Bilosomes as a promising nanoplatform for oral delivery of an alkaloid nutraceutical:improved pharmacokinetic profile and snowballed hypoglycemic effect in diabetic rats

Diabetes mellitus is a life-threatening metabolic disease. At the moment, there is no effective treatment available to combat it. In this study, we aimed to develop berberine-loaded bilosomes (BER-BLS) to boost the oral bioavailability and therapeutic efficacy of berberine, a natural antidiabetic medication. The BER-BLS was fabricated using a thin-film hydration strategy and optimized using a central composite design (face-centered). The average vesicle size, entrapment efficiency, and surface charge of the optimized BER-BLS preparation were 196.5 nm, 89.7%, (−) 36.4 mV, respectively. In addition, it exhibited higher stability and better-sustained release of berberine than the berberine solution (BER-SOL). BER-BLS and BER-SOL were administered to streptozocin-induced diabetic rats. The optimized BER-BLS formulation had a significant hypoglycemic impact, with a maximum blood glucose decrease of 41%, whereas BER-SOL only reduced blood glucose by 19%. Furthermore, the pharmacological effect of oral BER-BLS and BER-SOL corresponded to 99.3% and 31.7%, respectively, when compared to subcutaneous insulin (1 IU). A pharmacokinetic analysis found a 6.4-fold rise in the relative bioavailability of berberine in BER-BLS when compared to BER-SOL at a dosage of 100 mg/kg body weight. Histopathological investigation revealed that BER-BLS is suitable for oral administration. Our data demonstrate that BLS is a potential nanocarrier for berberine administration, enhancing its oral bioavailability and antidiabetic activity

Synthesis of new 1,2-disubstituted benzimidazole analogs as potent inhibitors of b-Glucuronidase and in silico study

New benzimidazole analogues (1–18) were synthesized and characterized through differ- ent spectroscopic techniques such as 1H NMR, 13C NMR and HREI-MS. All analogues were screened for b-glucuronidase inhibitory potential. All analogues showed varied degree of inhibitory potentials with IC50 values ranging between 1.10 – 0.10 to 39.60 – 0.70 lM when compared with standard D-saccharic acid-1,4- lactone having IC50 value 48.30 lM. Analogues 17, 11, 9, 6, 1 and 13 having IC50 values 1.10 – 0.10, 1.70 – 0.10, 2.30 – 0.10, 5.30 – 0.20, 6.20 – 0.20 and 8.10 – 0. 20 lM respectively, showed excellent b-glucuronidase inhibitory potential many folds better than the standard. All other analogues also showed good inhibitory potential better as compared to stan- dard. Structure activity relationships (SAR) has been established for all compounds. The results from molecular docking studies supports the established SAR and developed a strong correlation with the results from into vitro assay. The molecular docking results clearly highlighted how sub- stituents like nitro and chloro affect the binding position of the active compounds in the active site. The docking results were also used to properly establish the effect of bulky substituents of least active compounds on reduced b-glucuronidase inhibitory activity. Compounds 1–18 were found non-toxic

In vitro release and cytotoxicity study of encapsulated sulfasalazine within LTSP micellar/ liposomal and TSP micellar/niosomal nano-formulations

The micelles/liposome formulation for the first time has been constructed via thin-film hydration method containing soy lecithin (L), tween 80 (T), squalene (S), and polyvinyl alcohol (P) (LTSP nanoparticles). Similar ingredients except for lecithin were used for preparing micellar/niosomal vesicular SSZ nano formulation (TSP nanoparticles). The percent drug loading and encapsulation efficiency of SSZ was 7.39% and 98.5 ± 0.3 % for the 7.5:100 (w/w) ratio of SSZ: total weight of LTSP, while the percent drug loading and encapsulation efficiency of SSZ was 4.7% and 62.85 ± 0.3 % in the TSP nano formulation. Dynamic light scattering (DLS) and trans- mission electron microscopy (TEM) results showed that both formulations formed spherical micelles and vesicles with globule sizes of 25 ± 1.2 nm and 100 ± 20.5 nm respectively. The cell toxicity evaluations showed that both LTSP and TSP nano formulations without drug were nontoxic (at the range of this experiment) for Human Dermal Fibroblasts (HDF) as a normal cell line, but SSZ loaded nano formulation exhibited increased cell toxicity with half-maximal inhibitory concentration (IC50) of 940 mM for SSZ alone to near 240 mM for SSZ loaded nano formulation (approximately four times). In vitro release experiments exhibited sustained release of SSZ from both nano formulations. The LTSP micellar/liposomal and TSP micellar/niosomal nano formulation for SSZ delivery can be considered as appropriate approaches for improving its bioavailability and probably they are good candidates for future clinical investigations

