Implementing Nanovesicles for Boosting the Skin Permeation of Non-steroidal Anti-inflammatory Drugs.

The consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have increased lately around the world, as they are considered essential and popular drugs for effective reduction of pain and inflammation. They have analgesic, antipyretic, and anti-inflammatory activities; also, it was reported recently that they protect against various critical disorders like heart attacks and cancer. However, oral use of NSAIDs may cause several pulmonary, gastrointestinal, hepatic, cardiovascular, cerebral, and renal complications. Therefore, topical NSAIDs were recommended as a substitute to oral NSAIDs for the treatment of inflammation and pain. Still, the skin permeation of NSAIDs is considered a challenge, as the skin have an effective barrier function. Therefore, this review investigates various advanced vesicular nanocarriers and their applications through the skin, to augment the topical delivery of NSAIDs through stratum corneum over the conventional systems, enhance their effectiveness, and reduce the unwanted side effects. These innovative systems can manage bioavailability, solubility, stability, safety, and efficacy issues present in conventional systems.

Brij® integrated bilosomes for improving the transdermal delivery of niflumic acid for effective treatment of osteoarthritis: In vitro characterization, ex vivo permeability assessment, and in vivo study.

Bilosomes are innovative vesicular carriers containing bile salt with a non-ionic surfactant. Being highly flexible, bilosomes can squeeze themselves through the skin carrying the drug to the action site and improving its skin penetration. The objective of this research was to encapsulate niflumic acid (NA), a non-steroidal anti-inflammatory drug into Brij® integrated bilosomes (BIBs) for effective treatment of osteoarthritis through transdermal delivery. BIBs were formulated using 100 mg of Span 20 with different amounts of sodium cholate (NaC), sodium taurocholate (NaTC), or sodium glycocholate (NaGC) as bile salt, with the addition of 5 mg of Brij-93 or Brij-35. BIBs were prepared utilizing ethanol injection method with the application of (31 × 22) complete factorial design using Design-Expert® software. The optimal BIBs formulation determined was (B5) which contains 5 mg of NaTC used as bile salt and 5 mg of Brij-93. B5 exhibited entrapment efficiency% = 95.21 ± 0.00%, particle size = 373.05 ± 0.07 nm, polydispersity index = 0.27 ± 0.01, and zeta potential = -32.00 ± 0.00 mV. It also had a high elasticity with a spherical shape. B5 gel displayed a sustained release profile with a significantly 2.3 folds' higher drug permeation percent across rat skin than that permeated from NA gel. Moreover, in vivo anti-osteoarthritic and histopathological studies assured the efficacy and safety of B5 gel and its superiority over NA gel. Generally, the outcomes confirmed the great efficacy of NA loaded BIBs for the topical treatment of osteoarthritis.

Implementing Spanlastics for Improving the Ocular Delivery of Clotrimazole: In vitro Characterization, Ex vivo Permeability, Microbiological Assessment and In vivo Safety Study.

PURPOSE: The aim of this study was to encapsulate clotrimazole (CLT), an antifungal drug with poor water solubility characteristics, into spanlastics (SPs) to provide a controlled ocular delivery of the drug. METHODS: Span 60 was used in the formulation of SPs with Tween 80, Pluronic F127, or Kolliphor RH40 as an edge activator (EA). The presence of EA offers more elasticity to the membrane of the vesicles which is expected to increase the corneal permeation of CLT. SPs were prepared using ethanol injection method applying 32 complete factorial design to study the effect of formulation variables (ratio of Span 60: EA (w/w) and type of EA) on SPs characteristics (encapsulation efficiency percent (EE%), average vesicle size (VS), polydispersity index (PDI) and zeta potential (ZP)). Design-Expert software was used to determine the optimum formulation for further investigations. RESULTS: The optimum formulation determined was S1, which contains 20 mg of Tween 80 used as an EA and 80 mg of Span 60. S1 exhibited EE% = 66.54 ± 7.57%, VS = 206.20 ± 4.95 nm, PDI = 0.39 ± 0.00 and ZP = -29.60 ± 0.99 mV. S1 showed highly elastic sphere-shaped vesicles. Furthermore, S1 displayed a sustained release profile and a higher ex vivo permeation across rabbit cornea relative to CLT suspension. Also, S1 revealed superior inhibition of Candida albicans development compared to CLT suspension applying 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction technique. Moreover, in vivo histopathological examination assured the safety of S1 after ophthalmic application in mature male albino rabbits. CONCLUSION: Overall, the outcomes revealed the marked efficacy of SPs for ocular delivery of CLT.

