Improvement of Bioavailability of Sildenafil Citrate Through Taste Masked Orodispersible Film for Pulmonary Hypertension Management.

The oral bioavailability of sildenafil citrate is approximately 43%, primarily limited by the low aqueous solubility and first-pass effect. Considering the drug properties and biopharmaceutical considerations, this study aimed to develop an immediate release, taste masked orodispersible film (ODF) of sildenafil citrate for the efficient management of pulmonary arterial hypertension (PAH). The optimization was done by applying 32 full-factorial design. The drug-loaded film was prepared and evaluated for the physical and mechanical parameters like; thickness, disintegration time, tensile strength, elongation, swelling index, content uniformity, disintegration and in vitro drug release in pH 6.2 stimulated salivary fluid. The FTIR and DSC data proved excellent compatibility between the drug and polymers used. The time taken for disintegration by the optimized film was about 62.66 s, while the drug release was observed ~ 96% in 10 min. Pharmacokinetic studies exhibited better sildenafil plasma level (p < 0.05) and Cmax (p < 0.001) of orally disintegrating film which is significantly higher than the oral drug solution. The AUC0-8 (24874.425 ± 1234.45 ng. h/mL) in the oromucosal application was 1.2-fold more (p < 0.0001) than the control. The presence of sweetening and flavoring agents in the formulation masked the drug bitterness, resulting in a higher intake of the formulation in rats compared to the unmasked drug solution, as observed with in vivo taste masking studies. The importance of ODF as a feasible, effective, and optimal approach for delivering sildenafil citrate via oromucosal administration for the treatment of PAH was successfully highlighted by these results.

Design, Development, and Evaluation of Treprostinil Embedded Adhesive Transdermal Patch.

Clinical application of treprostinil in pulmonary arterial hypertension is hampered by adverse effects caused by its high dosing frequency. The objective of this investigation was to Formulate an adhesive-type transdermal patch of treprostinil and evaluate it both in vitro and in vivo. A 32-factorial design was utilized to optimize the selected independent variables (X1: drug amount, X2: enhancer concentration) on the response variables (Y1: drug release, Y2: transdermal flux). The optimized patch was evaluated for various pharmaceutical properties, skin irritation, and pharmacokinetics in rats. Optimization results signify considerable influence (p < 0.0001) of X1 on both Y1 and Y2, as compared to X2. The optimized patch possesses higher drug content (>95%), suitable surface morphology, and an absence of drug crystallization. FTIR analysis revealed compatibility of the drug with excipients, whereas DSC thermograms indicate that the drug exists as amorphous in the patch. The adhesive properties of the prepared patch confirm adequate adhesion and painless removal, while the skin irritation study confirms its safety. A steady drug release via Fickian diffusion and greater transdermal delivery (~23.26 µg/cm2/h) substantiate the potential of the optimized patch. Transdermal therapy resulted in higher treprostinil absorption (p < 0.0001) and relative bioavailability (237%) when compared to oral administration. Overall, the results indicate that the developed drug in the adhesive patch can effectively deliver treprostinil through the skin and could be a promising treatment option for pulmonary arterial hypertension.

Design, Development, Evaluation, and In Vivo Performance of Buccal Films Embedded with Paliperidone-Loaded Nanostructured Lipid Carriers.

The therapeutic effectiveness of paliperidone in the treatment of schizophrenia has been limited by its poor oral bioavailability; hence, an alternative route could be appropriate. This study investigates the feasibility of developing a buccal film impregnated with paliperidone-loaded nanostructured lipid carriers (NLCs) and assesses the potential to enhance its bioavailability. Box-Behnken-based design optimization of NLCs was performed by examining the particles' physical characteristics. The polymeric film was used to load optimized NLCs, which were then assessed for their pharmaceutical properties, permeability, and pharmacokinetics. The optimization outcomes indicated that selected formulation variables had a considerable (p < 0.05) impact on responses such as particle size, entrapment efficiency, and % drug release. Desired characteristics such as a negative charge, higher entrapment efficiency, and nanoparticles with ideal size distribution were shown by optimized NLC dispersions. The developed film demonstrated excellent physico-mechanical properties, appropriate texture, good drug excipient compatibility (chemically stable formulation), and amorphous drug nature. A sustained Weibull model drug release (p < 0.0005) and superior flux (~5-fold higher, p < 0.005) were seen in NLC-loaded film compared to plain-drug-loaded film. The pharmacokinetics profile in rabbits supports the goal of buccal therapy as evidenced by significantly higher AUC0-12 (p < 0.0001) and greater relative bioavailability (236%) than the control. These results support the conclusion that paliperidone-loaded NLC buccal film has the potential to be an alternate therapy for its effective administration in the treatment of schizophrenia.

