Folic acid tablet with improved stability and dissolution and preparation method thereof

Abstract

The present invention relates to a folic acid tablet and a preparation method thereof for improving stability and dissolution, wherein the folic acid tablet comprises the following raw materials according to each 100mg tablet: 0.4-5mg folic acid, 30-40mg calcium hydrogen phosphate, 25-30mg microcrystalline cellulose, 7-10mg low gelatinization degree starch, 15-20mg medium gelatinization degree starch, 2.2-3.5mg high gelatinization degree starch, 0.7-1mg colloidal silicon dioxide, 1-1.5mg stearate; the gelatinization degrees of low gelatinization degree starch, medium gelatinization degree starch, and high gelatinization degree starch are 10% to <25%, 25% to 40%, and 70% to 100% respectively. The present invention controls the dissolution rate of folic acid tablets and improves the compressibility of tablets, simplifies the preparation process, improves the stability of folic acid tablets, and simultaneously adds different proportions of gelatinization degree starch to control the early release rate of folic acid tablets.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a folic acid tablet with improved stability and dissolution and a preparation method thereof. Background Art

[0002] Natural folic acid is a low molecular weight B-group water-soluble vitamin that cannot be synthesized and converted by the human body. It participates in almost all methylated biochemical metabolic processes in the body. Folic acid deficiency can cause a variety of clinical diseases, such as folic acid deficiency megaloblastic anemia and neonatal neural tube defects. Folic acid has poor stability and is sensitive to acid, alkali, moisture, heat and light. Therefore, how to solve the stability and dispersibility of folic acid tablets has become a problem that needs to be solved. The wet granulation preparation process is a conventional process for the preparation of pharmaceutical tablets, but it requires water addition and drying. The quality of folic acid is unstable in the wet granulation process, and impurities are generated, especially impurity A, which is easy to exceed the standard. The Chinese Pharmacopoeia has very strict requirements on impurity A. Therefore, higher requirements are placed on the stability of folic acid tablets. In addition, the absorption of folic acid mainly occurs in the epithelial cells of the small intestinal villi. The pH of the small intestine environment is about 4.5-5.5, and folic acid is also relatively uncertain under this pH environment. Folic acid is unstable under both acidic and alkaline conditions and will degrade into various impurities. Folic acid will quickly transform into various impurities in the highly acidic environment of gastric juice, reducing the beneficial activity of folic acid. In order to slow down the dissolution of folic acid tablets in gastric juice, high-density insoluble calcium hydrogen phosphate is added to slow down the dissolution of folic acid tablets in gastric juice. However, on the one hand, a large amount of high-density insoluble inorganic components will also affect the dissolution of folic acid in the small intestine; on the other hand, calcium hydrogen phosphate is a brittle auxiliary material with poor compressibility, resulting in low hardness of folic acid tablets, which are easily bumped and damaged during transportation; and the folic acid content in folic acid tablets is low, and the use of calcium hydrogen phosphate will reduce the dispersion uniformity of folic acid tablets.

[0003] CN115969799A discloses a method for preparing folic acid tablets, comprising the following steps: (1) premixing folic acid, microcrystalline cellulose, disintegrant, and colloidal silicon dioxide in a wet mixing granulator, wherein the specific parameters of the premixing are: a stirring speed of 80-100 rpm / min, a cutting speed of 1300-2200 rpm / min, and a premixing time of 3-30 min; (2) adding calcium hydrogen phosphate and a lubricant to mix the mixture to obtain a total mixed powder, wherein the specific parameters of the total mixed powder are: a mixing speed of 8-15 rpm / min, and a total mixed time of 10-30 min; (3) tableting the total mixed powder. This patent uses wet granulation, which inevitably causes instability of folic acid tablets. CN114767645A discloses a folic acid tablet and a preparation method thereof, comprising the following raw material components in mass percentage: 1% to 10% folic acid; 8% to 55% microcrystalline cellulose; 8% to 35% pregelatinized starch; 0.1% to 1% silicon dioxide; 0.5% to 1.5% stearic acid and / or its metal salt; 15% to 65% calcium hydrogen phosphate; the silicon dioxide is selected from one or both of EVONIK R972 and EVONIK200. This patent uses specific silicon dioxide to improve the fluidity of the material, and the early control of drug release can slow down 5-10 percentage points, and improve the final dissolution of folic acid. However, this patent still cannot avoid the dissolution of folic acid tablets under the acidic conditions of gastric juice (pH about 1.2), and still causes the dissolution and loss of folic acid tablets in gastric juice. CN112336692A discloses a folic acid tablet and a preparation method thereof, which is composed of folic acid and acceptable auxiliary materials including stabilizers, excipients, and lubricants, and is prepared by dry granulation and tableting technology; the folic acid tablet contains 0.4-1.0 mg of folic acid in a unit preparation; the amount of the stabilizer is 10-20 mg, the amount of the excipient is 80-100 mg, and the amount of the lubricant is 0.5-2 mg. The stabilizer is selected from one or more combinations of hydroxypropyl methylcellulose, povidone, polyethylene glycol, stearic acid, behenic acid glyceride, palm wax, and sodium stearyl fumarate. This patent uses stabilizers to enable folic acid tablets to dissolve quickly under pH 5-7 conditions, but the problem of dissolution loss in gastric juice has not yet been solved. Summary of the invention

