Minocycline hydrochloride capsule and preparation method thereof

Abstract

The invention discloses a minocycline hydrochloride capsule and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The capsule consists of a minocycline hydrochloride composition and a hollow capsule, wherein the minocycline hydrochloride composition comprises minocycline hydrochloride, a cyclodextrin derivative inclusion carrier, a freeze-drying protective agent, a hollow calcium carbonate microsphere light filler and a sodium stearyl fumarate lubricant. The hollow calcium carbonate microspheres are prepared by a specific method, have the characteristics of low density, high porosity and rapid disintegration, and can improve the powder flowability and the drug dissolution rate. The preparation method comprises the following steps: dissolving the inclusion carrier and the freeze-drying protective agent in ice water, adding the cross-linking enhancer, minocycline hydrochloride and hollow calcium carbonate microspheres, freeze-drying, crushing, and filling into hollow capsules. The problem of impurity generation caused by high temperature, high humidity or an organic solvent in the prior art is solved, and the stability, the dissolution rate and the bioavailability of the medicine are remarkably improved.

Description

Technical Field

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

[0002] Minocycline hydrochloride, a thermosensitive tetracycline antibiotic, plays a crucial role in the treatment of infectious diseases. However, its molecular structure is susceptible to epimerization to form the toxic impurity epiminocycline when exposed to high temperatures (40°C), high humidity (RH ≥ 75%), or when exposed to organic solvents such as ethanol. This impurity not only reduces antimicrobial activity but can also trigger adverse reactions such as allergies. Therefore, controlling the heat and humidity environment and solvents during formulation preparation is a core challenge in ensuring drug quality. Currently, the industrial production of minocycline hydrochloride capsules faces the dual challenges of process stability and impurity control. Traditional preparation techniques struggle to meet the safety and efficacy requirements of modern formulations.

[0003] Existing wet granulation / coating processes have significant drawbacks: the use of organic solvents such as ethanol can disrupt the drug's crystal structure and promote molecular isomerization, while the drying process requires maintaining a high temperature environment >40°C (e.g., 60-80°C hot air drying), further accelerating the formation of diastereoisomerized minocycline. While direct powder filling avoids the effects of high temperatures, it relies on pregelatinized starch to improve flowability, resulting in insufficient drug stability in high humidity environments (RH 75%) and increased total impurity content. Furthermore, its dissolution behavior deviates from that of the reference formulation, making it difficult to ensure consistent clinical efficacy.

[0004] The limitations of fillers further constrain the development of existing technologies: corn starch's poor fluidity leads to substandard capsule content uniformity; while pregelatinized starch improves fluidity, it cannot isolate the drug from external moisture, failing to address chemical degradation in high-humidity environments. Furthermore, traditional excipient systems lack the ability to regulate the drug's microenvironment, failing to form an effective protective barrier during preparation and storage. This results in capsules produced using existing processes generally having a short shelf life and significant batch-to-batch quality fluctuations. There is an urgent need for excipient innovation and process optimization to achieve stable formulations for heat-sensitive drugs.

[0005] Therefore, based on the limitations of the above-mentioned related technologies, there is an urgent need to develop a minocycline hydrochloride capsule and a preparation method thereof. Summary of the Invention

[0006] In view of this, the object of the present invention is to provide a minocycline hydrochloride capsule and a preparation method thereof, which is used to solve the problem in the prior art that minocycline hydrochloride is converted into diastereomeric minocycline impurities due to high temperature, high humidity or organic solvents, while improving the fluidity, content uniformity and stability of the preparation.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] The first aspect of the present invention provides a minocycline hydrochloride capsule, which is composed of a minocycline hydrochloride composition and a hollow capsule. The weight parts of the raw materials in the minocycline hydrochloride composition are as follows: 18-25 parts of minocycline hydrochloride, 20-30 parts of inclusion carrier, 8-16 parts of lyoprotectant, 32-36 parts of lightweight filler, 1.4-2.1 parts of cross-linking enhancer, 1-2 parts of glidant and 1-2 parts of lubricant.

