Albendazole solid dispersant and its preparation method and use

Abstract

This application, which belongs to the field of microbiology, discloses an albendazole solid dispersant, its preparation method, and use. The albendazole solid dispersant comprises albendazole, glyceryl monostearate, and hypromellose acetate succinate; the albendazole is present in an amorphous state in the albendazole solid dispersant. This dispersant significantly increases the solubility of albendazole in water by 3.15 times, effectively prevents drug release in acidic environments, and maintains slow drug release in weakly alkaline environments. The invention also provides a preparation method and use of the albendazole solid dispersant.

Description

Technical Field

[0001] The present invention relates to the field of new materials, and in particular to an albendazole solid dispersant, a preparation method and application thereof. Background Art

[0002] Solid dispersants (co-precipitated compounds) are drugs that are poorly soluble and dispersed in a physiologically inert and water-soluble carrier in the form of molecules, colloids or ultrafine particles through methods such as co-dissolution or spray encapsulation. After entering the gastrointestinal tract, the water-soluble carrier dissolves rapidly, and the drug is quickly and completely released from the carrier into particles that are much smaller than micronized particles, thereby producing a highly efficient and fast-acting effect. At the same time, it also has the advantages of drug stability, no gastric obstruction, masking of bitterness, and improved bioavailability.

[0003] Albendazole (ABZ), a BCS class II alkaline drug, has therapeutic and preventive effects on whipworm infection. However, due to its poor solubility and pH sensitivity, oral administration of ABZ has a suboptimal therapeutic effect, and high doses can easily cause developmental toxicity in animals.

[0004] After oral absorption and entry into the bloodstream, ABZ undergoes a strong first-pass metabolism and is rapidly metabolized into albendazole sulfoxide (ABZSO) and albendazole sulfone (ABZSO2). ABZ and ABZSO are the main components with insecticidal activity. However, clinical studies have shown that the cure rate of oral ABZ for whipworm infection remains low, and high-dose albendazole may cause developmental toxicity in animals. This is likely due to ABZ's low solubility, easy crystallization, and pH sensitivity. This leads to its dissolution and rapid absorption in the acidic environment of the stomach, while unabsorbed drug enters the small and large intestines (the primary parasitic habitats of gastrointestinal nematodes) with gastric emptying. It rapidly crystallizes and precipitates as the pH rises, thus compromising drug efficacy. Although various formulation strategies have been explored to improve its aqueous solubility, including the addition of surfactants such as Tween 80 and bile salts, the development of self-microemulsifying formulations, solid lipid nanoparticles, the preparation of solid dispersions, cyclodextrin inclusion complexes, and cocrystals, these strategies, while improving ABZ solubility, inevitably increase peak blood concentrations. This may lead to a further increase in the toxic side effects of ABZ.

[0005] The following techniques can be used to prepare solid dispersions of ABZ:

[0006] Publication number CN114099529A is a subject matter of an albendazole-ivermectin premix, a preparation method, and an application thereof. It states: first, the glyceryl monostearate is heated to 85-95°C and stirred until melted, then the polyethylene glycol is added, and after melting, the mixture is kept warm at 85-95°C for 8-12 minutes, followed by the addition of the activated carbon, which is kept warm at 85-95°C and stirred for 8-12 minutes; then, the albendazole and ivermectin are added, and the drug suspension is spray-dried to condense into spherical particles.

[0007] The suspension prepared by this method is a solid dispersion; the peak plasma concentration of this solid dispersion is 0.4 μg / ml, reaching peak concentration within 6 hours, maintaining concentration for 24 hours, and achieving bioavailability exceeding 80%. However, the pharmacokinetic study described in the protocol does not specify whether albendazole or ivermectin was tested, nor does it clearly state the concentration used in the animals.

[0008] The problem that this program needs to solve: How to reduce the peak blood concentration of albendazole and delay the time to peak. Summary of the Invention

[0009] The present invention aims to provide an albendazole solid dispersant, which can significantly increase the solubility of albendazole in water by 3.15 times, effectively prevent drug release in an acidic environment, and maintain slow drug release in a weakly alkaline environment.

[0010] At the same time, the present invention also provides a preparation method and application of the albendazole solid dispersant.

[0011] To achieve the above-mentioned object, the present application discloses an albendazole solid dispersant, comprising albendazole, glyceryl monostearate, and hypromellose acetate succinate; the albendazole exists in an amorphous form in the albendazole solid dispersant.