Qbd-Based Approach to Optimize Niosomal Gel of Levosulpiride for Transdermal Drug Delivery.

Poor aqueous solubility besides extensive hepatic first effect significantly decreases the oral absorption of levosulpiride, which in turn minimizes its therapeutic effectiveness. Niosomes have been extensively investigated as a transdermal vesicular nanocarrier to increase the delivery of low permeable compounds into and across the skin. This research work was to design, develop and optimize levosulpiride-loaded niosomal gel and to evaluate its prospects for transdermal delivery. The Box-Behnken design was used to optimize niosomes by analyzing the impact of three factors (cholesterol; X1, Span 40; X2, and sonication time; X3) on the responses (particle size, Y1, and entrapment efficiency, Y2). Optimized formulation (NC) was incorporated into gel and evaluated for pharmaceutical properties, drug release study, ex vivo permeation, and in vivo absorption. The design experiment data suggest that all three independent variables influence both response variables significantly (p < 0.01). Pharmaceutical characteristics of NC vesicles showed the absence of drug excipient interaction, nanosize (~102.2 nm), narrow distribution (~0.218), adequate zeta potential (-49.9 mV), and spherical shape, which are suitable for transdermal therapy. The levosulpiride release rates varied significantly (p < 0.01) between niosomal gel formulation and control. Greater flux (p < 0.01) was observed with levosulpiride-loaded niosomal gel than with control gel formulation. Indeed, the drug plasma profile of niosomal gel was significantly higher (p < 0.005), with ~3 folds higher Cmax and greater bioavailability (~500% higher; p < 0.0001) than its counterpart. Overall, these findings imply that the use of an optimized niosomal gel formulation can increase the therapeutic efficacy of levosulpiride and may represent a promising alternative to conventional therapy.

Intranasal Delivery of Darunavir-Loaded Mucoadhesive In Situ Gel: Experimental Design, In Vitro Evaluation, and Pharmacokinetic Studies.

The clinical efficacy of antiretroviral therapy in NeuroAIDS is primarily limited by the low perfusion of the drug to the brain. The objective of the current investigation was to design and develop an in situ mucoadhesive gel loaded with darunavir to assess the feasibility of brain targeting through the intranasal route. Preliminary batches (F1−F9) were prepared and evaluated for various pharmaceutical characteristics. A full factorial design of the experiment was applied to optimize and assess the effect of two influencing variables (Carbopol 934P (X1) and Poloxamer 407 (X2)) on the response effects (gelation temperature (Y1) and % drug release (Y2) at 8 h). The data demonstrate that both influencing variables affect the response variables significantly (p < 0.05). The optimized formulation (F7) exhibited favorable rheological properties, adequate mucoadhesion, sustained drug release, and greater permeation across the nasal mucosa. An in vitro ciliotoxicity study confirms the nontoxicity of the optimized in situ gel (D7) on the nasal mucosa. An in vivo pharmacokinetic study in rats was performed to assess drug targeting to the brain following the nasal application of the selected in situ gel (D7). Significantly higher (p < 0.0001) Cmax (~4-fold) and AUC0-α (~3.5-fold) values were noticed in the brain after nasal application, as compared to the intravenous route. However, less systemic exposure to darunavir was noticed with nasal therapy, which confirms the low absorption of the drug into the central compartment. Overall, the data here demonstrate that the optimized in situ mucoadhesive nasal gel is effective in targeting darunavir to the brain by the nasal route and could be a viable option for the treatment of NeuroAIDS.