Berberine hydrochloride sustained-release solid dispersion and preparation method thereof

Abstract

The invention relates to the technical field of solid dispersions, and particularly discloses a berberine hydrochloride sustained-release solid dispersion and a preparation method thereof. The invention discloses a berberine hydrochloride preservative which comprises berberine hydrochloride and ethyl cellulose in a mass ratio of (0.8-1.2): (3.8-4.2). In-vitro experiment research shows that the solid dispersion releases about 35% in 0.5 h and about 50% in 2 h in a phosphate buffer solution with the pH value of 6.8, no burst release occurs, about 85% is released in 12 h, drug release in 24 h is basically complete, and the solid dispersion has an obvious stable slow release characteristic; compared with the drug berberine hydrochloride, the bioavailability is improved by more than 8 times, so that various adverse effects caused by multiple times of administration every day can be reduced; in addition, the berberine hydrochloride solid dispersion provided by the invention also has excellent stability, does not have a deterioration phenomenon after being stored for 2 months under high-temperature and high-humidity conditions, and has a relatively high practical value in the field of pharmacy.

Description

Technical Field

[0001] The present invention relates to the technical field of solid dispersions, and in particular to a berberine hydrochloride sustained-release solid dispersion and a preparation method thereof. Background Art

[0002] Berberine hydrochloride (BBH) has a structure as shown in formula (I), which is the hydrochloride form of berberine. Berberine is a quaternary amine isoquinoline alkaloid extracted from plants such as Berberaceae and Rutaceae, mainly derived from Chinese medicines such as Coptis chinensis, Phellodendron chinense and Tripterygium wilfordii, and has a wide range of pharmacological effects, and has good clinical effects in terms of antibacterial, anti-inflammatory, antiviral, anti-tumor and improving intestinal flora of poultry and livestock. However, berberine hydrochloride has poor oral absorption and frequent administration, which limits its clinical application.

[0003]

[0004] In order to improve the bioavailability of berberine hydrochloride, domestic and foreign scholars have carried out a large number of studies on sustained-release preparations, such as tablets, capsules, microspheres, liposomes, gels, nanoparticles and solid dispersions. Solid dispersion refers to a solid dispersion system formed by highly dispersing one or more active ingredients in a suitable carrier. Although there are literature reports that berberine hydrochloride is made into a sustained-release preparation with a sustained-release skeleton material or an additive, which improves the dissolution rate of berberine hydrochloride solid preparations to a certain extent, the preparation method is complicated and the preparation ingredients are complicated, and the ability to improve blood drug concentration and bioavailability is limited. Therefore, there is an urgent need for a new method to improve the drug release time of berberine hydrochloride and improve its bioavailability. Summary of the invention

[0005] In view of the problems of poor oral absorption and frequent administration of existing berberine hydrochloride, the present invention provides a berberine hydrochloride sustained-release solid dispersion and a preparation method thereof. The berberine hydrochloride sustained-release solid dispersion has good stability, can significantly prolong the biological half-life of berberine hydrochloride, and effectively improve its bioavailability and medication safety.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[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 the 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 with the prior art, the berberine hydrochloride sustained-release solid dispersion provided by the present invention uses ethyl cellulose as a sustained-release carrier to encapsulate berberine hydrochloride, and forms a porous film on the outside of berberine hydrochloride, thereby realizing the stable and slow release of berberine hydrochloride. In a phosphate buffer solution of pH=6.8, about 35% is released in 0.5h, about 50% is released in 2h, and no sudden release occurs. About 75% is released in 8h, about 85% is released in 12h, and the drug release is basically complete in 24h, and it has obvious stable and sustained-release characteristics; and compared with the drug berberine hydrochloride, C max , AUC 0～72 and t 1 / 2 The bioavailability is increased by about 1.5 times, 8.4 times and 7.9 times respectively, and the bioavailability is significantly improved. The bioavailability is increased by more than 8 times compared with berberine hydrochloride, thereby reducing various adverse effects of multiple daily administrations, especially the adverse effects on the liver and kidneys, which is beneficial to improving the safety of medication and the medication compliance of patients; in addition, the berberine hydrochloride solid dispersion provided by the present invention also has excellent stability, and there is no deterioration when stored for 2 months under high temperature and high humidity conditions, and has high practical value in the pharmaceutical field.