Fabrication of Highly Deformable Bilosomes for Enhancing the Topical Delivery of Terconazole: In Vitro Characterization, Microbiological Evaluation, and In Vivo Skin Deposition Study.

The current study aimed to load terconazole (TCZ), an antifungal agent with low permeability characteristics, into highly deformable bilosomes (HBs) for augmenting its topical delivery. HBs contain edge activator in addition to the constituents of traditional bilosomes (Span 60, cholesterol, and bile salts). More elasticity is provided to the membrane of vesicles by the existence of edge activator and is expected to increase the topical permeation of TCZ. HBs were formulated using ethanol injection technique based on 24 complete factorial design to inspect the impact of various formulation variables (bile salt type and amount, edge activator type, and sonication time) on HBs characteristics (entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP)). The optimum formula (HB14) was decided based on Design-Expert® software and was utilized for further explorations. HB14 exhibited EE% = 84.25 ± 0.49%, PS = 400.10 ± 1.69 nm, PDI = 0.23 ± 0.01, and ZP = - 56.20 ± 0.00 mV. HB14 showed spherical vesicles with higher deformability index (9.94 ± 1.91 g) compared to traditional bilosomal formula (3.49 ± 0.49 g). Furthermore, HB14 showed superior inhibition of Candida albicans growth relative to TCZ suspension using XTT (2,3-bis(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reduction assay. Moreover, in vivo skin deposition studies revealed superior TCZ deposition inside the skin from HB14 compared to traditional bilosomal formula and TCZ suspension. Moreover, histopathological examination in rats assured the safety of HB14 for topical use. Concisely, the obtained outcomes confirmed the pronounced efficacy of HBs for topical delivery of TCZ.

Use of Novasomes as a Vesicular Carrier for Improving the Topical Delivery of Terconazole: In Vitro Characterization, In Vivo Assessment and Exploratory Clinical Experimentation.

PURPOSE: This manuscript aimed at encapsulating an antifungal terconazole (TCZ) into innovative novasomes for improving its penetration into the skin and clinically modulating its therapeutic efficacy. METHODS: Novasomes containing free fatty acid (FFA) as a penetration enhancer were formulated using ethanol injection technique based on 24 full factorial design to explore the impact of various formulation variables on novasomes characteristics regarding entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimum formulation was chosen using Design-Expert® software and utilized for further explorations. RESULTS: The chosen formulation (N15; including 100 mg lipid components and Span 80 to oleic acid in a ratio of 2:1 (w/w)) exhibited an EE% = 99.45 ± 0.78%, PS = 623.00 ± 2.97 nm, PDI = 0.40 ± 0.04, and ZP = -73.85 ± 0.64 mV. N15 showed spherical vesicles with a higher deformability index (DI) (9.62 ± 0.15 g) compared to traditional niosomal formulation (0.92 ± 0.12 g). Further, N15 showed superior inhibition of Candida albicans growth relative to TCZ suspension using XTT (2,3-bis-(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reduction assay. Moreover, in vivo skin deposition tests revealed a superior TCZ deposition inside the skin from N15 in comparison to traditional niosomal formulation and TCZ suspension. Furthermore, histopathological examination for rats assured the safety of N15 for topical use. A clinical study conducted on infants suffering from napkin candidiasis proved the superiority of N15 to placebo in providing a complete cure of such fungal infections. CONCLUSION: Concisely, the obtained outcomes confirmed the pronounced efficacy of N15 to successfully treat skin fungal infections.

