Limited solubility and hepatic first-pass metabolism are the main causes of low bioavailability of anti-schizophrenic drug, Clozapine (CZP). The objective of the study was to develop and validate nanoemulsion (NE) based in-situ gel of CZP for intranasal administration as an approach for bioavailability enhancement. Solubility of CZP was initially investigated in different oils, surfactants and co-surfactants, then pseudoternary phase diagrams were constructed to select the optimized ratio of oil, surfactant and co-surfactant. Clear and transparent NE formulations were characterized in terms of droplet size, viscosity, solubilization capacity, transmission electron microscopy, in-vitro drug release and compatibility studies. Selected NEs were incorporated into different in-situ gel bases using combination of two thermosensitive polymers; Pluronic® F-127 (PF127) and F-68 (PF68). NE-based gels (NG) were investigated for gelation temperature, viscosity, gel strength, spreadability and stability. Moreover, selected NGs were evaluated for ex-vivo permeation, mucoadhesive strength and nasal ciliotoxicity. Peppermint oil, tween 80 and transcutol P were chosen for NE preparation owing to their maximum CZP solubilization. Clear NE points extrapolated from tween 80:transcutol P (1:1) phase diagram and passed dispersibility and stability tests, demonstrated globule size of 67.99 to 354.96 nm and zeta potential of −12.4 to −3.11 mV with enhanced in-vitro CZP release (>90% in some formulations). After incorporation of the selected N3 and N9 formulations of oil:Smix of 1:7 and 2:7, respectively to a mixture of PF127 and PF68 (20:2% w/w), the resultant NG formulations exhibited optimum gelation temperature and viscosity with enhanced CZP permeation and retention through sheep nasal mucosa. Ciliotoxicity examinations of the optimum NGs displayed no inflammation or damage of the lining epithelium and the underlying cells of the nasal mucosa. In conclusion, NE-based gels may be a promising dosage form of CZP for schizophrenia treatment.

High percentage of diabetic people are diagnosed as type 2 who require daily dosing of an antidiabetic drug such as Linagliptin (Lina) to manage their blood glucose levels. This study aimed to develop injectable Lina-loaded biodegradable poly (lactic-co-glycolic acid) (PLGA) in-situ implants (ISIs) to deliver a desired burst effect of Lina followed by a sustained release over several days for controlling the blood glucose levels over prolonged time periods. The morphological, pharmacokinetic, and pharmacodynamic assessments of the Lina-loaded ISIs were performed. Scanning electron microscopy (SEM) study revealed the rapid exchange between the water miscible solvent (N-methyl-2-pyrrolidone; NMP) and water during the ISI preparation, hence enhancing the initial burst Lina release. While, triacetin of lower water affinity could lead to formation of more compact and dense ISI structure with slower drug release. By comparing various ISI formulations containing different solvents and different PLGA concentrations, the ISI containing 40 % PLGA and triacetin was selected for its sustained release of Lina (93.06 ± 1.50 %) after 21 days. The pharmacokinetic results showed prolonged half life (t_1/2) and higher area under the curve (AUC) values of the selected Lina-loaded ISI when compared to those of oral Lina preparation. The single Lina-ISI injection produced a hypoglycemic control in the diabetic rats very similar to the daily oral administration of Lina after 7 and 14 days. In conclusion, PLGA-based ISIs confirmed their suitability for prolonging Lina release in patients receiving long-term antidiabetic therapy, thereby achieving more enhanced patient compliance and reduced dosing frequency.

The aim of the study was to design injectable long-acting poly (lactide-co-glycolide) (PLGA)-based in situ gel implants (ISGI) loaded with the anti-diabetic alogliptin. Providing sustained therapeutic exposures and improving the pharmacological responses of alogliptin were targeted for achieving reduced dosing frequency and enhanced treatment outputs. In the preliminary study, physicochemical characteristics of different solvents utilized in ISGI preparation were studied to select a proper solvent possessing satisfactory solubilization capacity, viscosity, water miscibility, and affinity to PLGA. Further, an optimization technique using a 2³ factorial design was followed. The blood glucose levels of diabetic rats after a single injection with the optimized formulation were compared with those who received daily oral alogliptin. N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), as highly water-miscible and low viscous solvents, demonstrated their effectiveness in successful ISGI preparation and controlling the burst alogliptin release. The impact of increasing lactide concentration and PLGA amount on reducing the burst and cumulative alogliptin release was represented. The optimized formulation comprising 312.5 mg of PLGA (65:35) and DMSO manifested a remarkable decrease in the rats’ blood glucose levels throughout the study period in comparison to that of oral alogliptin solution. Meanwhile, long-acting alogliptin-loaded ISGI systems demonstrated their feasibility for treating type 2 diabetes with frequent dosage reduction and patient compliance enhancement.

