A minocycline hydrochloride capsule and a method for preparing the same

Abstract

The application discloses a kind of minocycline hydrochloride capsules and preparation method thereof, belong to pharmaceutical preparation technical field.The capsule is composed of minocycline hydrochloride composition and hollow capsule, and the minocycline hydrochloride composition includes minocycline hydrochloride, hydroxypropyl-beta-cyclodextrin inclusion carrier, freeze-drying protective agent, hollow calcium carbonate microspheres light filling agent and sodium stearyl fumarate lubricant.Hollow calcium carbonate microspheres are prepared by a specific method, with low density, high porosity and fast disintegration characteristics, which can improve the powder flowability and drug dissolution rate.Preparation method includes dissolving inclusion carrier and freeze-drying protective agent in ice water, adding crosslinking enhancer, minocycline hydrochloride and hollow calcium carbonate microspheres, crushing after freeze-drying and filling into hollow capsule.The application solves the impurity generation problem caused by high temperature, high humidity or organic solvent in the prior art, significantly improves the stability, dissolution rate and bioavailability of the drug.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a minocycline hydrochloride capsule and a preparation method thereof. BACKGROUND

[0002] As a heat-sensitive antibiotic of the tetracycline class, minocycline hydrochloride has important value in the treatment of infectious diseases, but its molecular structure is prone to epimerization to generate toxic impurity epiminocycline at high temperature (40℃), high humidity (RH≥75%) or contact with organic solvents such as ethanol. This impurity not only reduces the antibacterial activity, but also may cause adverse reactions such as allergy, so the control of the wet and hot environment and the solvent during preparation is the core challenge to ensure the quality of the drug. At present, the industrial production of minocycline hydrochloride capsules faces the dual problems of process stability and impurity control, and the traditional preparation technology cannot meet the requirements of modern preparations for safety and effectiveness.

[0003] The existing wet granulation / coating process has significant defects: the use of organic solvents such as ethanol can destroy the crystal structure of the drug and promote molecular isomerization, and the drying process needs to maintain a high temperature environment of >40℃ (such as 60-80℃ hot air drying), which further accelerates the generation of epiminocycline. Although the powder direct filling process avoids the influence of high temperature, it relies on pregelatinized starch to improve the flowability, but the drug stability is insufficient in a high humidity environment (RH 75%), and the total impurity content increases; at the same time, its dissolution behavior deviates from the reference preparation, making it difficult to ensure the consistency of clinical efficacy.

[0004] The limitations of fillers further restrict the development of existing technologies: corn starch has poor flowability, resulting in unqualified content uniformity of the capsule contents; although pregelatinized starch can improve flowability, it cannot isolate the drug from external moisture, and cannot solve the problem of chemical degradation in a high humidity environment. In addition, the traditional excipient system lacks the ability to regulate the microenvironment of the drug, and cannot form an effective protective barrier during preparation and storage, resulting in a generally short shelf life of capsules prepared by existing processes, and significant quality fluctuations between batches, which urgently needs to be addressed through excipient innovation and process optimization to achieve stable preparation of heat-sensitive drugs.

[0005] Therefore, in view of the limitations of the above-mentioned related technologies, it is urgent to develop a minocycline hydrochloride capsule and a preparation method thereof. SUMMARY

[0006] Therefore, the purpose of the present application is to provide a minocycline hydrochloride capsule and a preparation method thereof, which can solve the problem of the conversion of minocycline hydrochloride to epiminocycline impurity caused by high temperature, high humidity or organic solvents in the prior art, and improve the flowability, content uniformity and stability of the preparation.

[0007] The purpose of the present application can be achieved by the following technical solutions:

[0008] The first aspect of the present application provides a minocycline hydrochloride capsule, which is composed of a minocycline hydrochloride composition and a hollow capsule, wherein the minocycline hydrochloride composition comprises the following components in the following proportions: minocycline hydrochloride 18-25 parts, inclusion carrier 20-30 parts, freeze-drying protective agent 8-16 parts, light filler 32-36 parts, cross-linking reinforcing agent 1.4-2.1 parts, flow aid 1-2 parts, and lubricant 1-2 parts.

[0009] Preferably, the light filler is hollow calcium carbonate microspheres, and the preparation method of the hollow calcium carbonate microspheres is as follows:

[0010] A1: Add trehalose to deionized water, add tricalcium phosphate, and stir to form a phosphated sugar template solution;

[0011] A2: Add a phase separation agent to the phosphated sugar template solution, heat to melt the phase separation agent, quickly pour into an ice ethanol bath for quenching, after quenching, filter to obtain trehalose-PEG phase separation gel balls;

[0012] A3: Immerse the trehalose-PEG phase separation gel balls in a CaCl2 solution, stir, transfer to a Na2CO3 solution, and react to form composite microspheres;

[0013] A4: Immerse the composite microspheres in an aqueous citric acid solution, stir, filter to obtain hollow calcium carbonate microspheres.

