Dotenorad tablet capable of being efficiently dissolved out and preparation method of dotenorad tablet

Abstract

The invention discloses an efficient-dissolution dotenorad tablet and a preparation method thereof, and relates to the technical field of tablet preparation. The tablet consists of 5-20 parts of a dotenorad active component, 10-30 parts of a disintegrating agent, 40-70 parts of a filling agent, 0.5-5 parts of a surfactant, 0.5-3 parts of a lubricant, 1-5 parts of an adhesive and 0.5-1 part of an antioxidant. The preparation method comprises the following steps: premixing active components and auxiliary materials, carrying out high-shear wet granulation to form porous structure particles, carrying out precise temperature-control drying through a fluidized bed, carrying out micronization treatment to regulate the specific surface area of the particles, and finally, carrying out high-pressure tablet forming through a magnesium stearate / aerosil compound lubrication system. The dissolution rate of the tablet in a medium with the pH value of 6.8 for 15 minutes reaches 85% or above, meanwhile, long-term stability is achieved by inhibiting oxidative degradation, and the tablet has the dual advantages of quick effect taking and stable storage.

Description

Technical Field

[0001] The present invention relates to the technical field of tablet preparation, and particularly relates to a multi-ternolol tablet with high dissolution rate and its preparation method. Background Art

[0002] In the preparation of multi-ternolol tablets, there are dual challenges of dissolution rate and stability. In the prior art, the dissolution rate of multi-ternolol tablets is often slow due to poor drug solubility, and the dissolution rate at 15 minutes only reaches 60-70%, making it difficult to take effect quickly. The reason is that there are multiple hydrophobic groups in the molecular structure of multi-ternolol, which limits its solubility in the gastrointestinal physiological environment and affects the rapid absorption of the drug.

[0003] In terms of antioxidant properties, multi-ternolol contains a conjugated double bond structure that is easily oxidized, and it is prone to oxidative degradation during storage in the presence of conventional tablet excipients. Traditional antioxidants such as vitamin E have poor compatibility with multi-ternolol and are easily inactivated due to high temperature and mechanical friction during the tableting process, resulting in a 3-5% decrease in content after a 6-month accelerated test, affecting the stability of clinical efficacy.

[0004] Existing tablet preparation processes mostly use dry granulation or low-humidity granulation, which cannot effectively break the original crystal lattice structure of the drug, resulting in low particle porosity and difficult penetration of the dissolution medium. At the same time, when the dosage of conventional lubricants exceeds 1%, the dissolution rate will be significantly reduced, and it is difficult to balance lubricity and dissolution performance in the prior art. In addition, when the hardness of traditional tablets is controlled at 30-40 N, lamination is likely to occur, and increasing the hardness will lead to a decrease in the dissolution rate, forming a technical contradiction. These problems make it difficult for existing multi-ternolol tablets to meet the dual clinical requirements of rapid onset and long-term stability, and it is urgent to develop new formulations and preparation processes to overcome the above defects. Summary of the Invention

[0005] The purpose of the present invention is to provide a multi-ternolol tablet with high dissolution rate that combines rapid dissolution and long-term stability and its preparation method in view of the problems existing in the prior art.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is: a multi-ternolol tablet with high dissolution rate, which is composed of the following mass ratio components: 5-20 parts of multi-ternolol active ingredient, 10-30 parts of disintegrant, 40-70 parts of filler, 0.5-5 parts of surfactant, 0.5-3 parts of lubricant, 1-5 parts of binder, 0.5-1 part of antioxidant;

[0007] Among them, the lubricant is a compound of magnesium stearate and colloidal silica (1-3):1;

[0008] Among them, the disintegrant is a compound of croscarmellose sodium and low-substituted hydroxypropyl cellulose in the ratio of (1-3):1;

[0009] The structure of the antioxidant is as follows:

[0010] Furthermore, the surfactant is sodium dodecyl sulfate or polysorbate 80.

[0011] Furthermore, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the two is (1 - 2):1.

[0012] Furthermore, the binder is an aqueous solution of hypromellose with a concentration of 3 - 8% w / v.

