Comprehensive chemo-profiling of coumarins enriched extract derived from Aegle marmelos (L.) Correa fruit pulp, as an anti-diabetic and anti-inflammatory agent.

Aegle marmelos (L.) Correa is an Indian medicinal plant known for its vast therapeutic activities. In Ayurveda, the plant is known to balance "vata," "pitta," and "kapha" dosh. Recent studies suggest anti-inflammatory, anti-microbial, and anti-diabetic potential but lack in defining the dosage over the therapeutic activities. This study aims to determine the chemical profile of Aegle marmelos fruit extract; identification, enrichment, and characterization of the principal active component(s) having anti-inflammatory and anti-diabetic potential. Targeted enrichment of total coumarins, focusing on marmelosin, marmesin, aegeline, psoralen, scopoletin, and umbelliferone, was done from Aegle marmelos fruit pulp, and characterized using advanced high-throughput techniques. In vitro and in silico anti-diabetic and anti-inflammatory activities were assessed to confirm their efficacy and affinity as anti-diabetic and anti-inflammatory agents. The target compounds were also analysed for toxicity by in silico ADMET study and in vitro MTT assay on THP-1 and A549 cell lines. The coumarins enrichment process designed, was found specific for coumarins isolation as it resulted into 48.61% of total coumarins enrichment, which includes 31.2% marmelosin, 8.9% marmesin, 4% psoralen, 2% scopoletin, 1.7% umbelliferone, and 0.72% aegeline. The quantification with HPTLC and qNMR was found to be correlated with the HPLC assay results. The present study validates the potential use of Aegle marmelos as an anti-inflammatory and anti-diabetic agent. Coumarins enriched from the plant fruit have good therapeutic activity and can be used for Phytopharmaceutical ingredient development. The study is novel, in which coumarins were enriched and characterized by a simple and sophisticated methodology.

Effect of Food on the Pharmacokinetics of 2 Formulations of DRL-17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males.

DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, and area under plasma concentration-time curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.

Development and Pharmacokinetic Evaluation of New Oral Formulations of Diacerein.

The present research investigates development and in vivo evaluation of oral diacerein formulations with quicker and complete absorption. In vivo, diacerein gets completely metabolized to its active metabolite rhein in gut and liver, which is the only analyte detected in plasma. Incomplete absorption of diacerein from the formulation leads to colonic availability of rhein, which is associated with increased laxative effect as one of the side effects of diacerein therapy. Thus solubility improved immediate release formulation (IR) and a gastroretentive formulation (GR) was designed to achieve rapid absorption preferentially through upper part of gastro-intestinal tract; thus controlling the amount of rhein reaching to colon and minimizing the associated increased laxative effect. In vitro drug release studies of the developed formulations revealed faster and complete release of diacerein from IR and GR formulations compared to commercially available diacerein capsule Art50. Comparative bioavailability studies conducted in healthy human volunteers revealed 1.7 fold and 1.2 fold rise in AUC(0-6h) for IR and GR formulations respectively, compared to Art50 capsules. A Levy plot analysis comparing association between the time of in vitro dissolution (Tvitro) of diacerein and time of in vivo absorption (Tvivo) of rhein confirmed faster release and absorption from upper part of gastrointestinal region for both the optimized formulations.

Improved immune response from biodegradable polymer particles entrapping tetanus toxoid by use of different immunization protocol and adjuvants.

Poly lactide-co-glycolide (PLGA) and polylactide (PLA) particles entrapping immunoreactive tetanus toxoid (TT) were prepared using the solvent evaporation method. The effect of different formulation parameters such as polymer hydrophobicity, particle size and use of additional adjuvants on the generation of immune responses in experimental animals was evaluated. Immune responses from hydrophobic polymer particles were better than those from hydrophilic polymer. Immunization with physical mixtures of different size particles resulted in further improvement in anti-TT antibody titers in Wistar rats. Physical mixture of nano and microparticles resulted in early as well as high antibody titers in experimental animals. Immunization with polymer particles encapsulating stabilized TT elicited anti-TT antibody titers, which persisted for more than 5 months and were higher than those obtained with saline TT. However, antibody responses generated by single point immunization of either particles or physical mixture of particles were lower than the conventional two doses of alum-adsorbed TT. Immunization with nanoparticles along with alum resulted in very high and early immune response: high anti-TT antibody titers were detected as early as 15 days post-immunization. Use of a squalene emulsion along with the particles during immunization enhanced the level of anti-TT antibody titers considerably. Single point immunization with admixtures of PLA microparticles and alum resulted in antibody response very close to that achieved by two injections of alum-adsorbed TT; the antibody titers were more than 50 microg/ml over a period of 6 months. These results indicated that the judicious choice of polymer and particles size, protecting the immunoreactivity of the entrapped antigen and the appropriate design of immunization protocol along with suitable adjuvant can lead to the generation of long lasting immune response from single dose vaccine formulation using polymer particles.

Correlation between in vitro release and in vivo immune response from biodegradable polymer particles entrapping tetanus toxoid.

Release of immunoreactive antigen from biodegradable polymer particles in a manner mimicking the normal vaccination schedule is one of the most important requirements for the successful development of single dose vaccine formulation. Tetanus toxoid (TT) was used as a model antigen to develop single dose vaccine formulations using poly(lactide-co-glycolide) and poly(lactide)polymers. An amphiphilic stabilizer such as RSA or PVA was used at an optimal concentration in the internal aqueous phase during preparation of immunoreactive TT particles using the multiple emulsion solvent evaporation method. Particles made from different polymers released immunoreactive TT continuously for more than 4 months in vitro and release profiles were in accordance with the degradation characteristics of the polymer. Initial burst release of antigen from the particles was controlled by incorporation of different concentrations of PVA in the internal aqueous phase during particle formulation. The extent of antigen release from the particles was varied by changing the aqueous to organic phase volume during the primary emulsification stage of particles formulation. Use of above formulation variables resulted in the formulation of polymer particles having different in vitro release characteristics. Anti-TT antibody titers in vivo were also in accordance with the in vitro release characteristics of immunoreactive TT from the particles. Anti-TT antibody titers from the stabilized particles were much better than that observed from particles made without stabilizers. These results indicate the importance of stabilizers and different formulation variables for the preparation of polymer particles having desired in vitro release characteristics.