Berberine hydrochloride sustained-release solid dispersion and a preparation method thereof

Abstract

The application relates to the technical field of solid dispersion, and particularly discloses a berberine hydrochloride sustained-release solid dispersion and a preparation method thereof. The solid dispersion comprises berberine hydrochloride and ethyl cellulose with a mass ratio of (0.8-1.2):(3.8-4.2). In vitro experimental research shows that the solid dispersion releases about 35% in 0.5h, about 50% in 2h, no burst release occurs, about 85% in 12h, and basically complete drug release in 24h in a phosphate buffer solution with pH=6.8, and the solid dispersion has obvious stable sustained-release characteristics. Compared with the drug berberine hydrochloride, the bioavailability is increased by more than 8 times, so that various adverse effects of multiple daily dosing can be reduced. In addition, the berberine hydrochloride solid dispersion provided by the application has excellent stability, and no deterioration phenomenon exists in high-temperature and high-humidity storage for 2 months, so that the berberine hydrochloride solid dispersion has high practical value in the pharmaceutical field.

Description

Technical Field

[0001] This invention relates to the field of solid dispersion technology, and in particular to a sustained-release solid dispersion of berberine hydrochloride and its preparation method. Background Technology

[0002] Berberine hydrochloride (BBH), with the structure shown in formula (I), is the hydrochloride form of berberine. Berberine is a quaternary ammonium isoquinoline alkaloid extracted from plants of the Berberidaceae and Rutaceae families, primarily derived from traditional Chinese medicines such as Coptis chinensis, Phellodendron chinense, and Trifolium repens. It possesses a wide range of pharmacological effects, exhibiting good clinical efficacy in antibacterial, anti-inflammatory, antiviral, antitumor, and improvement of intestinal flora in poultry and livestock. However, the poor oral absorption of berberine hydrochloride, requiring frequent administration, limits its clinical application.

[0003]

[0004] To improve the bioavailability of berberine hydrochloride, scholars both domestically and internationally have conducted extensive research on sustained-release formulations, such as tablets, capsules, microspheres, liposomes, gels, nanoparticles, and solid dispersions. Solid dispersions refer to a solid dispersion system formed by highly dispersed one or more active ingredients in a suitable carrier. Although some literature reports the preparation of sustained-release formulations by combining berberine hydrochloride with sustained-release matrix materials or excipients, which has improved the dissolution rate of solid berberine hydrochloride formulations to some extent, the preparation methods are complex, the formulation composition is complex, and the ability to improve blood drug concentration and bioavailability is limited. Therefore, a new method is urgently needed to improve the drug release time of berberine hydrochloride and enhance its bioavailability. Summary of the Invention

[0005] To address the problems of poor oral absorption and frequent administration of existing berberine hydrochloride, this invention provides a sustained-release solid dispersion of berberine hydrochloride and its preparation method. This sustained-release solid dispersion of berberine hydrochloride has good stability, can significantly prolong the biological half-life of berberine hydrochloride, and effectively improve its bioavailability and drug safety.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] In a first aspect, the present invention provides a berberine hydrochloride sustained-release solid dispersion comprising berberine hydrochloride and a sustained-release carrier, wherein the mass ratio of berberine hydrochloride to the sustained-release carrier is (0.8-1.2):(3.8-4.2), and the sustained-release carrier is ethyl cellulose.

[0008] Compared to existing technologies, the berberine hydrochloride sustained-release solid dispersion provided by this invention uses ethyl cellulose as a sustained-release carrier to encapsulate berberine hydrochloride, forming a porous film on the outside of the berberine hydrochloride. This achieves a stable and slow release of berberine hydrochloride. In a phosphate buffer solution at pH 6.8, approximately 35% is released in 0.5 hours, approximately 50% in 2 hours (with no burst release), approximately 75% in 8 hours, approximately 85% in 12 hours, and almost complete release in 24 hours, exhibiting significant stable sustained-release characteristics. Furthermore, compared to the drug berberine hydrochloride, C... max AUC 0～72 and t 1 / 2 The bioavailability was increased by approximately 1.5 times, 8.4 times, and 7.9 times respectively, with a significant improvement in bioavailability. The bioavailability was more than 8 times higher than that of berberine hydrochloride, which can reduce the various adverse effects of multiple daily dosing, especially the adverse effects on the liver and kidneys, and is conducive to improving medication safety and patient compliance. In addition, the berberine hydrochloride solid dispersion provided by this invention also has excellent stability, and there is no deterioration after two months of storage under high temperature and high humidity conditions, which has high practical value in the pharmaceutical field.

