Zein-alpha lipoic acid-loaded nanoparticles to enhance the oral bioavailability of dapoxetine: optimization and clinical pharmacokinetic evaluation.

BACKGROUND: Premature ejaculation (PE) is the most common type of male sexual disorder with important psychological consequences. Dapoxetine (DPX), a recently approved drug for the treatment of PE, suffers from low bioavailability with large variability that ranges from 15-76% (mean 42%) after oral administration. The objective of this study is to optimize the parameters for the preparation of DPX-Zein-alpha lipoic acid (ALA) nanoparticles (NPs) to improve the bioavailability of DPX and consequently decrease therapeutic dose and adverse effect, leading to patient satisfaction and compliance. METHODS: We investigated the effect of ALA concentration, PVA concentration and stirring rate on nanoparticle size (Y1), zeta potential (Y2), initial DPX release (Y3) and cumulative DPX release (Y4). In addition, in vivo pharmacokinetic study was performed for the optimized DPX formulation on human healthy volunteers compared with marketed DPX tablet. RESULTS: The optimized DPX-loaded NPs showed Y1, Y2, Y3, and Y4 of 159.24 nm, 19.14 mV, 25.31% and 95.9 %, respectively. A single oral dose of 30 mg of optimized DPX-loaded NPs to human volunteers resulted in 2-fold improvement of AUC (1376.145±339.592 vs 709.178±146.307 in DPX), 4-fold increase in tmax (2.5±0.314 vs 0.583±0.144), prolongation of MRT (7.637±1.373 compared to 6.031±1.826 h), but with reduction in t1/2 (5.283±1.077 vs 8.452±2.813). CONCLUSION: The clinical findings suggest 194% enhancement of relative bioavailability of the optimized DPX-loaded NPs, potentially leading to a decrease in therapeutic dose and associated side effects in the treatment of PE.

Superiority of TPGS-loaded micelles in the brain delivery of vinpocetine via administration of thermosensitive intranasal gel.

Background: Vinpocetine (VPN) is a synthetic derivative of the Vinca minor alkaloids. The drug is characterized by a short half-life, limited water solubility and high hepatic first-pass effect. The objective was to develop different lipid-based nanocarriers (NCs) loaded into a thermosensitive in situ gelling (ISG) system to improve VPN bioavailability and brain targeting via intranasal (IN) delivery. Methods:  Different lipid-based NCs were developed and characterized for vesicle size, zeta potential, VPN entrapment efficiency (EE) and morphological characterization using transmission electron microscope (TEM). The prepared NCs were loaded into ISG formulations and characterized for their mucoadhesive properties. Ex-vivo permeation and histological study of the nasal mucosa were conducted. Pharmacokinetic and brain tissue distribution were investigated and compared to a marketed VPN product following administration of a single dose to rats. Results: VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. Conclusion: VPN-loaded TPGS-micelles ISG formulation is a successful brain drug delivery system with enhanced bioavailability for drugs with poor bioavailability and those that are frequently administered.

Optimized vinpocetine-loaded vitamin E D-α-tocopherol polyethylene glycol 1000 succinate-alpha lipoic acid micelles as a potential transdermal drug delivery system: in vitro and ex vivo studies.

BACKGROUND: Vinpocetine (VNP), a semisynthetic natural product, is used as a vasodilator for cerebrovascular and age-related memory disorders. VNP suffers from low oral bioavailability owing to its low water solubility and extensive first-pass metabolism. This work aimed at utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and alpha lipoic acid (ALA) to develop efficient micellar system for transdermal delivery of VNP. MATERIALS AND METHODS: VNP-TPGS-ALA micelles were prepared, characterized for particle size using particle size analyzer, and investigated for structure using transmission electron microscope. Optimization of VNP-TPGS-ALA micelles-loaded transdermal films was performed using Box-Behnken experimental design. The investigated factors were percentage of ALA in TPGS (X1), citral concentration (X2), and propylene glycol concentration (X3). Elongation percent (Y1), initial permeation after 2 hours (Y2), and cumulative permeation after 24 hours (Y3) were studied as responses. RESULTS: Statistical analysis revealed optimum levels of 16.62%, 3%, and 2.18% for X1, X2, and X3, respectively. Fluorescent laser microscopic visualization of skin penetration of the optimized transdermal film revealed marked widespread fluorescence intensity in skin tissue after 0.5, 2, and 4 hours compared with raw VNP transdermal film formulation, which indicated enhancement of VNP skin penetration. CONCLUSION: The obtained results highlighted the potentiality of VNP nanostructure-based films for controlling the transdermal permeation of the drug and improving its effectiveness.