[0012] The present invention adopts the poorly soluble auxiliary material glyceryl monostearate and the pH-sensitive reagent hypromellose acetate succinate to achieve the purpose of solubilizing albendazole, preventing its release in an acidic environment, releasing it in a slightly alkaline environment, and achieving sustained release.

[0013] Glyceryl monostearate has very low solubility in water and is a good sustained-release agent. In the intestine, under the action of bile, it will slowly dissolve and release albendazole;

[0014] Hydroxypropyl methylcellulose acetate succinate is a commonly used enteric coating material that is insoluble in gastric juice but dissolves slowly in the intestine.

[0015] Glyceryl monostearate and hydroxypropyl methylcellulose acetate succinate have similar dissolution rates in the intestine, which can enable the albendazole solid dispersion to slowly dissolve layer by layer, releasing albendazole and avoiding excessively high peak blood drug concentrations.

[0016] Compared with other enteric coating materials, Hydroxypropyl methylcellulose acetate succinate and albendazole can bond through hydrogen bonds in an alkaline environment, achieving more effective solubilization of albendazole and preventing albendazole from becoming crystals when released.

[0017] Compared with commercially available products, its peak blood concentration is lower, the time to peak is prolonged, and its bioavailability is consistent with that of commercially available products.

[0018] In the above-mentioned albendazole solid dispersion, the mass ratio of albendazole, glyceryl monostearate, and hypromellose acetate succinate is 5-25:65-75:10-20.

[0019] In the above-mentioned albendazole solid dispersant, the particle size of the albendazole solid dispersant is 20 to 50 meshes.

[0020] In the above-mentioned albendazole solid dispersant, the particle size of the albendazole solid dispersant is 20-30 mesh, 30-40 mesh or 40-50 mesh.

[0021] In the above-mentioned albendazole solid dispersion, the mass ratio of albendazole, glyceryl monostearate, and hypromellose acetate succinate is 10-25:65-75:10-15;

[0022] At the same time, the invention also discloses a preparation method of albendazole solid dispersant, which comprises the steps of melting and blending albendazole, glyceryl monostearate and hydroxypropyl methylcellulose acetate succinate, and cooling the mixture.

[0023] In the above-mentioned preparation method of albendazole solid dispersion, the mass ratio of albendazole, glyceryl monostearate, and hydropropyl methylcellulose acetate succinate is 5-25:65-75:10-20; preferably, the mass ratio of albendazole, glyceryl monostearate, and hydropropyl methylcellulose acetate succinate is 10-25:65-75:10-15.

[0024] Finally, the present invention also discloses the use of the albendazole solid dispersion as described above in preparing medicine for treating whipworm disease.

[0025] The beneficial effects of this application are:

[0026] The present invention utilizes the poorly soluble excipient glyceryl monostearate in combination with the pH-sensitive reagent hydropropyl methylcellulose acetate succinate to achieve solubilization of albendazole, prevent its release in acidic environments, release it in alkaline environments, and achieve sustained release. Compared to commercially available products, the drug achieves lower peak plasma concentrations, a longer time to peak concentration, and consistent bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the in vitro release curve of the first part of the sample under pH 1.2 conditions;

[0028] Figure 2 This is the in vitro release curve of the first part of the sample under pH 4.3 conditions;

[0029] Figure 3 This is the in vitro release curve of the first part of the sample at pH 6.8;

[0030] Figure 4 This is the in vitro release curve of the second part of the formulation at pH 1.2;

[0031] Figure 5 This is the in vitro release curve of the second part of the formulation at pH 4.3;

[0032] Figure 6 This is the in vitro release curve of the second part of the formulation at pH 6.8;

[0033] Figure 7a SEM image of ABZ;

[0034] Figure 7b SEM image of ABZ-pHs-SD;

[0035] Figure 7c is the SEM image of the physical mixture;

[0036] Figure 7d is the SEM image of GM;

[0037] Figure 7e is the SEM image of HPMC-AS;

[0038] Figure 8 PXRD results of ABZ, ABZ-pHs-SD, physical mixture, GM and HPMC-AS;

[0039] Figure 9 DSC thermograms of ABZ, ABZ-pHs-SD, physical mixture, GM, and HPMC-AS;