[0014] Preferably, the temperature of the deionized water in A1 is 60-68°C.

[0015] Preferably, the specific steps of A2 are as follows: add a phase separation agent to the phosphated sugar template solution, heat to 78-85°C to melt the phase separation agent, quickly pour into an ethanol bath at -20 to -25°C for quenching, after quenching, filter to obtain trehalose-PEG phase separation gel balls.

[0016] Preferably, the specific steps of A3 are as follows: immerse the trehalose-PEG phase separation gel balls in a CaCl2 solution, stir at 0-2°C for 8-10h, transfer to a Na2CO3 solution, react at 5-8°C for 2-5h, filter to obtain composite microspheres.

[0017] Preferably, the specific steps of A4 are as follows: immerse the composite microspheres in an aqueous citric acid solution, stir at 60-70°C for 10-15min at a stirring speed of 100-160rpm, filter, and vacuum dry at 60-80°C for 4-6h to obtain hollow calcium carbonate microspheres.

[0018] Preferably, the average outer diameter of the hollow calcium carbonate microspheres is 127-158 μm, and the average wall thickness is 12.3-16.8 μm.

[0019] Preferably, the phase separation agent is any one of PEG-4000, PEG-6000 and PEG-8000.

[0020] Preferably, in the preparation method of the hollow calcium carbonate microspheres, the weight fractions of trehalose, deionized water, tricalcium phosphate, phase separation agent, CaCl2 solution, Na2CO3 solution and citric acid aqueous solution are as follows: trehalose 20-24 parts, deionized water 300-360 parts, tricalcium phosphate 2-4 parts, phase separation agent 12-16 parts, CaCl2 solution 160-200 parts, Na2CO3 solution 160-200 parts, and citric acid aqueous solution 340-600 parts.

[0021] Preferably, the concentration of the CaCl2 solution is 0.3-0.8 mol / L.

[0022] Preferably, the concentration of the Na2CO3 solution is 0.3-0.8 mol / L.

[0023] Preferably, the volume ratio of citric acid to water in the citric acid aqueous solution is 1:10-20.

[0024] Preferably, the lyophilization protective agent is composed of mannitol and trehalose, and the mass ratio of the mannitol to the trehalose is 5:3-5.

[0025] Preferably, the inclusion carrier is hydroxypropyl-β-cyclodextrin, the flow aid is colloidal silicon dioxide, and the lubricant is sodium stearyl fumarate.

[0026] Preferably, the primary particle size of the colloidal silicon dioxide is 10-15 nm.

[0027] Another aspect of the present application provides a preparation method of minocycline hydrochloride capsules, which comprises the following preparation steps:

[0028] Step S1: the inclusion carrier, lyophilization protective agent and deionized water are stirred until clear, the cross-linking enhancer and light filler are added and stirred to react, the minocycline hydrochloride is added, and the mixture is stirred uniformly under cooling and light shielding to obtain a cross-linked inclusion solution;

[0029] Step S2: the cross-linked inclusion solution is freeze-dried to obtain a porous freeze-dried block, the porous freeze-dried block is crushed by an airflow crusher to obtain a cross-linked inclusion powder, the cross-linked inclusion powder, flow aid and lubricant are mixed uniformly to obtain a minocycline hydrochloride composition, and the minocycline hydrochloride composition is filled into a hollow capsule to obtain a minocycline hydrochloride capsule.

[0030] Preferably, the specific steps of step S1 are: adding the inclusion carrier, the freeze-drying protective agent into deionized water, stirring until clear, adding the cross-linking enhancer and the light filler, stirring at 60-80 DEG C for 45-65 min, cooling to 0-5 DEG C, adding minocycline hydrochloride, stirring in the dark for 20-40 min, to obtain a cross-linked inclusion solution.

[0031] Preferably, in step S1, the mass ratio of the inclusion carrier to deionized water is 1:10.

[0032] Preferably, the cross-linking enhancer consists of tannic acid and epigallocatechin gallate, and the mass ratio of tannic acid to epigallocatechin gallate is 0.9-1.3:0.5-0.8.

[0033] Preferably, the particle size distribution characteristics of the cross-linked inclusion powder are D 90 between 300-500 mu m.

[0034] Preferably, the freeze-drying conditions are: drying at -20 to -30 DEG C for 48-60 h, and drying at 15 to 20 DEG C for 12-16 h.

[0035] Preferably, the hollow capsule is a hypromellose hollow capsule.

[0036] Preferably, the minocycline hydrochloride capsule has a controlled loading difference of ±3%, and the target loading is 303.5 mg / capsule.