[0009] The present invention selects ethyl cellulose (EC) as a carrier, which is an inert hydrophobic polymer with the advantages of being non-toxic, having good storage stability, good compressibility, and having good hydrophobicity and swelling properties. Berberine hydrochloride and ethyl cellulose are made into a solid dispersion, which can effectively prevent the hydrolysis of chloride ions in berberine hydrochloride, and some of the hydroxyl groups contained in it react with the benzene ring in berberine hydrochloride to form a phenol structure that is insoluble in water, maintaining the stability of the amorphous drug during storage. At the same time, the prepared berberine hydrochloride solid dispersion can form a porous film on its surface after swelling in water, ensuring that the drug slowly dissolves in the gastrointestinal tract and providing a constant drug concentration, thereby ensuring 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 solid in the "amorphous" solid form of the present invention means that it is in a non-crystalline state.

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

[0012] The preferred type and addition ratio of the sustained-release carrier are beneficial to further improve the stability, sustained-release effect and bioavailability of the berberine hydrochloride solid dispersion.

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

[0014] The berberine hydrochloride and the sustained-release carrier are mixed in proportion, dry-milled, ground, and sieved to obtain a berberine hydrochloride sustained-release solid dispersion.

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

[0016] The sustained-release carrier and berberine hydrochloride are mixed uniformly to obtain a dispersed powder; the dispersed powder is placed in a ball mill, and after ball milling, a sample is taken out, ground, sieved, and a berberine hydrochloride sustained-release dispersion is obtained, which is placed in a drying oven for later use.

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

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

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

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

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

[0022] In a fourth aspect, the present invention further provides a pharmaceutical preparation comprising any one of the above-mentioned berberine hydrochloride sustained-release solid dispersions or pharmaceutical compositions.

[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 the present invention can be prepared into various dosage forms by conventional preparation processes in the art to facilitate different types of patients to take it. The present invention does not specifically limit the preparation method of each dosage form, and the existing technology can be used.

[0026] In view of the problem that berberine hydrochloride has poor bioabsorption, which requires multiple administrations to maintain effective drug concentrations, the present invention provides a berberine hydrochloride solid dispersion. In vitro experimental studies have shown that the solid dispersion has excellent storage stability, can effectively prolong the drug release time of berberine hydrochloride, and effectively improves the bioavailability of berberine hydrochloride, thereby reducing the number of administrations, reducing the adverse reactions caused by multiple administrations, and enhancing patient compliance. At the same time, the present invention adopts dry ball milling to prepare the berberine hydrochloride solid dispersion, the preparation method is simple, the preparation efficiency is high, and the preparation process does not involve organic solvents, which further ensures the safety and effectiveness of the drug, and has broad application prospects in the field of pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

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

[0029] Figure 2 is a powder X-ray diffraction (PXRD) pattern of berberine hydrochloride (BBH), hydroxypropyl methylcellulose (HPMC) and BBH-HPMC (1:4) samples in Comparative Example 3 of the present invention;

[0030] Figure 3 is a powder X-ray diffraction (PXRD) pattern of berberine hydrochloride (BBH), methacrylic acid-ethyl acrylate copolymer (ME) and BBH-ME (1:4) samples in Comparative Example 4 of the present invention;

[0031] Figure 4 It is a differential scanning calorimetry (DSC) diagram of berberine hydrochloride (BBH), ethyl cellulose (EC), the berberine hydrochloride sustained-release solid dispersion (BBH-EC (1:4)) in Example 1, and the PM-2 sample in Comparative Example 2;

[0032] Figure 5It is a Fourier transform infrared spectrum (FT-IR) diagram 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;

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

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

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

[0036] Fig. 9 is a powder X-ray diffraction (PXRD) pattern of berberine hydrochloride (BBH), ethyl cellulose (EC), and berberine hydrochloride sustained-release solid dispersion (BBH-EC (1:4)) in Example 1 of the present invention placed under high temperature and high humidity conditions for different periods of time;

[0037] Fig.10 The in vitro dissolution curve of the berberine hydrochloride sustained-release solid dispersion (BBH-EC (1:4)) in Example 1 of the present invention placed under high temperature and high humidity conditions for different time periods;

[0038] Fig.11 It is a blood drug concentration change curve of berberine hydrochloride (BBH) and berberine hydrochloride sustained-release solid dispersion (BBH-EC (1:4)) in Example 1 of the present invention. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0040] Example 1

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

[0042] The preparation method of the 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 well, add to a ball mill, and ball mill for 90 minutes at a speed of 1200 r / min. After the ball milling, take out the drug, grind it, pass it through an 80-mesh sieve, and obtain a berberine hydrochloride sustained-release dispersion, which is placed in a drying oven for use.

