Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches

Arteannuin B (AB) has been found to demonstrate obvious anti-tumor activity. However, AB is not available for clinical use due to its very low solubility and very short half-life. This study aimed to develop AB long sustained-release microspheres (ABMs) to improve the feasibility of clinical applications. Firstly, AB-polylactic-co-glycolic acid (PLGA) microspheres were prepared by a single emulsification method. In vitro characterization studies showed that ABMs had a low burst release and stable in vitro release for up to one week. The particle size of microspheres was 69.10 μm (D50). The drug loading is 37.8%, and the encapsulation rate is 85%. Moreover, molecular dynamics modeling was firstly used to simulate the preparation process of microspheres, which clearly indicated the molecular image of microspheres and provided in-depth insights for understanding several key preparation parameters. Next, in vivo pharmacokinetics (PK) study was carried out to evaluate its sustained release effect in Sprague-Dawley (SD) rats. Subsequently, the methyl thiazolyl tetrazolium (MTT) method with human lung cancer cells (A549) was used to evaluate the in vitro efficacy of ABMs, which showed the IC50 of ABMs (3.82 μM) to be lower than that of AB (16.03 μM) at day four. Finally, in vivo anti-tumor activity and basic toxicity studies were performed on BALB/c nude mice by subcutaneous injection once a week, four times in total. The relative tumor proliferation rate T/C of AMBs was lower than 40% and lasted for 21 days after administration. The organ index, organ staining, and tumor cell staining indicated the excellent safety of ABMs than Cis-platinum. In summary, the ABMs were successfully developed and evaluated with a low burst release and a stable release within a week. Molecular dynamics modeling was firstly applied to investigate the molecular mechanism of the microsphere preparation. Moreover, the ABMs possess excellent in vitro and in vivo anti-tumor activity and low toxicity, showing great potential for clinical applications.

Formulation Development and Optimization of Sustained Release Microspheres of Acebrophylline

Objectives: Aim of present work is to prepare and evaluate Sustained release microspheres of Acebrophylline for treatment of Asthma. Experimental work: In present investigation, attempt was made to prepare sustained release microspheres of Acebrophylline with different polymer ratio using Ionic gelation method. Drug- excipient compatibility studies were performed by FTIR. The best suited Microspheres formulation was found on the basis production yield, entrapment efficiency and in vitro release study. Optimized batch of microspheres (B2) was characterized for FTIR, DSC, and SEM analysis. The drug release data of optimized batch was fitted into different release kinetic models. The optimized batch of microspheres (B2) was subjected for the short term stability study at 40 ± 2°C with RH of 75% for a period of 1 month. Results and discussion: There was no interaction found between drug and excipients. Sodium alginate (2%) concentration, Eudragit RS-100 (1:2) ratio gave highest sustainable property and CaCl2 (2.5%) concentration had a good cross linking property. This observation done on the basis of production yield, entrapment efficiency and In vitro release study. The Microspheres prepared from Ionic gelation method had Drug : Eudragit RS100 (1:2), 2 % Sodium alginate and 2.5 % CaCl2 (B2) give 99.2 % drug release over the periods of 12 hr. The drug release from optimized microspheres formulation (B2) follows first order release kinetic. DSC study showed the melting behavior of drug present into microspheres. SEM studies showed that optimized microspheres were spherical and rough surface. Stability study proved that optimized formulation (B2) was stable. Conclusion: Drug: Polymer ratio and Volume of CaCl2 had significant effect on % Entrapment efficiency and Drug release. From the Scanning Electron Microscopy (SEM) study observed that microspheres was spherical and rough surface. Non Fickian diffusion was the mode of drug release from Acebrophylline- loaded microspheres. After stability study no physical changes & almost same drug release was observed in microspheres. Hence, the formulation B2 was stable.