[0037] The beneficial effects of the present application are:

[0038] 1. The present application uses hollow calcium carbonate microspheres as a light filler, which significantly improves the flowability and content uniformity of the powder due to its low density and high porosity characteristics. The ultra-light characteristics and ultra-low friction flowability of the hollow calcium carbonate microspheres significantly reduce the repose angle of the powder, making it extremely flowable and suitable for high-speed filling. At the same time, this filler ensures the content uniformity (RSD value meets the standard), solving the problem of poor flowability and uneven mixing of traditional fillers.

[0039] 2. The present application realizes the customization of the dissolution rate of minocycline hydrochloride by controlling the wall thickness of the hollow calcium carbonate microspheres. Hollow calcium carbonate microspheres can quickly disintegrate under acidic conditions, promoting the release of minocycline hydrochloride. Customized dissolution behavior not only improves the bioavailability of minocycline hydrochloride, but also ensures the consistency of clinical efficacy.

[0040] 3、The application significantly improves the dissolution rate and bioavailability of the drug through the synergistic effect of the cyclodextrin inclusion technology and the hollow calcium carbonate microspheres. The inclusion effect of hydroxypropyl-beta-cyclodextrin not only protects the drug molecules, but also realizes the rapid release of minocycline hydrochloride through the rapid disintegration characteristics of the hollow calcium carbonate microspheres, improves the absorption efficiency of minocycline hydrochloride in the body, and thus enhances the bioavailability of minocycline hydrochloride. DETAILED DESCRIPTION

[0041] The technical solutions in the embodiments of the application will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the application.

[0042] The primary particle size of colloidal silicon dioxide used in the embodiments of the application is 10nm-15nm.

[0043] Embodiment 1

[0044] A preparation method of a minocycline hydrochloride capsule, comprising the following preparation steps:

[0045] S1: 20 parts of trehalose are dissolved in 60℃ 300 parts of deionized water, 2 parts of tricalcium phosphate are added, and stirring is uniformly performed to form a phosphatized sugar template solution.

[0046] S2: 12 parts of PEG-4000 are added to the phosphatized sugar template solution, the temperature is raised to 78℃, the PEG-4000 is melted, and then the melted PEG-4000 is quickly poured into an ethanol bath at -20℃ for quenching. After quenching, filtration is performed to obtain trehalose-PEG phase separation gel balls.

[0047] S3: The trehalose-PEG phase separation gel balls are immersed in 160 parts of 0.3mol / L CaCl2 solution, stirring is performed at 0℃ for 10h, and then the trehalose-PEG phase separation gel balls are transferred to 160 parts of 0.3mol / L Na2CO3 solution, reaction is performed at 5℃ for 5h, and then filtration is performed to obtain composite microspheres.

[0048] S4: The composite microspheres are immersed in 340 parts of a citric acid aqueous solution prepared by mixing citric acid and water at a volume ratio of 1:10, stirring is performed at 60℃ for 15min at a stirring speed of 100rpm, filtration is performed, and vacuum drying is performed at 60℃ for 6h to obtain hollow calcium carbonate microspheres. The average outer diameter of the hollow calcium carbonate microspheres is 127μm, and the average wall thickness is 12.3μm.

[0049] S5: 20 parts of hydroxypropyl-β-cyclodextrin, 5 parts of mannitol, 3 parts of trehalose were added into 200 parts of deionized water, stirred until clear, 0.9 parts of tannic acid, 0.5 parts of epigallocatechin gallate and 32 parts of hollow calcium carbonate microspheres were added, stirred at 60℃ for 65 min, 18 parts of minocycline hydrochloride was added, cooled to 0℃, stirred in the dark for 40 min, to obtain a cross-linked inclusion solution.

[0050] S6: The cross-linked inclusion solution obtained in step S5 was dried at -20℃ for 48h, and at 20℃ for 12h to obtain a porous freeze-dried block. The porous freeze-dried block was crushed by an airflow crusher to obtain a cross-linked inclusion powder. The D50 of the cross-linked inclusion powder was 300μm. The cross-linked inclusion powder, 1 part of colloidal silicon dioxide and 1 part of sodium stearyl fumarate were stirred uniformly to obtain a minocycline hydrochloride composition. The minocycline hydrochloride composition was filled into a hydroxypropyl methyl cellulose hollow capsule to obtain a minocycline hydrochloride capsule. The average loading of the minocycline hydrochloride capsule was 302.7mg per capsule. 90

[0051] Example 2

[0052] A preparation method of a minocycline hydrochloride capsule, comprising the following preparation steps:

[0053] S1: 22 parts of trehalose were dissolved in 65℃ of 340 parts of deionized water, 3.2 parts of tricalcium phosphate was added and stirred uniformly to form a phosphatized sugar template solution.

[0054] S2: 14 parts of PEG-6000 was added to the phosphatized sugar template solution, and the temperature was raised to 82℃ to melt the PEG-6000. The molten PEG-6000 was quickly poured into an ethanol bath at -22.5℃ for quenching. After quenching, filtration was performed to obtain trehalose-PEG phase separation gel balls.