[0004] In order to solve the poor stability and dissolution problems of folic acid tablets in the prior art, the present invention provides a folic acid tablet with improved stability and dissolution and a preparation method thereof, which improves the stability, uniform dispersibility and dissolution of folic acid tablets through the reasonable combination of various components, especially the compound use of starches with different gelatinization degrees. Specifically, the present invention provides the following technical solutions to solve the above technical problems:

[0005] A folic acid compressed tablet with improved stability and dissolution, comprising the following raw materials per 100 mg tablet: 0.4-5 mg folic acid, 30-40 mg calcium hydrogen phosphate, 25-30 mg microcrystalline cellulose, 7-10 mg low gelatinization degree starch, 15-20 mg medium gelatinization degree starch, 2.2-3.5 mg high gelatinization degree starch, 0.7-1 mg colloidal silicon dioxide, 1-1.5 mg stearate; the gelatinization degree of the low gelatinization degree starch is 10% to <25%, the gelatinization degree of the medium gelatinization degree starch is 25% to 40%, and the gelatinization degree of the high gelatinization degree starch is 70% to 100%.

[0006] Pregelatinized starch is obtained by gelatinizing starch granules, and can serve as a binder, diluent, and disintegrant in pharmaceutical tablets. The degree of gelatinization is tested by the glucoamylase method. Gelatinized starches with different degrees of gelatinization can be homemade or purchased commercially. The source of starch is not particularly limited, such as corn. The preparation process of gelatinized starches with different degrees of gelatinization is well known in the art. Starch is treated at different temperatures, and gelatinized starches with different degrees of gelatinization can be obtained by adjusting the temperature and treatment time. If the degree of gelatinization is 100%, it is completely gelatinized starch. Starches with different gelatinization degrees have different viscosities. The compounding according to the above-mentioned specific ratio can improve the dissolution rate of the folic acid tablets in the early stage, reduce the dissolution under the acidic condition of pH=1-2, reduce the degree of damage to folic acid by the acidic medium, and dissolve well under the condition of pH 4.5-6.5 in the environment of the small intestine, which is the main absorption site of folic acid. The specific ratio of starches with different gelatinization degrees can improve the compressibility of the tablets, and the stability is also improved. Through the use of the above-mentioned compounded gelatinized starch, the folic acid tableting of the present invention can reduce the use of calcium hydrogen phosphate, so the dispersion uniformity of the folic acid in the tablets is also guaranteed.

[0007] Furthermore, the degree of gelatinization of the low-gelatinization starch is 10% to 15%, the degree of gelatinization of the medium-gelatinization starch is 25% to 30%, and the degree of coking of the high-gelatinization starch is 90% to 100%.

[0008] Furthermore, the microcrystalline cellulose is PH-102 and PH-112 with good fluidity; the specific surface area of ​​colloidal silicon dioxide is 175m 2 / g~225m 2 / g; the calcium hydrogen phosphate is calcium hydrogen phosphate dihydrate, and the particle size D50 is 0.15-0.2nm.

[0009] Furthermore, the stearate is selected from at least one of magnesium stearate and calcium stearate.

[0010] The present invention also provides a method for preparing the folic acid tablets with improved stability and dissolution, which comprises the following steps: mixing the materials uniformly and then tableting.