[0009] This invention selects ethyl cellulose (EC) as a carrier, which is an inert hydrophobic polymer with advantages such as non-toxicity, good storage stability, good compressibility, and good hydrophobicity and swelling properties. Preparing berberine hydrochloride and ethyl cellulose into a solid dispersion effectively prevents the hydrolysis of chloride ions in berberine hydrochloride. Some of the hydroxyl groups in ethyl cellulose react with the benzene ring in berberine hydrochloride to form a water-insoluble phenol structure, maintaining the stability of the amorphous drug during storage. Simultaneously, the prepared berberine hydrochloride solid dispersion swells in water, forming a porous film on its surface, ensuring slow dissolution of the drug in the gastrointestinal tract and providing a constant drug concentration, thereby guaranteeing the therapeutic effect of berberine hydrochloride and improving its bioavailability.

[0010] It should be noted that in the berberine hydrochloride sustained-release solid dispersion, berberine hydrochloride exists in an amorphous state. The term "amorphous" solid in this invention refers to its non-crystalline state.

[0011] Furthermore, the mass ratio of berberine hydrochloride to the sustained-release carrier is 1:4.

[0012] The optimal type and proportion of sustained-release carrier can further improve the stability, sustained-release effect, and bioavailability of berberine hydrochloride solid dispersion.

[0013] Secondly, the present invention provides a method for preparing a sustained-release solid dispersion of berberine hydrochloride, comprising the following steps:

[0014] Berberine hydrochloride and a sustained-release carrier were mixed in a certain proportion, dry-milled, ground, and sieved to obtain a sustained-release solid dispersion of berberine hydrochloride.

[0015] As a specific embodiment of the present invention, the preparation method of the berberine hydrochloride sustained-release solid dispersion specifically includes the following steps:

[0016] The sustained-release carrier and berberine hydrochloride were mixed evenly to obtain a dispersed powder. The dispersed powder was placed in a ball mill, milled, and the sample was taken out, ground, and sieved to obtain a sustained-release dispersion of berberine hydrochloride, which was then placed in a drying oven for later use.

[0017] Furthermore, the rotational speed of the dry ball mill is 1200 r / min to 1400 r / min.

[0018] Furthermore, the dry ball milling time is 60 min to 180 min.

[0019] Furthermore, the sieving is performed through an 80-mesh sieve.

[0020] The preparation method of berberine hydrochloride sustained-release solid dispersion provided by the present invention is simple to operate, has good reproducibility, and low production cost. Moreover, the preparation process does not involve toxic or low-toxicity organic solvents, further ensuring the effectiveness and safety of the drug and making it suitable for large-scale production of berberine hydrochloride sustained-release solid dispersion.

[0021] Thirdly, the present invention also provides a pharmaceutical composition comprising the berberine hydrochloride sustained-release solid dispersion.

[0022] Fourthly, the present invention also provides a pharmaceutical formulation comprising the berberine hydrochloride sustained-release solid dispersion or the pharmaceutical composition described in any one of the preceding claims.

[0023] Furthermore, the pharmaceutical preparation also includes pharmaceutically acceptable excipients.

[0024] Furthermore, the dosage form of the pharmaceutical preparation includes tablets, capsules, granules, pills, powders, or suspensions.

[0025] It should be noted that the berberine hydrochloride sustained-release solid dispersion provided by this invention can be formulated into various dosage forms using conventional formulation processes in the art to facilitate administration to different types of patients. This invention does not impose any special limitations on the preparation methods for each dosage form; existing technologies can be used.

[0026] To address the issue of poor bioabsorption of berberine hydrochloride, which necessitates multiple administrations to maintain effective drug concentrations, this invention provides a berberine hydrochloride solid dispersion. In vitro studies have shown that this solid dispersion exhibits excellent storage stability, effectively prolongs the drug release time of berberine hydrochloride, and significantly improves its bioavailability, thereby reducing the frequency of administration, minimizing adverse reactions associated with multiple administrations, and enhancing patient compliance. Furthermore, this invention utilizes dry ball milling to prepare the berberine hydrochloride solid dispersion, a simple and efficient preparation method that avoids the use of organic solvents, further ensuring drug safety and efficacy. This invention has broad application prospects in the field of pharmaceutical formulations. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0028] Figure 1 These are powder X-ray diffraction (PXRD) patterns of berberine hydrochloride (BBH), ethyl cellulose (EC), the sustained-release solid dispersion of berberine hydrochloride obtained in Example 1 (BBH-EC(1:4)), sample powders of different proportions prepared in Comparative Example 1 (BBH-EC(1:2), BBH-EC(1:6)), and physical blend sample powders of different proportions prepared in Comparative Example 2 (PM-1, PM-2, PM-3);

[0029] Figure 2 These are powder X-ray diffraction (PXRD) patterns of berberine hydrochloride (BBH), hydroxypropyl methylcellulose (HPMC), and BBH-HPMC (1:4) samples in Comparative Example 3 of this invention.