[0055] S3: The trehalose-PEG phase separation gel balls were immersed in 180 parts of 0.5mol / L CaCl2 solution, stirred at 1℃ for 9h, transferred to 180 parts of 0.5mol / L Na2CO3 solution, reacted at 6℃ for 4h, and filtered to obtain composite microspheres.

[0056] S4: The composite microspheres were immersed in 500 parts of a citric acid aqueous solution prepared by mixing citric acid and water at a volume ratio of 1:15, treated at 65℃ for 12.5min at a stirring speed of 130rpm, filtered, and vacuum dried at 70℃ for 5h to obtain hollow calcium carbonate microspheres. The average outer diameter of the hollow calcium carbonate microspheres was 148μm, and the average wall thickness was 14.6μm.

[0057] ​S5: Hydroxypropyl-β-cyclodextrin 25 parts, mannitol 6 parts and trehalose 5 parts were added into 250 parts of deionized water, stirred until clear, tannic acid 1.1 parts, epigallocatechin gallate 0.6 parts and hollow calcium carbonate microspheres 35 parts were added, stirred at 70℃ for 56 min, minocycline hydrochloride 21.5 parts was added, cooled to 2℃, stirred for 30 min in the dark, to obtain a cross-linked inclusion solution.

[0058] S6: The cross-linked inclusion solution obtained in step S5 was dried at -25℃ for 54 h, and at 17℃ for 14 h to obtain a porous freeze-dried block. The porous freeze-dried block was crushed by an airflow crusher to obtain a cross-linked inclusion powder. The D50 of the cross-linked inclusion powder was 400 μm. 90 The cross-linked inclusion powder, colloidal silicon dioxide 1.5 parts and sodium stearyl fumarate 1.5 parts were stirred uniformly to obtain a minocycline hydrochloride composition. The minocycline hydrochloride composition was filled into a hydroxypropyl methyl cellulose hollow capsule to obtain a minocycline hydrochloride capsule. The average loading of the minocycline hydrochloride capsule was 303.1 mg per capsule.

[0059] Example 3

[0060] A preparation method of a minocycline hydrochloride capsule, comprising the following preparation steps:

[0061] S1: 24 parts of trehalose were dissolved in 360 parts of deionized water at 68℃, 4 parts of tricalcium phosphate were added and stirred uniformly to form a phosphatized sugar template solution.

[0062] S2: 16 parts of PEG-8000 were added to the phosphatized sugar template solution, and the temperature was raised to 85℃ to melt the PEG-8000. The molten PEG-8000 was quickly poured into an ethanol bath at -25℃ for quenching. After quenching, the trehalose-PEG phase separation gel balls were obtained by filtration.

[0063] S3: The trehalose-PEG phase separation gel balls were immersed in 200 parts of 0.8 mol / L CaCl2 solution, stirred at 2℃ for 8 h, transferred to 200 parts of 0.8 mol / L Na2CO3 solution, reacted at 8℃ for 2 h, and filtered to obtain composite microspheres.

[0064] S4: The composite microspheres were immersed in 600 parts of a citric acid aqueous solution prepared by mixing citric acid and water at a volume ratio of 1:20, treated at 70℃ for 10 min, stirred at a speed of 160 rpm, filtered, and vacuum dried at 80℃ for 4 h to obtain hollow calcium carbonate microspheres. The average outer diameter of the hollow calcium carbonate microspheres was 158 μm, and the average wall thickness was 16.8 μm.

[0065] S5: Hydroxypropyl-β-cyclodextrin 30 parts, mannitol 8 parts, trehalose 8 parts were dissolved in 300 parts of deionized water at 5°C, stirred until clear, added tannic acid 1.3 parts, epigallocatechin gallate 0.8 parts and hollow calcium carbonate microspheres 36 parts, stirred at 80°C for 45 min, added minocycline hydrochloride 25 parts, cooled to 5°C, stirred in the dark for 20 min, to obtain a cross-linked inclusion solution.

[0066] S6: The cross-linked inclusion solution obtained in step S5 was dried at -30°C for 60h, and at 15°C for 16h to obtain a porous freeze-dried block. The porous freeze-dried block was crushed by an airflow crusher to obtain a cross-linked inclusion powder. The D50 of the cross-linked inclusion powder was 500μm. 90 The cross-linked inclusion powder was stirred uniformly with colloidal silicon dioxide 2 parts and sodium stearyl fumarate 2 parts to obtain a minocycline hydrochloride composition. The minocycline hydrochloride composition was filled into a hydroxypropyl methyl cellulose hollow capsule to obtain a minocycline hydrochloride capsule. The average loading of the minocycline hydrochloride capsule was 303.4mg / capsule.