[0040] Figure 10FT-IR spectra of original ABZ, ABZ-pHs-SD, physical mixture, GM, and HPMC-AS;

[0041] Figure 11a ABZ-pHs-SD, Release curve at pH 1.2;

[0042] Figure 11b ABZ-pHs-SD, Release curve at pH 4.3;

[0043] Figure 11c ABZ-pHs-SD, Release curve at pH 6.8;

[0044] Figure 11d ABZ-pHs-SD, Release curve at pH 7.4;

[0045] Figure 12a is the plasma concentration-time curve of ABZ;

[0046] Figure 12b This is the plasma concentration-time curve of ABZSO;

[0047] Figure 12c This is the blood concentration-time curve of ABZSO2;

[0048] Figure 13a shows the relationship between ABZ-pHs-SD and Histogram of ABZ drug concentration in intestinal contents and ileal tissue;

[0049] Figure 13b shows the ABZ-pHs-SD and Bar graph of ABZSO drug concentrations in intestinal contents and ileal tissues. DETAILED DESCRIPTION

[0050] The present invention will be described clearly and completely below in conjunction with the examples of the present invention. In the description of the present invention, it should be noted that, where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer were used. Reagents or instruments used where the manufacturer is not specified are conventional products that can be purchased commercially.

[0051] Part I Reagents and Instruments

[0052] Albendazole (batch number: 20210125) was provided by Ningxia Hui Autonomous Region Da Mo Pharmaceutical Co., Ltd.

[0053] Hydroxypropyl methylcellulose acetate succinate (Batch No.: 220603) was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0054] Ethyl cellulose and glyceryl monostearate (batch number: 20230501) were purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0055] Polyacrylic acid resin (batch number: B220803211) was purchased from Shanghai Changwei Pharmaceutical Excipients Technology Co., Ltd.

[0056] Hydroxypropyl methylcellulose phthalate was purchased from Luofu Pharmaceutical Technology (Shanghai) Co., Ltd.

[0057] Cellulose acetate phthalate was purchased from Jiangsu Leien Environmental Protection Technology Co., Ltd.

[0058] Albendazole standard (batch number: 2353168), albendazole sulfoxide standard (batch number: 2357608), albendazole sulfoxide standard (batch number: 2354296), and mebendazole standard (MBZ, batch number: 2204156) were purchased from Shanghai Anpu Cuishi Standard Technology Service Co., Ltd.

[0059] Albendazole granules Purchased from Shanghai Quanyu Biotechnology (Zhumadian) Animal Pharmaceutical Co., Ltd.;

[0060] Chromatographic grade acetonitrile and methanol were purchased from Thermo Fisher Scientific.

[0061] Part II In vitro release experiment of ABZ

[0062] Albendazole is a BCS II alkaline drug. Its release in the stomach does not achieve the therapeutic and preventive effects on whipworm disease, and rapid release in the intestine can cause developmental toxicity in animals. Therefore, the purpose of the screening in the present invention is to obtain a composition that can achieve low release of albendazole in an acidic environment and slow release in a neutral environment to load albendazole.

[0063] Many enteric-coated materials can achieve the goal of less release in the stomach and more release in the intestines. However, most enteric-coated materials do not have the effect of sustained release in the intestines.

[0064] The relevant materials screened by the present invention are as follows:

[0065] Polyacrylic acid resin, cellulose acetate phthalate, ethyl cellulose, hypromellose phthalate, hypromellose acetate succinate;

[0066] The specific method of in vitro release experiment is as follows:

[0067] Dissolution studies were performed using a paddle apparatus (RCY-808T, Haiyida, Tianjin, China) in 1000 mL of dissolution medium containing the following: hydrochloric acid (pH 1.2), acetate buffer (pH 4.3), and phosphate buffer (pH 6.8). Except for the hydrochloric acid, all other media contained 1% Tween. The dissolution medium temperature was controlled at 37 ± 0.5°C, and the stirring speed was maintained at 75 rpm. The two formulations, equivalent to 4 mg of ABZ (satisfying the sink condition), were added to the dissolution vials. The solution (5 mL) for each test was collected at 0.1, 0.25, 0.5, 1, 1.5, and 2 h; 0.1, 0.25, 0.5, 1, 2, and 4 h; and 0.1, 0.25, 0.5, 1, 2, 4, 6, 8, and 12 h. After each collection, 5 mL of isothermal medium was immediately added. The collected solutions were filtered through a 0.22 mm microporous membrane and analyzed by HPLC. Each test was repeated three times.

