D-optimal mixture design for optimization of topical dapsone niosomes: in vitro characterization and in vivo activity against Cutibacterium acnes

This study aimed to illustrate the use of D-optimal mixture design (DOMD) for optimization of an enhancer containing Dapsone niosomal formula for acne topical treatment. Mixture components (MixCs) studied were: Span 20, Cholesterol, and Cremophor RH. Different responses were measured. Optimized formula (OF) was selected to minimize particle size and maximize absolute zeta potential and entrapment efficiency. Optimized formula gel (OF-gel) was prepared and characterized. OF-gel in vivo skin penetration using confocal laser scanning microscopy and activity against Cutibacterium acnes in acne mouse model were studied. Based on DOMD results analysis, adequate models were derived. Piepel and contour plots were plotted accordingly to explain how alteration in MixCs L-pseudo values affected studied responses and regions for different responses’ values. The OF had suitable predicted responses which were in good correlation with the actually measured ones. The OF-gel showed suitable characterization and in vivo skin penetration up to the dermis layer. In vivo acne mouse-model showed that OF-gel-treated group (OF-gel-T-gp) had significantly better recovery (healing) criteria than untreated (UT-gp) and Aknemycin^®-treated (A-T-gp) groups. This was evident in significantly higher reduction of inflammation percent observed in OF-gel-T-gp than both UT-gp and A-T-gp. Better healing in OF-gel-T-gp compared with other groups was also verified by histopathological examination. Moreover, OF-gel-T-gp and A-T-gp bacterial loads were non-significantly different from each other but significantly lower than UT-gp. Thus, DOMD was an adequate statistical tool for optimization of an appropriate enhancer containing Dapsone niosomal formula that proved to be promising for topical treatment of acne.     

Fabrication of novel elastosomes for boosting the transdermal delivery of diacerein: statistical optimization,ex-vivo permeation,in-vivo skin deposition and pharmacokinetic assessment compared to oral formulation

Diacerein (DCN) is a hydrophobic osteoarthritis (OA) drug with short half-life and low oral bioavailability. Furthermore, DCN oral administration is associated with diarrhea which represents obstacle against its oral use. Hence, this article aimed at developing elastosomes (edge activator (EA)-based vesicular nanocarriers) as a novel transdermal system for delivering DCN efficiently and avoiding its oral problems. For achieving this goal, elastosomes were prepared according to 4¹.2¹ full factorial design using different EAs in varying amounts. The prepared formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and deformability index (DI). Desirability function was employed using Design-Expert^® software to select the optimal elastosomes (E1) which showed EE% of 96.25?±?2.19%, PS of 506.35?±?44.61?nm, PDI of 0.46?±?0.09, ZP of ?38.65?±?0.91?mV, and DI of 12.74?±?2.63?g. In addition, E1 was compared to DCN-loaded bilosomes and both vesicles exhibited superior skin permeation potential and retention capacity compared to drug suspension. In-vivo histopathological study was performed which ensured the safety of E1 for topical application. Furthermore, the pharmacokinetic study conducted in albino rabbits demonstrated that there was no significant difference in the rate and extent of DCN absorption from topically applied E1 compared to oral suspension. Multiple level C in-vitro in-vivo correlation showed good correlation between in-vitro release and in-vivo drug performance for E1 and DCN oral suspension. Overall, results confirmed the admirable potential of E1 to be utilized as novel carrier for transdermal delivery of DCN and bypassing its oral side effects.     

Utilization of propranolol hydrochloride mucoadhesive invasomes as a locally acting contraceptive: in-vitro,ex-vivo,and in-vivo evaluation