[0030] Figure 3 These are powder X-ray diffraction (PXRD) patterns of berberine hydrochloride (BBH), methacrylate-ethyl acrylate copolymer (ME), and BBH-ME (1:4) samples in Comparative Example 4 of this invention;

[0031] Figure 4 These are differential scanning calorimetry (DSC) images of berberine hydrochloride (BBH), ethyl cellulose (EC), berberine hydrochloride sustained-release solid dispersion (BBH-EC(1:4)) in Example 1, and PM-2 sample in Comparative Example 2.

[0032] Figure 5These are Fourier transform infrared (FT-IR) spectra of berberine hydrochloride (BBH), ethyl cellulose (EC), the sustained-release solid dispersion of berberine hydrochloride (BBH-EC(1:4)) in Example 1, and the PM-2 sample in Comparative Example 2.

[0033] Figure 6 This is an in vitro dissolution curve of berberine hydrochloride (BBH) of the present invention, the berberine hydrochloride sustained-release solid dispersion (BBH-EC(1:4)) in Example 1, the BBH-EC(1:6) sample powder prepared in Comparative Example 1, and the PM-2 and PM-3 samples in Comparative Example 2.

[0034] Figure 7 This is an in vitro dissolution curve of berberine hydrochloride (BBH) and BBH-ME (1:4) samples in Comparative Example 4 of this invention;

[0035] Figure 8 This is an in vitro dissolution curve of berberine hydrochloride (BBH) and BBH-S100 (1:4) samples in Comparative Example 5 of this invention;

[0036] Figure 9 These are powder X-ray diffraction (PXRD) images of berberine hydrochloride (BBH), ethyl cellulose (EC), and berberine hydrochloride sustained-release solid dispersion (BBH-EC(1:4)) placed under high temperature and high humidity conditions for different times in Example 1 of this invention.

[0037] Figure 10 The above are in vitro dissolution curves of berberine hydrochloride sustained-release solid dispersion (BBH-EC(1:4)) in Example 1 of the present invention after being placed under high temperature and high humidity conditions for different times.

[0038] Figure 11 This is a graph showing the changes in blood drug concentrations of berberine hydrochloride (BBH) and berberine hydrochloride sustained-release solid dispersion (BBH-EC(1:4)) in Example 1 of this invention. Detailed Implementation

[0039] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0040] Example 1

[0041] This invention provides a sustained-release solid dispersion of berberine hydrochloride, wherein the mass ratio of berberine hydrochloride (BBH) to ethyl cellulose (EC) is 1:4.

[0042] The preparation method of the above-mentioned berberine hydrochloride sustained-release solid dispersion is as follows:

[0043] Accurately weigh 20 mg of berberine hydrochloride raw material, add ethyl cellulose at a mass ratio of 1:4, mix evenly, add to a ball mill, and ball mill at 1200 r / min for 90 min. After ball milling, remove the drug, grind it, and pass it through an 80 mesh sieve to obtain berberine hydrochloride sustained-release dispersion, which is then placed in a drying oven for later use.

[0044] Example 2

[0045] This invention provides a sustained-release solid dispersion of berberine hydrochloride, wherein the mass ratio of berberine hydrochloride (BBH) to ethyl cellulose (EC) is 0.8:4.2.

[0046] The preparation method of the above-mentioned berberine hydrochloride sustained-release solid dispersion is as follows:

[0047] Accurately weigh 20 mg of berberine hydrochloride raw material, add ethyl cellulose at a mass ratio of 0.8:4.2, mix evenly, add to a ball mill, and ball mill at 1300 r / min for 180 min. After ball milling, remove the drug, grind it, and pass it through an 80 mesh sieve to obtain berberine hydrochloride sustained-release dispersion BBH-EC (1:4), which is then placed in a drying oven for later use.

[0048] Example 3

[0049] This invention provides a sustained-release solid dispersion of berberine hydrochloride, wherein the mass ratio of berberine hydrochloride (BBH) to ethyl cellulose (EC) is 1.2:3.8.

[0050] The preparation method of the above-mentioned berberine hydrochloride sustained-release solid dispersion is as follows:

[0051] Accurately weigh 20 mg of berberine hydrochloride raw material, add ethyl cellulose at a mass ratio of 1.2:3.8, mix evenly, add to a ball mill, and ball mill at 1400 r / min for 60 min. After ball milling, remove the drug, grind it, and pass it through an 80 mesh sieve to obtain berberine hydrochloride sustained-release dispersion, which is then placed in a drying oven for later use.

[0052] Comparative Example 1

[0053] The only difference between this comparative example and Example 1 is that the mass ratio of berberine hydrochloride to ethyl cellulose is replaced with 1:2 and 1:6, respectively. Sample powders BBH-EC (1:2) and BBH-EC (1:6) were prepared using the same method as in Example 1.

