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

Lipid nanocarriers overlaid with chitosan for brain delivery of berberine via the nasal route

This research aimed to design, optimize, and evaluate berberine-laden nanostructured lipid carriers overlaid with chitosan (BER-CTS-NLCs) for efficient brain delivery via the intranasal route. The nanostructured lipid carriers containing berberine (BER-NLCs) were formulated via hot homogenization and ultrasonication strategy and optimized for the influence of a variety of causal variables, including the amount of glycerol monostearate (solid lipid), poloxamer 407 (surfactant) concentration, and oleic acid (liquid lipid) amount, on size of the particles, entrapment, and the total drug release after 24 h. The optimal BER-NLCs formulation was then coated with chitosan. Their diameter, in vitro release, surface charge, morphology, ex vivo permeability, pH, histological, and in vivo (pharmacokinetics and brain uptake) parameters were estimated. BER-CTS-NLCs had a size of 180.9 ± 4.3 nm, sustained-release properties, positive surface charge of 36.8 mV, and augmented ex-vivo permeation via nasal mucosa. The histopathological assessment revealed that the BER-CTS-NLCs system is safe for nasal delivery. Pharmacokinetic and brain accumulation experiments showed that animals treated intranasally with BER-CTS-NLCs had substantially greater drug levels in the brain. The ratios of BER brain/blood levels at 30 min, AUCbrain/AUCblood, drug transport percentage, and drug targeting efficiency for BER-CTS-NLCs (IN) were higher compared to BER solution (IN), suggesting enhanced brain targeting. The optimized nanoparticulate system is speculated to be a successful approach for boosting the effect of BER in treating CNS diseases, such as Alzheimer’s disease, through intranasal therapy

Innovative pulmonary targeting of terbutaline sulfate-laded novasomes for non-invasive tackling of asthma: statistical optimization and comparative in vitro/in vivo evaluation.

Asthma represents a globally serious non-communicable ailment with significant public health outcomes for both pediatrics and adults triggering vast morbidity and fatality in critical cases. The β2-adrenoceptor agonist, terbutaline sulfate (TBN), is harnessed as a bronchodilator for monitoring asthma noising symptoms. Nevertheless, the hepatic first-pass metabolism correlated with TBN oral administration mitigates its clinical performance. Likewise, the regimens of inhaled TBN dosage forms restrict its exploitation. Consequently, this work is concerned with the assimilation of TBN into a novel non-phospholipid nanovesicular paradigm termed novasomes (NVS) for direct and effective TBN pulmonary targeting. TBN-NVS were tailored based on the thin film hydration method and Box-Behnken design was applied to statistically optimize the formulation variables. Also, the aerodynamic pattern of the optimal TBN-NVS was explored via cascade impaction. Moreover, comparative pharmacokinetic studies were conducted using a rat model. TBN elicited encapsulation efficiency as high as 70%. The optimized TBN-NVS formulation disclosed an average nano-size of 223.89 nm, ζ potential of −31.17 mV and a sustained drug release up to 24 h. Additionally, it manifested snowballed in vitro lung deposition behavior in cascade impactor with a fine particle fraction of 86.44%. In vivo histopathological studies verified safety of intratracheally-administered TBN-NVS. The pharmacokinetic studies divulged 3.88-fold accentuation in TBN bioavailability from the optimum TBN-NVS versus the oral TBN solution. Concisely, the results proposed that NVS are an auspicious nanovector for TBN pulmonary delivery with integral curbing of the disease owing to target specificity

Tunable polymeric mixed micellar nanoassemblies of Lutrol F127/Gelucire 44/14 for oral delivery of praziquantel: a promising nanovector against hymenolepis nana in experimentally-infected rats

Hymenolepiasis represents a parasitic infection of common prevalence in pediatrics with intimidating impacts, particularly amongst immunocompromised patients. The present work aimed to snowball the curative outcomes of the current mainstay of hymenolepiasis chemotherapy, praziquantel (PRZ), through assembly of polymeric mixed micelles (PMMs). Such innovative nano-cargo could consolidate PRZ hydrosolubility, extend its circulation time and eventually upraise its bioavailability, thus accomplishing a nanoparadigm for hymenolepiasis tackling at lower dose levels. For consummating this goal, PRZ-PMMs were tailored via thin-film hydration technique integrating a binary system of Lutrol F127 and Gelucire 44/14. Box-Behnken design was planned for optimizing the nanoformulation variables employing Design-Expert® software. Also, in Hymenolepis nana-infected rats, the pharmacodynamics of the optimal micellar formulation versus the analogous crude PRZ suspension were scrutinized on the 1st and 3rd days after administration of a single oral dose (12.5 or 25 mg/kg). Moreover, in vitro ovicidal activity of the monitored formulations was estimated utilizing Fuchsin vital stain. Furthermore, the in vivo pharmacokinetics were assessed in rats. The optimum PRZ-PMMs disclosed conciliation between thermodynamic and kinetic stability, high entrapment efficiency (86.29%), spherical nanosized morphology (15.18 nm), and controlled-release characteristics over 24 h (78.22%). 1H NMR studies verified PRZ assimilation within the micellar core. Additionally, the in vivo results highlighted a significant boosted efficacy of PRZ-PMMs manifested by fecal eggs output and worm burden reduction, which was clearly evident at the lesser PRZ dose, besides a reversed effect for the intestinal histological disruptions. At 50 µg/mL, PRZ-PMMs increased the percent of non-viable eggs to 100% versus 47% for crude PRZ, whilst shell destruction and loss of embryo were only clear with the applied nano-cargo. Moreover, superior bioavailability by 3.43-fold with elongated residence time was measured for PRZ-PMMs compared to PRZ suspension. Practically, our results unravel the potential of PRZ-PMMs as an oral promising tolerable lower dose nanoplatform for more competent PRZ mass chemotherapy