[0067] Comparative Example 1

[0068] In this comparative example, “tricalcium phosphate” was replaced by the same amount of “calcium chloride” compared with Example 1, and the other steps and parameters were the same. The final minocycline hydrochloride capsule was obtained.

[0069] Comparative Example 2

[0070] In this comparative example, “hollow calcium carbonate microspheres” were replaced by the same amount of “hollow calcium carbonate” compared with Example 1, and the other steps and parameters were the same. The final minocycline hydrochloride capsule was obtained. The preparation method of hollow calcium carbonate is as follows:

[0071] Glycine was added to a 0.3mol / L CaCl2 solution to obtain a CaCl2 mixed solution. The amount ratio of glycine to CaCl2 solution was 1g:100mL. The CaCl2 mixed solution and a 0.3mol / L Na2CO3 solution were cooled to 0°C respectively. Equal volumes of the CaCl2 mixed solution and the 0.3mol / L Na2CO3 solution cooled to 0°C were mixed under mechanical stirring at a speed of 400rpm to generate white suspensions. The white suspensions were filtered, washed and dried at 80°C under normal pressure for 6h to obtain hollow calcium carbonate.

[0072] Comparative Example 3

[0073] In this comparative example, step S4 was omitted compared with Example 1. “Hollow calcium carbonate microspheres” were replaced by the same amount of “composite microspheres prepared in step S3”. The other steps and parameters were the same. The final minocycline hydrochloride capsule was obtained.

[0074] Comparative Example 4

[0075] The present comparative example is compared with Example 1, the amount of crosslinking enhancer is controlled unchanged, only tannic acid is selected as the crosslinking enhancer, the remaining steps and parameters are the same, the present comparative example is not repeated, and finally the minocycline hydrochloride capsules are obtained.

[0076] Comparative Example 5

[0077] The present comparative example is compared with Example 1, the amount of crosslinking enhancer is controlled unchanged, only tannic acid is selected as the crosslinking enhancer, the remaining steps and parameters are the same, the present comparative example is not repeated, and finally the minocycline hydrochloride capsules are obtained.

[0078] Comparative Example 6

[0079] A preparation method of minocycline hydrochloride capsules, comprising the following preparation steps:

[0080] S1: 20 parts of trehalose is dissolved in 60℃ 300 parts of deionized water, 2 parts of tricalcium phosphate is added, and stirred uniformly to form a phosphatized sugar template solution.

[0081] S2: 12 parts of PEG-4000 is added to the phosphatized sugar template solution, heated to 78℃, and the PEG-4000 is melted, then quickly poured into an ethanol bath at -20℃ for quenching, after quenching, filtration is performed to obtain trehalose-PEG phase separation gel balls.

[0082] S3: The trehalose-PEG phase separation gel balls are immersed in 160 parts of 0.3 mol / L CaCl2 solution, stirred at 0℃ for 10h, transferred to 160 parts of 0.3 mol / L Na2CO3 solution, reacted at 5℃ for 5h, filtered to obtain composite microspheres.

[0083] S4: The composite microspheres are immersed in 340 parts of a citric acid aqueous solution prepared by mixing citric acid and water at a volume ratio of 1:10, stirred at 60℃ for 15min at a stirring speed of 100rpm, filtered, and vacuum dried at 60℃ for 6h to obtain hollow calcium carbonate microspheres, the average outer diameter of the hollow calcium carbonate microspheres is 127μm, and the average wall thickness is 12.3μm.

[0084] S5: 20 parts of hydroxypropyl-β-cyclodextrin, 5 parts of mannitol, and 3 parts of trehalose are added to 250 parts of deionized water, stirred until clear, 0.9 parts of tannic acid and 0.5 parts of epigallocatechin gallate are added, stirred and reacted at 60℃ for 65min, 18 parts of minocycline hydrochloride is added, cooled to 0℃, and stirred in the dark for 40min to obtain an inclusion solution.

[0085] S6: The inclusion solution obtained in step S5 was dried at -20 °C for 48 h and at 20 °C for 12 h to obtain a porous freeze-dried block, which was crushed by an airflow crusher to obtain an inclusion powder, and the D50 of the inclusion powder was 300 pm. 90 The inclusion powder, hollow calcium carbonate microspheres 32 parts, colloidal silicon dioxide 1 part, and sodium stearyl fumarate 1 part were stirred uniformly to obtain a minocycline hydrochloride composition, which was filled into a hydroxypropyl methylcellulose hollow capsule to obtain a minocycline hydrochloride capsule, and the average loading of the minocycline hydrochloride capsule was 302.7 mg per capsule.

[0086] The minocycline hydrochloride compositions prepared in Examples 1-3 and Comparative Examples 1-6 were detected, and the detection was as follows:

[0087] Dissolution test: The minocycline hydrochloride composition was detected according to the Chinese Pharmacopoeia 2020 edition, and the detection conditions were: pH 1.2 hydrochloric acid solution & pH 4.5 buffer, 37 °C, 50 rpm, UV detection at 348 nm, and the detailed results are shown in Table 1.