Formulation of Genistein-HP β Cyclodextrin-Poloxamer 188 Ternary Inclusion Complex: Solubility to Cytotoxicity Assessment

The current study was designed to prepare the inclusion complex Genistein (GS) using Hydroxypropyl β cyclodextrin (HP β CD) and poloxamer 188 (PL 188). The binary inclusion complex (GS BC) and ternary inclusion complex (GS TC) were developed by microwave irradiation technique and evaluated for a comparative dissolution study. Further, the samples were assessed for FTIR, DSC, XRD, and NMR for the confirmation of complex formation. Finally, antioxidant and antimicrobial studies and cytotoxicity studies on a breast cancer (MCF-7) cell line were conducted. The dissolution study result showed a marked increment in GS dissolution/release after incorporation in binary (GS: HP β CD, 1:1) and ternary (GS: HP β CD: PL 188; 1:1:0.5) inclusion complexes. Moreover, the ternary complex exhibited a significant enhancement (p < 0.05) in dissolution than did the binary complexes. This might be due to the presence of PL 188, which helps in solubility enhancement of GS. DSC, XRD and SEM evaluation confirmed the modification in the structure of GS. FTIR and NMR results indicated the formation of an inclusion complex. The antioxidant and antimicrobial activity results revealed that GS TC has shown significant (p < 0.05) higher activity than pure GS. The cytotoxicity study results also depicted concentration-dependent cytotoxicity. GS TC exhibited significantly (p < 0.05) high cytotoxicity to cancer cells (IC50 = 225 µg/mL) than pure GS (IC50 = 480 µg/mL). Finally, it was concluded that a remarkable enhancement in the dissolution was observed after the inclusion of GS in the ternary complex and it therefore has significant potential for the treatment of breast cancer

Formulation of Miconazole-Loaded Chitosan–Carbopol Vesicular Gel: Optimization to In Vitro Characterization, Irritation, and Antifungal Assessment

Miconazole nitrate (MN) is a poorly water-soluble and antifungal drug used for fungal infections. The present research work was designed to develop topical MN-loaded bilosomes (BSs) for the improvement of therapeutic efficacy. MZBSs were prepared by using the thin-film hydration method and further optimized by using the Box–Behnken statistical design (BBD). The optimized miconazole bilosome (MZBSo) showed nano-sized vesicles, a low polydispersity index, a high entrapment efficiency, and zeta potential. Further, MZBSo was incorporated into the gel using carbopol 934P and chitosan polymers. The selected miconazole bilosome gel (MZBSoG2) demonstrated an acceptable pH (6.4 ± 0.1), viscosity (1856 ± 21 cP), and spreadability (6.6 ± 0.2 cm2). Compared to MZBSo (86.76 ± 3.7%), MZBSoG2 showed a significantly (p Candida albicans and Aspergillus niger. The stability study results showed no significant changes after stability testing under accelerated conditions. MZ-loaded gels could serve as effective alternative carriers for improving therapeutic efficacy

Formulation of Miconazole-Loaded Chitosan–Carbopol Vesicular Gel: Optimization to In Vitro Characterization, Irritation, and Antifungal Assessment