It was found that propranolol hydrochloride (PNL), which is a beta-blocker used for hypertension treatment, has a potent spermicidal activity through local anesthetic activity or beta-blocking effect on sperm cells subsequently it could be used as a contraceptive remedy. This study aimed to entrap PNL into invasomes (INVs) and then formulate it as a locally acting contraceptive gel. PNL-loaded mucoadhesive INVs were prepared via the thin-film hydration technique. The D-optimal design was utilized to fabricate INVs employing lipid concentration (X₁), terpenes concentration (X₂), terpenes type (X₃), and chitosan concentration (X₄) as independent variables, while their impact was observed for entrapment efficiency percent (Y₁; EE%), particle size (Y₂; PS), zeta potential (Y₃; ZP), and amount of drug released after 6 h (Y₄; Q6h). Design Expert® was bestowed to nominate the desired formula. The selected INV was subjected to further studies and formulated into a mucoadhesive gel for ex-vivo and in-vivo investigations. The optimum INV showed a spherical shape with EE% of 65.01 ± 1.24%, PS of 243.75 ± 8.13 nm, PDI of 0.203 ± 0.01, ZP of 49.80 ± 0.42 mV, and Q6h of 53.16 ± 0.73%. Differential scanning calorimetry study asserted the capability of INVs to entrap PNL. Permeation studies confirmed the desired sustained effect of PNL-loaded INVs-gel compared to PNL-gel, INVs, and PNL solution. Sperm motility assay proved the potency of INVs-gel to inhibit sperm motility. Besides, the histopathological investigation verified the tolerability of the prepared INVs-gel. Taken together, the gained data justified the efficacy of PNL-loaded INVs-gel as a potential locally acting contraceptive.     

Spironolactone hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism: in silico studies,statistical optimization,ex vivo,and in vivo studies

Spironolactone (SP) is a potassium sparing diuretic with antiandrogenic properties. This study aimed at formulating SP into hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism. HAECs were prepared by ethanol injection method, according to D-optimal design, after a proper in silico study. HAECs were evaluated by measuring their entrapment efficiency (EE%), particle size (PS), and polydispersity index (PDI). Optimal hyaluronic acid enriched cerosomes (OHAECs) were subjected to further in vitro and ex-vivo and in-vivo studies. The in silico study concluded better interactions between SP and phosphatidyl choline in presence of hyaluronic acid (HA) and high stability of their binding in water. The prepared HAECs had acceptable EE%, PS, and PDI values. The statistical optimization process suggested OHAEC containing 10.5 mg ceramide III and 15 mg HA, utilizing Kolliphor^® RH40. OHAEC had EE% and PS of 89.3 ± 0.3% and 261.8 ± 7.0 nm, respectively. OHAEC was stable for up to 3 months. It also showed a mixed tubular and vesicular appearance under transmission electron microscope. The ex vivo and in vivo studies concluded better skin deposition and accumulation of SP from OHAEC. The histopathological study demonstrated the safety of OHAEC for topical application. Therefore, OHAEC could be considered as effective system for topical application of SP to manage hirsutism, with prolonged action, coupled with minimized side effects.     

Optimization and Appraisal of Chitosan-Grafted PLGA Nanoparticles for Boosting Pharmacokinetic and Pharmacodynamic Effect of Duloxetine HCl Using Box-Benkhen Design

Duloxetine HCl (DXH) is a psychiatric medicine employed for treating major depressive disorder. Nonetheless, its low water solubility, high first-pass metabolism, and acid instability diminish the absolute oral bioavailability to 40%, thus necessitating frequent administration. Therefore, the aim of the current study was to formulate DXH as nasal chitosan-grafted polymeric nanoparticles to improve its pharmacokinetic and pharmacodynamic properties. Applying the Box-Behnken design, DXH loaded PLGA-Chitosan nanoparticles (DXH-PLGA-CS-NPs) were fabricated and optimized using polylactide-co-glycolic acid (PLGA), chitosan (CS), and polyvinyl alcohol (PVA) as the independent factors. Particle size, entrapment efficiency, release percent, and cumulative amount permeated after 24 h of DXH-PLGA-CS-NPs (dependent variables) were evaluated. The in-vivo biodistribution and pharmacodynamic studies were done in male Wistar rats. The optimized DXH-PLGA-CS-NPs had a vesicle size of 122.11 nm and EE% of 66.95 with 77.65% release and Q₂₄ of 555.34 (µg/cm²). Ex-vivo permeation study revealed 4-folds increase in DXH permeation from DXH-PLGA-CS-NPs after 24 h compared to DXH solution. Intranasal administration of optimized DXH-PLGA-CS-NPs resulted in significantly higher (p < 0.05) C_max, AUC_total, t_1/2, and MRT in rat brain and plasma than oral DXH solution. Pharmacodynamics investigation revealed that intranasally exploited optimal DXH-PLGA-CS-NPs could be deemed a fruitful horizon for DXH as a treatment for depression.     