[0009] Preferably, the lightweight 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 phosphorylated sugar template solution;

[0011] A2: Add a phase separation agent to the phosphorylated sugar template solution, heat it to melt the phase separation agent, and quickly pour it into an ice-ethanol bath to quench it. After quenching, filter it to obtain trehalose-PEG phase separation gel spheres;

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

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

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

[0015] Preferably, the specific steps of A2 are: adding a phase separation agent to the phosphorylated sugar template solution, heating to 78°C-85°C to melt the phase separation agent, quickly pouring it into a -20°C to -25°C ethanol bath for quenching, and after quenching, filtering to obtain trehalose-PEG phase separation gel balls.

[0016] Preferably, the specific steps of A3 are: immersing the trehalose-PEG phase separation gel balls in a CaCl2 solution, stirring at 0°C-2°C for 8h-10h, transferring to a Na2CO3 solution, reacting at 5°C-8°C for 2h-5h, filtering, and obtaining composite microspheres.

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

[0018] Preferably, the average outer diameter of the hollow calcium carbonate microspheres is 127 μm-158 μm, and the average wall thickness is 12.3 μm-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 proportions of trehalose, deionized water, tricalcium phosphate, phase separator, CaCl2 solution, Na2CO3 solution and citric acid aqueous solution are: 20-24 parts of trehalose, 300-360 parts of deionized water, 2-4 parts of tricalcium phosphate, 12-16 parts of phase separator, 160-200 parts of CaCl2 solution, 160-200 parts of Na2CO3 solution, and 340-600 parts of citric acid aqueous solution.

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

[0022] Preferably, the concentration of the Na2CO3 solution is 0.3 mol / L-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 lyoprotectant consists of mannitol and trehalose, and the mass ratio of mannitol to trehalose is 5:3-5.

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

[0026] Preferably, the primary particle size of the colloidal silica is 10 nm to 15 nm.

[0027] Another aspect of the present invention provides a method for preparing minocycline hydrochloride capsules, comprising the following steps:

[0028] Step S1: adding the inclusion carrier and lyophilization protectant to deionized water, stirring until clear, adding the cross-linking enhancer and the lightweight filler, stirring to react, adding minocycline hydrochloride, cooling, protecting from light and stirring evenly to obtain a cross-linked inclusion solution;

[0029] Step S2: freeze-drying the cross-linked inclusion solution to obtain a porous freeze-dried block, crushing the porous freeze-dried block by a jet mill to obtain a cross-linked inclusion powder, uniformly mixing the cross-linked inclusion powder, a glidant, and a lubricant to obtain a minocycline hydrochloride composition, and filling the minocycline hydrochloride composition into hollow capsules to obtain minocycline hydrochloride capsules.

[0030] Preferably, the specific steps of step S1 are: adding the inclusion carrier and the lyophilization protectant to deionized water, stirring until clear, adding the cross-linking enhancer and the lightweight filler, stirring and reacting at 60°C-80°C for 45min-65min, cooling to 0°C-5°C, adding minocycline hydrochloride, stirring in the dark for 20min-40min, and obtaining 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 is composed 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 characteristic of the cross-linked inclusion powder is D 90 Between 300μm-500μm.

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

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

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

[0037] Beneficial effects of the present invention:

[0038] 1. This invention uses hollow calcium carbonate microspheres as a lightweight filler. Their low density and high porosity significantly improve powder flowability and content uniformity. The ultra-lightweight nature and ultra-low friction flow of the hollow calcium carbonate microspheres significantly reduce the powder's angle of repose, resulting in excellent flowability and suitability for high-speed filling. Furthermore, this filler ensures content uniformity (RSD values ​​meet standards), resolving the poor flowability and uneven mixing associated with traditional fillers.

[0039] 2. This invention achieves customized minocycline hydrochloride dissolution rate by controlling the wall thickness of the hollow calcium carbonate microspheres. The hollow calcium carbonate microspheres rapidly disintegrate under acidic conditions, promoting the release of minocycline hydrochloride. This customized dissolution behavior not only improves the bioavailability of minocycline hydrochloride but also ensures consistent clinical efficacy.

[0040] 3. The present invention significantly improves the drug's dissolution rate and bioavailability through the synergistic effect of cyclodextrin inclusion technology and hollow calcium carbonate microspheres. The inclusion of the cyclodextrin derivative not only protects the drug molecules, but also rapidly releases minocycline hydrochloride through the rapid disintegration properties of the hollow calcium carbonate microspheres, improving its absorption efficiency in the body and thus enhancing its bioavailability. DETAILED DESCRIPTION

[0041] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0042] The primary particle size of the colloidal silica used in the examples of the present invention is 10 nm to 15 nm.