In situ misemgel as a multifunctional dual-absorption platform for nasal delivery of raloxifene hydrochloride: formulation, characterization, and in vivo performance.

BACKGROUND: Raloxifene hydrochloride (RLX) is approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis, in addition to reducing the risk of breast cancer in postmenopausal women. RLX has the disadvantages of low aqueous solubility, extensive presystemic intestinal glucuronidation, and first-pass metabolism, resulting in a limited bio-availability of only 2%. The aim of this work was to enhance the bioavailability of RLX via the formulation of an in situ nasal matrix (misemgel) comprising micelles made of vitamin E and D-α-tocopheryl polyethylene glycol 1000 succinate and nanosized self-emulsifying systems (NSEMS). MATERIALS AND METHODS: Optimization of the RLX-loaded NSEMS was performed using a mixture design. The formulations were characterized by particle size and then incorporated into an in situ nasal gel. Transmission electron microscopy, bovine nasal mucosa ex vivo permeation, and visualization using a fluorescence laser microscope were carried out on the RLX in situ misemgel comparing with raw RLX in situ gel. In addition, the in vivo performance was studied in rats. RESULTS: The results revealed improved permeation parameters for RLX misemgel compared with control gel, with an enhancement factor of 2.4. In vivo studies revealed a 4.79- and 13.42-fold increased bioavailability for RLX in situ misemgel compared with control RLX in situ gel and commercially available tablets, respectively. The obtained results highlighted the efficacy of combining two different formulations to enhance drug delivery and the benefits of utilizing different possible paths for drug absorption. CONCLUSION: The developed in situ misemgel matrix could be considered as a promising multifunctional platform for nasal delivery which works based on a dual-absorption mechanism.

Finasteride nano-transferosomal gel formula for management of androgenetic alopecia: ex vivo investigational approach.

INTRODUCTION: Finasteride (FIN) is known as type II 5α-reductase inhibitor, which has been approved for the treatment and prevention of androgenetic alopecia. Administration of FIN by oral route has led to undesirable systemic side effects that include mood disturbance, gynecomastia, decreased libido, erectile dysfunction, and ejaculation disorder. The aim was to improve FIN delivery through skin layers and hair follicles that could possibly reduce its major side effects resulting from long-term oral administration for the treatment and prevention of male pattern baldness. MATERIALS AND METHODS: FIN was formulated as nano-transferosomal (NTF) gel formulations (F1-3). The prepared formulations were characterized for encapsulation efficiency, particle size, ex vivo skin permeation, and kinetic modeling. In addition, visualization of NTF skin penetration using a fluorescence laser microscope was carried out for the selected formula (F2). RESULTS AND DISCUSSION: The results showed that FIN encapsulation efficiency percentage was 69.72 ± 8.36, 89.43 ± 6.82, and 93.1 ± 1.93 for F1, F2, and F3, respectively. FIN-NTF average vesicle sizes were 299.6 ± 45.6, 171 ± 25.6, and 197.4 ± 29.1 nm for F1, F2, and F3, respectively. FIN-NTF formulations (F1-3) showed enhancement and improvement in the amount of FIN permeated compared with raw FIN gel formula. The NTF formula revealed uniform fluorescence (rhodamine) intensity across rat skin, which indicated improved delivery through skin layers compared with control gel formula. CONCLUSION: These results indicated that NTF gel formula showed the ability to boost FIN delivery across skin layers and could be applied as an alternative for oral therapy.