[0054] Comparative Example 2

[0055] This comparative example provides three physical mixtures. Each component was weighed according to the mass ratio of berberine hydrochloride to ethyl cellulose of 1:2, 1:4 and 1:6 respectively. The weighed components were then placed in a mortar and ground with a pestle to obtain physical mixtures PM-1 (1:2), PM-2 (1:4) and PM-3 (1:6).

[0056] Comparative Example 3

[0057] The only difference between this comparative example and Example 1 is that ethyl cellulose is replaced with an equal amount of hydroxypropyl methyl cellulose (HPMC). That is, the sample powder provided in this comparative example includes berberine hydrochloride and hydroxypropyl methyl cellulose in a mass ratio of 1:4.

[0058] BBH-HPMC (1:4) sample powder was prepared using the same method as in Example 1.

[0059] Comparative Example 4

[0060] The only difference between this comparative example and Example 1 is that ethyl cellulose is replaced with an equal amount of methacrylic acid-ethyl acrylate copolymer (ME). That is, the sample powder of this comparative example includes berberine hydrochloride and methacrylic acid-ethyl acrylate copolymer in a mass ratio of 1:4.

[0061] BBH-ME (1:4) sample powder was prepared using the same method as in Example 1.

[0062] Comparative Example 5

[0063] This comparative example provides a berberine hydrochloride solid dispersion comprising berberine hydrochloride and Eudragit S100 in a mass ratio of 1:4.

[0064] The preparation method of the above-mentioned berberine hydrochloride solid dispersion includes the following steps:

[0065] Accurately weigh 20 mg of berberine hydrochloride raw material, weigh Eudragit S100 at a mass ratio of 1:4, mix thoroughly, add 95% ethanol solution at a total mass concentration of 30 g / L, heat and stir at 45°C for 30 min until completely dissolved; then transfer to a distillation flask, remove solvent under reduced pressure, dry at 40°C for 48 h, and pass through a 100-mesh sieve to obtain BBH-S100(1:4) sample powder.

[0066] Sample determination and structural characterization

[0067] To better illustrate the characteristics of the BBH-EC(1:4) samples prepared in the embodiments of the present invention, the sample powders prepared in Example 1 and Comparative Examples 1 to 5 were measured and characterized structurally. The specific methods are as follows:

[0068] 1. Powder X-ray Diffraction (PXRD)

[0069] Powder X-ray diffraction (PXRD) was performed using a TD-3700 X-ray diffractometer (Dandong Tongda Technology Co., Ltd.). Before measuring the sample, a silicon sample was used for calibration, and the sample was measured after meeting the requirements.

[0070] Measurement conditions: Cu Kα radiation The tube voltage is 40kV, the tube current is 15mA, the test step size is 0.01°, the scan speed is 20° / min, the scan range is 5°~35°, and the test temperature is room temperature (20℃~30℃).

[0071] After sieving, the powder samples of BBH, EC, BBH-EC (1:4) prepared in Example 1, and powder samples of different proportions prepared in Comparative Examples 1 and 2 were spread evenly in the sample trough and tested under the conditions described above. The results are as follows: Figure 1 As shown.

[0072] from Figure 1 As can be seen, BBH exhibits obvious crystal diffraction peaks at 2θ = 8.92°, 15.21°, 22.84°, 25.47°, and 26.35°, indicating that BBH is a crystalline drug. EC, on the other hand, shows no obvious characteristic diffraction peaks, indicating that EC is an amorphous form. The BBH-EC (1:4) sample prepared in Example 1 did not show any crystal diffraction peaks, proving that BBH completely transformed from a crystalline state to an amorphous state dispersed in the carrier. That is, the BBH-EC (1:4) sample prepared in this embodiment of the invention is an amorphous solid dispersion.

[0073] The powder samples BBH-EC (1:2) prepared in Comparative Example 1 showed a crystal diffraction peak at 25.47°, while the BBH-EC (1:6) sample did not show any crystal diffraction peak. This indicates that BBH in the BBH-EC (1:2) sample in Comparative Example 1 did not completely form an amorphous state, while BBH in the BBH-EC (1:6) sample completely transformed from a crystalline state to an amorphous state and dispersed in the support.

[0074] The physical mixtures PM-1, PM-2, and PM-3 prepared in Comparative Example 2 also showed characteristic diffraction peaks, and the positions of the diffraction peaks were the same as those of BBH, but the peak intensities were weaker than those of BBH, indicating that crystalline BBH was also present in the three physical mixtures prepared in Comparative Example 2.

[0075] The PXRD patterns of BBH, HPMC, and BBH-HPMC (1:4) prepared in Comparative Example 3 are shown below. Figure 2 As shown.

