Progesterone enteric-coated tablet processing technology

Abstract

The invention discloses a progesterone enteric-coated tablet processing technology. The technology comprises the following steps: 1, preparing a tablet core; 2, coating an isolating layer; 3, coating an enteric-coated layer; and 4, coloring layer coating. According to the processing technology of the progesterone enteric-coated tablet, the overall technological steps, technological parameters in all the technological steps and the raw material formula are optimized, the steps are simple, operation is easy, the quality of all layers of coatings can be effectively controlled, the stability and consistency of the final product are ensured, the prepared progesterone enteric-coated tablet can stably release medicine in the intestinal tract, and the bioavailability of the product is improved. The absorption speed is high, and the medication comfort and compliance of a patient are improved, so that the requirements of clinical treatment are better met.

Description

Technical Field

[0001] This invention relates to a progesterone drug, and more particularly to a processing method for progesterone enteric-coated tablets. Background Technology

[0002] Progesterone is a type of progestin with a negative feedback regulatory effect. It can inhibit its own secretion and also inhibit the secretion of estrogen. In the body, it has a significant morphological effect on the endometrium stimulated by estrogen. It is essential for maintaining pregnancy and has a good therapeutic effect on amenorrhea in clinical practice. Capsules are generally absorbed faster than tablets, therefore, capsules are currently the most common dosage form for progesterone. For example, Chinese patent application CN112999187A, published on June 22, 2021, discloses a progesterone capsule and its preparation method. The progesterone capsule and preparation method include progesterone powder and capsule shell. The progesterone powder mainly includes: 15%-40% active ingredient progesterone, 10%-60% carrier glyceryl monostearate, 15%-25% acetone solvent, 1%-4% sodium octadecyl sulfate, 0.5%-1% micronized silica gel, 0.5%-1% magnesium stearate, 3%-15% starch, and 2%-10% sucrose. The capsule shell mainly includes: 15%-30% gelatin and 70%-85% starch. However, progesterone capsules are absorbed directly in the stomach, and the release rate is affected by the gastric transit time. At the same time, when the drug comes into direct contact with the gastric mucosa, it can irritate the stomach, leading to symptoms such as nausea and stomach discomfort. This reduces the patient's comfort and compliance with the medication. Summary of the Invention

[0003] The present invention addresses the aforementioned problems of existing progesterone capsules by providing a simple and highly operable processing method for progesterone enteric-coated tablets. The resulting progesterone enteric-coated tablets exhibit a stable drug release rate and rapid absorption, improving patient comfort and compliance, and better meeting clinical treatment needs.

[0004] To achieve the above objectives, the present invention adopts the following technical solution: A processing method for progesterone enteric-coated tablets according to the present invention includes the following steps: I. Preparation of wafer cores (a) Granulation (1) Weighing: Weigh the following raw materials in 100 parts by weight: 1.47 parts progesterone, 4.4 parts ethyl oleate, 17.58 parts polyethylene glycol 1000 vitamin E succinate, 1.47 parts benzyl alcohol, 0.1 parts sodium sulfite, 0.15 parts disodium ethylenediaminetetraacetate, 11.94 parts mannitol, 28.57 parts colloidal silica, 2.05 parts talc, 28.78 parts low-substituted hydroxypropyl cellulose, 1.99 parts povidone K30, and the balance magnesium stearate.

[0005] (2) Wet granulation: After mixing progesterone, ethyl oleate and benzyl alcohol, nitrogen gas is introduced under the liquid surface and heated. Stirring is carried out until the progesterone is completely dissolved. Sodium sulfite and disodium ethylenediaminetetraacetate are added and stirred. Polyethylene glycol 1000 vitamin E succinate is added and stirred evenly. Then, part of mannitol and part of colloidal silica are added. Wet granulation is carried out using a wet granulator to obtain progesterone wet granules.

[0006] (3) Dry granulation: The progesterone wet granules are mixed with a portion of mannitol, a portion of colloidal silica, polyvinyl ketone K30 and a portion of low-substituted hydroxypropyl cellulose and then granulated by a pulverizer and then granulated by a dry granulator to obtain progesterone dry granules.

[0007] (4) Total mixture: After mixing the progesterone dry particles with the remaining colloidal silica, talc and the remaining low-substituted hydroxypropyl cellulose evenly, magnesium stearate is added to obtain the total mixture particles.

[0008] (5) Tableting: Add the total mixed particles into the hopper of the tablet press, adjust the loading amount and perform the tableting operation to obtain tablet cores.