Preparation of Temozolomide Nano SustainedRelease Microsphere Material and Its Application in Treatment of Glioma

The polylactic acid/glycolic acid (PLGA) sustained-release microspheres are used as the main material for local sustained-release in the study. Ultrasonic emulsification-solvent evaporation method is applied to combine the sustained-release microspheres material with temozolomide to form a composite sustained-release microsphere (TMZ-PLGA-W). The ratio of lactic acid (LA) and glycolic acid (GA) was adjusted so as to test the morphological characteristics of TMZ-PLGA-W at different ratios. The amount of drug released and the encapsulation rate of the material at different time periods were calculated. The C6 glioma system was implanted into the right caudate nucleus of Wistar rats to obtain a rat intracranial glioma model. The models were divided into 5 groups according to different sustained-release materials, and each group had 10 rats. The brain tumor at different times were compared and the survival time of rats was statistically calculated. The TMZ-PLGA-W sustained-release microsphere material with LA/GA ratio of 25%/75% was selected and placed in C6 cells culturing incubator according to different drug loadings. The cell activity according to the culture time was observed. The results showed that the TMZ-PLGA-W sustained-release microspheres prepared in the study were stable in structure, uniform in size, and free of cracks. At the same time, the sustained-release curve showed that the microsphere material conformed to the biodynamic law, which could reduce the burst effect and prolong the sustained release of the drug. The application of TMZ-PLGA-W sustained-release microspheres can effectively inhibit the increase in the area of brain tumors in rats, and at the same time improve the survival rate of rats. The increase in the drug loading of the microspheres can further inhibit the growth of glioma cells.

Microspheres scar formation glaucoma filtration surgery area therapeutic effect—Based on rapamycin-chitosan-calcium alginate sustained-release

To study the efficacy of rapamycin (RAPA)-chitosan (CS)-calcium alginate (CA) sustained-release microspheres on scar formation in a rabbit model of glaucoma filtration surgery. Eighty New Zealand white rabbits were randomly divided into four groups and a glaucoma filtration model was established by scleral bite through the eyes. RAPA-CS-CA sustained-release microspheres were implanted in the right eye of 40 rabbits (Group A) and CS blank sustained-release microspheres were implanted in the left eye (Group B). Another 40 rabbits were treated with a 0.2 g·L-1 RAPA cotton sheet in the right eye (Group C) and the left eye underwent a simple sclerotomy (Group D). The intraocular pressure, filter bleb, anterior chamber inflammation, complications, and corneal endothelial cell density were observed after the operation. Rabbits were euthanized for pathological examination 7 days, 14 days, and 21 days after the operation. The drug loading rate of RAPA-CS-CA sustainedrelease microspheres was (34.58±1.47)% and the encapsulation rate was (56.23±1.55)%. The microsphere release in vitro was relatively stable. The release rate of the microspheres during the burst was only 16.54%. After 49 days, the cumulative release rate of the microspheres reached 94.07% and the sustained release effect was significant within 45 days. Group A maintained low-level intraocular pressure for the longest period of time, followed by Group C, and then Group B and D. The survival time of filter vesicles in Group A was longer than that in other groups. There were no postoperative complications in each group. The conjunctival epithelium of Group A had better integrity and fewer subconjunctival fibroblasts than other groups. There was no obvious inflammation or infiltration around the filtering mouth and there were fewer new collagen fibers. RAPA-CS-CA slow-release microspheres safely and effectively inhibited the proliferation of fibroblasts and neonatal collagen fibers in rabbit glaucoma filtration surgery and significantly improved the success rate of glaucoma filtration surgery.

Improved Stability of Rifampicin in the Presence of Gastric-Resistant Isoniazid Microspheres in Acidic Media

The degradation of rifampicin (RIF) in an acidic medium to form 3-formyl rifamycin SV, a poorly absorbed compound, is accelerated in the presence of isoniazid, contributing to the poor bioavailability of rifampicin. This manuscript presents a novel approach in which isoniazid is formulated into gastric-resistant sustained-release microspheres and RIF into microporous floating sustained-release microspheres to reduce the potential for interaction between RIF and isoniazid (INH) in an acidic environment. Hydroxypropyl methylcellulose acetate succinate and Eudragit® L100 polymers were used for the manufacture of isoniazid-loaded gastric-resistant sustained-release microspheres using an o/o solvent emulsification evaporation approach. Microporous floating sustained-release microspheres for the delivery of rifampicin in the stomach were manufactured using emulsification and a diffusion/evaporation process. The design of experiments was used to evaluate the impact of input variables on predefined responses or quality attributes of the microspheres. The percent degradation of rifampicin following 12 h dissolution testing in 0.1 M HCl pH 1.2 in the presence of isoniazid gastric-resistant sustained-release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be reduced by encapsulation of both active pharmaceutical ingredients to ensure release in different segments of the gastrointestinal tract, potentially improving the bioavailability of rifampicin.