[0076] from Figure 2 As can be seen, BBH exhibits obvious crystal diffraction peaks at 2θ = 8.92°, 15.21°, 22.84°, 25.47°, and 26.35°, indicating that BBH is a crystalline drug. HPMC, on the other hand, shows no obvious characteristic diffraction peaks, indicating that HPMC is in an amorphous state. The BBH-HPMC (1:4) prepared in Comparative Example 3 shows obvious crystal diffraction peaks at 2θ = 7.97° and 20.01°, indicating that BBH in BBH-HPMC (1:4) did not completely transform from a crystalline state to an amorphous state.

[0077] The PXRD patterns of BBH, ME, and BBH-ME (1:4) prepared as control 4 are shown below. Figure 3 As shown.

[0078] from Figure 3 As can be seen, BBH exhibits distinct crystal diffraction peaks at 2θ = 8.92°, 15.21°, 22.84°, 25.47°, and 26.35°, indicating that BBH is a crystalline drug. ME, on the other hand, shows no obvious characteristic diffraction peaks, indicating that ME is an amorphous form. The BBH-ME (1:4) prepared in Comparative Example 4 did not show any crystal diffraction peaks, demonstrating that in BBH-ME (1:4), BBH completely transforms from a crystalline state to an amorphous state dispersed in the support.

[0079] 2. Differential Scanning Calorimetry (DSC)

[0080] Differential scanning calorimetry (DSC) was performed on BBH, EC, BBH-EC (1:4) prepared in Example 1, and PM-2 prepared in Comparative Example 2. The testing procedure was as follows:

[0081] After grinding, sieving, drying and removing water from 4 mg of the sample, place it in a standard aluminum pan and seal it. The test conditions are: temperature range 25℃~250℃, heating rate 10℃ / min, nitrogen protection, and nitrogen flow rate 50mL / min.

[0082] from Figure 4As can be seen from the BBH graph, there are dehydration peaks of BBH at 116℃ and 134℃, and a sharp endothermic peak at 195℃, which is the melting point peak of BBH. EC did not show any endothermic peaks during the temperature rise. In the BBH-EC (1:4) prepared in Example 1, the dehydration peak of BBH disappeared, and the endothermic peak became smaller and shifted to 177℃, indicating that BBH was dispersed in the carrier in an amorphous state, which is consistent with the above PXRD results. In the physical mixture PM-2 prepared in Comparative Example 2, a dehydration peak appeared, and the melting point peak of BBH was visible at 195℃, indicating the presence of crystalline BBH in PM-2, and also proving that the carrier and the active pharmaceutical ingredient in Comparative Example 2 were physically mixed.

[0083] 3. Fourier Transform Infrared Spectroscopy (FT-IR)

[0084] The tableting method was used. First, potassium bromide was ground and sieved into a powder smaller than 2 μm, then dried for later use. At a mass ratio of 1:100 (sample to potassium bromide), 2 mg of the sample and potassium bromide powder were placed in a mortar, ground and mixed thoroughly, and then compressed into tablets. The testing conditions were: wavenumber range 4000 cm⁻¹. -1 ~400cm -1 The resolution is 0.1cm. -1 .

[0085] Infrared detection was performed on BBH, EC, BBH-EC (1:4) prepared in Example 1, and PM-2 prepared in Comparative Example 2. The results are as follows: Figure 5 As shown.

[0086] from Figure 5 As can be seen from this, BBH is 3402cm -1 There is a stretching vibration peak representing nitrogen-benzene at 1599 cm⁻¹. -1 1505cm -1 and 1387cm -1 It has a C=C stretching vibration peak at 1034 cm⁻¹. -1 It exhibits a stretching vibration peak at -COC-. EC is at 3486 cm⁻¹. -1 There is a stretching vibration peak of OH at 2978 cm⁻¹. -1 There is a CH stretching vibration peak at 1113 cm⁻¹. -1 A stretching vibration peak is present at -COC-. In the BBH-EC (1:4) prepared in Example 1, the benzene ring of BBH reacts with the OH group of EC, causing a blue shift in the stretching vibration peak of the nitrogen-based benzene in BBH, from 3402 cm⁻¹. -1 Migration to 3476cm -1 The stretching vibration of the OH group in EC undergoes a redshift from 3486 cm⁻¹. -1 Migration to 3476cm -1The absorption band intensity of the stretching vibration peak increases and narrows; the -COC- stretching vibration peak of BBH undergoes a blue shift, from 1034 cm⁻¹. -1 Migration to 1107cm -1 The -COC- stretching vibration peak of EC undergoes a redshift, from 1113 cm⁻¹. -1 Migration to 1107cm -1 The increased intensity and broadening of the stretching vibration peak absorption band indicate that an interaction has occurred between BBH and EC molecules, and the solid dispersion has been successfully prepared. In contrast, the physical mixture PM-2 prepared in Comparative Example 2 showed functional group bands for both BBH and EC, indicating that no interaction occurred between BBH and the support molecules; it was simply a physical mixture.