Miconazole nitrate (MN) is a poorly water-soluble and antifungal drug used for fungal infections. The present research work was designed to develop topical MN-loaded bilosomes (BSs) for the improvement of therapeutic efficacy. MZBSs were prepared by using the thin-film hydration method and further optimized by using the Box–Behnken statistical design (BBD). The optimized miconazole bilosome (MZBSo) showed nano-sized vesicles, a low polydispersity index, a high entrapment efficiency, and zeta potential. Further, MZBSo was incorporated into the gel using carbopol 934P and chitosan polymers. The selected miconazole bilosome gel (MZBSoG2) demonstrated an acceptable pH (6.4 ± 0.1), viscosity (1856 ± 21 cP), and spreadability (6.6 ± 0.2 cm2). Compared to MZBSo (86.76 ± 3.7%), MZBSoG2 showed a significantly (p < 0.05) slower drug release (58.54 ± 4.1%). MZBSoG2 was found to be a non-irritant because it achieved a score of zero (standard score) in the HET-CAM test. It also exhibited significant antifungal activity compared to pure MZ against Candida albicans and Aspergillus niger. The stability study results showed no significant changes after stability testing under accelerated conditions. MZ-loaded gels could serve as effective alternative carriers for improving therapeutic efficacy

Formulation and Evaluation of Moxifloxacin Loaded Bilosomes In-Situ Gel: Optimization to Antibacterial Evaluation

In this study, moxifloxacin (MX)-loaded bilosome (BS) in situ gel was prepared to improve ocular residence time. MX-BSs were prepared using the thin-film hydration method. They were optimized using a Box–Behnken design (BBD) with bile salt (A, sodium deoxycholate), an edge activator (B, Cremophor EL), and a surfactant (C, Span 60) as process variables. Their effects were assessed based on hydrodynamic diameter (Y1), entrapment efficacy (Y2), and polydispersity index (Y3). The optimized formulation (MX-BSop) depicted a low hydrodynamic diameter (192 ± 4 nm) and high entrapment efficiency (76 ± 1%). Further, MX-BSop was successfully transformed into an in situ gel using chitosan and sodium alginate as carriers. The optimized MX-BSop in situ gel (MX-BSop-Ig4) was further evaluated for gelling capacity, clarity, pH, viscosity, in vitro release, bio-adhesiveness, ex vivo permeation, toxicity, and antimicrobial properties. MX-BSop-Ig4 exhibited an optimum viscosity of 65.4 ± 5.3 cps in sol and 287.5 ± 10.5 cps in gel states. The sustained release profile (82 ± 4% in 24 h) was achieved with a Korsmeyer–Peppas kinetic release model (R2 = 0.9466). Significant bio-adhesion (967.9 dyne/cm2) was achieved in tear film. It also exhibited 1.2-fold and 2.8-fold higher permeation than MX-Ig and a pure MX solution, respectively. It did not show any toxicity to the tested tissue, confirmed by corneal hydration (77.3%), cornea histopathology (no internal changes), and a HET-CAM test (zero score). MX-BSop-Ig4 exhibited a significantly (p < 0.05) higher antimicrobial effect than pure MX against Staphylococcus aureus and Escherichia coli. The findings suggest that bilosome in situ gel is a good alternative to increase corneal residence time, as well as to improve therapeutic activity

Formulation and Optimization of Nano Lipid Based Oral Delivery Systems for Arthritis

Rheumatoid arthritis is an autoimmune disease characterized by chronic synovitis that leads to tissue dysfunction as well as loss of complete function. There are several synthetic NSAIDs, glucocorticoids and biological drugs that are commonly used to treat arthritis. These drugs have severe life-threatening side effects. The use of a bioactive compound (Apigenin) could be an alternative to synthetic conventional delivery systems. It is a poorly water-soluble drug having a wide range of pharmacological activities. It has been reported for potential anti-inflammatory and anti-arthritic activity. In the present study, Apigenin (APG) solid lipid nanoparticles were prepared using the solid lipid (glyceryl mono stearate, GMS), surfactant (d -α-Tocopheryl polyethylene glycol 1000 succinate, TPGS) and sonication time (ST). The optimized APG SLNs showed a particle size of 161.7 nm and encapsulation efficiency of 80.44 ± 4.11%. It was further coated with 0.1% w/v chitosan (APG-CH-SLNs) and showed the particle size, PDI and zeta potential of 185.4 nm, 0.45 + 26.7 mV, respectively. The significant (p < 0.001) enhancement in drug release, permeation and mucoadhesive study was observed after chitosan coating. The antioxidant study results depicted an increase in antioxidant property. Finally, the anti-arthritic biochemical parameters revealed marked changes in the results in comparison to arthritic control animals. From the study, it was concluded that APG-loaded mucoadhesive lipid nanoparticles are an alternative to the synthetic oral delivery systems

