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Flibanserin (FLB) was approved by FDA for the treatment of pre-menopausal female hypoactive sexual desire disorder (HSDD). FLB suffers from low oral bioavailability (33%) which might be due to hepatic first-pass metabolism in addition to its poor aqueous solubility. The sublingual route could be a promising alternative for FLB due to the avoidance of enterohepatic circulation. However, the drug needs to dissolve in the small volume of saliva in order to be absorbed through the sublingual mucosa. Therefore, FLB nanocrystals were prepared by sono-precipitation technique according to 23 full factorial design. FLB-nanocrystals were formulated using two surfactants (PVP K30 and PL F127) in two different amounts (200 and 400 mg) and the volume of ethanol was either 3 or 5 mL. Nanocrystal formulation was optimized according to the desirability function to have a minimum particle size, zeta potential, polydispersity index, and maximum saturated solubility. The optimized formula had a particle size of 443.12 ± 14.91 nm and a saturated solubility of 23.27 ± 4.62 mg/L which is five times the saturated solubility of FLB. Nanocrystal dispersion of the optimized formula was solidified by freeze-drying and used to prepare rapidly disintegrating sublingual tablets containing Pharmaburst® as superdisintegrant. Sublingual tablet formulation with the shortest disintegration time (36 s) was selected for the in vivo study. FLB nanocrystal-based sublingual tablets exhibited a two-fold increase in bioavailability with a faster onset of action compared to the commercially available oral formulation. These findings prove the potential application of FLB nanocrystal-based sublingual tablets in the treatment of HSDD.

Marianne Joseph Naguib,1 Ibrahim Elsayed,1,2 Mahmoud Hassan Teaima1 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2Department of Pharmaceutical Sciences, College of Pharmacy and Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab EmiratesCorrespondence: Marianne Joseph NaguibDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, EgyptEmail marian.naguib@pharma.cu.edu.egPurpose: Ivabradine hydrochloride is selective pacemaker current (If) ion channel inhibitor used in case of chronic heart failure (CHF) with superior efficacy and lower side effects than most β-blockers. However, the drug suffers from low bioavailability (≈40%) due to extensive first-pass metabolism. Hence, this work aims to formulate nanovesicular platforms to enhance their bioavailability both orally and transdermally.Materials and Methods: A central composite face-centered design was employed to formulate the nanovesicles, both phosphatidylcholine: drug ratio and percentage of pluronic F68 were used as independent variables. The nine developed formulae were characterized in terms of vesicle size (nm), polydispersity index, zeta potential (mV), entrapment efficiency (%). Decreasing vesicle size, increasing negative value of the zeta potential, and increasing entrapment efficiency were the chosen constraints to optimize the engineered nanovesicles. The candidate formula was subjected to further investigation including lyophilization, loading into carbopol gel, in vitro release, imaging with a transmission electron microscope, histopathological examination, in vitro cytotoxicity study and in vivo pharmacokinetics.Results: The optimized nanovesicular formula was composed of lipid: drug ratio of 3.91:1 and 100% pluronic as a stabilizer. It has particle size, zeta potential and entrapment efficiency of 337.6 nm, − 40.5 mV and 30.5, respectively. It was then lyophilized in the presence of 5% trehalose as a cryoprotectant, dispersed in 0.5% carbopol to develop the transdermal gel. The two different forms of the candidate formula (lyophilized and gel form) displayed sustained drug release in comparison to drug solution. The histopathological and cytotoxicity studies showed that the optimized formula was safe and highly biocompatible. The pharmacokinetics parameters measured declared a higher Cmax and half-life of both formulae in comparison to market product (Procoralan®) with a 2.54- and 1.85-folds increase in bioavailability, respectively.Conclusion: Hence, the developed nanovesicles can be reported as the first nanoplatforms to be used for simultaneous ivabradine delivery by both oral and topical routes with enhanced oral and transdermal drug delivery. The developed nanoplatforms hence can be further used to formulate other drugs that suffer from low bioavailability due to extensive first-pass metabolism.Keywords: ivabradine, oral, transdermal, central composite, lyophilized, extensive first pass