[0088] Stability test: The minocycline hydrochloride compositions prepared in Examples 1-3 and Comparative Examples 1-6 were placed for 60 °C / 30 days, RH 75% / 30 days, and light 4500 lux / 15 days, and the HPLC measured the difference between the minocycline and the total impurities, and the liquid phase method used the Chinese Pharmacopoeia 2020 method: using octylsilane bonded silica gel as the filler; using 0.2 mol / L ammonium acetate-dimethylformamide-tetrahydrofuran (600:398:2, containing 0.01 mol / L disodium ethylenediaminetetraacetate) as the mobile phase; the detection wavelength was 280 nm; the injection volume was 10 mΐ, and the detailed results are shown in Table 2.

[0089] Powder performance test: The angle of repose, content uniformity RSD, and drug loading shedding rate of the minocycline hydrochloride compositions prepared in Examples 1-3 and Comparative Examples 1-6 were tested, and the detailed results are shown in Table 3.

[0090] Repose angle detection method: fixed funnel method (referring to the Chinese Pharmacopoeia 2020 edition general method 0982 powder flowability determination method), the funnel was fixed on a horizontal support, the lower opening of the funnel was 50 mm away from the horizontally placed glass flat plate, 100 g of the minocycline hydrochloride composition sample was slowly poured into the funnel until the powder pile was formed, the height (H) and the bottom outer diameter (D) of the powder pile were measured, and the angle of repose was calculated: .

[0091] Detection standard:

[0092] Premium: θ ≤ 30° (excellent flowability, suitable for high-speed filling).

[0093] Pass: 30° < θ ≤ 40° (good fluidity, meet the regular production).

[0094] Fail: θ > 40° (poor fluidity, process adjustment is needed).

[0095] Content uniformity RSD detection method: HPLC method (referring to the method for checking content uniformity in Chinese Pharmacopoeia 2020 edition 0941):

[0096] Randomly take 10 capsules, accurately weigh, and place in a 50 mL volumetric flask; add the mobile phase (0.2 mol / L ammonium acetate-dimethylformamide-tetrahydrofuran = 600:398:2) to dissolve and constant volume. HPLC conditions: octylsilane bonded silica gel column (4.6 x 250 mm, 5 μm), flow rate 1.0 mL / min.

[0097] Detection wavelength is 280 nm, injection volume is 10 μL, calculate the minocycline content of each capsule, and then calculate the RSD of 10 capsules: .

[0098] Detection standard:

[0099] Premium: SD ≤ 1.0% (excellent uniformity).

[0100] Pass: 1.0% < RSD ≤ 2.0% (meet the requirements of pharmacopoeia).

[0101] Fail: RSD > 2.0% (uniformity does not meet the standard).

[0102] Drug shedding rate detection method: accurately weigh 100 mg of minocycline hydrochloride composition prepared in examples 1-3 and comparative examples 1-6, add 5 mL of mobile phase (0.2 mol / L ammonium acetate-dimethylformamide-tetrahydrofuran = 600:398:2, containing 0.01 mol / L EDTA-2Na), vortex for 1 minute; transfer to a centrifuge tube, centrifuge at 8000 rpm for 1 min, and precipitate the hollow calcium carbonate microspheres; accurately pipette 1 mL of supernatant, dilute 10 times with mobile phase, filter through a 0.22 μm filter membrane, and detect the free drug concentration by HPLC (octylsilane bonded silica gel column, flow rate 1.0 mL / min, detection wavelength 280 nm, injection volume 10 μL). Calculate the shedding rate: .

[0103] Detection standard:

[0104] Premium: shedding rate ≤ 1.0% (firm anchoring).

[0105] Pass: 1.0% < shedding rate ≤ 5.0% (acceptable range).

[0106] Fail: Shedding rate > 5.0% (anchoring failure).

[0107] Table 1

[0108]

[0109] Table 2

[0110]

[0111] Table 3

[0112]

[0113] According to the data in Table 1, Table 2 and Table 3, the minocycline hydrochloride composition prepared by the application has excellent dissolution performance, strong resistance to high temperature, high humidity and light, excellent fluidity, high content uniformity and strong drug loading stability.

