disintegrant, magnesium aluminum silicate, microcrystalline cellulose, a binder, a wetting agent and a lubricant, wherein the lubricant is a combination of silicon dioxide, sodium stearyl fumarate and polyethylene glycol.

[0009] Furthermore, in some embodiments of the present invention, the lipoic acid tablet comprises, by weight, 90-105 parts of lipoic acid, 40-50 parts of a disintegrant, 4-8 parts of magnesium aluminum silicate, 8-15 parts of microcrystalline cellulose, 25-40 parts of a binder, 3-6 parts of a wetting agent, and 12-18 parts of a lubricant.

[0010] Furthermore, in some embodiments of the present invention, the mass ratio of silicon dioxide, sodium stearyl fumarate and polyethylene glycol in the lubricant is 5-8:2-4:2-4. The inventors of the present invention have found through multiple experiments that when and only when the lubricant is a combination of silicon dioxide, sodium stearyl fumarate and polyethylene glycol, and the mass ratio is 5-8:2-4:2-4, the lipoic acid tablets prepared by the present invention are free of sticking during the tableting process, and the stability of the obtained tablets is better than that of using other lubricants.

[0011] Furthermore, in some embodiments of the present invention, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, pregelatinized starch, and cross-linked sodium carboxymethyl cellulose.

[0012] Preferably, in some embodiments of the present invention, the disintegrant is low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose.

[0013] More preferably, in some embodiments of the present invention, the mass ratio of the low-substituted hydroxypropyl cellulose to the cross-linked sodium carboxymethyl cellulose is 1:2-4.

[0014] Furthermore, in some embodiments of the present invention, the binder is selected from one or more of hydroxypropyl methylcellulose, povidone, starch slurry, dextrin, polyvinyl acetate, polyvinyl alcohol, vinyl pyrrolidone-vinyl acetate copolymer, and sodium carboxymethyl cellulose.

[0015] Preferably, in some embodiments of the present invention, the binder is hydroxypropyl methylcellulose.

[0016] Further, in some embodiments of the present invention, the wetting agent is selected from one or more of ethoxylated triglycerides, sodium lauryl sulfate, sorbitan monopalmitate, and sorbitan monooleate.

[0017] Preferably, in some embodiments of the present invention, the wetting agent is sodium lauryl sulfate.

[0018] Furthermore, the present invention also provides a method for preparing the aforementioned lipoic acid tablets, the method comprising:

[0019] (1) respectively micronizing lipoic acid, a disintegrant, a binder, and magnesium aluminum silicate, and sieving;

[0020] (2) dissolving a micronized binder and a wetting agent in an ethanol aqueous solution, adding micronized lipoic acid and polyethylene glycol, and stirring to obtain a mixed solution;

[0021] (3) spraying the obtained mixed solution onto a mixture of micronized magnesium aluminum silicate, a disintegrant and microcrystalline cellulose to obtain granules;

[0022] (4) the obtained granules are sieved, mixed evenly with sodium stearyl fumarate and colloidal silicon dioxide, and tabletted;

[0023] (5) Optionally, the tablet obtained in step (4) is film-coated.

[0024] Furthermore, in some embodiments of the present invention, the sieving in step (1) is through a 20-150 mesh sieve.

[0025] Furthermore, in some embodiments of the present invention, the ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 90-96% by volume.

[0026] Furthermore, in some embodiments of the present invention, the mass volume ratio of the binder to the ethanol aqueous solution is 1 g: 25-30 ml.

[0027] Compared with the prior art, the advantages of the present invention are as follows:

[0028] (1) The present invention selects three specific lubricants, namely silicon dioxide, sodium stearyl fumarate and polyethylene glycol, and first adds polyethylene glycol with excellent lubricity, moisture retention, dispersibility and adhesion during the preparation process, and then adds silicon dioxide and sodium stearyl fumarate after obtaining the granules and before tableting. The obtained tablets have high stability, are not easy to stick, and have rapid dissolution.