The work aimed to improve both absorption and hepatic availability of sofosbuvir. Bilosomes and galactose-anchored bilosomes were investigated as potential nanocarriers for this purpose. Sofosbuvir is a class III drug with high solubility and low permeability. Thus, the drug entrapment into lipid-based galactose-anchored carriers would enhance drug permeability and improve its liver availability. The galactosylated taurocholate was designed and synthesized based on molecular docking studies, where both galactose and taurocholate molecules were connected in a way to avoid affecting crucial interactions and avoid steric clashes with their cellular uptake receptors. The suggested nano-carriers were prepared using a thin-film hydration technique with sodium taurocholate and span 60 as stabilizers. The prepared formulae were statistically optimized using a central composite design. The optimized plain and galactosylated formulae, composed of SAA to drug ratio of 1:1 w/w and sodium taurocholate to span ratio of 10:1 w/w, have a vesicular size, zeta potential and entrapment efficiency in the range of 140–150 nm, −50 mV and 85%, respectively. The optimized formulae were lyophilized to increase their physical stability and facilitate accurate drug dosing. In vivo results showed that Sofosbuvir availability in the liver was significantly increased after oral administration of the plain and the galactosylated bilosomal formulae when compared to the oral drug solution with relative targeting efficiencies (RTIs) of 1.51 and 3.66, respectively. These findings confirmed the hypothesis of considering the galactosylated bilosomes a promising nanocarrier to efficiently target sofosbuvir to the liver.

Cytomegalovirus (CMV) retinitis is a vision-threatening disease that principally afflicts immunosuppressed patients. For the management of the disease, Ganciclovir (GCV) is usually administered systemically, where patients may suffer severe untoward effects. The ocularly-applied alternatives are either the intravitreal injections, which are frequently administered due to GCV short half-life, or the sustained-release implants, which require surgical removal upon drug depletion. Both therapies are invasive and should be completed by a medical expert. The objective of this research was to formulate a non-invasive alternative represented in GCV loaded ultra-fluidic glycerosomes (UFGs), which are glycerosomes containing sodium taurocholate as an edge activator (EA), then incorporating the optimal UFGs in polylactic acid (PLA)-based 3D printed ocusert to prolong the release of GCV. The experimental design, the statistical analysis, and the optimization were performed via Design-Expert® software. The optimal formulation (UFGs 6; composed of 600 mg Phosphatidylcholine (PC), 20 mg cholesterol, 0.1:1 weight molar ratio of EA: PC and 1 gm glycerol) possessed nanovesicles (441.70 ± 1.13 nm) that entrapped 69.33 ± 0.28 % of GCV, with zeta potential value of −37.00 ± 0.42 mV and deformability index value of 74.68 ± 0.71. The confocal microscopy results showed the supreme penetration power of UFGs through the rabbit’s cornea, compared to edge-activated vesicles and conventional glycerosomes from the laden ocusert. Moreover, the topical application of the ocusert laden with the optimal GCV loaded UFGs to the rabbits’ eyes evidenced their safety as per the histopathological findings. Furthermore, a pharmacokinetic study in the rabbit’s aqueous humor demonstrated the sustained release of GCV from the ocusert laden with the optimal GCV loaded UFGs over 5 days. Inclusively, the ocusert laden with UFGs could be considered as a non-invasive sustaining drug delivery system of GCV for the management of CMV retinitis.