[0068] Sample formulas refer to Table 1;

[0069] Table 1 Recipe

[0070]

[0071] In vitro release curve reference of pH 1.2, pH 4.3 and pH 6.8 Figures 1 to 3 ;

[0072] pass Figures 1 to 3 It can be seen that polyacrylic acid resin and hydroxypropyl methylcellulose acetate succinate are two products that release a large amount under neutral conditions and a small amount under acidic conditions. However, the early release of polyacrylic acid resin under neutral conditions is too fast, far exceeding the metabolic rate of ABZ in animals, which can easily lead to developmental toxicity and is not sustainable for the treatment of whipworm disease.

[0073] We also evaluated two commercial products, an albendazole-ivermectin premix and albendazole granules produced by Wuhan Danongren Biotechnology Co., Ltd.

[0074] The release rate of albendazole-ivermectin premix under acidic conditions (pH 1.2) is about 40 wt%, and the release rate under neutral (pH 6.8) and alkaline (pH 7.4) conditions is about 20 wt%.

[0075] The release rate of albendazole granules under acidic conditions (pH 1.2) is about 80 wt%, and the release rates under neutral (pH 6.8) and alkaline (pH 7.4) conditions are both about 30 wt%.

[0076] After the above experiments, it was screened that hydropropyl methylcellulose acetate succinate was the most suitable enteric material. Its release rate under acidic conditions was not less than 20%, and its release rate under neutral and alkaline conditions was about 80%. Moreover, its release rate was relatively slow, and it took 12 hours to achieve 80% release.

[0077] Part II Verification of the optimal ratio of glyceryl monostearate and hydropropyl methylcellulose acetate succinate

[0078] The above-mentioned in vitro release experiment was used, and the formulation was referred to Table 2;

[0079] Table 2 Recipe

[0080]

[0081]

[0082] In vitro release curve reference of pH 1.2, pH 4.3 and pH 6.8 Figures 4 to 6 ;

[0083] pass Figures 4 to 6 It can be seen that the dosage of hydropropyl methylcellulose acetate succinate is a very important parameter. Although prescription 1 can maintain low release in an acidic environment, it also has low release in a neutral environment. When the dosage of hydropropyl methylcellulose acetate succinate is increased to 10wt%, prescription 2 maintains the effect of low release in an acidic environment and high release in a neutral environment. This situation shows the same rule when the dosage of monostearate is 70wt%. When the dosage of monostearate is 75wt%, the dosage of hydropropyl methylcellulose acetate succinate needs to be increased to 15wt%.

[0084] In addition, the particle size of the product also has a certain impact on the release. The smaller the size, the more is released. It can be seen that under the premise of the same amount of monostearate, prescriptions 2, 4 and 9 release more.

[0085] Part III In vitro and in vivo studies of pH-sensitive solid dispersions loaded with albendazole

[0086] Preparation of ABZ-pHs-SD

[0087] To prepare a solid dispersion, weigh the required ABZ, GM (glyceryl monostearate), and HPMC-AS (hydroxypropyl methylcellulose acetate succinate) in a mass ratio of 25:65:10. Melt the GM in a waterbath, then add HPMC-AS and ABZ sequentially. Stir the melt at 80°C at a constant speed until the drugs are completely dispersed. Pour the melt onto a pre-chilled glass plate and freeze in a -20°C refrigerator overnight. Dry the frozen mixture in a watertight incubator for 24 hours, remove it, crush, and sieve (40-50 mesh) to obtain ABZ-pHs-SD.

[0088] Characterization of ABZ-pHs-SD

[0089] 3.2.1.SEM

[0090] The surface morphology of ABZ, ABZ-pHs-SD, GM, and HPMC-AS was investigated using a Sigma 300 scanning electron microscope (ZEISS, Germany). The samples were mounted on an aluminum sample holder and coated with gold. SEM images were then acquired at an accelerating voltage of 10 kV to observe the surface morphology of the samples.

[0091] SEM images of ABZ, ABZ-pHs-SD, physical mixture, GM and HPMC-AS are shown in Figures 7a to 7e Physical mixture refers to the simple physical blending of ABZ, GM and HPMC-AS according to the proportions shown in Section 3.1.