[0011] Furthermore, the method for preparing the folic acid tablets with improved stability and dissolution comprises the following steps:

[0012] 30-50wt% of stearate, low gelatinization starch, medium gelatinization starch, high gelatinization starch and colloidal silicon dioxide are added to a three-dimensional mixer and mixed for 5-10 minutes to pre-lubricate the surface of the mixing equipment, thereby reducing the adsorption of the equipment to the raw materials and improving the uniformity of the mixed powder content. Folic acid, calcium hydrogen phosphate and microcrystalline cellulose are then added and mixed for 20-30 minutes. Finally, the remaining stearate is added and the mixing is continued for 5-10 minutes, and tableting is performed to obtain the product folic acid tablets.

[0013] Furthermore, the rotation speed of the three-dimensional mixer is 30-50 Hz, and the hardness of the tablets after tableting is 20-50N.

[0014] The present invention also provides a method for storing folic acid tablets with improved stability and dissolution, which is to use an opaque bottle with a desiccant for packaging; preferably, the bottle cap of the bottle has a desiccant; more preferably, the bottle is made of polypropylene.

[0015] The present invention also provides the use of the folic acid compressed tablets with improved stability and dissolution in the preparation of medicines for treating anemia, developmental delay, leukopenia and neural tube malformations.

[0016] The folic acid tablet provided by the present invention has the uniformity of folic acid dispersion in the tablet, small average content dispersion, low RSD, good stability, and good stability when tested under high temperature, high humidity and light conditions. In addition, the folic acid tablet of the present invention has dissolution performance that conforms to the human body, has a low dissolution rate under acidic conditions of pH 1-2, but has a high dissolution rate under conditions of a simulated small intestine of pH 4.5-5.5, thereby ensuring the absorption and utilization of the folic acid tablet in the organism. DETAILED DESCRIPTION

[0017] The technical solution of the present invention is further explained and illustrated by specific embodiments below.

[0018] Some pregelatinized starch was purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd., and the grades are as follows according to the degree of gelatinization: ZW-10, degree of gelatinization 10%; ZW-15, degree of gelatinization 15%; ZW-20, degree of gelatinization 20%; ZW-25, degree of gelatinization 25%; ZW-30, degree of gelatinization 30%; ZW-40, degree of gelatinization 40%; ZW-70, degree of gelatinization 70%; ZW-90, degree of gelatinization 90%; fully gelatinized starch was purchased from Roquette Pharmaceutical Excipients Co., Ltd., brand LYCATAB PGS.

[0019] The specific surface area of ​​colloidal silica is 200 m 2 / g.

[0020] Example 1

[0021] The raw material ingredients of the folic acid tablets of Example 1 are shown in Table 1 below:

[0022] Table 1 Formula of folic acid tablets

[0023] .

[0024] The preparation process of folic acid tablets is as follows:

[0025] Take 1 / 2 of magnesium stearate, ZW-15, ZW-30, ZW-90, and colloidal silicon dioxide and add them to a three-dimensional mixer, mix at 30 Hz for 5 minutes, then add folic acid, calcium hydrogen phosphate, and microcrystalline cellulose, continue mixing at 30 Hz for 20 minutes, add the remaining magnesium stearate, and continue mixing for 10 minutes. Use a high-speed tablet press to compress the tablets, with a hardness of 20N.

[0026] Example 2

[0027] The raw material ingredients of the folic acid tablets of Example 2 are shown in Table 2 below:

[0028] Table 2 Folic acid tablet formula

[0029] .

[0030] Take 1 / 2 of magnesium stearate, ZW-10, ZW-25, LYCATAB PGS, and colloidal silicon dioxide and add them to a three-dimensional mixer, mix at 30 Hz for 5 minutes, then add folic acid, calcium hydrogen phosphate, and microcrystalline cellulose, continue mixing at 30 Hz for 20 minutes, add the remaining magnesium stearate, and continue mixing for 10 minutes. Use a high-speed tablet press to compress the tablets, with a hardness of 20N.

[0031] Example 3

[0032] The raw material ingredients of the folic acid tablets of Example 3 are shown in Table 3 below:

[0033] Table 3 Folic acid tablet formula

[0034] .

[0035] Take 1 / 2 of magnesium stearate, ZW-20, ZW-40, ZW-90, and colloidal silicon dioxide and add them to a three-dimensional mixer, mix at 30 Hz for 5 minutes, then add folic acid, calcium hydrogen phosphate, and microcrystalline cellulose, continue mixing at 30 Hz for 20 minutes, add the remaining magnesium stearate, and continue mixing for 10 minutes. Use a high-speed tablet press to compress the tablets, with a hardness of 20N.