[0043] Example 1

[0044] A method for preparing minocycline hydrochloride capsules comprises the following steps:

[0045] S1: Dissolve 20 parts of trehalose in 300 parts of deionized water at 60°C, add 2 parts of tricalcium phosphate, and stir evenly to form a phosphorylated sugar template solution.

[0046] S2: Add 12 parts of PEG-4000 to the phosphorylated sugar template solution, heat to 78°C to melt the PEG-4000, and quickly pour into a -20°C ethanol bath to quench. After quenching, filter to obtain trehalose-PEG phase separation gel spheres.

[0047] S3: Immerse the trehalose-PEG phase separation gel spheres in 160 parts of 0.3 mol / L CaCl2 solution, stir at 0°C for 10 h, transfer to 160 parts of 0.3 mol / L Na2CO3 solution, react at 5°C for 5 h, and filter to obtain composite microspheres.

[0048] S4: The composite microspheres were immersed in 340 parts of a citric acid aqueous solution prepared by citric acid and water in a volume ratio of 1:10, stirred at 60°C for 15 minutes at a stirring speed of 100 rpm, filtered, and vacuum dried at 60°C for 6 hours to obtain hollow calcium carbonate microspheres. The average outer diameter of the hollow calcium carbonate microspheres was 127 μm and the average wall thickness was 12.3 μm.

[0049] S5: Add 20 parts of hydroxypropyl-β-cyclodextrin, 5 parts of mannitol, and 3 parts of trehalose to 200 parts of deionized water, stir until clear, add 0.9 parts of tannic acid, 0.5 parts of epigallocatechin gallate, and 32 parts of hollow calcium carbonate microspheres, stir and react at 60°C for 65 minutes, add 18 parts of minocycline hydrochloride, cool to 0°C, and stir in the dark for 40 minutes to obtain a cross-linked inclusion solution.

[0050] S6: The cross-linked inclusion solution obtained in step S5 was dried at -20°C for 48 hours and then at 20°C for 12 hours to obtain a porous freeze-dried block, which was then crushed by a jet mill to obtain a cross-linked inclusion powder. 90 The cross-linked inclusion powder, 1 part of colloidal silicon dioxide and 1 part of sodium stearyl fumarate were uniformly stirred to obtain a minocycline hydrochloride composition, and the minocycline hydrochloride composition was filled into hollow hydroxypropyl methylcellulose capsules to obtain minocycline hydrochloride capsules. The average filling amount of the minocycline hydrochloride capsules was 302.7 mg / capsule.

[0051] Example 2

[0052] A method for preparing minocycline hydrochloride capsules comprises the following steps:

[0053] S1: Dissolve 22 parts of trehalose in 340 parts of deionized water at 65°C, add 3.2 parts of tricalcium phosphate, and stir evenly to form a phosphorylated sugar template solution.

[0054] S2: Add 14 parts of PEG-6000 to the phosphorylated sugar template solution, heat to 82°C to melt the PEG-6000, and quickly pour into a -22.5°C ethanol bath to quench. After quenching, filter to obtain trehalose-PEG phase separation gel spheres.

[0055] S3: Immerse the trehalose-PEG phase separation gel spheres in 180 parts of 0.5 mol / L CaCl2 solution, stir at 1°C for 9 hours, transfer to 180 parts of 0.5 mol / L Na2CO3 solution, react at 6°C for 4 hours, and filter to obtain composite microspheres.

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

[0057] S5: Add 25 parts of hydroxypropyl-β-cyclodextrin, 6 parts of mannitol and 5 parts of trehalose to 250 parts of deionized water, stir until clear, add 1.1 parts of tannic acid, 0.6 parts of epigallocatechin gallate and 35 parts of hollow calcium carbonate microspheres, stir and react at 70°C for 56 minutes, add 21.5 parts of minocycline hydrochloride, cool to 2°C, and stir in the dark for 30 minutes to obtain a cross-linked inclusion solution.