[0092] ABZ presents irregular small particles with prominent edges and corners ( Figure 7a ) This may be the main reason why ABZ exhibits hydrophobicity. No ABZ crystals were detected in the solid dispersion ( Figure 7b However, irregular particles can still be observed in physical mixtures, indicating that the crystal structure of ABZ has not disappeared due to physical mixing ( Figure 7c Scanning electron microscopy shows that the surface of PM has a prominent groove shape ( Figure 7d ), HPMC-AS is dispersed in an amorphous state ( Figure 7e ). These findings confirm that ABZ can be well encapsulated in polymers via solid dispersion techniques.

[0093] 3.2.2.PXRD

[0094] PXRD analysis was performed at ambient temperature using (Empyrean) Cu Kα radiation ( The diffraction data were collected at 40 kV and 40 mA (generator settings). The diffraction data were collected in a 2θ scan range of 5-40°, with a step size of 0.0084° and a counting time of 2 seconds per step.

[0095] The PXRD results of ABZ, ABZ-pHs-SD, physical mixture, GM and HPMC-AS are shown in Figure 8 The spectrum of pristine ABZ exhibits a series of high-intensity peaks at 2θ values ​​of approximately 7.04°, 11.66°, 18.01°, 22.19°, and 39.18° ( Figure 8 The curve a in Figure 1 shows that it has high crystallinity. The spectrum of HPMC-AS has no crystalline peak, which means that it is basically amorphous ( Figure 8 Curve b in Figure 2). For GM, the PXRD spectrum shows a series of high-intensity peaks at approximately 5.62, 7.45, 19.66, and 22.85°, indicating that the carrier GM has a certain crystalline structure ( Figure 8 The PXRD patterns of the physical mixture and solid dispersion are highly consistent with those of GM ( Figure 8 The peak intensity is significantly reduced and the peak shape is broadened, indicating that the crystalline structure is reduced. These results indicate that ABZ may transform into an amorphous state in the solid dispersion.

[0096] 3.2.3.DSC

[0097] Thermal analysis of ABZ, ABZ-pHs-SD, the physical mixture, GM, and HPMC-AS was performed by differential scanning calorimetry (DSC25, USA). Samples (5.8 mg) were weighed, placed in a sealed aluminum pan, and scanned from 25°C to 300°C at 5°C / min under flowing nitrogen. Thermograms were recorded.

[0098] The DSC thermograms of ABZ, ABZ-pHs-SD, physical mixture, GM and HPMC-AS are shown in Figure 9 The DSC thermogram of ABZ shows a unique sharp endothermic peak at 213.6℃, ​​indicating its crystalline state ( Figure 9 HPMC-AS does not show any absorption peak, indicating the absence of crystallization ( Figure 9 GM has an obvious absorption peak at 73.4℃, which is consistent with the melting point of GM ( Figure 9 The DSC curves of the physical mixture and ABZ-pHs-SD showed strong endothermic peaks (73.3°C, 69.9°C) and weak endothermic peaks (167.7°C, 168.0°C). Compared with the API, their intensity was significantly reduced and the initial position changed significantly ( Figure 9(See curves d and e in Figure 3). Typically, when the crystallinity is below 2%, DSC often fails to detect the drug's melting peak. However, after solid dispersion formation, the drug's endothermic peak completely disappears from the thermogram, confirming an ABZ phase transition. These results further demonstrate that the drug is highly dispersed in the solid dispersion, transitioning from a crystalline state to an amorphous state.

[0099] 3.2.4. FTIR

[0100] FT-IR spectra of ABZ, ABZ-pHs-SD, GM, and HPMC-AS were obtained using a PerkinElmer Frontier Fourier Transform Infrared Spectrometer. The data were obtained at 4000-500 cm -1 Collect between.