[0036] Example 4

[0037] The raw material ingredients of the folic acid tablets of Example 4 are shown in Table 4 below:

[0038] Table 4 Folic acid tablet formula

[0039] .

[0040] Take 1 / 2 of magnesium stearate, ZW-15, ZW-30, ZW-70, and colloidal silicon dioxide and add them to a three-dimensional mixer, mix at 30 Hz for 5 minutes, then add folic acid, calcium hydrogen phosphate, and microcrystalline cellulose, continue mixing at 30 Hz for 20 minutes, add the remaining magnesium stearate, and continue mixing for 10 minutes. Use a high-speed tablet press to compress the tablets, with a hardness of 20N.

[0041] Comparative Example 1

[0042] The raw material ingredients of the folic acid tablets of Comparative Example 1 are shown in Table 5 below:

[0043] Table 5 Folic acid tablet formula

[0044] .

[0045] Take 1 / 2 of magnesium stearate, ZW-30, ZW-90, and colloidal silicon dioxide and add them to a three-dimensional mixer, mix at 30 Hz for 5 minutes, then add folic acid, calcium hydrogen phosphate, and microcrystalline cellulose, continue mixing at 30 Hz for 20 minutes, add the remaining magnesium stearate, and continue mixing for 10 minutes. Use a high-speed tablet press to compress the tablets, with a hardness of 20N.

[0046] Comparative Example 2

[0047] The raw material ingredients of the folic acid tablets of Comparative Example 2 are shown in Table 6 below:

[0048] Table 6 Folic acid tablet formula

[0049] .

[0050] Take 1 / 2 of magnesium stearate, ZW-15, ZW-90, and colloidal silicon dioxide and add them to a three-dimensional mixer, mix at 30 Hz for 5 minutes, then add folic acid, calcium hydrogen phosphate, and microcrystalline cellulose, continue mixing at 30 Hz for 20 minutes, add the remaining magnesium stearate, and continue mixing for 10 minutes. Use a high-speed tablet press to compress the tablets, with a hardness of 20N.

[0051] Comparative Example 3

[0052] The raw material ingredients of the folic acid tablets of Comparative Example 3 are shown in Table 7 below:

[0053] Table 7 Folic acid tablet formula

[0054] .

[0055] Take 1 / 2 of magnesium stearate, ZW-15, ZW-30, and colloidal silicon dioxide and add them to a three-dimensional mixer, mix at 30 Hz for 5 minutes, then add folic acid, calcium hydrogen phosphate, and microcrystalline cellulose, continue mixing at 30 Hz for 20 minutes, add the remaining magnesium stearate, and continue mixing for 10 minutes. Use a high-speed tablet press to compress the tablets, with a hardness of 20N.

[0056] Application Example 1

[0057] Take 10 folic acid tablets prepared in the embodiment of the present invention and the comparative example as the experimental group, take 1 folic acid tablet with the same drug content on the market as the control group, and use the same method to determine the content uniformity. Take 10 samples and place them in a 10ml volumetric bottle, add about 5ml of 0.5wt% ammonia solution, heat in a hot water bath for 20 minutes, shake to dissolve the folic acid, cool, dilute with water to the scale, shake well, filter, and take the filtrate as the test solution; take about 10mg of folic acid reference substance, accurately weigh, place in a 50ml volumetric bottle, add 0.5% ammonia solution to dilute to the scale, shake well, and use it as the reference solution. Test the folic acid content according to the following conditions: use octadecylsilane bonded silica gel as a filler; use phosphate buffer (pH6.3) as the mobile phase; and the detection wavelength is 254nm. The number of theoretical plates is not less than 1500 based on the folic acid peak. The results are shown in Table 8 below.

[0058] Table 8 Folic acid tablet mixing uniformity test results

[0059] .

[0060] Application Example 2

[0061] The samples prepared with different prescription compositions were compared with the 74th batch of reference preparations published by HMPA, marketed in the EU (marketed in France), trade name: SPECIAFOLDINE, licensee: MERUS LABS LUXCO S.à RL / MERUSLABS LUXCO Ⅱ S.à RL, specification 5 mg, batch number: 22FA458 and 23FA408 for in vitro dissolution comparison. The dissolution results at pH = 1.2 are shown in Table 9, and the dissolution results at pH = 5.0 are shown in Table 10. Dissolution method: blue method 100rpm, dissolution volume 900mL.