[0114] Traditional fillers such as corn starch and pregelatinized starch cannot simultaneously consider fluidity, stability and dissolution behavior. In the application, tricalcium phosphate is added to a trehalose solution to form a phosphorylated sugar template solution, PEG is added to the phosphorylated sugar template solution, and the temperature is raised to melt the PEG and then rapidly quench it. By taking advantage of the solubility difference between PEG and trehalose, a phase separation pore is formed, and calcium carbonate is deposited at the trehalose-PEG phase interface. The tricalcium phosphate provides structural support for the deposition of calcium carbonate, and the calcium ions dissociated from the tricalcium phosphate in the solution can participate in the deposition process of calcium carbonate. The phosphate groups of tricalcium phosphate can physically adsorb to the calcium carbonate particles, and the calcium carbonate will grow along the surface of the tricalcium phosphate during the deposition process, forming a composite structure. After the deposition reaction of calcium carbonate is completed, the trehalose and PEG are washed away by citric acid aqueous solution to form hollow calcium carbonate microspheres. The prepared tricalcium phosphate on the surface of the hollow calcium carbonate microspheres is activated by citric acid, exposing more phosphate molecules to create conditions for the subsequent compounding of hollow calcium carbonate microspheres and inclusion carriers. The hollow calcium carbonate microspheres prepared by the application have the characteristics of low density, ultra-low friction fluidity and thin wall. The ultra-light characteristics and ultra-low friction fluidity of the hollow calcium carbonate microspheres are used to improve the fluidity, and the wall thickness is controlled to achieve customized dissolution. The hollow calcium carbonate microspheres rapidly disintegrate under acidic conditions, promoting the release of minocycline hydrochloride.

[0115] In the application, minocycline hydrochloride is included in the cavity of the inclusion carrier hydroxypropyl-beta-cyclodextrin, which blocks the contact of water and oxygen, significantly improving the stability to heat and humidity. The hollow calcium carbonate microspheres and the inclusion carrier are cross-linked and compounded by a cross-linking enhancer. Tannic acid and epigallocatechin gallate form metal coordination (Ca 2+To form stable complexes, the excess carboxyl groups (-COOH) in the polyphenol molecules and the hydroxyl groups (-OH) in the hydroxypropyl-β-cyclodextrin undergo esterification under mild heating to form covalent bonds, fixing the hydroxypropyl-β-cyclodextrin on the surface of the microspheres.

[0116] Compared with Example 1, the "tricalcium phosphate" in Comparative Example 1 is replaced by the same amount of "calcium chloride". The effect of Example 1 is obviously better than that of Comparative Example 1, which shows that tricalcium phosphate plays a key role in the preparation of hollow calcium carbonate microspheres. Specifically, it not only serves as a template to help form a stable phosphatized sugar template solution, but also provides structural support for the deposition of calcium carbonate; the phosphate groups of tricalcium phosphate can also physically adsorb calcium carbonate particles, promoting the deposition of calcium carbonate at the trehalose-PEG phase interface to form a composite structure. The lack of phosphoric groups on the surface of the microspheres in Comparative Example 1 affects the complex cross-linking of the hollow calcium carbonate microspheres and the inclusion carrier, which leads to an unstable structure of the microspheres, affecting the uniform distribution of minocycline hydrochloride, and causing the content uniformity RSD to increase.

[0117] Compared with Example 1, Comparative Example 2 directly generates hollow calcium carbonate by reacting sodium carbonate and calcium chloride, and does not limit the size and wall thickness of hollow calcium carbonate by trehalose-PEG phase separation gel balls. The uniformity of the prepared hollow calcium carbonate microspheres cannot be guaranteed, and in addition, the lack of phosphoric ions prevents stable cross-linking with hydroxypropyl-β-cyclodextrin, affecting the uniform distribution of minocycline hydrochloride, resulting in an increase in the content uniformity RSD and an increase in the drug shedding rate.

[0118] Compared with Example 1, Comparative Example 3 replaces the "hollow calcium carbonate microspheres" with the same amount of "composite microspheres prepared in step S3", and omits step S4, resulting in insufficient activation of the tricalcium phosphate on the surface of the microspheres, which cannot form stable cross-linking with hydroxypropyl-β-cyclodextrin. This causes the minocycline hydrochloride carrier to partially fall off during the mixing process, affecting the uniform distribution of minocycline hydrochloride, resulting in an increase in the content uniformity RSD. At the same time, the unactivated microspheres disintegrate slowly under acidic conditions, affecting the rapid release of minocycline hydrochloride.

[0119] Compared with Example 1, Comparative Example 4 uses only tannic acid as a cross-linking enhancer, which reduces the binding force between the inclusion carrier and the hollow calcium carbonate microspheres, resulting in an increase in the drug shedding rate, affecting the uniform distribution of minocycline hydrochloride, and causing the content uniformity RSD to increase.

[0120] Compared with Example 1, Comparative Example 5 uses only epigallocatechin gallate as a cross-linking enhancer, which reduces the binding force between the inclusion carrier and the hollow calcium carbonate microspheres, resulting in an increase in the drug shedding rate, affecting the uniform distribution of minocycline hydrochloride, and causing the content uniformity RSD to increase.

[0121] Compared with Example 1, the inclusion solution and the hollow calcium carbonate microspheres are mixed after being prepared respectively in Comparative Example 6, and there is no cross-linking reaction, the combination between the inclusion carrier and the microspheres is not firm, which leads to partial shedding of the inclusion carrier during the mixing process, affecting the uniform distribution of minocycline hydrochloride, and leading to the increase of the content uniformity RSD.