[0013] The preparation process of the highly dissolvable dolutegravir tablets described above includes the following steps:

[0014] S1. Mix the dolutegravir active ingredient, disintegrant, filler, surfactant, and antioxidant to obtain a premixed powder;

[0015] S2. Add the solution of the binder to the premixed powder, perform wet granulation, with a stirring speed of 200 - 500 rpm and a shearing time of 3 - 8 minutes to obtain wet granules;

[0016] S3. Dry the wet granules in a fluidized bed until the moisture content ≤ 2% to obtain dry granules;

[0017] S4. Total mix the dry granules and the lubricant and then press them into tablets to obtain dolutegravir tablets.

[0018] Furthermore, the end - point control of the wet granulation is: the particle size D50 is 100 - 300 μm, and the particle porosity is 15 - 35%.

[0019] Furthermore, the fluidized bed drying temperature is 40 - 60 °C, the air inlet volume is 20 - 40 m 3 / h, and the drying time is 20 - 40 minutes.

[0020] Furthermore, it also includes performing micronization treatment on the dry granules before tableting in S4, and controlling the specific surface area of the particles to be 0.8 - 1.5 m 2 / g.

[0021] Furthermore, the hardness of the tablets after tableting is controlled at 50 - 100 N.

[0022] A highly dissolvable dolutegravir tablet has a dissolution rate of ≥ 85% in pH 6.8 phosphate buffer solution within 15 minutes and ≥ 95% within 30 minutes.

[0023] The antioxidant described in the present invention interrupts the free - radical chain reaction by providing hydrogen atoms and forms specific protection for the conjugated double bonds in the dolutegravir molecule. The antioxidant molecule can chelate the residual Fe 3+ / Cu 2+Metal catalysts such as etc. reduce the oxidation degradation rate initiated by the Fenton reaction. Sodium dodecyl sulfate forms micelles in the solution, loading antioxidants into the hydrophobic core of the micelles to increase the local antioxidant concentration. When sodium carboxymethylcellulose cross-linked and hypromellose are compounded at a ratio of 2:1, a three-dimensional swelling network is formed, enabling the antioxidants to migrate directionally to the drug-solvent interface during the disintegration process.

[0024] The disintegration principle described in the present invention is based on the spatiotemporal synergistic effect of the biphasic disintegrant and the process optimization synergistic mechanism: a three-dimensional penetration channel is established through the rapid swelling of sodium carboxymethylcellulose cross-linked, combined with the gradient hydration of hypromellose to maintain the continuous disintegration power. Supplementary to this are the core-shell structure formed by high-shear granulation, the open pores regulated by dry phase change, and the rapid wetting mediated by surfactants, jointly achieving the efficient disintegration of the internal binding force of the tablet. This system significantly improves the disintegration efficiency through the multi-dimensional synergy of physical swelling, chemical penetration, interfacial stress matching, and microstructure optimization, ensuring rapid drug dissolution.

[0025] Compared with the prior art, the beneficial effects of the present invention are:

[0026] 1. Significantly improve the drug dissolution efficiency: Through the synergistic effect of specific disintegrant compounding (sodium carboxymethylcellulose cross-linked / hypromellose) and surfactants, combined with the optimization of the wet granulation process, rapid disintegration of the tablet and efficient drug dissolution are achieved, meeting the clinical requirement for rapid onset.

[0027] 2. Long-term antioxidant protection and enhanced stability: Adopting a new antioxidant molecular structure and surfactant micelle encapsulation technology to precisely inhibit the oxidative degradation of the active ingredient of the drug, ensuring the stable content of the tablet during long-term storage and extending the expiration date.

[0028] 3. Synergistic optimization of the process and formulation: Innovating the lubricant compounding system and high-pressure tablet process design to avoid loss of dissolution performance while ensuring the mechanical strength of the tablet; combined with the regulation of fluidized bed drying parameters to achieve efficient and stable industrial production. Specific Embodiments

[0029] Next, the technical solutions of the present invention will be clearly and completely described in conjunction with the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art without creative efforts based on the embodiments of the present invention belong to the scope of protection of the present invention.