[0062] Table 9 Dissolution test under pH=1.2

[0063] .

[0064] Table 10 Dissolution test under pH=5.0

[0065] .

[0066] From the results of Tables 9 and 10, it can be seen that the evaluation results of the folic acid tablets prepared by the present invention in the in vitro dissolution test at pH=5.0 are similar to those of the reference tablet batches: 22FA458 and 23FA408, and both have good solubility. However, the folic acid tablets of the present invention have a significantly slowed dissolution in the in vitro dissolution at pH=1.2. This indicates that the folic acid tablets of the present invention dissolve less under the strongly acidic conditions of gastric juice (pH about 1.2), while the dissolution at the end of the small intestine (pH=4.5-5.5) is not affected, reaching a dissolution close to that of the reference 22FA458 and 23FA408.

[0067] Application Example 3

[0068] The stability test of the folic acid tablets of the above examples and comparative examples was carried out under high temperature 60±2°C and high humidity 75%±5%. The results are shown in Table 11 below.

[0069] Table 11 High temperature and high humidity stability test

[0070] .

[0071] It can be seen from Table 11 that the folic acid tablets prepared by the present invention have excellent stability under high temperature conditions, and the impurities meet the specified requirements. It can be seen that the present invention uses a compound of starches with different gelatinization degrees to simultaneously improve the dispersion uniformity of folic acid tablets, the dissolution problem under acidic conditions of pH=1-2, and the stability of folic acid tablets.

Claims

1. A folic acid tablet with improved stability and dissolution, characterized in that: Each 100 mg tablet contains the following ingredients: 0.4-5mg folic acid, 30-40mg calcium hydrogen phosphate, 25-30mg microcrystalline cellulose, 7-10mg low gelatinization degree starch, 15-20mg medium gelatinization degree starch, 2.2-3.5mg high gelatinization degree starch, 0.7-1mg colloidal silicon dioxide, 1-1.5mg stearate; the gelatinization degree of the low gelatinization degree starch is 10% to <25%, the gelatinization degree of the medium gelatinization degree starch is 25% to 40%, and the gelatinization degree of the high gelatinization degree starch is 70% to 100%.

2. The folic acid tablet with improved stability and dissolution according to claim 1, characterized in that: The low-gelatinization degree starch has a gelatinization degree of 10% to 15%, the medium-gelatinization degree starch has a gelatinization degree of 25% to 30%, and the high-gelatinization degree starch has a coking degree of 90% to 100%.

3. The folic acid tablet with improved stability and dissolution according to claim 1, wherein the microcrystalline cellulose is selected from at least one of PH-102 and PH-112; and the colloidal silicon dioxide has a specific surface area of ​​175 m 2 / g~225 m 2 / g; the calcium hydrogen phosphate is calcium hydrogen phosphate dihydrate, and the particle size D50 is 0.15-0.2nm.

4. The folic acid tablet with improved stability and dissolution according to claim 1, wherein the stearate is selected from at least one of magnesium stearate and calcium stearate.

5. The method for preparing the folic acid tablet with improved stability and dissolution according to any one of claims 1 to 4, characterized in that: The following steps are involved: Mix all materials evenly and then compress them into tablets.

6. The method for preparing the folic acid tablet with improved stability and dissolution according to any one of claims 1 to 4, characterized in that: The following steps are involved: Take 30-50wt% of stearate, low gelatinization degree starch, medium gelatinization degree starch, high gelatinization degree starch, and colloidal silicon dioxide and add them to a three-dimensional mixer, mix for 5-10 minutes, then add folic acid, calcium hydrogen phosphate, and microcrystalline cellulose, mix for 20-30 minutes, finally add the remaining stearate, continue mixing for 5-10 minutes, and tablet to obtain the product folic acid tablet.

7. The preparation method according to claim 6, characterized in that: The rotation speed of the three-dimensional mixer is 30-50Hz, and the hardness of the tablets after tableting is 20-50N.

8. The method for storing the folic acid compressed tablets with improved stability and dissolution according to any one of claims 1 to 4, characterized in that: The product is packaged in a light-proof bottle with a desiccant; the bottle cap of the bottle has a desiccant.

9. The storage method according to claim 8, characterized in that: The bottle is made of polypropylene.

10. Use of the folic acid compressed tablets with improved stability and dissolution according to any one of claims 1 to 4 in the preparation of drugs for treating anemia, developmental delay, leukopenia, and neural tube defects.