[0009] II. Insulation Layer Coating (1) Preparation of isolation layer coating solution: Weigh the following raw materials in 100 parts by weight: 40 parts of Opadry 03K19229, 20 parts of colloidal silica, and 40 parts of talc. Add Opadry 03K19229 to an appropriate amount of 75% ethanol solution and stir until completely dissolved. Then add colloidal silica and talc and stir evenly to obtain the isolation layer coating solution.

[0010] (2) Spray coating of the isolation layer: After preheating the tablet core, spray the isolation layer coating liquid, pre-dry, weigh the material, and then dry it until the isolation layer mass is 5-8% of the tablet core mass before discharging. The coating is done using a conventional coating pan.

[0011] III. Enteric Coating (1) Preparation of enteric coating solution: Weigh the following raw materials in 100 parts by weight: 32.61 parts of Eutrich L100, 32.61 parts of Eutrich S100, 19.61 parts of talc, 11.27 parts of triethyl citrate, and the balance TWEEN-80; Add an appropriate amount of 95% ethanol to Eutrich L100 and Eutrich S100 and stir until completely dissolved, then add talc, triethyl citrate and TWEEN-80, and stir evenly to obtain enteric coating solution.

[0012] (2) Spray coating of enteric coating: After preheating the tablet core with the isolation layer, spray the enteric coating liquid, pre-dry, weigh the material, and then dry it until the mass of the enteric coating is controlled to be 5.8~6.3% of the mass of the tablet core with the isolation layer, and then discharge the material.

[0013] IV. Color Coating (1) Preparation of color coating solution: Add Opadry 85F18422 to water and stir evenly to obtain color coating solution.

[0014] (2) Spray coating of coloring layer: After preheating the tablet core with the enteric coating layer, spray the coloring coating liquid, pre-dry, weigh the material, and then dry it until the mass of the coloring layer is greater than or equal to 1.5% of the mass of the tablet core with the enteric coating layer. Discharge the material to obtain progesterone enteric-coated tablets. The amount of progesterone enteric-coated tablets can be set as needed.

[0015] Preferably, in step (1) of step one, colloidal silica and mannitol are passed through a 30-mesh sieve; sodium sulfite and disodium ethylenediaminetetraacetate are passed through a 200-mesh sieve.

[0016] Preferably, in step (2) of step one, nitrogen gas is introduced below the liquid surface and heated to 50~70°C.

[0017] As a preferred option, in step (3) of step one, the feeding speed of the pulverizer is 6-8 Hz, the pulverizing speed is 5-7 Hz, the upper screen is 5.0 mm, and the lower screen is 1.5 mm; the bulk density of the progesterone dry granules obtained by granulation is greater than 0.51 g / ml.

[0018] Preferably, in step (5) of step one, the weight error range of the core is ±5%, the average hardness is ≥30N, and the brittleness is <1.0%.

[0019] As a preferred option, in step (2) of step two, the core is preheated to above 40°C; and pre-drying is maintained at a temperature of 35-40°C for 30 minutes.

[0020] As a preferred option, in step (2) of step three, the core of the film with the isolation layer is preheated to above 40°C; the pre-drying is maintained at a temperature of 30-35°C for 10 minutes.

[0021] As a preferred option, in step (2) of step four, the tablet core with the enteric coating is preheated to above 40°C; and pre-drying is maintained at a temperature of 35-40°C for 30 minutes.

[0022] Therefore, the present invention has the following beneficial effects: (1) The progesterone enteric-coated tablets processing technology of the present invention optimizes the overall process steps, process parameters and raw material formulations in each process step. Not only are the steps simple and easy to operate, but the quality of each coating layer can also be effectively controlled to ensure the stability and consistency of the final product. (2) The prepared progesterone enteric-coated tablets can stably release the drug in the intestine and absorb it quickly, which improves the patient's medication comfort and compliance, thereby better meeting the needs of clinical treatment. Detailed Implementation

[0023] The present invention will be further described below through specific embodiments.