Preparation and evaluation of optimized zolmitriptan niosomal emulgel.

Objective: Novel niosomal formulation may be successfully applied to treat a systemic disease such as migraine through transdermal drug delivery system (TDDS), moreover, the treatment of topical diseases such as mycotic infections by targeting and localizing the drug to the stratum corneum. The current study aims to formulate zolmitriptan (Zt) in niosomal vesicles to potentiate its transdermal effect. Significance: The development of a promising niosomal formulation will push the scaling up of pharmaceutical industry in this field. Methods: Design- Expert 10 was used to design twelve formulations using Box-Behnken. Zt loaded niosomes were prepared by the thin film hydration method using Span 60(S 60), Span 80(S 80) along with cholesterol(Ch) at three different levels. The optimized formulation (F11) was formulated in Emulgel (1:1 emulsion/gel ratio). Results: The vesicles revealed vesicle size (VS) ranging from 133.1 to 851.3 nm, zeta potential (ZP) -43.8 to -82.8 mV, entrapment efficiency (EE%) from 66.7 to 88.7%, and Zt release after 4 h up to 67%. Optimized niosomal formulation (F11) depicted the smallest VS (133.1 nm), highest EE (88.7%), high ZP (-80.6 mV) and satisfactory release after 4 h (61.5%). There was a significant difference (p <.05) in drug permeation after 8 h for niosomal F11(460.98 ug/cm2) and niosomal F11 loaded Emulgel (336.92 ug/cm2) compared to plain Zt loaded emulgel (160.83 ug/cm2). Niosomal F11 loaded emulgel showed thixotropic behavior of rapid recovery, significant bioavailability and pharmacokinetic parameters as compared to the plain Zt-loaded Emulgel. Conclusion: Optimized F11 represents a promising formulation for transdermal drug delivery system to treat both topical and systemic diseases.

Implementing Central Composite Design for Developing Transdermal Diacerein-Loaded Niosomes: Ex vivo Permeation and In vivo Deposition.

BACKGROUND: Niosomes are surfactant-based vesicular nanosystems that proved their efficiency in transdermal delivery by overcoming skin inherent anatomic barrier; startum corneum. Central composite design is an efficient tool for developing and optimizing niosomal formulations using fewer experiments. OBJECTIVE: The objective of this study was to prepare niosomes as a transdermal delivery system of diacerein using film hydration technique, employing central composite design, for avoiding its oral gastrointestinal problems. METHODS: Three-level three-factor central composite design was employed for attaining optimal niosomes formulation with the desired characteristics. Three formulation variables were assessed: amount of salt in hydration medium (X1), lipid amount (X2) and number of surfactant parts (X3). DCNloaded niosomes were evaluated for entrapment efficiency percent (Y1), particle size (Y2), polydispersity index (Y3) and zeta potential (Y4). The suggested optimal niosomes were subjected to further characterization and utilized as a nucleus for developing elastic vesicles for comparative ex vivo and in vivo studies. RESULTS: The values of the independent variables (X1, X2 and X3) in the optimal niosomes formulation were 0 g, 150 mg and 5 parts, respectively. It showed entrapment efficiency percentage of 95.63%, particle size of 436.65 nm, polydispersity index of 0.47 and zeta potential of -38.80 mV. Results of ex vivo permeation and skin deposition studies showed enhanced skin permeation and retention capacity of the prepared vesicles than drug suspension. CONCLUSION: Results revealed that a transdermal niosomal system was successfully prepared and evaluated using central composite design which will result in delivering diacerein efficiently, avoiding its oral problems.

Fabrication of Nanosuspension Directly Loaded Fast-Dissolving Films for Enhanced Oral Bioavailability of Olmesartan Medoxomil: In Vitro Characterization and Pharmacokinetic Evaluation in Healthy Human Volunteers.