Surface-Modified Bilosomes Nanogel Bearing a Natural Plant Alkaloid for Safe Management of Rheumatoid Arthritis Inflammation

Rheumatoid arthritis (RA) is a chronic inflammatory illness affecting the joints. The characteristic of RA is gradual joint deterioration. Current RA treatment alleviates signs such as inflammation and pain and substantially slows the progression of the disease. In this study, we aimed to boost the transdermal delivery of berberine (a natural product) by encapsulating it in chitosan, surface-modified bilosomes nanogel for better management of the inflammation of RA. The chitosan-coated bilosomes loaded with berberine (BER-CTS-BLS) were formulated according to the thin-film hydration approach and optimized for various causal variables, considering the effect of lipid, sodium deoxycholate, and chitosan concentrations on the size of the particles, entrapment, and the surface charge. The optimized BER-CTS-BLS has 202.3 nm mean diameter, 83.8% entrapment, and 30.8 mV surface charge. The optimized BER-CTS-BLS exhibited a delayed-release profile in vitro and increased skin permeability ex vivo. Additionally, histological examination revealed that the formulated BLS had no irritating effects on the skin. Furthermore, the optimized BER-CTS-BLS ability to reduce inflammation was evaluated in rats with carrageenan-induced paw edema. Our results demonstrate that the group treated with topical BER-CTS-BLS gel exhibited a dramatic reduction in rat paw edema swelling percentage to reach 24.4% after 12 h, which was substantially lower than other groups. Collectively, chitosan-coated bilosomes containing berberine have emerged as a promising therapeutic approach to control RA inflammation

Intratracheally Inhalable Nifedipine-Loaded Chitosan-PLGA Nanocomposites as a Promising Nanoplatform for Lung Targeting: Snowballed Protection via Regulation of TGF-β/β-Catenin Pathway in Bleomycin-Induced Pulmonary Fibrosis

Pulmonary fibrosis is a serious ailment that may progress to lung remodeling and demolition, where the key participants in its incidence are fibroblasts responding to growth factors and cellular calcium swinging. Calcium channel blockers, like nifedipine (NFD), may represent auspicious agents in pulmonary fibrosis treatment. Unfortunately, NFD bears complicated pharmacodynamics and a diminished systemic bioavailability. Thus, the current study aimed to develop a novel, non-invasive nanoplatform for NFD for direct/effective pulmonary targeting via intratracheal instillation. A modified solvent emulsification–evaporation method was adopted for the fabrication of NFD-nanocomposites, integrating poly(D,L-lactide-co-glycolide) (PLGA), chitosan (CTS), and polyvinyl alcohol, and optimized for different physiochemical properties according to the 32 full factorial design. Additionally, the aerodynamic behavior of the nanocomposites was scrutinized through cascade impaction. Moreover, the pharmacokinetic investigations were conducted in rats. Furthermore, the optimum formulation was tested in bleomycin-induced pulmonary fibrosis in rats, wherein fibrotic and oxidative stress parameters were measured. The optimum nanocomposites disclosed a nanosized spherical morphology (226.46 nm), a high entrapment efficiency (61.81%) and a sustained release profile over 24 h (50.4%). As well, it displayed a boosted in vitro lung deposition performance with a mass median aerodynamic diameter of 1.12 µm. Pharmacokinetic studies manifested snowballed bioavailability of the optimal nanocomposites by 3.68- and 2.36-fold compared to both the oral and intratracheal suspensions, respectively. The intratracheal nanocomposites revealed a significant reduction in lung fibrotic and oxidative stress markers notably analogous to normal control besides repairing abnormality in TGF-β/β-catenin pathway. Our results conferred a compelling proof-of-principle that NFD-CTS-PLGA nanocomposites can function as a promising nanoparadigm for pulmonary fibrosis management

Loratadine bioavailability via buccal transferosomal gel: formulation, statistical optimization, in vitro/in vivo characterization, and pharmacokinetics in human volunteers