[0101] The FT-IR spectra of original ABZ, ABZ-pHs-SD, physical mixture, GM and HPMC-AS are shown in Figure 10 The ABZ peaks are located at 3340 (NH stretching), 2957 (CH stretching), 1632 (C=N stretching), 1443 (CH bending) and 1388 cm -1 (CN stretching)( Figure 10 The spectra of HPMC-AS are 3455 (OH stretching), 1738 (C=O stretching) and 1054 cm -1 (COC stretching)( Figure 10 The spectrum of GM appears at 2918 (CH stretching), 1732 (C=O stretching), 1469 (CH bending) and 1179 cm -1 (COC stretching)( Figure 10 The FTIR spectrum of the physical mixture is similar to that of ABZ, GM, and HPMC-AS, indicating that the chemical interactions in the physical mixture are weak ( Figure 10 In the FTIR spectrum of the solid dispersion, the absorption peaks of ABZ and HPMC-AS shifted from 3340 cm to 3455 cm. -1 Start moving to 3318cm -1 The broad wavenumber shift suggests that hydrogen bonding may occur between ABZ and the solid dispersion.

[0102] ABZ, ABZ-pHs-SD, and Solubility studies

[0103] Excess ABZ, ABZ-pHs-SD and Add to distilled water, while excess ABZ was added to the dissolution media at pH 1.2, 4.3, 6.8, and 7.5, respectively, to obtain supersaturated solutions. The samples were shaken at 37°C and 100 rpm for 24 hours. After centrifugation, the supernatant was filtered through a 0.22 μm membrane and analyzed by HPLC.

[0104] Evaluation of ABZ, ABZ-pHs-SD and The water solubility of ABZ and the solubility of ABZ in buffer media with different pH values. The initial solubility of ABZ is 0.61±0.03ug / mL. The solubility of ABZ was 1.60±0.10 ug / mL, but it increased significantly to 2.53±0.12 ug / mL after being prepared into a solid dispersion with HPMC-AS. Although ABZ could reach 633.50±5.23 ug / mL in a buffered medium at pH 1.2, it dropped sharply to 0.69±0.02 ug / mL, 0.64±0.03 ug / mL, and 0.43±0.01 ug / mL in weakly alkaline environments at pH 4.3, pH 6.8, and pH 7.5, respectively. This indicates that ABZ has low solubility and pH sensitivity.

[0105] 3.4. In vitro release studies

[0106] Dissolution studies were conducted using a dissolution testing apparatus (paddle method, RCY-808T, Haiyida, Tianjin, China) in 1000 mL of dissolution medium: hydrochloric acid (pH 1.2), acetate buffer (pH 4.3), phosphate buffer (pH 6.8), and phosphate buffer (pH 7.5). Except for hydrochloric acid, all other media contained 1% Tween. The dissolution medium temperature was controlled at 37 ± 0.5°C, and the stirring speed was maintained at 75 rpm. The two formulations, equivalent to 4 mg of ABZ (sink conditions), were added to the dissolution vials. The solution (5 mL) for each test was collected at 0.1, 0.25, 0.5, 1, 1.5, and 2 h; 0.1, 0.25, 0.5, 1, 2, and 4 h; and 0.1, 0.25, 0.5, 1, 2, 4, 6, 8, and 12 h. After each collection, 5 mL of isothermal medium was immediately replenished. The collected solution was filtered through a 0.22 mm microporous membrane and analyzed by HPLC. Each test was repeated three times and the dissolution rate was obtained from the standard regression curve equation.

[0107] refer to Figures 11a to 11d ; Figure 11a ABZ-pHs-SD, Release curve at pH 1.2; Figure 11b ABZ-pHs-SD, Release curve at pH 4.3; Figure 11cABZ-pHs-SD, Release curve at pH 6.8; Figure 11d ABZ-pHs-SD, Release curve at pH 7.4;

[0108] In solutions with pH 1.2 and pH 4.3 (1% Tween 80), the total cumulative release of ABZ-pHs-SD was only 13.74% and 23.21%, respectively. However, in solutions with pH 6.8 and 7.4 (1% Tween 80), the maximum release reached 82.24% and 72.85%. The maximum release amounts in these four buffers were 79.18%, 23.21%, 32.99% and 31.20% respectively. Release is rapid and complete in strongly acidic environments, but less so in weakly acidic and alkaline environments. ABZ-pHs-SD, on the other hand, exhibits sufficient acid resistance while ensuring slow drug release in weakly alkaline environments. This is likely due to the properties of HPMC-AS, which exhibits excellent acid resistance and can inhibit ABZ crystallization in weakly alkaline environments. Furthermore, the presence of GM can delay drug release, and the combination of these two factors can ultimately control drug release.