[0024] Example 1 I. Preparation of wafer cores (a) Granulation (1) Weighing: Weigh the following raw materials based on a total weight of 100kg: 1.47kg progesterone, 4.4kg ethyl oleate, 17.58kg polyethylene glycol 1000 vitamin E succinate, 1.47kg benzyl alcohol, 0.1kg sodium sulfite, 0.15kg disodium EDTA, 11.94kg mannitol, 28.57kg colloidal silica, 2.05kg talc, 28.78kg low-substituted hydroxypropyl cellulose, 1.99kg povidone K30, and the balance magnesium stearate; among which colloidal silica and mannitol pass through a 30-mesh sieve; sodium sulfite and disodium EDTA pass through a 200-mesh sieve; (2) Wet granulation: After mixing progesterone, ethyl oleate and benzyl alcohol, nitrogen gas is introduced under the liquid surface and heated to 55°C. Stir until the progesterone is completely dissolved, add sodium sulfite and disodium ethylenediaminetetraacetate and stir; add polyethylene glycol 1000 vitamin E succinate and stir evenly, then add 2.93 kg mannitol and 13.92 kg colloidal silica, and perform wet granulation using a wet granulator to obtain progesterone wet granules; (3) Dry granulation: The progesterone wet granules are mixed with the remaining mannitol, 13.77 kg of colloidal silica, povidone K30 and 19.05 kg of low-substituted hydroxypropyl cellulose and then granulated by a pulverizer. The feeding speed of the pulverizer is 6 Hz, the pulverizing speed is 5 Hz, the upper screen is 5.0 mm and the lower screen is 1.5 mm. After granulation, the progesterone dry granules with a bulk density greater than 0.51 g / ml are obtained by a dry granulator. (4) Total mixture: After the progesterone dry granules are mixed evenly with the remaining colloidal silica, talc and the remaining low-substituted hydroxypropyl cellulose, magnesium stearate is added to obtain the total mixture granules. (5) Tableting: Add the total mixed particles into the hopper of the tablet press, adjust the loading amount and perform tableting to obtain tablet cores. The tablet weight error range of the tablet cores is ±5%, the average hardness is ≥30N, and the brittleness is <1.0%. II. Insulation Layer Coating (1) Preparation of isolation layer coating solution: Weigh the following raw materials based on a total weight of 100kg: 40kg of Opadry 03K19229, 20kg of colloidal silica, and 40kg of talc. Add Opadry 03K19229 to an appropriate amount of 75% ethanol solution and stir until completely dissolved. Then add colloidal silica and talc and stir evenly to obtain the isolation layer coating solution. (2) Spray coating of the isolation layer: After preheating the core to 45°C, spray the isolation layer coating liquid, maintain the temperature at 40°C for 30 minutes for pre-drying, discharge and weigh, and then dry until the mass of the isolation layer is % of the mass of the core before discharge; III. Enteric Coating (1) Preparation of enteric coating solution: Weigh the following raw materials based on a total weight of 100 kg: 32.61 kg of Euterich L100, 32.61 kg of Eutrich S100, 19.61 kg of talc, 11.27 kg of triethyl citrate, and the balance TWEEN-80; add an appropriate amount of 95% ethanol to Eutrich L100 and Eutrich S100 and stir until completely dissolved. Add talc, triethyl citrate and TWEEN-80, and stir evenly to obtain an enteric coating solution. (2) Spray coating of enteric coating: After preheating the tablet core with the isolation layer to 45°C, spray the enteric coating liquid and maintain the temperature at 30°C for 10 minutes for pre-drying. Weigh the material and dry it until the mass of the enteric coating is controlled to be 5.8% of the mass of the tablet core with the isolation layer. Discharge the material. IV. Color Coating (1) Preparation of color coating solution: Add Opadry 85F18422 to water and stir evenly to obtain color coating solution; (2) Spray coating of coloring layer: After preheating the tablet core with the enteric coating layer to 45°C, spray the coloring coating liquid and maintain it at 40°C for 30 minutes for pre-drying. Discharge and weigh the material, and then dry it until the weight of the coloring layer is 1.5% of the weight of the tablet core with the enteric coating layer. Discharge the material to obtain 25mg / tablet progesterone enteric-coated tablets.

[0025] The pharmacokinetic characteristics of progesterone and its metabolite allogestrinone were compared in healthy beagle dogs after oral administration of the test formulation progesterone tablets T (Example 1) and the reference formulation progesterone soft capsules R in a fasting state.

[0026] I. Test Drugs Test formulation T: Progesterone tablets (Example 1), specification: 25mg / tablet, batch number: S20220301, certificate holder: Zhejiang Shengbokang Pharmaceutical Co., Ltd.; administration method: oral (2 tablets / animal); storage conditions: store at room temperature (after opening, please store the drug in the original packaging bottle). All drugs of the same specification used in the test animals came from the same batch number.

[0027] Reference preparation R: Progesterone soft capsules (specification: 100 mg / capsule, batch number: 204591, license holder Besins Healthcare Benelux; production date: December 13, 2021; validity period: 36 months; content: 96.8%; administration method: oral administration (2 capsules / animal); storage condition: stored at room temperature, and the drugs of the same specification for the test animals are from the same batch number).