[0030] Preparation Example 1

[0031] Synthesis of antioxidants:

[0032]

[0033] Under a nitrogen atmosphere, 20 g of raw material 1, 10.84 g of raw material 2, 6.20 g of concentrated sulfuric acid and 200 g of toluene were added to the reaction system. The reaction system was heated to 80 °C and stirred for 6 h. After the reaction ended, the pH of the system was adjusted to neutral with 0.1 mol / L aqueous sodium bicarbonate solution. 200 g of water was added, and the mixture was shaken and separated. The organic phase was retained, dried with magnesium sulfate, the organic phase was rotary evaporated, purified by silica gel column chromatography, using petroleum ether / ethyl acetate as the eluent, and the solution was rotary evaporated to obtain 25.16 g of antioxidant, MS(MS+1): 714.

[0034] Of the antioxidant 1 HNMR (deuterochloroform) δ 7.95 - 7.87 (m, 2H), 7.87 - 7.79 (m, 1H), 7.74 - 7.67 (m, 2H), 7.60 (t, 1H), 7.53 - 7.42 (m, 2H), 7.40 - 7.33 (m, 1H), 7.23 (s, 2H), 7.07 - 6.94 (m, 2H), 6.52 (s, 1H), 5.17 (p, 1H), 4.98 (p, 1H), 3.83 (s, 3H), 3.05 - 2.93 (m, 3H), 2.83 (m, 2H), 2.75 - 2.65 (m, 4H), 2.57 - 2.44 (m, 5H), 2.17 (m, 2H), 2.03 (m, 1H), 1.77 (m, 1H), 1.43 (s, 3H), 1.31 (s, 3H).

[0035] Performance test of the preparation example:

[0036] 1. The biological toxicity of the preparation example was tested by the MTT colorimetric method. The specific steps are as follows:

[0037] HepG2 cells were cultured in a saturated humidity incubator at 37 °C and 5% CO2, and the culture medium was DMEM. Among them, Dulbecco’s Modified Eagle Medium (DMEM) culture medium was purchased from Wuhan Punosai Life Science Co., Ltd.; the liver cancer cell line HepG2 was purchased from the Shanghai Institute of Cell Biology, Chinese Academy of Sciences. Then, in a 96-well plate, 5×10 3 cells were seeded at 180 μL per well. Then, the cells were cultured with a series of concentrations of the compound prepared in the preparation example at 37 °C for 48 h, and then 20 μL of MTT solution (5 mg / mL) was added and cultured for 4 h. Then, all the solutions were removed, and 150 μL of DMSO was added to each well to dissolve the formed formazan crystals. After shaking in a constant temperature water bath shaker (37 °C, 100 rpm) for 10 min, the absorbance value at 490 nm was measured, and the cell growth inhibition rate was calculated using the following formula.

[0038] The calculation formula of cell growth inhibition rate is:

[0039] In the concentration range of 10-100 μM, the growth inhibition rate of HepG2 cells treated with stabilizers was less than (2.1±0.2)%, indicating that the cells were non-toxic.

[0040] 2. Evaluation of the in vitro antioxidant activity of the compounds prepared in the preparation examples The in vitro antioxidant capacity of the compounds prepared in the preparation examples was determined by the DPPH method and ABTS method described in GB / T 39100-2020. The results were as follows: IC 50 IC value for scavenging ABTS free radicals: 0.8 μM 50 is: 1.5μM.

[0041] Example 1

[0042] Preparation of a highly dissolving polytinol tablet:

[0043] S1. The polytinol active ingredient (5 parts), disintegrant (crosslinked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose in a ratio of 3:1, 10 parts), filler (a mixture of microcrystalline cellulose and mannitol in a mass ratio of 1:1, 40 parts), surfactant (sodium lauryl sulfate, 0.5 parts), antioxidant (prepared in Preparation Example 1, 0.5 parts) are prepared to obtain a premixed powder;

[0044] S2. Add the binder (hydroxypropyl methylcellulose aqueous solution, concentration 8% w / v, 1 part) solution to the premixed powder, adopt wet granulation, stirring speed 200-500 rpm, shear time 3-8 minutes, to obtain wet granules (particle size D50 is 300 μm, particle porosity 35%);

[0045] S3. The wet granules are dried in a fluidized bed (drying temperature is 60°C, air volume is 40m 3 / h, drying time 40 minutes) until the moisture content is ≤ 2% to obtain dry granules;

[0046] S4. Dry particles (the dry particles are micronized and the particle specific surface area is controlled to be 1.5m 2 / g) and the lubricant (magnesium stearate and micro-powder silica gel in a ratio of 3:1, 0.5 parts) were mixed and tableted to obtain dotinorel tablets (the tablet hardness was controlled at 100N).