[0109] In vivo pharmacokinetic studies

[0110] SD rats (280±20 g) were fasted for 12 h. Rats were randomly divided into two groups (n=8) and received ABZ-pHs-SD or The drug dose was 45 mg / kg (equivalent to ABZ). Blood samples (0.5 mL) were collected at 0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, and 96 hours after administration. Each blood sample was centrifuged at 4000 rpm for 10 minutes at 4°C to obtain plasma, which was then frozen at -20°C for further analysis.

[0111] Rats were orally administered with ABZ-pHs-SD and The mean plasma ABZ and its metabolite concentration-time curves after Figures 12a to 12c .

[0112] Figure 12a is the concentration-time curve of ABZ metabolites;

[0113] Figure 12b is the concentration-time curve of ABZSO metabolites;

[0114] Figure 12c This is the concentration-time curve of ABZSO2 metabolites;

[0115] Among them, the main active ingredients ABZ and ABZSO were lower than ABZ-pHs-SD at all time points in the first 4 hours. This indicates that solid dispersion preparations can avoid the rapid peak of ABZ and ABZSO plasma levels. Compared with ABZ, ABZ-pHs-SD decreased the Cmax and increased the Tmax after oral administration. Statistically, the Cmax of ABZ-pHs-SD was 0.10±0.05 and 4.70±1.16 μg / mL in ABZ and ABZSO, respectively. (0.19±0.07, 6.83±0.66ug / mL) were significantly decreased (47.4% and 31.2%) (p<0.01). The Tmax of ABZSO was 3.75±0.71h, which was significantly delayed by 1.75h compared with ABZ-pHs-SD (5.5±0.93h) (p<0.01). This may be due to the strong acid resistance of GM and HPMC-AS, which prevented the rapid dissolution and absorption of ABZ in gastric acid. In comparison, the AUC of ABZSO, the main active metabolite of pH-sensitive solid dispersion 0－t and AUC 0－∞ The values ​​of C were not statistically different. This shows that while it improves the safety of oral ABZ, it does not max The decrease in the bioavailability of ABZ-pHs-SD may be due to the solubilization effect of the solid dispersion technology and the hydrogen bond formed between HPMC-AS and ABZ. At the same time, the MRT values ​​of ABZ, ABZSO, and ABZSO2 in ABZ-pHs-SD (3.68±1.30, 14.01±2.00, and 27.32±5.76h) were significantly lower than those in ABZ-pHs-SD. (2.83±0.59, 11.87±0.88, 19.93±3.94h) were significantly improved (p<0.05), indicating that oral ABZ-pHs-SD has a longer residence time in the animal body, which will be beneficial for the treatment and prevention of parasitic diseases.

[0116] 3.6. Intestinal Drug Concentration Studies

[0117] SD rats (280±20 g) were fasted for 12 h. Rats were randomly divided into two groups (n=5) and received ABZ-pHs-SD or The drug dose was 12.6 mg (calculated as ABZ). 24 hours after administration, the rats were euthanized, and the contents of the jejunum, ileum, cecum, colon, and ileum tissue were collected and then frozen at -20°C for further analysis.

[0118] Rats were orally administered with ABZ-pHs-SD and Drug concentrations in intestinal contents and colon tissue 24 hours after administration are shown in Figures 13a and 13b.

[0119] Figure 13a shows the relationship between ABZ-pHs-SD and Histogram of ABZ drug concentration in intestinal contents and colonic tissue;

[0120] Figure 13b shows the ABZ-pHs-SD and Histogram of ABZSO drug concentration in intestinal contents and colon tissue;

[0121] Statistically, the ABZ and ABZSO levels in cecal contents of ABZ-pHs-SD (234.32±38.47, 20.80±6.42ug / g) were significantly higher than those in (45.46±12.10, 2.62±0.90ug / g) (p<0.001), the ABZ and ABZSO levels of ABZ-pHs-SD in the colon contents (221.73±37.36, 45.66±6.00ug / g) were significantly higher than those of (58.11±19.23, 2.78±0.70ug / g) (p<0.001), and the ABZ level in colon tissue of ABZ-pHs-SD (0.89±0.39ug / g) was significantly higher than that of (0.16±0.01ug / g) (p<0.01).

[0122] The results showed that In comparison, ABZ-pHs-SD significantly increased drug levels in the cecum and colon, indicating that pH-sensitive solid dispersions have stronger targeting to the cecum and colon, which will help improve the clinical efficacy of ABZ. Furthermore, the increased levels of ABZ in colonic tissue may provide insights into improving the preventive effects of albendazole on colon cancer.