The aim of the present study was the formulation of a novel chewable tablet containing the non-steroidal anti-inflammatory bumadizone calcium (BZ) to deliver the drug to the colon for the local treatment of ulcerative colitis. Colon targeted granules were prepared following 3 2 full factorial design. The effect of two independent variables, namely, polymer type (Eudragit ® S100, Eudragit ® L100, and a mixture of both in the ratio of 4:1) and drug to polymer ratio (1:1, 1:3& 1:5) on the % of BZ released for 12 h was studied. In order to produce chewability, candidate formulae were then mixed with different amount of maize starch and mannitol, and compressed into tablets. F11 tablets(composed of drug: Eudragit ® S100 in the ratio of 1:3, 250 mg mannitol and 50 mg maize starch with a desirability of 0.925) achieved the required release profile i.e: lowest release before target area (pH 1.2 & 6.8) reaching only 11.00% at the end of the fourth hour, and 100.27% after 12 h (pH7.4). Histopathological studies results declared clearly the ability of the chewable colon targeted tablets F11 to locally treat acetic acid induced colitis. Furthermore, the measurements of myeloperoxidase enzyme activities in colon specimens showed that F11 achieved a significantly lower levels in comparison to both untreated group and group that received the marketed tablets (p

The objective of the present study was to optimize and evaluate a buccal mucoadhesive tenoxicam (TNX) local delivery system for the treatment of chronic periodontitis. Full 32 factorial design was adopted to evaluate the effect of the concentration of chitosan and polyvinyl pyrrolidone (PVP) on buccal film characteristics. The results showed that PVP concentration exerted a significant synergistic effect on film swelling, while chitosan slightly, but insignificantly, retarded film swelling. In addition, chitosan exhibited the only significant agonistic effect on mechanical film properties. Furthermore, PVP significantly enhanced the Higuchi diffusion slope of the drug release from buccal films, while it was antagonized by chitosan. The optimized formula showed adequate mechanical properties for buccal films. The in vivo salivary pharmacokinetic study of the optimized film revealed rapid and sustained salivary TNX delivery in the buccal cavity. This study indicated that the optimized TNX mucoadhesive buccal film is an optimal alternative dosage form to oral therapy for the treatment of chronic periodontitis and can provide a means to overcome the off-targeted side effects of orally delivered drug.

Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 h in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine.

The objective of this study was the development of a colon-targeted microspheres which were compressed into tablets containing the non-steroidal anti-inflammatory bumadizone calcium hemihydrate. [corrected]. A 3(2) full factorial design was adopted for the evaluation of the prepared microspheres. The effect of two independent variables namely polymer type (Eudragit RS100, ethyl cellulose and cellulose acetate butyrate), and drug: polymer ratio (1:1, 9:1 and 18:1) was studied on the entrapment efficiency and in vitro drug release for 12 h. Colon targeting aims to minimize the release of the drug off target area (pH 1.2 and 6.8) and to maximize the release of the drug in target area (pH 7.4). Candidate formulae were compressed into core tablets and colon targeting was achieved using the enzyme-dependent polymer (pectin) as coat in three different concentrations 50, 75 and 90%. Candidate formula F15 (microspheres prepared using BDZ:CAB in a ratio of 18:1 and compressed into tablets using 50% pectin and 50% Avicel in the coat) was able to adequately modulate drug release avoiding drug release in the gastric ambient, and reaching the colonic targeting where 99.7% release was achieved within 12 h following zero-order model. In vivo studies showed that F15 achieved significant decrease in myeloperoxidase activity and inflammation with delayed Tmax (4 h) and lower Cmax (2700 ng/ml) when compared to marketed product.

Clonazepam (CZ) is an anti-epileptic drug used mainly in status epilepticus (SE). The drug belongs to Class II according to BCS classification with very limited solubility and high permeability and it suffers from extensive first-pass metabolism. The aim of the present study was to develop CZ-loaded polymeric micelles (PM) for direct brain delivery allowing immediate control of SE. PM were prepared via thin film hydration (TFH) technique adopting a central composite face-centered design (CCFD). The seventeen developed formulae were evaluated in terms of entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro release. For evaluating the in vivo behavior of the optimized formula, both biodistrbution using 99mTc-radiolabeled CZ and pharmacodynamics studies were done in addition to ex vivo cytotoxicty. At a drug:Pluronic® P123:Pluronic® L121 ratio of 1:20:20 (PM7), a high EE, ZP, Q8h, and a low PDI was achieved. The biodistribution studies revealed...