[0044] Example 2

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

[0046] The preparation method of the 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 well, add to a ball mill, and ball mill for 180 min at a speed of 1300 r / min. After the ball milling, take out 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 placed in a drying oven for use.

[0048] Example 3

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

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

[0051] Accurately weigh 20 mg of berberine hydrochloride raw material, add ethyl cellulose according to the mass ratio of 1.2:3.8, mix well, add to the ball mill, and ball mill for 60 minutes at a speed of 1400r / min. After the ball milling, take out the drug, grind it, pass it through an 80-mesh sieve, and obtain the berberine hydrochloride sustained-release dispersion, which is placed in a drying oven for 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) are prepared in exactly the same manner as in Example 1.

[0054] Comparative Example 2

[0055] This comparative example provides three physical mixtures, and each component is weighed according to the mass ratio of berberine hydrochloride to ethyl cellulose of 1:2, 1:4 and 1:6, and then the weighed components are 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 difference between this comparative example and Example 1 is that ethyl cellulose is replaced by 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] The BBH-HPMC (1:4) sample powder was prepared in exactly the same manner 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 by an equal amount of methacrylic acid-ethyl acrylate copolymer (Methacrylic Acid-Ethyl Acrylate Copolyme, 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] The BBH-ME (1:4) sample powder was prepared in exactly the same manner 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 berberine hydrochloride solid dispersion comprises the following steps:

[0065] Accurately weigh 20 mg of berberine hydrochloride raw material, weigh Eudragit S100 at a mass ratio of 1:4, mix well, add 95% ethanol solution by volume 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 the 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] In order to better illustrate the characteristics of the BBH-EC (1:4) sample prepared in the embodiment of the present invention, the sample powders prepared in Example 1 and Comparative Examples 1 to 5 were measured and characterized in structure. The specific method is 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.). Silicon samples were used for calibration before measuring the samples, and the samples were measured after meeting the requirements.

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

[0071] BBH, EC, BBH-EC (1:4) sample prepared in Example 1, and powder samples of different proportions prepared in Comparative Examples 1 and 2 were sieved and spread flat in the sample tank for testing under the above conditions. The results are as follows: Figure 1 shown.

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

[0073] The powder samples BBH-EC (1:2) of different proportions 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 the BBH in the BBH-EC (1:2) sample in Comparative Example 1 did not completely form an amorphous state, while the BBH in BBH-EC (1:6) was completely transformed from a crystalline state to an amorphous state and dispersed in the carrier.

[0074] The physical mixtures PM-1, PM-2, and PM-3 samples prepared in Comparative Example 2 also show characteristic diffraction peaks, and the positions of the diffraction peaks are the same as those of BBH, but the peak intensity is weaker than that of BBH, indicating that crystalline BBH also exists 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 in Figure 2 shown.

[0076] from Figure 2 It can be seen that BBH has obvious crystal diffraction peaks at 2θ=8.92°, 15.21°, 22.84°, 25.47°, and 26.35°, indicating that BBH is a crystalline drug, while HPMC has no obvious characteristic diffraction peaks, indicating that HPMC is amorphous. BBH-HPMC (1:4) prepared in Comparative Example 3 has obvious crystal diffraction peaks at 2θ=7.97° and 20.01°, which shows that BBH in BBH-HPMC (1:4) has not completely transformed from a crystalline state to an amorphous state.

[0077] The PXRD patterns of BBH, ME and BBH-ME (1:4) prepared by comparison 4 are shown in Figure 3 shown.

[0078] from Figure 3 It can be seen that BBH has obvious crystal diffraction peaks at 2θ=8.92°, 15.21°, 22.84°, 25.47°, and 26.35°, indicating that BBH is a crystalline drug, while ME has no obvious characteristic diffraction peaks, indicating that ME is amorphous. BBH-ME (1:4) prepared in Comparative Example 4 does not show any crystal diffraction peaks, which indicates that in BBH-ME (1:4), BBH is completely transformed from a crystalline state to an amorphous state and dispersed in the carrier.