[0123] HPLC analysis

[0124] All samples were analyzed using HPLC (Agilent 1100 series) coupled with a UV detector at 295 nm. For in vitro studies, an Agilent Extend-C18 analytical column (250 × 4.6 mm × 5 μm) was used at 35°C. The mobile phase consisted of methanol and water (v / v = 75:25). The flow rate was 1 mL / min, and the injection volume was 10 μL.

[0125] Plasma, intestinal contents, and ileal tissue samples were processed by adding 50 μL of 0.4 M NaOH, 100 μL of MBZ (10 μg / mL), 1.0 mL of acetonitrile, and 1.0 mL of ethyl acetate, sequentially, to 200 μL of plasma, 100 mg of intestinal contents, and 100 mg of ileal tissue. The mixture was then vortexed for 3 minutes and centrifuged at 12,000 rpm for 10 minutes at 4°C. The supernatant was aspirated and transferred to another centrifuge tube, and 1.0 mL of ethyl acetate was added to the first tube. The vortexing and centrifugation were repeated. The supernatants were combined, dried with nitrogen at 40°C, and the residue was dissolved in 200 μL of mobile phase and centrifuged at 12,000 rpm for 10 minutes at 4°C. The supernatant was then filtered through a 0.22 μm filter for HPLC analysis. Chromatographic separation was performed using an Agilen Extend-C18 analytical column (250 × 4.6 mm × 5 μm) using isocratic elution. The mobile phase was a mixture of sodium acetate solution (0.02 M) at pH 5.0 and acetonitrile (V / V = 65:35), with a flow rate of 1.0 mL / min, a temperature of 40° C., and an injection volume of 20 uL.

[0126] Statistical analysis

[0127] The data were analyzed by one-way ANOVA and plotted using GraphPad Prism 8.0.1 (GraphPad Prism Inc., USA). The main pharmacokinetic parameters were calculated using the non-compartmental model using Phoenix WinNonlin 8.1 (Certara Inc., USA).

[0128] 3.9 Conclusion

[0129] DSC, FTIR, PXRD, and SEM showed that the drug existed in an amorphous state in ABZ-pHs-SD, indicating that ABZ was stably dispersed in the solid dispersion. In the in vitro solubility and release studies, ABZ-pHs-SD significantly increased the solubility of ABZ in water by 3.15 times ( It can effectively prevent drug release in strong acid and weak acid environments, while ensuring slow release of drugs in weak alkaline environments. In addition, in the pharmacokinetic study in rats, In comparison, ABZ-pHs-SD had a lower Cmax and a higher Tmax while having almost no effect on bioavailability, and had higher drug concentration levels in the cecum and colon. These results indicate that compared to The pH-sensitive solid dispersion prepared with GM and HPMC-AS as excipients can be used as a promising drug delivery strategy to improve the solubility, safety, and efficacy of ABZ. This provides a theoretical basis and experimental guidance for the future development of new ABZ formulations.

Claims

1. An albendazole solid dispersant, characterized in that, The invention comprises albendazole, glyceryl monostearate, and hydroxypropyl methylcellulose acetate succinate; the albendazole exists in an amorphous form in the albendazole solid dispersant; The mass ratio of albendazole, glyceryl monostearate, and hypromellose acetate succinate is 15-25:65-70:10-15; Alternatively, the mass ratio of albendazole, glyceryl monostearate, and hypromellose acetate succinate is 25:70:5; Alternatively, the mass ratio of albendazole, glyceryl monostearate, and hydroxypropyl methylcellulose acetate succinate is 10:75:

15.

2. The albendazole solid dispersion according to claim 1, wherein The particle size of the albendazole solid dispersant is 20 to 50 meshes.

3. The albendazole solid dispersion according to claim 2, wherein The particle size of the albendazole solid dispersant is 20-30 meshes, 30-40 meshes or 40-50 meshes.

4. A method for preparing the albendazole solid dispersion according to any one of claims 1 to 3, characterized in that: Albendazole, glyceryl monostearate, and hypromellose acetate succinate were melt-blended and cooled.

5. Use of the albendazole solid dispersion according to any one of claims 1 to 3 in preparing a medicament for treating whipworm disease.

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