[0029] (2) Magnesium aluminum silicate is added to the lipoic acid tablets of the present invention to improve the stability of the tablets. Microcrystalline cellulose is added because of the presence of hydrogen bonds between its molecules. When compressed, the tablets have a high degree of compressibility and also have the functions of a diluent and a binder. They also have certain lubricating and disintegrating effects. Compared with the addition of other fillers such as lactose monohydrate, the addition of microcrystalline cellulose overcomes the problems of easy sticking and color spots of lipoic acid tablets. The obtained tablets have high dispersion uniformity, good stability, and rapid dissolution, and will not affect the efficacy and safety of the drug. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. Additional aspects and advantages of the present invention will be given in part in the following description, and part will become apparent from the following description, or will be understood through the practice of the present invention. It should be understood that the following description is only used to explain the present invention and is not intended to limit the present invention.

[0031] As used herein, the terms "comprises," "including," "having," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0032] The conjunction "consisting of excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed-ended so that it does not include materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than immediately following the subject matter, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0033] When amount, concentration or other value or parameter is expressed as range, preferred range or a series of upper preferred value and lower preferred value limit range, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value and any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when disclosing range "1 to 5", described range should be interpreted as including range "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5" etc. When numerical range is described in this article, unless otherwise stated, the range is intended to include its end value and all integers and fractions within the range.

[0034] Singular forms include plural references unless the context clearly indicates otherwise. "Optional" or "either" means that the subsequently described event or incident may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0035] Approximate terms in the specification and claims are used to modify quantities, indicating that the present invention is not limited to the specific quantity, but also includes acceptable and modified parts close to the quantity without causing changes in the relevant basic functions. Accordingly, the use of "about", "approximately", etc. to modify a numerical value means that the present invention is not limited to the exact numerical value. In some examples, the approximate terms may correspond to the accuracy of the instrument for measuring the numerical value. In the specification and claims of this application, range limitations can be combined and / or interchanged, and if not otherwise stated, these ranges include all subranges contained therein.

[0036] The indefinite articles "a" and "an" before the elements or components of the present invention have no limitation on the quantity requirements (i.e. the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and the elements or components in the singular form also include the plural form, unless the quantity obviously refers to the singular form only.

[0037] In addition, the descriptions of the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" described below mean that the specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0038] Example 1

[0039] Prepare API and excipients according to the following dosage (based on 200 tablets):

[0040]

[0041] The lipoic acid tablets were prepared as follows:

[0042] (1) Powder lipoic acid, disintegrant, binder and magnesium aluminum silicate respectively and pass through an 80-mesh sieve:

[0043] (2) dissolving a micronized binder and a wetting agent in an ethanol aqueous solution, adding micronized lipoic acid and polyethylene glycol, and stirring to obtain a mixed solution;

[0044] (3) spraying the obtained mixed solution onto a mixture of micronized magnesium aluminum silicate, a disintegrant and microcrystalline cellulose to obtain granules;

[0045] (4) The obtained granules are sieved, mixed evenly with sodium stearyl fumarate and colloidal silicon dioxide, and pressed into tablets with a diameter of 6 mm.

[0046] The ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 95% by volume, and the mass volume ratio of the binder to the ethanol aqueous solution is 1g:25ml.

[0047] Example 2

[0048] Prepare API and excipients according to the following dosage (based on 200 tablets):

[0049]

[0050] The lipoic acid tablets were prepared as follows:

[0051] (1) Powder lipoic acid, disintegrant, binder and magnesium aluminum silicate respectively and pass through an 80-mesh sieve:

[0052] (2) dissolving a micronized binder and a wetting agent in an ethanol aqueous solution, adding micronized lipoic acid and polyethylene glycol, and stirring to obtain a mixed solution;

[0053] (3) spraying the obtained mixed solution onto a mixture of micronized magnesium aluminum silicate, a disintegrant and microcrystalline cellulose to obtain granules;

[0054] (4) The obtained granules are sieved, mixed evenly with sodium stearyl fumarate and colloidal silicon dioxide, and pressed into tablets with a diameter of 6 mm.

[0055] The ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 95% by volume, and the mass volume ratio of the binder to the ethanol aqueous solution is 1g:25ml.

[0056] Comparative Example 1

[0057] Prepare API and excipients according to the following dosage (based on 200 tablets):

[0058]

[0059] The lipoic acid tablets were prepared as follows:

[0060] (1) Powder lipoic acid, disintegrant, binder and magnesium aluminum silicate respectively and pass through an 80-mesh sieve:

[0061] (2) mixing the micronized lipoic acid and the binder, adding a wetting agent and an ethanol aqueous solution, and then adding a mixture of micronized magnesium aluminum silicate, a disintegrant and microcrystalline cellulose, and drying and granulating;

[0062] (3) The obtained granules are sieved, mixed evenly with polyethylene glycol, sodium stearyl fumarate and colloidal silicon dioxide, and pressed into tablets with a diameter of 6 mm.