[0047] Example 2

[0048] Preparation of a highly dissolving polytinol tablet:

[0049] S1. Mix the multi-ternolol active ingredient (5 parts), disintegrant (a 3:1 compound of cross-linked carboxymethyl cellulose sodium and low-substituted hydroxypropyl cellulose, 30 parts), filler (a mixture of microcrystalline cellulose and mannitol with a mass ratio of 1:1, 70 parts), surfactant (sodium dodecyl sulfate, 5 parts), and antioxidant (prepared in Preparation Example 1, 1 part) to obtain a premixed powder;

[0050] S2. Add the solution of the binder (hydroxypropyl methylcellulose aqueous solution with a concentration of 8% w / v, 5 parts) to the premixed powder, and granulate by wet granulation at a stirring speed of 200 - 500 rpm for a shearing time of 3 - 8 minutes to obtain wet granules (with a particle size D50 of 300 μm and a particle porosity of 35%);

[0051] S3. Dry the wet granules in a fluidized bed dryer (at a drying temperature of 60 °C, an air inlet volume of 40 m 3 / h and a drying time of 40 minutes) until the moisture content is ≤ 2% to obtain dry granules;

[0052] S4. Total mix the dry granules (after micronization of the dry granules with a controlled particle specific surface area of 1.5 m 2 / g) with the lubricant (a 3:1 compound of magnesium stearate and colloidal silicon dioxide, 3 parts) and then press tablets to obtain multi-ternolol tablets (with the tablet hardness controlled at 100 N).

[0053] Example 3

[0054] Preparation of a multi-ternolol tablet with high dissolution rate:

[0055] S1. Mix the multi-ternolol active ingredient (5 parts), disintegrant (a 3:1 compound of cross-linked carboxymethyl cellulose sodium and low-substituted hydroxypropyl cellulose, 15 parts), filler (a mixture of microcrystalline cellulose and mannitol with a mass ratio of 1:1, 55 parts), surfactant (sodium dodecyl sulfate, 2.5 parts), and antioxidant (prepared in Preparation Example 1, 0.75 part) to obtain a premixed powder;

[0056] S2. Add the solution of the binder (hydroxypropyl methylcellulose aqueous solution with a concentration of 8% w / v, 2.5 parts) to the premixed powder, and granulate by wet granulation at a stirring speed of 200 - 500 rpm for a shearing time of 3 - 8 minutes to obtain wet granules (with a particle size D50 of 300 μm and a particle porosity of 35%);

[0057] S3. Dry the wet granules in a fluidized bed dryer (at a drying temperature of 60 °C, an air inlet volume of 40 m 3 / h and a drying time of 40 minutes) until the moisture content is ≤ 2% to obtain dry granules;

[0058] S4. Dry granules (after micronization of the dry granules with a controlled particle specific surface area of 1.5 m2 After mixing with the lubricant (a 3:1 compound of magnesium stearate and colloidal silicon dioxide, 1.5 parts) and then tabletting, tenofovir tablets are obtained (the tablet hardness is controlled at 100 N).

[0059] Comparative Example 1

[0060] Referring to the preparation method of Example 1, the antioxidant therein is not added, and the rest is the same as that of Example 1.

[0061] Comparative Example 2

[0062] Referring to the preparation method of Example 1, the disintegrant therein is replaced with croscarmellose sodium, and the rest is the same as that of Example 1.

[0063] Performance test:

[0064] It is carried out in pH 6.8 phosphate buffer solution (900 mL, 37 ± 0.5 °C). The second method (paddle method) for dissolution determination in the Chinese Pharmacopoeia (2020 edition) is adopted, the rotation speed is 50 rpm, and after sampling, it is filtered through a 0.45 μm filter membrane, and the tenofovir content is determined by HPLC method.