[0058] S6: The cross-linked inclusion solution obtained in step S5 was dried at -25°C for 54 hours and at 17°C for 14 hours to obtain a porous freeze-dried block, which was crushed by a jet mill to obtain a cross-linked inclusion powder. The D of the cross-linked inclusion powder was 90 The cross-linked inclusion powder, 1.5 parts of colloidal silicon dioxide and 1.5 parts of sodium stearyl fumarate were uniformly stirred to obtain a minocycline hydrochloride composition, and the minocycline hydrochloride composition was filled into hollow hydroxypropyl methylcellulose capsules to obtain minocycline hydrochloride capsules. The average filling amount of the minocycline hydrochloride capsules was 303.1 mg / capsule.

[0059] Example 3

[0060] A method for preparing minocycline hydrochloride capsules comprises the following steps:

[0061] S1: Dissolve 24 parts of trehalose in 360 parts of deionized water at 68°C, add 4 parts of tricalcium phosphate, and stir evenly to form a phosphorylated sugar template solution.

[0062] S2: Add 16 parts of PEG-8000 to the phosphorylated sugar template solution, heat it to 85°C to melt the PEG-8000, and quickly pour it into a -25°C ethanol bath to quench it. After quenching, filter it to obtain trehalose-PEG phase separation gel balls.

[0063] S3: Immerse the trehalose-PEG phase separation gel balls in 200 parts of 0.8 mol / L CaCl2 solution, stir at 2°C for 8 hours, transfer to 200 parts of 0.8 mol / L Na2CO3 solution, react at 8°C for 2 hours, and filter to obtain composite microspheres.

[0064] S4: The composite microspheres were immersed in 600 parts of a citric acid aqueous solution prepared by citric acid and water in a volume ratio of 1:20, treated at 70°C for 10 minutes, stirred at 160 rpm, filtered, and vacuum dried at 80°C for 4 hours 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: Dissolve 30 parts of hydroxypropyl-β-cyclodextrin, 8 parts of mannitol, and 8 parts of trehalose in 300 parts of deionized water at 5°C, stir until clear, add 1.3 parts of tannic acid, 0.8 parts of epigallocatechin gallate, and 36 parts of hollow calcium carbonate microspheres, stir and react at 80°C for 45 minutes, add 25 parts of minocycline hydrochloride, cool to 5°C, and stir in the dark for 20 minutes to obtain a cross-linked inclusion solution.

[0066] S6: The cross-linked inclusion solution obtained in step S5 was dried at -30°C for 60 hours and at 15°C for 16 hours to obtain a porous freeze-dried block, which was crushed by a jet mill to obtain a cross-linked inclusion powder. The D of the cross-linked inclusion powder was 90 The cross-linked inclusion powder, 2 parts of colloidal silicon dioxide and 2 parts of sodium stearyl fumarate were uniformly stirred to obtain a minocycline hydrochloride composition, and the minocycline hydrochloride composition was filled into hollow hydroxypropyl methylcellulose capsules to obtain minocycline hydrochloride capsules. The average filling amount of the minocycline hydrochloride capsules was 303.4 mg / capsule.

[0067] Comparative Example 1

[0068] Compared with Example 1, this comparative example replaces "tricalcium phosphate" with "calcium chloride" of equal mass. The remaining steps and parameters are the same and will not be repeated in this comparative example. Finally, minocycline hydrochloride capsules are obtained.

[0069] Comparative Example 2

[0070] Compared with Example 1, this comparative example replaces the "hollow calcium carbonate microspheres" with "hollow calcium carbonate" of equal mass. The remaining steps and parameters are the same and will not be repeated in this comparative example. Finally, minocycline hydrochloride capsules are obtained. The preparation method of the hollow calcium carbonate is as follows:

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

[0072] Comparative Example 3

[0073] Compared with Example 1, this comparative example omitted step S4, and the "hollow calcium carbonate microspheres" were replaced with "composite microspheres prepared in step S3" of equal mass. The remaining steps and parameters were the same and will not be repeated in this comparative example. Finally, minocycline hydrochloride capsules were obtained.