Implementing polymeric pseudorotaxanes for boosting corneal permeability and antiaspergillus activity of tolnaftate: formulation development,statistical optimization,ex vivo permeation and in vivo assessment

Fungal keratitis (FK) is a devastating ocular disease that can cause corneal opacity and blindness if not treated effectively. Tolnaftate (TOL) is a selective fungicidal drug against Aspergillus spp. which are among the most common causes of mycotic keratitis. TOL is lipophilic drug with low water solubility and permeation which act as obstacles for its clinical ocular efficacy. Hence, this study aimed to statistically optimize a novel polymeric pseudorotaxanes (PSRs) containing TOL for enhancing its ocular permeability and antifungal effect. For achieving this goal, a full 3¹.2² factorial design was fashioned for preparing and optimizing TOL-PSRs using film hydration technique. Three formulation variables were studied: drug amount (X₁), weight ratio of Pluronics to HPβCD (X₂) and Pluronic system (X₃). Entrapment efficiency percent (EE%) (Y₁), particle size (PS) (Y₂) and zeta potential (ZP) (Y₃) were set as dependent variables. The selected optimal TOL-PSRs (PSR1) showed EE% of 71.55 ± 2.90%, PS of 237.05 ± 12.80 nm and ZP of −32.65 ± 0.92 mV. In addition, PSR1 was compared to conventional polymeric mixed micelles (PMMs) and both carriers significantly increased the drug flux and resulted in higher amount permeated per unit area in 8 h compared to drug suspension. The histopathological studies assured the safety of PSR1 for ocular use. The in vivo susceptibility testing using Aspergillus niger confirmed that PSR1 displayed sustained antifungal activity up to 24 h. The obtained results revealed the admirable potential of PSR1 to be used as novel nanocarriers for promoting TOL ocular delivery.     

Fenticonazole nitrate loaded trans-novasomes for effective management of tinea corporis: design characterization,in silico study,and exploratory clinical appraisal

The current investigation aimed for loading fenticonazole nitrate (FTN), an antifungal agent with low aqueous solubility, into trans-novasomes (TNs) for management of tinea corporis topically. TNs contain Brij^® as an edge activator besides the components of novasomes (cholesterol, Span 60, and oleic acid) owing to augment the topical delivery of FTN. TNs were fabricated applying ethanol injection method based on D-optimal experiment. TNs were evaluated with regard to entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). Further explorations were conducted on the optimum formulation (F7). F7 showed spherical appearance with EE%, PS, PDI, and ZP of 100.00 ± 1.10%, 358.60 ± 10.76 nm, 0.51 ± 0.004, and −30.00 ± 0.80 mV, respectively. The in silico study revealed the ability of the FTN–cholesterol complex to maintain favorable interactions throughout the molecular dynamics simulation (MDS) study. Moreover, Trichophyton mentagrophytes growth was inhibited effectively by F7 than by FTN suspension applying 2,3-bis(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay. Furthermore, a clinical appraisal on patients with tinea corporis fungal lesions confirmed the superiority of F7 compared to Miconaz^® cream in the magnitude of clinical cure of tinea corporis. Thereby, TNs could be considered as promising vesicles for enhancing the antifungal potential of FTN for the topical management of tinea corporis.     

Statistical optimization of bile salt deployed nanovesicles as a potential platform for oral delivery of piperine: accentuated antiviral and anti-inflammatory activity in MERS-CoV challenged mice

The objective of this paper is to confine piperine, a poor oral bioavailable herbal drug into bile salt based nano vesicles for improving its aqueous solubility, hence, its therapeutic activity. Piperine-loaded bilosomes were fabricated adopting thin film hydration technique according to 3².2¹ full factorial design to investigate the impact of different formulation variables on the characters of bilosomes: entrapment efficiency (EE%), particle size, and % of drug released post 8 h (Q8hr). The selected optimum formula was F2 (enclosing 1% bile salt, brij72 as a surfactant, and ratio of surfactant:cholesterol was 9:1) with desirability value 0.801, exhibiting high EE% (97.2 ± 0.8%) nanosized spherical vesicles (220.2 ± 20.5 nm) and Q8hr (88.2%±5.6). The superiority of the optimized formula (F2) over the drug suspension was revealed via ex vivo permeation study, also pharmacokinetic study denoted to the boosted oral bioavailability of piperine-loaded bilosome compared to piperine suspension. Moreover, antiviral activity and safety margin of F2 was significantly higher than that of the drug suspension. The ability of piperine to interact with the key amino acids in the receptor binding domain 4L3N as indicated by its docking configuration, rationalized its observed activity. Furthermore, F2 significantly reduce oxidant markers, inflammatory cytokines in MERS-CoV-infected mice. Hence, bilosomes can be considered as a carrier of choice for piperine with potential antiviral and anti-inflammatory activities.     