[0065] Group 15-minute dissolution rate 30-minute dissolution rate Disintegration time (s) Porosity (%) Example 1 89.2±1.3％ 97.5±0.8％ 42±3 33.5±1.2 Example 2 86.7±1.1％ 96.8±0.9％ 38±2 34.8±0.9 Example 3 88.5±1.5％ 97.1±1.2％ 40±2 34.2±1.1 Comparative Example 1 85.9±1.4％ 93.3±1.0％ 48±3 30.8±1.3 Comparative Example 2 72.3±2.1％ 88.6±1.7％ 85±5 28.4±1.5

[0066] Accelerated stability test, at 40 °C ± 2 °C / 75% RH ± 5%, aluminum-plastic blister packaging, sampling cycle: 0, 1, 3, 6 months:

[0067] Group 0 month 1 month 3 months 6 months Example 1 100.0％ 99.8％ 99.5％ 99.2％ Example 2 99.9％ 99.6％ 99.3％ 98.9％ Example 3 100.1％ 99.7％ 99.4％ 99.0％ Comparative Example 1 99.8％ 98.2％ 96.4％ 94.5％ Comparative Example 2 99.7％ 97.5％ 95.1％ 92.3％

[0068] Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. An improved dissolution of Doravirine tablets, characterized in that, It consists of the following parts by mass: 5 - 20 parts of the active ingredient of dolutegravir, 10 - 30 parts of disintegrant, 40 - 70 parts of filler, 0.5 - 5 parts of surfactant, 0.5 - 3 parts of lubricant, 1 - 5 parts of binder, and 0.5 - 1 part of antioxidant; Among them, the lubricant is a compound of magnesium stearate and colloidal silicon dioxide in a ratio of (1 - 3):1; Among them, the disintegrant is a compound of croscarmellose sodium and low-substituted hydroxypropyl cellulose in a ratio of (1 - 3):1; The structure of the antioxidant is as follows:

2. The multi - tenofovir tablets with high - efficiency dissolution according to claim 1, characterized in that, The surfactant is sodium dodecyl sulfate or polysorbate 80.

3. An efficient dissolution Dutogliptin tablet according to claim 1, characterized in that, The filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the two is (1 - 2):

1.

4. The multi - tenofovir tablets with high - efficiency dissolution according to claim 1, characterized in that, The binder is an aqueous solution of hydroxypropyl methylcellulose with a concentration of 3 - 8% w / v.

5. The preparation process of the multi - tenofovir tablets with high dissolution rate according to any one of claims 1 - 4, characterized in that, It includes the following steps: S1. Mix the active ingredient of dolutegravir, disintegrant, filler, surfactant, and antioxidant to obtain a premixed powder; S2. Add the solution of the binder to the premixed powder, perform wet granulation, with a stirring speed of 200 - 500 rpm and a shearing time of 3 - 8 minutes to obtain wet granules; S3. Dry the wet granules in a fluidized bed until the moisture content ≤ 2% to obtain dry granules; S4. Mix the dry granules with the lubricant and then press them into tablets to obtain dolutegravir tablets.

6. The preparation process of the multi - tenofovir tablets with high - efficiency dissolution according to claim 5, characterized in that, The end-point control of the wet granulation is: the particle size D50 is 100 - 300 μm, and the particle porosity is 15 - 35%.

7. The preparation process of the multi - tenofovir tablets with high - efficiency dissolution according to claim 5, characterized in that, The fluidized bed drying temperature is 40 - 60 °C, the air intake is 20 - 40 m 3 / h, and the drying time is 20 - 40 minutes.

8. The preparation process of the multi-tenorex tablets with high dissolution efficiency according to claim 5, characterized in that, It also includes micronizing the dry granules before tabletting as described in S4, and controlling the specific surface area of the granules to be 0.8 - 1.5 m 2 / g.

9. The preparation process of the multi - tenofovir tablets with high - efficiency dissolution according to claim 5, characterized in that, The hardness of the tablets after pressing is controlled at 50 - 100 N.

10. The multi - tenofovir tablets with high dissolution rate according to any one of claims 1 - 4, characterized in that, Its dissolution rate in pH 6.8 phosphate buffer solution is ≥ 85% at 15 minutes and ≥ 95% at 30 minutes.

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