[0087] 4. In vitro dissolution test

[0088] 4.1 Example 1 and Comparative Examples 1-2

[0089] Weigh 450 mg of berberine hydrochloride and ethyl cellulose in the corresponding proportion, and prepare sample powders according to the methods of Example 1 and Comparative Examples 1-2, respectively, to obtain solid dispersions BBH-EC (1:4) and BBH-EC (1:6) containing 450 mg of BBH raw material and physical mixtures PM-2 and PM-3.

[0090] The solid dispersion, physical mixture, and 450 mg of BBH active pharmaceutical ingredient obtained above were added to 900 mL of pH 6.8 phosphate buffer solution. In vitro dissolution tests were conducted at (37±5)℃ and 200 rpm. Timing was initiated from the start of powder contact with the medium. At 0.17 h, 0.33 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, 0.5 mL of solution was collected and immediately replenished with an equal volume of medium. The collected solution was then immediately filtered through a 0.22 μm filter and measured three times in parallel at a wavelength of 350 nm. The average value was taken, and the cumulative dissolution rate of the drug at each time point was calculated. The cumulative dissolution results of each sample powder are shown below. Figure 6 As shown.

[0091] from Figure 6As can be seen, BBH achieved a cumulative dissolution rate of 98.02% after 10 minutes and 100% after 30 minutes. In Comparative Example 1, BBH-EC (1:6) had a cumulative dissolution rate of 40.67% after 10 minutes and 62.61% after 2 hours, continuing to rise. The cumulative dissolution rate reached 78.62% after 12 hours and 81.39% after 24 hours; however, the increase in cumulative dissolution rate was slower at 12 hours and did not reach over 90% at 24 hours. In Comparative Example 2, PM-2 achieved a cumulative dissolution rate of 70.37% after 10 minutes and 96.03% after 2 hours, then tended to stabilize. In Comparative Example 2, PM-3 achieved a cumulative dissolution rate of 73.87% after 10 minutes and 95.11% after 2 hours, then tended to stabilize. The cumulative dissolution rate of BBH-EC (1:4) prepared in Example 1 was only 29.47% at 10 min, and 50.22% after 2 h, and continued to rise, reaching 93.88% at 24 h. This indicates that the berberine hydrochloride solid dispersion prepared by ball milling with ethyl cellulose as a carrier significantly prolongs the release time of BBH, and BBH-EC (1:4) is superior to BBH-EC (1:6).

[0092] 4.2 Comparative Example 4

[0093] Weigh 450 mg of berberine hydrochloride and 1.8 g of methacrylate-ethyl acrylate copolymer, and prepare sample powder according to the method of Comparative Example 4 to obtain a solid dispersion BBH-ME (1:4) containing 450 mg of BBH active pharmaceutical ingredient.

[0094] The in vitro dissolution test was performed using the same method as described above, and the results are as follows: Figure 7 As shown.

[0095] from Figure 7 As can be seen, the cumulative dissolution rate of BBH reaches over 90% within 10 minutes and tends to be stable. The BBH-ME (1:4) prepared in Comparative Example 4 has a cumulative dissolution rate of 56.55% within 10 minutes, 88.31% within 1 hour, and over 90% within 2 hours, also tending to be stable. Therefore, it can be concluded that BBH-ME (1:4) prepared by ball milling can prolong the release time of BBH to some extent, but the effect is not significant.

[0096] 4.3 Comparative Example 5

[0097] Weigh 15 mg of berberine hydrochloride and 60 mg of Eudragit S100, and prepare sample powder according to the method of Comparative Example 5 to obtain a solid dispersion BBH-S100 (1:4) containing 15 mg of BBH raw material.

[0098] The BBH-S100 (1:4) solid dispersion and 15 mg of BBH active pharmaceutical ingredient were added to 750 mL of pH 6.8 phosphate buffer solution at (37±0.5)℃ and 200 rpm for in vitro dissolution testing. 0.5 mL of solution was taken at 0.17 h, 0.33 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, and an equal volume of medium was immediately added. The collected solutions were then immediately filtered through a 0.22 μm filter membrane, and the absorbance was measured at 350 nm. Trials were performed, and the average value was taken. The results are shown below. Figure 8 As shown.

[0099] from Figure 8 As can be seen, the cumulative dissolution rate of BBH reaches over 90% within 10 minutes and tends to be stable. The BBH-S100 (1:4) prepared in Comparative Example 5 has a cumulative dissolution rate of 24.84% within 10 minutes, 47.92% within 1 hour, 54.1% within 2 hours and tends to be stable, and 57.99% within 24 hours. Therefore, BBH-S100 (1:4) prepared by solvent evaporation can prolong the release time of BBH to some extent, but the effect is not significant. The specific cumulative dissolution rate data of the above examples and comparative examples at different times are shown in Table 1.

[0100] Table 1. Cumulative dissolution rate (%) of different sample powders in pH 6.8 phosphate buffer.