Preparation of optimized Naproxen nano liposomes using response surface methodology

The aim of this study was to prepare and optimize a liposomal delivery system for Naproxen (NPX), a practically water insoluble drug. NPX liposomes, which were consisted of cholesterol (CH) and phosphatidylcholine (PC) in different molar ratios, were prepared by modified ethanol injection method and optimized employing response surface methodology (RSM). Proportion of PC:CH and total lipid:drug ratio were selected as the independent variables while the particle size (PS), encapsulation efficiency percent (EE%) and drug release of the liposomes over 24 h (D_24h) were considered as dependent variables. The effects of PC:CH and total lipid:drug ratios were studied and optimized to obtain the liposomal vesicles with desired quality. Graphical response surface and contour plots were also employed to understand the interaction of different variables. The optimum points for the variables were obtained from the optimization plot. The mean PS, EE% and D_24h of NPX liposomes were about 178.11 nm, 53.14 and 46.62 % respectively. The results indicated that PC:CH and total lipids:drug ratios were the major contributing variables for EE% and D_24h. However, only PC:CH ratio was the main contributing variable for PS. The optimum formulation of NPX liposomes, in which PC:CH ratio and lipids:drug ratio were 3.81 and 2.98 respectively, had high EE% (58 %) and D_24h (>50 %) as well as appropriate PS (<162.4 nm). Ethanol injection method besides RSM, are simple, rapid and beneficial approaches for liposome preparation and optimization.     

Pharmacodynamic and pharmacokinetic comparison of two formulations of lorazepam and placebo

Nine healthy male volunteers took part in a comparison of the pharmacokinetic profiles and effects on psychomotor performance and memory following single dosing with an experimental sustained release (SR) and a conventional release (CR) formulation of lorazepam. There was evidence of a sustained release profile for the SR formulation which had a later t_max (median 8 h) and significantly lower peak serum concentration (mean 12·1 ng ml^?1) compared with CR lorazepam (2 h and 21.8 ng ml^?1 respectively). The effect of SR lorazepam on pharmacodynamic variables occurred later and was less intense than with CR lorazepam. Good correlations were obtained between most of the pharmacodynamic parameters measured and the logarithm of the serum concentration for both formulations, with the exception of the choice reaction time test for SR lorazepam. However, both formulations produced a similar degree of impairment of 24h recall.     

Cationic Polymeric Nanoparticles for Improved Ocular Delivery and Antimycotic Activity of Terconazole

Terconazole (TCZ) is a broad-spectrum antifungal triazole that is particularly active against Candida species, but its poor water solubility hinders its ocular absorption and restricts its application. This study aims to fabricate TCZ-loaded cationic polymeric nanoparticles to enhance the ocular delivery and antimycotic activity of terconazole. TCZ-loaded nanoparticles were developed by nanoprecipitation method employing Eudragit RLPO®. They were characterized by entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), morphology, Fourier transform infrared spectroscopy (FT-IR), and X-ray powder diffraction (XRPD). In-vitro antimycotic activity was evaluated by measuring zone of inhibition (ZI), minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). The developed nanoparticles were spherical with moderate to high EE% (44.03–71.14%), a nanometric PS (49.41–78.72 nm), and a positively charged ZP (≥ +21.47). In-vitro release studies revealed sustained release of drug up to 24 h. FT-IR of TCZ-loaded nanoparticles revealed distinctive peaks for Eudragit RLPO® and Poloxamer-188, with disappearance of the TCZ characteristic peaks. XRPD revealed the amorphous state of TCZ within the polymer matrix. Mucoadhesive studies proved the mucoadhesive property of the developed TCZ nanoparticles. In-vitro antimycotic studies, assessed by ZI, MIC and MFC, revealed enhanced antimycotic activity of TCZ-loaded nanoparticles against Candida albicans, relative to plain TCZ. No irritation or abnormal changes to the rabbits’ eyes for plain and medicated polymeric nanoparticles were found by the in-vivo Draize test. These findings reveal that the cationic polymeric nanoparticles can be regarded as a potential drug delivery system for enhancing the ocular antimycotic activity of TCZ.     