[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 test process is:

[0081] 4 mg of the sample to be tested was ground, sieved, dried and dehydrated, and then placed in a standard aluminum pan and sealed. The measurement conditions were: temperature range 25℃~250℃, heating rate 10℃ / min, nitrogen protection, and nitrogen flow rate 50mL / min.

[0082] from Figure 4It can be seen from the BBH graph that there are dehydration peaks of BBH at 116°C and 134°C, and a sharp endothermic peak at 195°C, which is the melting point peak of BBH. EC did not show any endothermic peaks during the temperature rise process. The dehydration peak of BBH in BBH-EC (1:4) prepared in Example 1 disappeared, and the endothermic peak became smaller and moved to 177°C, indicating that BBH was dispersed in the carrier in an amorphous state, which is consistent with the above PXRD results. A dehydration peak appeared in the physical mixture PM-2 prepared in Comparative Example 2, and the melting point peak of BBH was visible at 195°C, which indicates that there is crystalline BBH in PM-2, and it also proves that the carrier and the raw material drug in Comparative Example 2 are physically mixed.

[0083] 3. Fourier transform infrared spectroscopy (FT-IR)

[0084] The tableting method is adopted. First, the potassium bromide is ground and sieved into powder below 2μm, and dried for use. According to the mass ratio of the sample to be tested and potassium bromide of 1:100, 2mg of the sample to be tested and potassium bromide powder are placed in a mortar, ground and mixed evenly, and tableted. The test conditions are: wave number range 4000cm -1 ~400cm -1 , resolution 0.1cm -1 .

[0085] BBH, EC, BBH-EC (1:4) prepared in Example 1, and PM-2 prepared in Comparative Example 2 were subjected to infrared detection. The results are as follows: Figure 5 shown.

[0086] from Figure 5 It can be seen that BBH is at 3402cm -1 There is a stretching vibration peak representing nitrogen benzene at 1599cm -1 、1505cm -1 and 1387cm -1 There is a stretching vibration peak of C=C, 1034cm -1 There is a stretching vibration peak of -COC-. EC is at 3486cm -1 There is a stretching vibration peak of OH at 2978cm -1 There is a CH stretching vibration peak at 1113cm -1 In the BBH-EC (1:4) prepared in Example 1, the benzene ring of BBH reacts with the OH of EC, and the stretching vibration peak of the nitrogen benzene of BBH blue-shifts from 3402 cm -1 Migrate to 3476cm -1 The stretching vibration of OH in EC red-shifts from 3486 cm -1 Migrate to 3476cm -1The stretching vibration peak absorption band intensity increases and narrows; the -COC- stretching vibration peak of BBH blue shifts from 1034cm -1 Migrate to 1107cm -1 The -COC- stretching vibration peak of EC red-shifted from 1113 cm -1 Migrate to 1107cm -1 , the stretching vibration peak absorption band intensity increases and becomes wider, indicating that there is an interaction between BBH and EC molecules, and the solid dispersion has been successfully prepared. The physical mixture PM-2 prepared in Comparative Example 2 has both BBH and EC functional group bands, indicating that there is no interaction between BBH and the carrier molecules, and it is just a simple 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 a corresponding proportion of ethyl cellulose, and prepare sample powders according to the methods of Example 1 and Comparative Examples 1 to 2, respectively, to obtain solid dispersions BBH-EC (1:4), BBH-EC (1:6) and physical mixtures PM-2 and PM-3 containing 450 mg of BBH raw material.

[0090] The solid dispersion, physical mixture and 450 mg of BBH drug substance obtained above were added to 900 mL of pH 6.8 phosphate buffer at a temperature of (37±5)°C and a rotation speed of 200 rpm for in vitro dissolution test. Timing started from the time when the powder contacted the medium, and 0.5 mL of solution was taken out 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, respectively, and an equal volume of medium was immediately added. The taken out solution was then immediately filtered with 0.22 μm, and the measurement was performed 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 as follows: Figure 6 shown.