[0101]

[0102]

[0103] The results show that the berberine hydrochloride solid dispersions prepared from ethyl cellulose, methacrylate-ethyl acrylate copolymer and Eudragit S100 as carriers all have certain sustained-release properties.

[0104] Ethyl cellulose is an inert hydrophobic substance with non-toxicity, good storage stability, good compressibility, and hydrophobic and swelling capabilities, making it suitable for sustained-release formulations. This invention prepares a sustained-release solid dispersion by combining berberine hydrochloride and ethyl cellulose, ensuring slow drug release throughout the gastrointestinal tract and providing a constant drug concentration. The BBH-EC (1:6) prepared in Comparative Example 1 did not achieve a cumulative dissolution rate of 90% in pH 6.8 phosphate buffer, possibly due to an excessively high EC ratio, which reduced the pore size of the swollen film, ultimately hindering contact between some BBH and water, resulting in a final dissolution rate below 90%.

[0105] Methacrylate-ethyl acrylate copolymer is a type of polyacrylic acid resin that is non-irritating and non-toxic. It swells in water and is commonly used as a coating material for gastric, enteric, and sustained-release formulations. In this invention, the sustained-release effect of BBH-ME (1:4) is not significant, possibly due to a mismatch between the drug and the carrier.

[0106] Eudragit S100 is also a type of polyacrylic acid resin and a commonly used pH-dependent enteric coating material. It dissolves in media with a pH above 7.0, which can significantly reduce drug release in the stomach and small intestine. In this invention, the sustained-release effect of BBH-S100 (1:4) was not significant, which may be related to the pH dependence of the drug formulation and carrier.

[0107] In summary, the solid dispersion BBH-EC (1:4) prepared by mixing berberine hydrochloride and ethyl cellulose exhibits the best in vitro dissolution effect and sustained-release performance.

[0108] 5. Stability test

[0109] 30 mg of the BBH-EC (1:4) solid dispersion prepared in Example 1 was weighed and dispersed in a petri dish. The dish was placed in a drug stability test chamber at 40°C and 75% humidity. Samples were taken at 0, 15, 30, and 60 days for powder X-ray diffraction. The results are as follows: Figure 9 As shown, samples were taken at 7 days, 30 days, and 60 days for in vitro dissolution analysis, and the results are as follows. Figure 10 As shown.

[0110] from Figure 9 As can be seen, within the range of 0–60 days, the BBH-EC (1:4) solid dispersion prepared in Example 1 did not exhibit any diffraction peaks of any crystal form. Figure 10 As can be seen, the dissolution curves of 7d, 30d, and 60d almost coincide with the dissolution curve of the 0d sample, that is, the dissolution effect of BBH-EC(1:4) did not decrease after 60d of storage at 40℃ and 75%RH. Together with the PXRD results, it is proved that the BBH-EC(1:4) solid dispersion prepared by ball milling in this invention has excellent stability under high temperature and high humidity conditions.

[0111] 6. Pharmacokinetics test

[0112] Twenty male SD rats aged 7-8 weeks, weighing 250±20g, were purchased from Spiford (Beijing) Biotechnology Co., Ltd. After one week of acclimatization, they were randomly divided into two groups: the berberine hydrochloride group (BBH group) and the berberine hydrochloride sustained-release solid dispersant group obtained in Example 1 (BBH-EC(1:4) group). Both groups had free access to water and food during the acclimatization period, but were fasted for 12 hours before the experiment.

[0113] Drug administration and sampling

[0114] The BBH group and the BBH-EC (1:4) group obtained in Example 1 were dispersed in a 0.5 wt% sodium carboxymethyl cellulose solution. The rats were given the BBH solution by gavage at a dose of 100 mg / kg. Then, at 0.083 h, 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h and 72 h, respectively, about 0.5 mL of blood was collected from the posterior orbital venous plexus of the rats. The blood was placed in a centrifuge tube containing sodium heparin and centrifuged at 12000 r / min for 10 min. The plasma was then collected and stored at -20 °C for later use.

[0115] The plasma sample was processed as follows: 100 μL of plasma sample was added to 100 μL of acetonitrile, vortexed for 3 min, centrifuged at 12000 rpm for 10 min, and the supernatant was filtered through a 0.25 μm filter membrane. The BBH content was then determined by high performance liquid chromatography (HPLC).

[0116] The HPLC chromatographic conditions were as follows: column: Waters Sun Fire C18 (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile: 0.1% phosphoric acid aqueous solution = 0.25:0.75; flow rate: 1.0 mL / min; column temperature: 37 ℃; injection volume: 20 μL; detection wavelength: 345 nm.