Harnessing Lipid Polymer Hybrid Nanoparticles for Enhanced Oral Bioavailability of Thymoquinone: In Vitro and In Vivo Assessments

The clinical application of phytochemicals such as thymoquinone (THQ) is restricted due to their limited aqueous solubility and oral bioavailability. Developing mucoadhesive nanocarriers to deliver these natural compounds might provide new hope to enhance their oral bioavailability. Herein, this investigation aimed to develop THQ-loaded lipid-polymer hybrid nanoparticles (THQ-LPHNPs) based on natural polymer chitosan. THQ-LPHNPs were fabricated by the nanoprecipitation technique and optimized by the 3-factor 3-level Box–Behnken design. The optimized LPHNPs represented excellent properties for ideal THQ delivery for oral administration. The optimized THQ-LPHNPs revealed the particles size (PS), polydispersity index (PDI), entrapment efficiency (%EE), and zeta potential (ZP) of 85%, and >25 mV, respectively. THQ-LPHNPs represented excellent stability in the gastrointestinal milieu and storage stability in different environmental conditions. THQ-LPHNPs represented almost similar release profiles in both gastric as well as intestinal media with the initial fast release for 4 h and after that a sustained release up to 48 h. Further, the optimized THQ-LPHNPs represent excellent mucin binding efficiency (>70%). Cytotoxicity study revealed much better anti-breast cancer activity of THQ-LPHNPs compared with free THQ against MDA-MB-231 and MCF-7 breast cancer cells. Moreover, ex vivo experiments revealed more than three times higher permeation from the intestine after THQ-LPHNPs administration compared to the conventional THQ suspension. Furthermore, the THQ-LPHNPs showed 4.74-fold enhanced bioavailability after oral administration in comparison with the conventional THQ suspension. Therefore, from the above outcomes, mucoadhesive LPHNPs might be suitable nano-scale carriers for enhanced oral bioavailability and therapeutic efficacy of highly lipophilic phytochemicals such as THQ

Long-Acting Paliperidone Parenteral Formulations Based on Polycaprolactone Nanoparticles; the Influence of Stabilizer and Chitosan on In Vitro Release, Protein Adsorption, and Cytotoxicity

Long-acting preparations containing the antipsychotic paliperidone for intramuscular injection has drawn considerable attention to achieve harmless long-term treatment. This study aimed to develop paliperidone loaded polycaprolactone (PCL) nanoparticles and investigate the influence of PCL/drug ratio, stabilizer type, and chitosan coating on physicochemical properties, protein adsorption, and cellular toxicity. Results showed that chitosan coating produced enlarged particle sizes, shifted the surface charges from negative into positive and did not influence encapsulation efficiencies. Chitosan coating relatively sustained the drug release especially in pluronic stabilized formulations. Pluronic F127 based formulations exhibited the least protein adsorption (384.3 μg/mL). Chitosan coating of Tween 80 and polyvinyl alcohol stabilized formulations significantly (p < 0.05) increased protein adsorption. Cellular viability was concentration-dependent and negatively affected by stabilizers. All formulations did not show cellular death at 1.56 μg/mL. Inflammatory responses and oxidative stress were less affected by Tween 80 compared with other stabilizers. Chitosan minimized all aspects of cellular toxicity. Collectively, stabilizer type and chitosan coating play critical roles in developing safe and effective long-acting PCL nanoparticles intended for parenteral drug delivery. The coated formulations containing Tween 80 and Pluronic F127 as stabilizers are warranted a future in vivo study to delineate its safety and efficacy profiles