[0091] from Figure 6It can be seen that the cumulative dissolution rate of BBH reaches 98.02% in 10 minutes, and the cumulative dissolution rate reaches 100% after 30 minutes. The cumulative dissolution rate of BBH-EC (1:6) prepared in Comparative Example 1 is 40.67% in 10 minutes, and the cumulative dissolution rate is 62.61% after 2 hours, and it is still rising. The cumulative dissolution rate reaches 78.62% in 12 hours and 81.39% in 24 hours. However, the cumulative dissolution rate rises slowly in 12 hours, and does not reach more than 90% in 24 hours. The cumulative dissolution rate of PM-2 prepared in Comparative Example 2 reaches 70.37% in 10 minutes, and the cumulative dissolution rate reaches 96.03% after 2 hours, and tends to be stable. The cumulative dissolution rate of PM-3 prepared in Comparative Example 2 reaches 73.87% in 10 minutes, and the cumulative dissolution rate reaches 95.11% after 2 hours, and tends to be stable. The cumulative dissolution rate of BBH-EC (1:4) prepared in Example 1 was only 29.47% at 10 min, and the cumulative dissolution rate was 50.22% after 2 h, and it continued to rise, and the cumulative dissolution rate was 93.88% at 24 h. It can be seen that the berberine hydrochloride solid dispersion prepared by ball milling with ethyl cellulose as the carrier significantly prolonged the release time of BBH, and BBH-EC (1:4) was better than BBH-EC (1:6).

[0092] 4.2 Comparative Example 4

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

[0094] The in vitro dissolution test was carried out in the same manner as above. Figure 7 shown.

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

[0096] 4.3 Comparative Example 5

[0097] 15 mg of berberine hydrochloride and 60 mg of Eudragit S100 were weighed, and sample powder was prepared according to the method of Comparative Example 5 to obtain a solid dispersion BBH-S100 (1:4) containing 15 mg of BBH API.

[0098] The above-obtained BBH-S100 (1:4) solid dispersion and 15 mg of BBH raw material were added to 750 mL of pH 6.8 phosphate buffer at a temperature of (37 ± 0.5) °C and a rotation speed of 200 rpm for an in vitro dissolution test. Then, 0.5 mL of the 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 taken solution was immediately filtered with a 0.22 μm filter membrane, and the absorbance was measured at a wavelength of 350 nm. The results were repeated three times and the average value was taken. Figure 8 shown.

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

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

[0101]

[0102]

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

[0104] Ethyl cellulose is an inert hydrophobic substance that is non-toxic, has good storage stability, good compressibility, and has hydrophobicity and swelling ability, and is suitable for sustained-release preparations. The present invention prepares berberine hydrochloride and ethyl cellulose into a solid dispersion with sustained-release function, which can ensure that the drug is slowly released throughout the gastrointestinal tract and can provide a constant drug concentration. The cumulative dissolution rate of BBH-EC (1:6) prepared in Comparative Example 1 did not reach 90% in pH 6.8 phosphate buffer, which may be due to the high EC ratio, resulting in smaller pores in the film formed by swelling, which ultimately hindered the contact between part of BBH and water, so that the final dissolution rate did not reach more than 90%.

[0105] Methacrylic acid-ethyl acrylate copolymer is a kind of polyacrylic acid resin, which is non-irritating and non-toxic, swellable in water, and is usually used as a coating material for gastric, enteric and sustained release in preparations. In the present invention, the sustained release effect of BBH-ME (1:4) is not significant, which may be caused by the mismatch between the drug and the carrier.

[0106] Eudragit S100 is also a kind of polyacrylic acid resin, which is a commonly used pH-dependent enteric coating material. It dissolves in a medium above pH 7.0 and can greatly reduce the release of drugs in the stomach and small intestine. In the present invention, the sustained release effect of BBH-S100 (1:4) is not significant, which may be related to the pH dependence of the drug dosage form and carrier.

[0107] In summary, the solid dispersion BBH-EC (1:4) prepared by mixing berberine hydrochloride and ethyl cellulose has the best in vitro dissolution effect and the best 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 plate, and placed in a drug stability test box at a temperature of 40°C and a humidity of 75%. Appropriate amounts of samples were taken out at 0d, 15d, 30d, and 60d for powder X-ray diffraction. The results are as follows: Fig. 9 As shown, samples were taken at 7d, 30d, and 60d for in vitro dissolution analysis. The results are shown in Fig.10 shown.

[0110] from Fig. 9 It can be seen that within 0 to 60 days, the BBH-EC (1:4) solid dispersion prepared in Example 1 did not show any diffraction peaks of any crystal form. Fig.10 It can be seen that the dissolution curves of 7d, 30d and 60d are almost consistent with the dissolution curve of the 0d sample, that is, the dissolution effect of BBH-EC (1:4) does not decrease after being stored at 40°C and 75% RH for 60d. Together with the PXRD results, it is proved that the BBH-EC (1:4) solid dispersion prepared by the ball milling method in the present invention has excellent stability under high temperature and high humidity environment.