Lipid-based nano-formulation platform for eplerenone oral delivery as a potential treatment of chronic central serous chorioretinopathy: in-vitro optimization and ex-vivo assessment

PurposeEplerenone (EPL) is a selective mineralocorticoid receptor antagonist used for treatment of chronic central serous chorioretinopathy which characterized by accumulation of subretinal fluid causing a localized area of retinal detachment. unfortunately, EPL suffers from poor oral bioavailability due to poor aqueous solubility in addition to high hepatic first pass metabolism.MethodAiming to improve its oral bioavailability, EPL-loaded nanostructured lipid carriers (NLCs) were prepared by the emulsification solvent evaporation method and in-vitro evaluated for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE%). A D-optimal design was used for study the effect of liquid lipid to solid lipid ratio, surfactant type and percentage on PS, PDI, EE%, and for data optimization. The optimized EPL-loaded NLCs system was further evaluated using in-vitro drug release and ex-vivo permeation studies through rabbit intestine in comparison to EPL aqueous suspension. The physicochemical properties of the drug in the optimized system were further examined using FT-IR and X-ray diffraction studies.ResultsThe resultant NLCs showed small PS (100.85–346.60 nm), homogenous distribution (0.173–0.624), negatively charged particles (ZP −20.20 to −36.75 mV), in addition to EE% (34.31–70.64%). The optimized EPL-loaded NLCs system with a desirability value of 0.905 was suggested through the Design expert^® software, containing liquid to solid lipid ratio (2:1) in presence of 0.43%w/v Pluronic^® F127 as a surfactant. The optimized EPL-loaded NLCs system showed a PS of 134 nm and PDI of 0.31, in addition to high EE% (76 ± 6.56%w/w), and ZP (-32.37 mV). The ex-vivo permeation study showed two-fold higher drug permeation through rabbit intestine compared to that from the aqueous drug suspension after 24 h, confirming the ability of optimized EPL-loaded NLCs system as successful oral targeting delivery carrier.ConclusionOur results pave the way for a new oral nanotherapeutic approach toward CSCR treatment. In-vivo study is currently under investigation.     

Development,in vitro and in vivo characterization of Eudragit RL 100 nanoparticles for improved ocular bioavailability of acetazolamide

Abstract

Glaucoma is characterized by increased intra ocular pressure (IOP) which results in blindness if left untreated. Acetazolamide (ACZ) is used to treat glaucoma since long back. Since it is a Class IV drug [According to Biopharmaceutics Classification System (BCS)], so its topical delivery results in poor ocular bioavailability. Objective of the present study is to increase the topical ocular bioavailability and to sustain the release of drug for longer time. ACZ-loaded Eudragit® RL 100 nanoparticle suspension (ACZ-E-NPs) was prepared by the nanoprecipitation method. Ratio of organic to aqueous phase and composition of organic phase were altered to get the best formulation. Formulations prepared with acetone and methanol as organic phase were smallest in size. EE was in the range of 57.8% to 68.5%. According to drug release study almost all the formulations released 80% of drug in 8?h duration. The kinetics of drug release showed that the drug release pattern followed Higuchi’s model (highest R² values) and further it was fitted to the Korsemeyer–Peppas model, which showed the release was as per Fickian diffusion. IOP lowering effects of plain drug solution and ACZ-E-NPs were compared in adult male albino rabbits with a Riester Tonometer. The data revealed that the ACZ-E-NPs lower the IOP for longer time and of higher magnitude also. The difference was significant (p?<?0.001). Short-term stability study showed that none of the formulations was having remarked difference in their physicochemical properties after 6 months of storage at various temperatures.     