[0028] II. Test animals 8 Beagle dogs, male, weighing 9 - 12 kg, purchased from Hubei Yizhicheng Biotechnology Co., Ltd., animal production license number: SCXK(E)2021 - 0020, animal quality certificate number NO.42817300002083.

[0029] III. Test methods 8 healthy male Beagle dogs were used in a randomized two - period double - crossover trial design with a 7 - day washout period. They were given a single oral dose of either 50 mg of the test preparation progesterone tablets (specification: 25 mg / tablet, 2 tablets each time) or 200 mg of the reference preparation progesterone soft capsules (100 mg / capsule, 2 capsules each time), 2 (tablets / capsules) / time. Blood samples were collected from the cephalic vein on the medial side of the forelimb at 0 h (before dosing), and 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 8 h, 12 h, 24 h after dosing. The EDTA - K2 plasma progesterone and pregnenolone concentrations were determined by a validated LC - MS / MS method. The measured experimental data were analyzed using the non - compartmental model with Phoenix WinNonlin software (version 7.0) to calculate the pharmacokinetic parameters (C

[0031] , , , 1 / 2 , , z , , 0-∞ , , max , , <00XX000100>, 0-t ,

[0030] 、AUC 0-t 、AUC 0-∞ 、T max 、t 1 / 2 、λ z ), and the pharmacokinetic characteristics of progesterone and its metabolite pregnenolone in the test preparation and reference preparation were compared.

[0030] IV. Test results The pharmacokinetic parameter results of plasma progesterone and its metabolite pregnenolone in healthy Beagle dogs after fasting oral administration of the test preparation (50 mg) and reference preparation (200 mg) are shown in the following table: Main pharmacokinetic parameters of progesterone in plasma of Beagle dogs after fasting oral administration of the test preparation and reference preparation (Mean±SD(CV%), N = 8)

[0031] * T max Represented by the median (minimum, maximum). Key pharmacokinetic parameters of the metabolite allopregnenolone in plasma of beagle dogs after oral administration of the test and reference formulations on an empty stomach (Mean±SD(CV%), N=8)

[0032] * T max Represented by the median (minimum, maximum). The geometric mean and comparison of plasma progesterone and metabolite allopregnenolone pharmacokinetic parameters after oral administration of the test formulation (50 mg) and the reference formulation (200 mg) to healthy beagle dogs on an empty stomach are shown in the table below: Comparison of progesterone pharmacokinetic parameters after fasting oral administration of the test formulation and the reference formulation in beagle dogs (N=8)

[0033] Comparison of pharmacokinetic parameters of allogestrinone, a metabolite, after oral administration of the test and reference formulations to beagles on an empty stomach (N=8)

[0034] The pharmacokinetic parameters and geometric mean comparisons in the table above show that the Cmax of the 50mg test formulation (T) progesterone was 6.48 times that of the 200mg reference formulation (R), the AUC0-t was 2.68 times that of the reference formulation (R), and the Tmax (median 0.75h) was earlier than that of the reference formulation (median 2h). The Cmax of the metabolite allogestrinone was 3.11 times that of the reference formulation (R), the AUC0-t was comparable to that of the reference formulation (R), and the Tmax (median 0.75h) was earlier than that of the reference formulation (R) (median 2h). Compared with the 200mg reference formulation (R), the 50mg test formulation (T) significantly accelerated the absorption rate of progesterone and significantly increased its in vivo exposure, while there was no significant difference in the in vivo exposure of the metabolite allogestrinone. This indicates that the test formulation (T) can significantly improve the absorption of progesterone without increasing the exposure of the metabolite allogestrinone.