Irritable bowel syndrome (IBS); a widespread disorder in gastrointestinal tract especially in children, burdens their healthcare systems and upsets families. Great attention was paid to understand the pathophysiological cause of disorder. However, developing a convenient treatment especially for children remains a challenge. Phosphodiesterase inhibitors were recently introduced for IBS management. Vardenafil (VDF), a phosphodiesterase-5 inhibitor, exhibiting limited bioavailability when taken orally due to extensive first-pass effect, was the choice for study. This study aimed to formulate VDF jellies as a buccal dosage form to improve pediatric compliance and achieve maximum drug efficacy. VDF oral jellies were prepared by heat and congeal method, and were evaluated for their pH, content uniformity, physical stability, general appearance, and in-vitro drug release. VDF jellies (F1), with satisfactory organoleptic properties and highest percent of drug released compared to other formulations was selected as a master formula for further study to ensure in-vivo efficacy. cyclic Guanosine Mono Phosphate (cGMP), used as indicator of VDF concentration in blood, was highly increased after administration of VDF jellies (F1), compared to oral VDF suspension. Increased defecation with improved fecal consistency strongly favored oral jellies as a potential alternative route for VDF for IBS management with high pediatric acceptance.

Background/Objectives: Hyperlipidemia is a silent threat lurking in the bloodstream of millions worldwide. The nano-based platform has emerged as a promising drug delivery technology. Repaglinide, an anti-diabetic drug, was investigated recently as an antihyperlipidemic candidate that could supersede the available antihyperlipidemic drugs. Our goal was to optimize albumin-based nanoparticles loaded with Repaglinide for parenteral delivery and conduct in silico and in vivo studies to explore the efficacy of Repaglinide for the management of hyperlipidemia along with its anti-diabetic effect. Methods: The impact of three independent factors, the albumin%, acetone volume, and glutaraldehyde/albumin, on the particle size, zeta potential, and entrapment efficiency was investigated. Results: The optimized formulation was spherical, homogenous of an average diameter (~181.86 nm) with a narrow size distribution, a zeta potential of −24.26 mV, and 76.37% as the EE%. The in vitro release of Repaglinide from nanoparticles showed a sustained release pattern for 168 h, with an initial burst release after 24 h, and was fitted to the Fickian diffusion mechanism. A molecular docking simulation showed a strong affinity to several protein targets, and the results were very promising, where Repaglinide gave a score of −7.70 Kcal/mol compared to Mevastatin (−6.71 Kcal/mol) and Atorvastatin (−8.36 Kcal/mol). On conducting in vivo studies on animal models, the optimized formula recorded a statistically significant decrease in the serum levels of total cholesterol, triglyceride, and low-density lipoproteins, with an increased high-density lipoprotein. Conclusions: This study suggested albumin nanoparticles as potential nanocarriers for the parenteral delivery of Repaglinide to ameliorate its antihyperlipidemic benefits, especially in diabetic patients.

Clonazepam (CLZ), an antipsychotic drug reported for its efficiency in managing anxiety-related disorders, is being marketed only as conventional tablets. Some patients have abstention to swallow the conventional tablets; therefore, the proposed study was aimed at developing a buccal lozenge tablet by direct compression of two types of optimized granules. Conazepam’s water solubility was first enhanced by a solid dispersion technique for a fast and better dissolution of type 1 granules, while the impact of gelling polymers was investigated on controlled-release type 2 granules. The optimized formulae met the acceptable pharmacopeial limits for tablets’ evaluation. A differential scanning calorimetry study revealed the compatibility between the drug and used excipients. All formulae gave a burst release of CLZ in the first hour of investigation, followed by a sustained release over 24 h. The formula that showed the highest prolonged in vitro release (99.0 + 0.1%), following the Higuchi diffusion model (R² = 0.99), was then selected for further study. The formula succeeded in controlling the induced stress in a rat model with a significant impact on the behavioral tests throughout the experiment. The results were further confirmed by a pharmacokinetic study that showed a significant increase in Cmax, Tmax, and AUC (1.5, 2, and 3.9 folds), respectively, compared to oral suspension. The newly proposed delivery system has proven a better efficacy with a reduced dosing frequency.