[0122] The above is only an example and description of the concept of the present application. Those skilled in the art can make various modifications or supplements to the described specific examples or use similar ways to replace them, as long as they do not deviate from the concept of the present application or exceed the scope defined by the present claims, which shall belong to the protection scope of the present application.

Claims

1. A minocycline hydrochloride capsule characterized in that, The application relates to a minocycline hydrochloride capsule, which is composed of a minocycline hydrochloride composition and a hollow capsule, wherein the weight parts of each raw material in the minocycline hydrochloride composition are as follows: minocycline hydrochloride 18-25 parts, inclusion carrier 20-30 parts, freeze-drying protective agent 8-16 parts, light filler 32-36 parts, cross-linking reinforcing agent 1.4-2.1 parts, flow aid 1-2 parts and lubricant 1-2 parts. The light filler is hollow calcium carbonate microspheres, and the preparation method of the hollow calcium carbonate microspheres is as follows: A1: adding trehalose into deionized water, adding tricalcium phosphate, stirring to form a phosphatized sugar template solution; A2: adding a phase separation agent into the phosphatized sugar template solution, heating to melt the phase separation agent, quickly pouring into an ice ethanol bath for quenching, after quenching, filtering to obtain trehalose-PEG phase separation gel balls; A3: immersing the trehalose-PEG phase separation gel balls into a CaCl2 solution, stirring, transferring into a Na2CO3 solution, and reacting to form composite microspheres; A4: immersing the composite microspheres into an aqueous citric acid solution, stirring, filtering to obtain hollow calcium carbonate microspheres; The phase separation agent is any one of PEG-4000, PEG-6000 and PEG-8000; and the inclusion carrier is hydroxypropyl-beta-cyclodextrin. The preparation method of the minocycline hydrochloride capsule comprises the following steps: S1: adding the inclusion carrier and the freeze-drying protective agent into deionized water, stirring until clear, adding the cross-linking reinforcing agent and the light filler, stirring and reacting, adding the minocycline hydrochloride, uniformly stirring under cooling and light shielding to obtain a cross-linked inclusion solution; S2: freeze-drying the cross-linked inclusion solution to obtain a porous freeze-dried block, crushing the porous freeze-dried block by using an airflow crusher to obtain cross-linked inclusion powder, uniformly mixing the cross-linked inclusion powder, the flow aid and the lubricant to obtain a minocycline hydrochloride composition, filling the minocycline hydrochloride composition into the hollow capsule to obtain the minocycline hydrochloride capsule; The cross-linking reinforcing agent is composed of tannic acid and epigallocatechin gallate, and the mass ratio of the tannic acid to the epigallocatechin gallate is 0.9-1.3:0.5-0.

8.

2. The minocycline hydrochloride capsule according to claim 1, wherein In the preparation method of the hollow calcium carbonate microspheres, the weight parts of trehalose, deionized water, tricalcium phosphate, the phase separation agent, the CaCl2 solution, the Na2CO3 solution and the aqueous citric acid solution are as follows: trehalose 20-24 parts, deionized water 300-360 parts, tricalcium phosphate 2-4 parts, the phase separation agent 12-16 parts, the CaCl2 solution 160-200 parts, the Na2CO3 solution 160-200 parts and the aqueous citric acid solution 340-600 parts.

3. The minocycline hydrochloride capsule according to claim 1, wherein The concentration of the CaCl2 solution is 0.3mol / L-0.8mol / L, and the concentration of the Na2CO3 solution is 0.3mol / L-0.8mol / L.

4. The minocycline hydrochloride capsule according to claim 1, wherein The volume ratio of citric acid to water in the aqueous citric acid solution is 1:10-20.

5. The minocycline hydrochloride capsule according to claim 1, wherein The freeze-drying protective agent is composed of mannitol and trehalose, and the mass ratio of the mannitol to the trehalose is 5:3-5.

6. A process for the preparation of a minocycline hydrochloride capsule as claimed in any one of claims 1 to 5, characterized in that, The preparation method comprises the following steps: Step S1: add the inclusion carrier, freeze-drying protective agent into deionized water, stir until clear, add cross-linking reinforcing agent and light filler, stir and react, add minocycline hydrochloride, reduce temperature, stir uniformly in the dark, to obtain a cross-linked inclusion solution; Step S2: freeze-dry the cross-linked inclusion solution to obtain a porous freeze-dried block, crush the porous freeze-dried block with an airflow crusher to obtain a cross-linked inclusion powder, mix the cross-linked inclusion powder, flow aid and lubricant uniformly to obtain a minocycline hydrochloride composition, fill the minocycline hydrochloride composition into a hollow capsule to obtain a minocycline hydrochloride capsule.

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