Self-assembled biodegradable polymeric micelles to improve dapoxetine delivery across the blood-brain barrier.

BACKGROUND: Dapoxetine (DPX) is the drug of choice for the specific treatment of premature ejaculation. DPX is characterized by relatively low bioavailability (42%) and short half-life (1.5 h). The aim of this study was to improve DPX bioavailability and delivery across the blood-brain barrier (BBB) using a nanostructured DPX formulation for improved DPX efficacy and patient satisfaction. MATERIALS AND METHODS: DPX-loaded polymeric micelles (PMs) formulations (F1-F3) were characterized for particle sizes, entrapment efficiencies, and Fourier transform infrared spectroscopic and transmission electron microscopic evaluations. In addition, diffusion profiles of the prepared formulations were investigated. Animal model pharmacokinetic parameters in plasma and brain tissues were investigated and compared with commercial DPX tablets. RESULTS: Particle size analysis revealed that formulations of DPX PMs showed a narrow range of 62.7±9.3-45.45±9.1 nm for F1-F3. In addition, DPX PMs showed a sustained release pattern with 91.27%±7.64%, 79.43%±7.81%, and 63.78%±5.05% of DPX content permeated after 24 h for F1, F2, and F3, respectively. Plasma pharmacokinetic parameters for DPX PMs showed significant increase (P<0.05) for the area under drug concentration-time curves in plasma and brain tissues compared with commercial DPX tablets. CONCLUSION: DPX formulations in the form of PMs improved bioavailability and efficacy across the BBB. This DPX formulation provided improved brain delivery in order to enhance the convenience and compliance of patients.

Development and optimization of carvedilol orodispersible tablets: enhancement of pharmacokinetic parameters in rabbits.

BACKGROUND: Carvedilol (CVD) is used for the treatment of essential hypertension, heart failure, and systolic dysfunction after myocardial infarction. Due to its lower aqueous solubility and extensive first-pass metabolism, the absolute bioavailability of CVD does not exceed 30%. To overcome these drawbacks, the objective of this work was to improve the solubility and onset of action of CVD through complexation with hydroxypropyl-ß-cyclodextrin and formulation of the prepared complex as orodispersible tablets (ODTs). METHODS: Compatibility among CVD and all tablet excipients using differential scanning calorimetry and Fourier transform infrared spectroscopy, complexation of CVD with different polymers, and determination of the solubility of CVD in the prepared complexes were first determined. A Box-Behnken design (BBD) was used to study the effect of tablet formulation variables on the characteristics of the prepared tablets and to optimize preparation conditions. According to BBD design, 15 formulations of CVD-ODTs were prepared by direct compression and then evaluated for their quality attributes. The relative pharmacokinetic parameters of the optimized CVD-ODTs were compared with those of the marketed CVD tablet. A single dose, equivalent to 2.5 mg/kg CVD, was administered orally to New Zealand white rabbits using a double-blind, randomized, crossover design. RESULTS: The solubility of CVD was improved from 7.32 to 22.92 mg/mL after complexation with hydroxypropyl-ß-cyclodextrin at a molar ratio of 1:2 (CVD to cyclodextrin). The formulated CVD-ODTs showed satisfactory results concerning tablet hardness (5.35 kg/cm(2)), disintegration time (18 seconds), and maximum amount of CVD released (99.72%). The pharmacokinetic data for the optimized CVD-ODT showed a significant (P<0.05) increase in maximum plasma concentration from 363.667 to 496.4 ng/mL, and a shortening of the time taken to reach maximum plasma concentration to 2 hours in comparison with the marketed tablet. CONCLUSION: The optimized CVD-ODTs showed improved oral absorption of CVD and a subsequent acceleration of clinical effect, which is favored for hypertensive and cardiac patients.