[0035] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A process for the preparation of enteric coated progesterone tablets, characterized in that, Comprising the following steps: I. Preparation of the core (1) Weighing: 1.47 parts of progesterone, 4.4 parts of ethyl oleate, 17.58 parts of polyethylene glycol 1000 vitamin E succinate, 1.47 parts of benzyl alcohol, 0.1 part of sodium sulfite, 0.15 part of disodium ethylenediaminetetraacetate, 11.94 parts of mannitol, 28.57 parts of colloidal silicon dioxide, 2.05 parts of talc, 28.78 parts of low-substituted hydroxypropyl cellulose, 1.99 parts of povidone K30, the rest is magnesium stearate, based on 100 parts by weight; (2) Wet granulation: progesterone, ethyl oleate and benzyl alcohol are mixed, then nitrogen is introduced under the liquid surface and heated, and stirred until progesterone is completely dissolved. Add sodium sulfite and disodium ethylenediaminetetraacetate and stir. After stirring evenly, add part of mannitol and part of colloidal silicon dioxide, and use a wet granulator for wet granulation to obtain progesterone wet granules; (3) Dry granulation: mix the progesterone wet granules with part of the mannitol, part of the colloidal silicon dioxide, povidone K30 and part of the low-substituted hydroxypropyl cellulose, then pass through a crushing and granulating machine for granulation. After granulation, use a dry granulator to obtain progesterone dry granules; (4) Total mixing: mix the progesterone dry granules with the remaining colloidal silicon dioxide, talc and remaining low-substituted hydroxypropyl cellulose evenly, then add magnesium stearate to obtain total mixed granules; (5) Tabletting: add the total mixed granules to the hopper of the tablet press, adjust the loading amount and perform tabletting operation to obtain the core; II. Isolation layer coating (1) Preparation of isolation layer coating liquid: 40 parts of Opadry 03K19229, 20 parts of colloidal silicon dioxide, 40 parts of talc, based on 100 parts by weight, are weighed. Add Opadry 03K19229 to an appropriate amount of 75% ethanol solution, stir until completely dissolved, then add colloidal silicon dioxide and talc, and stir evenly to obtain the isolation layer coating liquid; (2) Spray isolation layer: preheat the core, spray the isolation layer coating liquid, pre-dry, weigh the output, and dry to 5-8% of the mass of the core, then output; III. Enteric layer coating (1) Preparation of enteric layer coating liquid: 32.61 parts of Eudragit L100, 32.61 parts of Eudragit S100, 19.61 parts of talc, 11.27 parts of triethyl citrate, and the rest is TWEEN-80, based on 100 parts by weight, are weighed. Add an appropriate amount of 95% ethanol to Eudragit L100 and Eudragit S100 and stir until completely dissolved. Add talc, triethyl citrate and TWEEN-80 and stir evenly to obtain the enteric layer coating liquid; (2) Spray enteric layer: preheat the core coated with the isolation layer, spray the enteric layer coating liquid, pre-dry, weigh the output, and dry to control the mass of the enteric layer to be 5.8-6.3% of the mass of the core coated with the isolation layer, then output; IV. Coloring layer coating (1) Preparation of coloring layer coating liquid: add Opadry 85F18422 to water and stir evenly to obtain the coloring layer coating liquid; (2) Spray the color layer: after preheating the tablet core with enteric coating, spray the color coating liquid, pre-dry, weigh, dry until the mass of the color layer is greater than or equal to 1.5% of the mass of the tablet core with enteric coating, discharge, and obtain the progesterone enteric-coated tablet.

2. The process for preparing progesterone enteric coated tablet as claimed in claim 1 wherein, In step (1) of step one, the colloidal silicon dioxide and mannitol are passed through a 30-mesh sieve; the sodium sulfite and disodium ethylenediaminetetraacetate are passed through a 200-mesh sieve.

3. The process for preparing progesterone enteric coated tablet as claimed in claim 1 wherein, In step (2) of step one, nitrogen is passed under the liquid surface and heated to 50-70°C.

4. The process for preparing progesterone enteric coated tablet as claimed in claim 1 wherein, In step (3) of step one, the feeding speed of the crushing and sizing machine is 6-8HZ, the crushing speed is 5-7HZ, the upper sieve mesh is 5.0mm, and the lower sieve mesh is 1.5mm; the bulk density of the progesterone dry granules obtained by granulation is greater than 0.51g / ml.

5. The process for preparing progesterone enteric coated tablet as claimed in claim 1 wherein, In step (5) of step one, the tablet core has a tablet weight error range of ±5%, an average hardness of ≥30N, and a friability of <1.0%.

6. The process for preparing progesterone enteric coated tablet as claimed in claim 1 wherein, In step (2) of step two, the tablet core is preheated to above 40°C; the pre-drying is performed at a temperature of 35-40°C for 30min.

7. The process for preparing progesterone enteric coated tablet as claimed in claim 1 wherein, In step (2) of step three, the tablet core with isolation layer is preheated to above 40°C; the pre-drying is performed at a temperature of 30-35°C for 10min.

8. The process for preparing progesterone enteric coated tablet according to claim 1 or 7, wherein, In step (2) of step four, the tablet core with enteric coating is preheated to above 40°C; the pre-drying is performed at a temperature of 35-40°C for 30min.

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