[0111] 6. Pharmacokinetics test

[0112] 20 male SD rats aged 7 to 8 weeks, weighing 250±20 g, were selected and purchased from Sibeifu (Beijing) Biotechnology Co., Ltd. After adaptive feeding for 1 week, they were randomly divided into 2 groups, namely, berberine hydrochloride group (BBH group) and berberine hydrochloride sustained-release solid dispersion group obtained in Example 1 (BBH-EC (1:4) group), during which they were free to drink water and eat, and fasted for 12 hours before the experiment, but were free to drink water.

[0113] Drug administration and sampling

[0114] The BBH group and the BBH-EC (1:4) group obtained in Example 1 were dispersed in a 0.5wt% sodium carboxymethyl cellulose solution and gavaged to rats at a BBH dose of 100 mg / kg. Then, about 0.5 mL of blood was collected from the retro-orbital venous plexus of the rats 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. The blood was placed in a centrifuge tube containing sodium heparin, and the plasma was collected after centrifugation at 12000 r / min for 10 min and stored at -20°C for later use.

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

[0116] The chromatographic conditions of HPLC were as follows: chromatographic 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° C.; injection volume: 20 μL; detection wavelength: 345 nm.

[0117] The pharmacokinetic data were analyzed using DAS2.0 software to analyze the area under the drug-time curve (AUC 0～∞ ), maximum blood concentration (C max ), peak time (T max ), half-life (T 1 / 2 ), residence time (MRT 0～∞ ) and other pharmacokinetic parameters were calculated and analyzed. SPSS23.0 software was used to analyze the data for significant differences. The results are shown in Table 2 and Fig.11 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: Data in the same row with different lowercase letters on the shoulders indicate significant differences (P<0.05); data with different uppercase letters on the shoulders indicate extremely significant differences (P<0.01); data with the same letters on the shoulders or no letters on the shoulders indicate no significant differences (P>0.05).

[0121] The results show that the peak time of BBH-EC (1:4) is Tmax From 1h to 2h, the peak concentration of BBH was 439.61μg / L, and the peak concentration of BBH-EC (1:4) (668.86μg / L) was significantly higher than the former (P < 0.01). The peak concentration of BBH-EC (1:4) was 1.52 times that of BBH. 1 / 2 Compared with BBH (1.83h), the AUC of BBH-EC (1:4) was extended to 11.02h. 0-24 (6498.695 μg·h / L) is 6.56 times that of BBH (990.647 μg·h / L). Within 72 hours, the AUC of BBH-EC (1:4) 0-72 and t 1 / 2 8338.493 μg·h / L and 14.47 h, AUC 0～72 It is 8.42 times that of BBH. 1 / 2 It is 7.91 times that of BBH.

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

[0123] The berberine hydrochloride prepared in Examples 2 to 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 modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A berberine hydrochloride sustained-release solid dispersion, characterized in that: The invention comprises berberine hydrochloride and a sustained-release carrier, wherein the mass ratio of the berberine hydrochloride to the 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 according to claim 1, characterized in that: The mass ratio of the berberine hydrochloride to the sustained-release carrier is 1:

4.

3. A method for preparing the berberine hydrochloride sustained-release solid dispersion according to claim 1 or 2, characterized in that: The following steps are involved: The berberine hydrochloride and the sustained-release carrier are mixed in proportion, dry-milled, ground, and sieved to obtain a berberine hydrochloride sustained-release solid dispersion.

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

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

6. The method for preparing the berberine hydrochloride sustained-release solid dispersion according to claim 3, characterized in that: The sieving is through an 80-mesh sieve.

7. A pharmaceutical composition, characterized in that The invention comprises the berberine hydrochloride sustained-release solid dispersion according to claim 1 or 2.

8. A pharmaceutical preparation, characterized in that The invention comprises the berberine hydrochloride sustained-release solid dispersion according to claim 2 or the pharmaceutical composition according to claim 7.

9. The pharmaceutical preparation according to claim 8, characterized in that Pharmaceutically acceptable excipients are also included.

10. The pharmaceutical preparation according to claim 8 or 9, characterized in that The dosage form of the pharmaceutical preparation includes tablets, capsules, granules, pills, powders or suspensions.

Images