Olmesartan medoxomil (OM) is an antihypertensive drug with poor water solubility and low oral bioavailability (28.6%). Accordingly, this study aimed to formulate and evaluate OM nanosuspension incorporated into oral fast-dissolving films (FDFs) for bioavailability enhancement. OM nanosuspension was prepared by antisolvent-precipitation-ultrasonication method and characterized regarding particle size (122.67 ± 5.03 nm), span value (1.40 ± 0.51), and zeta potential (- 46.56 ± 1.20 mV). Transmission electron microscopy (TEM) of the nanosuspension showed spherical non-aggregating nanoparticles. The nanosuspension was then directly loaded into FDFs by solvent casting technique. A full factorial design (22 × 31) was implemented for optimization of the FDFs using Design-Expert® software. Physical and mechanical characteristics in addition to dissolution profiles of the FDFs were investigated. The optimum formula (FDF1) showed 0.43 ± 0.02 kg/mm2 tensile strength, 20.50 ± 2.12 s disintegration time, and 87.53 ± 2.50 and 95.99 ± 0.25% OM dissolved after 6 and 10 min, respectively. Accelerated and long-term shelf stability studies confirmed the stability of FDF1. More than 75% OM was dissolved within 10 min from FDF1 compared with 9.80 and 47.80% for films prepared using coarse drug powder and market tablet, respectively. Relative bioavailability of FDF1 compared to market tablet was assessed in healthy human volunteers. The Cmax value increased significantly from 66.62 ± 14.95 to 179.28 ± 23.96 ng/mL for market tablet and FDF1, respectively. Similarly, the AUC0-72 value significantly increased from 498.36 ± 217.46 to 1083.67 ± 246.32 ng h/mL for market tablet and FDF1, respectively. Relative bioavailability of FDF1 was 209.28%. The highlighted results verified the effectiveness of OM nanosuspension-loaded FDFs in improving OM bioavailability.

Nanosizing of a poorly soluble drug: technique optimization, factorial analysis, and pharmacokinetic study in healthy human volunteers.

CONTEXT: Diacerein (DCN) has low aqueous solubility (3.197 mg/L) and, consequently, low oral bioavailability (35%-56%). To increase both the solubility and dissolution rate of DCN while maintaining its crystalline nature, high pressure homogenization was used but with only a few homogenization cycles preceded by a simple bottom-up technique. METHODS: The nanosuspensions of DCN were prepared using a combined bottom-up/top-down technique. Different surfactants - polyvinyl alcohol, sodium deoxycholate, and sodium dodecyl sulfate - with different concentrations were used for the stabilization of the nanosuspensions. Full factorial experimental design was employed to investigate the influence of formulation variables on nanosuspension characteristics using Design-Expert(®) Software. Particle size (PS), zeta potential, saturation solubility, in vitro dissolution, and drug crystallinity were studied. Moreover, the in vivo performance of the optimized formula was assessed by bioavailability determination in healthy human volunteers. RESULTS: The concentration of surfactant had a significant effect on both the PS and polydispersity index values. The 1% surfactant concentration showed the lowest PS and polydispersity index values compared with other concentrations. Both type and concentration of surfactant had significant effects on the zeta potential. Formula F8 (containing 1% sodium deoxycholate) and Formula F12 (containing 1% sodium dodecyl sulfate) had the highest desirability values (0.952 and 0.927, respectively). Hence, they were selected for further characterization. The saturated solubility and mean dissolution time, in the case of F8 and F12, were significantly higher than the coarse drug powder. Techniques utilized in the nanocrystals' preparation had no effect on DCN crystalline state. The selected formula (F12) showed a higher bioavailability compared to the reference market product with relative bioavailability of 131.4%. CONCLUSION: The saturation solubility, in vitro dissolution rate and relative bioavailability of DCN were significantly increased after nanocrystallization. Less time and power consumption were applied by the combination of bottom-up and top-down techniques.