[0117] The pharmacokinetic data were analyzed using DAS2.0 software to calculate the area under the curve (AUC) of the drug-time curve. 0～∞ ), maximum blood concentration (C max Peak time (T) max ), half-life (T) 1 / 2 ), stay time (MRT) 0～∞ Pharmacokinetic parameters such as pharmacokinetic parameters were calculated and analyzed. SPSS 23.0 software was used for significant difference analysis of the data, and the results are shown in Table 2 and... Figure 11 As shown.

[0118] Table 2 Comparison of pharmacokinetic parameters of oral BBH and BBH-EC (1:4) in rats (n=10)

[0119] Pharmacokinetic parameters BBH API BBH-EC (1:4) solid dispersion <![CDATA[T max (0~24)(h)]]> <![CDATA[1 b ]]> <![CDATA[2 a ]]> <![CDATA[C max (0~24)(μg / L)]]> <![CDATA[439.61±23.87 b ]]> <![CDATA[668.86±24.76 a ]]> <![CDATA[t 1 / 2 (0~24)(h)]]> <![CDATA[1.83±0.25 b ]]> <![CDATA[11.02±1.22 a ]]> <![CDATA[AUC 0～24 (μg·h / L)]]> <![CDATA[990.65±91.27 b ]]> <![CDATA[6498.70±255.21 a ]]> <![CDATA[t 1 / 2 (0~72)(h)]]> — 14.47±1.41 <![CDATA[AUC 0～72 (μg·h / L)]]> — 8338.49±446.91

[0120] Note: Different lowercase letters in the same row subscript indicate significant differences (P<0.05); different uppercase letters in the subscript indicate extremely significant differences (P<0.01); the same letter or no letter in the subscript indicates no significant differences (P>0.05).

[0121] The results show that the peak time T of BBH-EC(1:4) is...max Extending the time from 1 h to 2 h, the peak concentration of BBH was 439.61 μg / L, while the peak concentration of BBH-EC (1:4) (668.86 μg / L) was significantly higher (P < 0.01), and the peak concentration of BBH-EC (1:4) was 1.52 times that of BBH. The t-value of BBH-EC (1:4) was... 1 / 2 The AUC of BBH-EC (1:4) was extended to 11.02 h compared to BBH (1.83 h). 0-24 (6498.695 μg·h / L) is 6.56 times that of BBH (990.647 μg·h / L). Within 72 h, the AUC of BBH-EC (1:4) is... 0-72 and t 1 / 2 The concentrations were 8338.493 μg·h / L and 14.47 h, respectively, with AUC... 0～72 It is 8.42 times that of BBH, t 1 / 2 It is 7.91 times that of BBH.

[0122] Because BBH-EC (1:4) can be slowly released in the gastrointestinal tract, thereby slowing down the recrystallization rate of berberine hydrochloride during its absorption in the gastrointestinal tract, the bioavailability of the solid dispersion BBH-EC (1:4) is 8.42 times higher than that of berberine hydrochloride.

[0123] The berberine hydrochloride prepared in Examples 2 and 3 can achieve the same technical effect as that in Example 1.

[0124] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A sustained-release solid dispersion of berberine hydrochloride, characterized in that, It is composed of berberine hydrochloride and a sustained-release carrier, wherein the mass ratio of berberine hydrochloride to sustained-release carrier is (0.8~1.2):(3.8~4.2), and the sustained-release carrier is ethyl cellulose.

2. The berberine hydrochloride sustained-release solid dispersion as described in claim 1, characterized in that, The mass ratio of berberine hydrochloride to the sustained-release carrier is 1:

4.

3. A method for preparing the sustained-release solid dispersion of berberine hydrochloride as described in claim 1 or 2, characterized in that, Includes the following steps: Berberine hydrochloride and a sustained-release carrier were mixed in a certain proportion, dry-milled, ground, and sieved to obtain a sustained-release solid dispersion of berberine hydrochloride.

4. The method for preparing the sustained-release solid dispersion of berberine hydrochloride as described in claim 3, characterized in that, The rotational speed of the dry ball mill is 1200 r / min to 1400 r / min.

5. The method for preparing the sustained-release solid dispersion of berberine hydrochloride as described in claim 3, characterized in that, The dry ball milling time is 60 min to 180 min.

6. The method for preparing the sustained-release solid dispersion of berberine hydrochloride as described in claim 3, characterized in that, The sieving process is an 80-mesh sieve.

7. A pharmaceutical composition, characterized in that, Includes the berberine hydrochloride sustained-release solid dispersion as described in claim 1 or 2.

8. A pharmaceutical preparation, characterized in that, Includes the berberine hydrochloride sustained-release solid dispersion as described in claim 1 or 2, or the pharmaceutical composition as described in claim 7.

9. The pharmaceutical preparation according to claim 8, characterized in that, It also includes pharmaceutically acceptable excipients.

10. The pharmaceutical formulation as described in claim 8 or 9, characterized in that, The dosage forms of the pharmaceutical preparations include tablets, capsules, granules, pills, powders, or suspensions.

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