Loratadine (LTD) is an antihistaminic drug that suffers limited solubility, poor oral bioavailability (owing to extensive first-pass metabolism), and highly variable oral absorption. This study was undertaken to develop and statistically optimize transfersomal gel for transbuccal delivery of LTD. Transfersomes bearing LTD were prepared by conventional thin film hydration method and optimized using sequential Quality-by-Design approach that involved Placket–Burman design for screening followed by constrained simplex-centroid design for optimization of a Tween-80/Span-60/Span-80 mixture. The transferosomes were characterized for entrapment efficiency, particle size, and shape. Optimized transferosomes were incorporated in a mucoadhesive gel. The gel was characterized for rheology, ex vivo permeation across chicken pouch buccal mucosa, in vitro release, and mucoadhesion. Pharmacokinetic behavior of LTD formulations was investigated in healthy volunteers following administration of a single 10-mg dose. Optimal transferosomes characterized by submicron size (380 nm), spherical shape and adequate loading capacity (60%) were obtained by using quasi-equal ratio surfactant mixture. In terms of amount permeated, percentage released, and mucoadhesion time, the transferosomal gel proved superior to control, transferosome-free gel. Bioavailability of the transferosomal gel was comparable to Claritin® oral tablets. However, inter-individual variability in Cmax and AUC was reduced by 76 and 90%, respectively, when the buccal gel was used. Linear Correlation of in vitro release with in vivo buccal absorption fractions was established with excellent correlation coefficient (R2>0.97). In summary, a novel buccal delivery system for LTD was developed. However, further clinical investigation is warranted to evaluate its therapeutic effectiveness and utility

Fabrication and In Vitro/In Vivo Appraisal of Metronidazole Intra-Gastric Buoyant Sustained-Release Tablets in Healthy Volunteers

Helicobacter pylori is thought to be the most common cause of peptic and duodenal ulcers. Eradication of this organism is now considered one of the lines of treatment of gastric and duodenal ulcers. This can be achieved via local delivery of antibacterial agents in high concentrations. Accordingly, our objective was to fabricate and evaluate sustained release floating tablets for metronidazole to extend the gastric residence period and control the release rate of metronidazole. Floating tablets containing cellulose derivatives and Avicel were prepared using direct compression. The rate of metronidazole release from the floating tablets (K = 6.278 mg min−1/2) was significantly lower than that from conventional tablets (K = 10.666 mg min−1/2), indicating sustained drug release, according to the Higuchi model, for more than 6 h in an acidic medium of 0.1 N HCl. In vivo study in healthy volunteers revealed significantly improved bioavailability; increased Tmax, AUC, and MRT; and significantly lower absorption rate constant after a single oral dose of 150 mg metronidazole as floating tablets. In addition, the significant increase in MRT indicated an in vivo sustained drug release. The floating tablets provided several benefits, including ease of preparation, absence of effervescent ingredients, and reliance on a pH-independent gel-forming agent to deliver metronidazole in a sustained manner. In conclusion, the prepared tablets could be promising for enhancing both local and systemic metronidazole efficacy

Loratadine bioavailability via buccal transferosomal gel: formulation, statistical optimization, <i>in vitro</i>/<i>in vivo</i> characterization, and pharmacokinetics in human volunteers

<p>Loratadine (LTD) is an antihistaminic drug that suffers limited solubility, poor oral bioavailability (owing to extensive first-pass metabolism), and highly variable oral absorption. This study was undertaken to develop and statistically optimize transfersomal gel for transbuccal delivery of LTD. Transfersomes bearing LTD were prepared by conventional thin film hydration method and optimized using sequential Quality-by-Design approach that involved Placket–Burman design for screening followed by constrained simplex-centroid design for optimization of a Tween-80/Span-60/Span-80 mixture. The transferosomes were characterized for entrapment efficiency, particle size, and shape. Optimized transferosomes were incorporated in a mucoadhesive gel. The gel was characterized for rheology, <i>ex vivo</i> permeation across chicken pouch buccal mucosa, <i>in vitro</i> release, and mucoadhesion. Pharmacokinetic behavior of LTD formulations was investigated in healthy volunteers following administration of a single 10-mg dose. Optimal transferosomes characterized by submicron size (380 nm), spherical shape and adequate loading capacity (60%) were obtained by using quasi-equal ratio surfactant mixture. In terms of amount permeated, percentage released, and mucoadhesion time, the transferosomal gel proved superior to control, transferosome-free gel. Bioavailability of the transferosomal gel was comparable to Claritin® oral tablets. However, inter-individual variability in <i>C</i>_max and AUC was reduced by 76 and 90%, respectively, when the buccal gel was used. Linear Correlation of <i>in vitro</i> release with <i>in vivo</i> buccal absorption fractions was established with excellent correlation coefficient (<i>R²</i>>0.97). In summary, a novel buccal delivery system for LTD was developed. However, further clinical investigation is warranted to evaluate its therapeutic effectiveness and utility.</p