[0074] Comparative Example 4

[0075] Compared with Example 1, this comparative example controls the amount of the cross-linking enhancer to remain unchanged, and only selects tannic acid as the cross-linking enhancer. The remaining steps and parameters are the same and will not be repeated in this comparative example. Finally, minocycline hydrochloride capsules are obtained.

[0076] Comparative Example 5

[0077] Compared with Example 1, this comparative example kept the amount of the cross-linking enhancer unchanged, and only selected epigallocatechin as the cross-linking enhancer. The remaining steps and parameters were the same and will not be repeated in this comparative example. Finally, minocycline hydrochloride capsules were obtained.

[0078] Comparative Example 6

[0079] A method for preparing minocycline hydrochloride capsules comprises the following steps:

[0080] S1: Dissolve 20 parts of trehalose in 300 parts of deionized water at 60°C, add 2 parts of tricalcium phosphate, and stir evenly to form a phosphorylated sugar template solution.

[0081] S2: Add 12 parts of PEG-4000 to the phosphorylated sugar template solution, heat to 78°C to melt the PEG-4000, and quickly pour into a -20°C ethanol bath to quench. After quenching, filter to obtain trehalose-PEG phase separation gel spheres.

[0082] S3: Immerse the trehalose-PEG phase separation gel spheres in 160 parts of 0.3 mol / L CaCl2 solution, stir at 0°C for 10 h, transfer to 160 parts of 0.3 mol / L Na2CO3 solution, react at 5°C for 5 h, and filter to obtain composite microspheres.

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

[0084] S5: Add 20 parts of hydroxypropyl-β-cyclodextrin, 5 parts of mannitol, and 3 parts of trehalose to 250 parts of deionized water, stir until clear, add 0.9 parts of tannic acid and 0.5 parts of epigallocatechin gallate, stir and react at 60°C for 65 minutes, add 18 parts of minocycline hydrochloride, cool to 0°C, and stir in the dark for 40 minutes to obtain an inclusion solution.

[0085] S6: The inclusion solution obtained in step S5 was dried at -20°C for 48 hours and at 20°C for 12 hours to obtain a porous freeze-dried block, which was crushed by a jet mill to obtain an inclusion powder. The inclusion powder had a D 90 The minocycline hydrochloride composition is filled into hollow hydroxypropyl methylcellulose capsules to obtain minocycline hydrochloride capsules. The average filling amount of the minocycline hydrochloride capsules is 302.7 mg / capsule.

[0086] The minocycline hydrochloride compositions prepared in Examples 1-3 and Comparative Examples 1-6 were tested as follows:

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

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

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

[0090] Tapering angle detection method: Fixed funnel method (refer to the powder fluidity determination method in General Rules 0982 of the Chinese Pharmacopoeia 2020 Edition). Fix the funnel on a horizontal bracket, with the lower end of the funnel 50 mm away from the horizontally placed glass plate. Take 100 g of the minocycline hydrochloride composition sample and slowly pour it into the funnel until a powder pile is formed. Measure the height (H) and the outer diameter of the bottom (D) of the powder pile, and calculate the tapering angle: .

[0091] Detection standard:

[0092] Superior grade: θ ≤ 30° (excellent fluidity, suitable for high-speed filling).

[0093] Qualified: 30° < θ ≤ 40° (good fluidity, meeting the requirements of conventional production).

[0094] Unqualified: θ > 40° (poor fluidity, requiring process adjustment).

[0095] Content uniformity RSD detection method: HPLC method (refer to the content uniformity inspection method in General Rules 0941 of the Chinese Pharmacopoeia 2020 Edition):

[0096] Randomly select 10 capsule contents, accurately weigh them separately, and place them in a 50 mL volumetric flask; add the mobile phase (0.2 mol / L ammonium acetate - dimethylformamide - tetrahydrofuran = 600:398:2) to dissolve and make up the volume. HPLC conditions: Octadecylsilane bonded silica column (4.6 × 250 mm, 5 μm), flow rate of 1.0 mL / min.