[0063] The ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 95% by volume, and the mass volume ratio of the binder to the ethanol aqueous solution is 1g:25ml.

[0064] Comparative Example 2

[0065] Prepare API and excipients according to the following dosage (based on 200 tablets):

[0066]

[0067]

[0068] The lipoic acid tablets were prepared as follows:

[0069] (1) Micronize lipoic acid, disintegrant, and binder separately and pass through an 80-mesh sieve:

[0070] (2) dissolving a micronized binder and a wetting agent in an ethanol aqueous solution, adding micronized lipoic acid and polyethylene glycol, and stirring to obtain a mixed solution;

[0071] (3) spraying the obtained mixed solution onto a mixture of a micronized disintegrant and microcrystalline cellulose to obtain granules;

[0072] (4) The obtained granules are sieved, mixed evenly with sodium stearyl fumarate and colloidal silicon dioxide, and pressed into tablets with a diameter of 6 mm.

[0073] The ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 95% by volume, and the mass volume ratio of the binder to the ethanol aqueous solution is 1g:25ml.

[0074] Comparative Example 3

[0075] Prepare API and excipients according to the following dosage (based on 200 tablets):

[0076]

[0077] The lipoic acid tablets were prepared as follows:

[0078] (1) Powder lipoic acid, disintegrant, binder and magnesium aluminum silicate respectively and pass through an 80-mesh sieve:

[0079] (2) dissolving a micronized binder and a wetting agent in an ethanol aqueous solution, adding micronized lipoic acid, and stirring to obtain a mixed solution;

[0080] (3) spraying the obtained mixed solution onto a mixture of micronized magnesium aluminum silicate, a disintegrant and microcrystalline cellulose to obtain granules;

[0081] (4) The obtained granules are sieved, mixed evenly with sodium stearyl fumarate and colloidal silicon dioxide, and pressed into tablets with a diameter of 6 mm.

[0082] The ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 95% by volume, and the mass volume ratio of the binder to the ethanol aqueous solution is 1g:25ml.

[0083] Comparative Example 4

[0084] Prepare API and excipients according to the following dosage (based on 200 tablets):

[0085]

[0086] The lipoic acid tablets were prepared as follows:

[0087] (1) Powder lipoic acid, disintegrant, binder and magnesium aluminum silicate respectively and pass through an 80-mesh sieve:

[0088] (2) dissolving a micronized binder and a wetting agent in an ethanol aqueous solution, adding micronized lipoic acid and polyethylene glycol, and stirring to obtain a mixed solution;

[0089] (3) spraying the obtained mixed solution onto a mixture of micronized magnesium aluminum silicate, a disintegrant and microcrystalline cellulose to obtain granules;

[0090] (4) The obtained granules are sieved, mixed evenly with talcum powder and colloidal silicon dioxide, and pressed into tablets with a diameter of 6 mm.

[0091] The ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 95% by volume, and the mass volume ratio of the binder to the ethanol aqueous solution is 1g:25ml.

[0092] Comparative Example 5

[0093] Prepare API and excipients according to the following dosage (based on 200 tablets):

[0094]

[0095] The lipoic acid tablets were prepared as follows:

[0096] (1) Powder lipoic acid, disintegrant, binder and magnesium aluminum silicate respectively and pass through an 80-mesh sieve:

[0097] (2) dissolving a micronized binder and a wetting agent in an ethanol aqueous solution, adding micronized lipoic acid and polyethylene glycol, and stirring to obtain a mixed solution;

[0098] (3) spraying the obtained mixed solution onto a mixture of micronized magnesium aluminum silicate, a disintegrant and lactose monohydrate to obtain granules;

[0099] (4) The obtained granules are sieved, mixed evenly with sodium stearyl fumarate and colloidal silicon dioxide, and pressed into tablets with a diameter of 6 mm.

[0100] The ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 95% by volume, and the mass volume ratio of the binder to the ethanol aqueous solution is 1g:25ml.