Utilization of PEGylated cerosomes for effective topical delivery of fenticonazole nitrate: in-vitro characterization,statistical optimization,and in-vivo assessment

In this investigation, we focused on ceramide IIIB, a skin component whose depletion tends to augment multiple skin disorders and fungal infections. Ceramide IIIB was included into PEGylated surfactant-based vesicular phospholipid system to formulate ‘PEGylated cerosomes’ (PCs) loaded with fenticonazole nitrate (FTN). FTN is a potent antifungal agent adopted in the treatment of mixed mycotic and bacterial infections. The ceramide content of the vesicles may provide protective and regenerative skin activity whereas Brij^®; the PEGylated surfactant, can enhance drug deposition and skin hydration. Both components are expected to augment the topical effect of FTN. PCs were prepared by thin-film hydration technique. A 2³ full-factorial design was applied to study the effect of ceramide amount (X₁), Brij type (X₂) and Brij amount (X₃) on the physicochemical properties of the formulated PCs namely; entrapment efficiency (EE%;Y₁), particle size (PS;Y₂), polydispersity index (PDI;Y₃) and zeta potential (ZP;Y₄). The optimal formula was selected for further in-vivo dermatokinetic and histopathological study. The optimal FTN-loaded PC (PC6) showed nanosized cerosomes (551.60 nm) with high EE% (83.00%w/w), and an acceptable ZP value of 20.90 mV. Transmission electron micrographs of the optimal formula illustrated intertwined tubulation form deviated from the conventional spherical vesicles. Finally, the dermatokinetic study of PC6 showed higher drug concentration and localization of FTN in skin layers when compared with FTN suspension and the histopathological study confirmed its safety for topical application. The overall findings of our study verified the effectiveness of utilizing PEGylated cerosomes to augment the activity of FTN as a topical antifungal agent.     

Oil based nanocarrier for improved oral delivery of silymarin: In vitro and in vivo studies

In this study the influence of hydrogen bonding interaction between niosomal membrane and solutes on the drug loading and release was investigated. Salicylic acid (SA) and p-hydroxyl benzoic acid (p-BA) were selected as models. Niosomes were prepared with 1:1 molar ratios of various surfactants and cholesterol by film hydration technique, and the corresponding formulation variables were optimized to achieve the maximum entrapment efficiencies (EE%). The EE% of different formulations followed the trend Span 60>Span 40>Span 20>Span 80. Additionally, it was also found that the EE% of p-BA was much higher than that of SA. This difference may be due to the formation of hydrogen bond between p-BA and niosomal membrane, and the corresponding interaction diagram has been proposed and confirmed indirectly by UV spectroscopy method. The quantitative analysis of hydrogen binding interaction between solutes and niosome has been finished firstly, and the corresponding entrapment equilibrium constant K has been calculated as well. Moreover, in vitro the release of both drugs from niosomes was examined in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), respectively. The results indicated that the release of p-BA in SIF was much slower than that in SGF, and the release rate of SA in SGF is apparently slower than that in SIF. The possible mechanism was given as well.     

Circadian IOP-lowering efficacy of travoprost 0.004% ophthalmic solution compared to latanoprost 0.005%*

ABSTRACT

Purpose: The primary objective of this study was to determine the intraocular pressure- (IOP) lowering efficacy over two consecutive 24-h periods of travoprost 0.004% ophthalmic solution (Travatan^?) compared to latanoprost 0.005% (Xalatan^?) dosed once daily in patients with primary open-angle glaucoma or ocular hypertension.

Methods: This was a double-masked trial conducted at the Hospital Clínico San Carlos, Madrid, Spain. The primary objective of this study was to determine the IOP lowering efficacy of travoprost and latanoprost. During the eligibility visit, patients’ IOP was measured throughout two consecutive 24‐h periods every 4?h. Patients were then randomized to travoprost or latanoprost (one drop at 8 p.m. daily for 2 weeks). Sixty-two patients were randomized (travoprost n = 32; latanoprost n = 30). IOP was measured at week 2 every 4?h throughout two 24‐h periods. All measurements were taken in both supine and sitting positions with the aid of Perkins applanation tonometry. Limitations of the study include a small sample size (due to the difficulty in recruiting patients in a study of this type) which enrolled only Caucasian patients and a short study duration. However, with 25 subjects per group, there was at least 90% power to detect a mean IOP change from baseline of 2.9?mmHg and 80% power to detect a difference of 2.5?mmHg between treatments.