[0097] The detection wavelength is 280 nm, the injection volume is 10 μL, calculate the minocycline content in each capsule, and then calculate the RSD of 10 capsules: . <00​​​​​​​​​​​​​Drug shedding rate detection method: Accurately weigh 100 mg of the minocycline hydrochloride composition prepared in Examples 1-3 and Comparative Examples 1-6, respectively, add 5 mL of mobile phase (0.2 mol / L ammonium acetate-dimethylformamide-tetrahydrofuran = 600:398:2, containing 0.01 mol / L EDTA-2Na), and vortex stir for 1 minute; transfer to a centrifuge tube and centrifuge at 8000 rpm for 1 minute to precipitate the hollow calcium carbonate microspheres; accurately draw 1 mL of the supernatant, dilute 10 times with the 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] Testing standards:

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

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

[0106] Unqualified: shedding rate>5.0% (anchor 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 present invention 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 take into account fluidity, stability and dissolution behavior. The present invention adds tricalcium phosphate to a trehalose solution to form a phosphorylated sugar template solution, adds PEG to the phosphorylated sugar template solution, heats it to a temperature that melts the PEG, and then rapidly quenches it. By utilizing the solubility difference between PEG and trehalose, phase separation pores are formed, and calcium carbonate is deposited at the trehalose-PEG phase interface. The tricalcium phosphate provides structural support for the deposition of calcium carbonate. The calcium ions dissociated from the tricalcium phosphate in the solution can participate in the deposition process of calcium carbonate. The phosphate groups of the tricalcium phosphate can be physically adsorbed with the calcium carbonate particles. During the deposition process, calcium carbonate The hollow calcium carbonate microspheres are characterized by low density, ultra-low friction fluidity and thin walls. The ultra-light properties and ultra-low friction fluidity of the hollow calcium carbonate microspheres are utilized to improve fluidity, and customized dissolution is achieved by controlling the wall thickness of the microspheres. The microspheres rapidly disintegrate under acidic conditions, thereby promoting the release of minocycline hydrochloride.

[0115] The present invention includes minocycline hydrochloride in the cavity of the inclusion carrier hydroxypropyl-β-cyclodextrin to block the contact of moisture and oxygen, significantly improving the wet heat stability, and then cross-linking the hollow calcium carbonate microspheres and the inclusion carrier through a cross-linking enhancer. Tannic acid and epigallocatechin gallate are combined with the phosphate groups on the surface of the hollow calcium carbonate microspheres to form a metal coordination effect (Ca 2+ The excess carboxyl groups (-COOH) in the polyphenol molecules react with the hydroxyl groups (-OH) of hydroxypropyl-β-cyclodextrin under mild heating to form a covalent bond, fixing hydroxypropyl-β-cyclodextrin on the surface of the microspheres.

[0116] Comparative Example 1 Compared with Example 1, "tricalcium phosphate" is replaced with "calcium chloride" of equal mass. The effect of Example 1 is significantly 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 phosphorylated sugar template solution, but also provides structural support for the deposition of calcium carbonate; the phosphate group of tricalcium phosphate can also undergo physical adsorption with calcium carbonate particles, promoting the deposition of calcium carbonate at the trehalose-PEG phase interface to form a composite structure. Comparative Example 1 does not add tricalcium phosphate, resulting in a lack of phosphate groups on the surface of the microspheres, affecting the composite cross-linking of the hollow calcium carbonate microspheres with the inclusion carrier, which results in an unstable structure of the microspheres, affecting the uniform distribution of minocycline hydrochloride, and increasing the content uniformity RSD.

[0117] Compared with Example 1, Comparative Example 2 directly generates hollow calcium carbonate by reacting sodium carbonate and calcium chloride, and the size and wall thickness of the hollow calcium carbonate are not limited by trehalose-PEG phase separation gel balls. The uniformity of the prepared hollow calcium carbonate microspheres cannot be guaranteed. In addition, phosphate ions are not enriched, resulting in the inability to stably cross-link 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] Comparative Example 3 Compared with Example 1, the “hollow calcium carbonate microspheres” were replaced with “composite microspheres prepared in step S3” of equal mass, and step S4 was omitted, resulting in the tricalcium phosphate on the surface of the microspheres not being fully activated and unable to form stable crosslinks with hydroxypropyl-β-cyclodextrin. This caused the minocycline hydrochloride carrier to partially fall off during the mixing process, affecting the uniform distribution of minocycline hydrochloride and resulting in an increase in the content uniformity RSD. At the same time, the unactivated microspheres disintegrated slowly under acidic conditions, affecting the rapid release of minocycline hydrochloride.