[0101] Effect Example

[0102] 1. Stability test: The lipoic acid tablets prepared in the embodiment of the present invention and the comparative example were packaged in the same aluminum foil bag, and stability tests were carried out under the conditions of 40°C ± 2°C and 75% ± 5% RH. The contents of samples and related substances at different sampling time points were measured. The results are shown in Table 1.

[0103] Table 1 Stability test results of lipoic acid tablets obtained in each embodiment and comparative example

[0104]

[0105]

[0106] 2. Sticking test: The same embodiment or comparative example prescription was tableted 10 times to determine whether sticking occurred. The results are shown in Table 2, wherein occasional sticking refers to 1-2 stickings in 10 times, sometimes sticking refers to 4-5 stickings in 10 times, and often sticking refers to 7-8 stickings in 10 times.

[0107] The dissolution determination method adopts the method recommended by the United States Pharmacopoeia, namely the paddle method, with 900 ml of water as the dissolution medium. The dissolution rate in 60 minutes must be no less than 70%, and the test value is taken as the interval value of 10 tablets. The results are shown in Table 2.

[0108] Table 2 Results of viscosity test and dissolution test

[0109]

[0110]

[0111] It can be seen from the above experimental results that the lipoic acid tablets obtained by using the lipoic acid tablet formulation and the preparation method of the present invention have high stability, no sticking during the preparation process, and a dissolution rate of more than 95% in 60 minutes. However, if the lubricant of the present invention is replaced by other lubricants or some of the auxiliary materials and the preparation method are changed, the stability or dissolution of the obtained lipoic acid tablets will be significantly deteriorated.

[0112] Those skilled in the art will easily understand that the above descriptions are merely embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A lipoic acid tablet, characterized in that The lipoic acid tablet comprises lipoic acid and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is a disintegrant, magnesium aluminum silicate, microcrystalline cellulose, a binder, a wetting agent and a lubricant, wherein the lubricant is a combination of silicon dioxide, sodium stearyl fumarate and polyethylene glycol; the lipoic acid tablet comprises 90-105 parts of lipoic acid, 40-50 parts of a disintegrant, 4-8 parts of magnesium aluminum silicate, 8-15 parts of microcrystalline cellulose, 25-40 parts of a binder, 3-6 parts of a wetting agent and 12-18 parts of a lubricant by weight; the mass ratio of silicon dioxide, sodium stearyl fumarate and polyethylene glycol in the lubricant is 5-8:2-4:2-4; the disintegrant is low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose, and the mass ratio of the low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose is 1:2-4; the preparation method of the lipoic acid tablet comprises the following steps: (1) respectively micronizing lipoic acid, a disintegrant, a binder, and magnesium aluminum silicate, and sieving; (2) dissolving a micronized binder and a wetting agent in an ethanol aqueous solution, adding micronized lipoic acid and polyethylene glycol, and stirring to obtain a mixed solution; (3) spraying the obtained mixed solution onto a mixture of micronized magnesium aluminum silicate, a disintegrant and microcrystalline cellulose to obtain granules; (4) the obtained granules are sieved, mixed evenly with sodium stearyl fumarate and colloidal silicon dioxide, and tabletted; (5) Optionally, the tablet obtained in step (4) is film-coated.

2. The lipoic acid tablet according to claim 1, characterized in that The binder is selected from one or more of hydroxypropyl methylcellulose, povidone, starch slurry, dextrin, polyvinyl acetate, polyvinyl alcohol, vinyl pyrrolidone-vinyl acetate copolymer, and sodium carboxymethyl cellulose.

3. The lipoic acid tablet according to claim 1, characterized in that The binder is hydroxypropyl methylcellulose.

4. The lipoic acid tablet according to claim 1, characterized in that The wetting agent is selected from one or more of ethoxylated triglycerides, sodium lauryl sulfate, sorbitan monopalmitate, and sorbitan monooleate.

5. The lipoic acid tablet according to claim 1, characterized in that The wetting agent is sodium lauryl sulfate.

6. The lipoic acid tablet according to claim 1, characterized in that The sieving in step (1) is through a 20-150 mesh sieve.

7. The lipoic acid tablet according to claim 1, characterized in that The ethanol aqueous solution is an ethanol aqueous solution in which ethanol accounts for 90-96% by volume.

8. The lipoic acid tablet according to claim 1, characterized in that The mass volume ratio of the binder to the ethanol aqueous solution is 1g:25-30ml.

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