Results: Patients on travoprost therapy showed lower mean IOP levels than those on latanoprost. This difference was statistically significant (?p < 0.05) at 12, 16, 20, 24, 36, 40, and 48?h after the last dose for the supine position. The mean IOPs in the supine position throughout the first and the second 24‐h period of the week 2 visit as well as for the 48‐h visit were statistically lower (?p < 0.05) for the travoprost group. Adverse events were mild and included hyperemia and corneal staining. Travoprost and latanoprost were both well tolerated.

Conclusion: Mean IOP values were significantly lower for patients on travoprost for the majority of time points in the supine position.     

Bioavailability Enhancement of Polymyxin B With Novel Drug Delivery: Development and Optimization Using Quality-by-Design Approach

Polymyxin-B (Poly-B) is an effective antibiotic used to treat infections mainly caused due to sensitive gram-negative bacteria. They belong to the group of cyclic peptide antibiotics and are minimally absorbed from the gastrointestinal tract. This arises the need for bioavailability enhancement and is achieved in the present case using niosomes as carrier system. The Poly-B niosomes had been developed using Span 60 and cholesterol while optimization is achieved with quality-by-design (QBD) approach. In this QBD approach, 3 independent variables (Span 60:cholesterol, volume of phosphate-buffered saline [%], and amount of drug [mg]) each at 3 levels were studied. A total of 17 runs were suggested by the model which was further analyzed by optimizing 3 different responses (particle size, zeta potential, and entrapment efficiency [EE%]). The results had clearly shown that the optimum formulation selected by QBD was based on the criteria of attaining the maximum value of EE% and low value of size and zeta potential. Poly-B niosomes were further examined by in vitro antifungal, rat creatinine, and cytotoxicity assay. The pharmacokinetics and scintigraphy studies were also performed for in vivo behavior of Poly-B.     

Optimizing novel penetration enhancing hybridized vesicles for augmenting the in-vivo effect of an anti-glaucoma drug

Usually the topical delivery of ocular drugs poses a great challenge. Accordingly, the work in this study comprised the use of different hybrids of generally regarded as safe (GRAS) oils and surfactants in order to develop and optimize novel acetazolamide (AZD) entrapped-vesicular systems aiming at improving its ocular delivery and reaching better therapeutic outcomes in the treatment of glaucoma. The phospholipid/cholesterol bilayer of the vesicles was enriched with hybrids of Tween 80, Labrasol, Transcutol and Labrafac lipophile WL in different masses and proportions according to a mixture design viz. D-optimal mixture design. Three models were generated comprising three responses: particles size, percentage of entrapment efficiency and amount of drug released after 24?hours (Q24h). The results demonstrated the ability of the penetration enhancing hybrids in modulating the three responses compared to the conventional liposomes. Transmission electron microscope was used to characterize the selected formulations. Sterilization of selected formulations was carried out using gamma radiation and the effect of gamma radiations on entrapment, particle size and in vitro release were studied. The selected sterilized formulations were tested in-vivo on the eyes of albino rabbits in order to evaluate the efficiency of the novel delivery systems on the intra-ocular pressure reduction (IOP) compared to drug solution and the conventional liposomes. The novel formulations proved their efficiency in reducing the IOP to lower values compared to the conventional liposomes, which pose new successful platform for ocular delivery of AZD and other anti-glaucoma drug analogs.     

Effects of surfactant type and cholesterol level on niosomes physical properties and in vivo ocular performance using timolol maleate as a model drug

This study aimed at investigating the roles of both Span^® surfactant type (having a gel/liquid transition temperature range from <10 to 55 °C), and cholesterol level on in vitro characteristics and in vivo performance of timolol maleate niosomes. Span 20, Span 40 and Span 60 niosomes were prepared using the thin film hydration method. Span:cholesterol levels employed were 7:3 mol/mol (a minimum concentration for stable niosomes) and 1:1 mol/mol (a maximum concentration accommodated by niosomes). Niosomes were characterized for size, percentage entrapment efficiency, morphology, in vitro release and intra-ocular pressure (IOP) lowering activity in rabbits. The order of the area under IOP-time curve (AUC) was ranked as follows: Span 40 > Span 20 > Span 60. The AUC and IOP_max values for Span 40:cholesterol (7:3) niosomes were superior due to having a good compromise between thermo-responsiveness and efficient capacity for loading a significant drug cargo, compared with Span 20 and Span 60.