[0119] Compared with Example 1, Comparative Example 4 used only tannic acid as a cross-linking enhancer, which reduced the binding force between the inclusion carrier and the hollow calcium carbonate microspheres, thereby increasing the drug shedding rate, affecting the uniform distribution of minocycline hydrochloride, and increasing the content uniformity RSD.

[0120] Comparative Example 5 Compared with Example 1, the use of epigallocatechin gallate alone as a cross-linking enhancer reduced the binding force between the inclusion carrier and the hollow calcium carbonate microspheres, thereby increasing the drug shedding rate, affecting the uniform distribution of minocycline hydrochloride, and increasing the content uniformity RSD.

[0121] Compared with Example 1, in Comparative Example 6, the inclusion solution and the hollow calcium carbonate microspheres were prepared separately and then mixed. There was a lack of cross-linking reaction, and the bond between the inclusion carrier and the microspheres was not strong, resulting in partial detachment of the inclusion carrier during the mixing process, affecting the uniform distribution of minocycline hydrochloride and causing an increase in the content uniformity RSD.

[0122] The above content is merely an example and explanation of the concept of the present invention. Those skilled in the art may make various modifications or additions to the described specific embodiments or replace them in a similar manner. As long as they do not deviate from the concept of the invention or exceed the scope defined by the claims, they should all fall within the scope of protection of the present invention.

Claims

1. A minocycline hydrochloride capsule, characterized in that The invention comprises a minocycline hydrochloride composition and an empty capsule, wherein the weight parts of the raw materials in the minocycline hydrochloride composition are as follows: 18-25 parts of minocycline hydrochloride, 20-30 parts of inclusion carrier, 8-16 parts of lyoprotectant, 32-36 parts of lightweight filler, 1.4-2.1 parts of cross-linking enhancer, 1-2 parts of glidant and 1-2 parts of lubricant; The lightweight filler is hollow calcium carbonate microspheres, and the preparation method of the hollow calcium carbonate microspheres is as follows: A1: Add trehalose to deionized water, add tricalcium phosphate, and stir to form a phosphorylated sugar template solution; A2: Add a phase separation agent to the phosphorylated sugar template solution, heat it to melt the phase separation agent, and quickly pour it into an ice-ethanol bath to quench it. After quenching, filter it to obtain trehalose-PEG phase separation gel spheres; A3: Immerse the trehalose-PEG phase separation gel spheres in CaCl2 solution, stir, and transfer to Na2CO3 solution to react and form composite microspheres; A4: Immerse the composite microspheres in a citric acid aqueous solution, stir, and filter to obtain hollow calcium carbonate microspheres.

2. A minocycline hydrochloride capsule according to claim 1, characterized in that, The phase separation agent is any one of PEG-4000, PEG-6000 and PEG-8000.

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

4. A minocycline hydrochloride capsule according to claim 1, characterized in that, 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.

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

6. The minocycline hydrochloride capsule according to claim 1, characterized in that: The freeze-drying protective agent consists of mannitol and trehalose, and the mass ratio of mannitol to trehalose is 5:3-5.

7. The minocycline hydrochloride capsule according to claim 1, characterized in that: The inclusion carrier is a cyclodextrin derivative, the glidant is colloidal silicon dioxide, and the lubricant is sodium stearyl fumarate.

8. A method for preparing minocycline hydrochloride capsules according to any one of claims 1 to 7, characterized in that: The method comprises the following preparation steps: Step S1: adding the inclusion carrier and lyophilization protectant to deionized water, stirring until clear, adding the cross-linking enhancer and the lightweight filler, stirring to react, adding minocycline hydrochloride, cooling, protecting from light and stirring evenly to obtain a cross-linked inclusion solution; Step S2: freeze-drying the cross-linked inclusion solution to obtain a porous freeze-dried block, crushing the porous freeze-dried block by a jet mill to obtain a cross-linked inclusion powder, uniformly mixing the cross-linked inclusion powder, a glidant, and a lubricant to obtain a minocycline hydrochloride composition, and filling the minocycline hydrochloride composition into hollow capsules to obtain minocycline hydrochloride capsules.

9. The method for preparing minocycline hydrochloride capsules according to claim 8, wherein: 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.

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