Mechanism of enhanced oral absorption of akebia saponin D by a self-nanoemulsifying drug delivery system loaded with phospholipid complex

Akebia saponin D (ASD) exhibits a variety of pharmacological activities, such as anti-osteoporosis, neuroprotection, hepatoprotection, but has poor oral bioavailability. A self-nanoemulsifying drug delivery system loaded with akebia saponin D - phospholipid complex (APC-SNEDDS) (composition: Peceol: Cremophor^® EL: Transcutol HP: ASD: phospholipid; ratio: 10:45:45:51:12.3, w:w:w:w:w) was first developed to improve the oral absorption of saponins and it was found to significantly enhance ASD’s oral bioavailability by 4.3 - fold (p?<?.01). This study was conducted to elucidate the mechanism of enhanced oral absorption of ASD by the drug delivery system of APC-SNEDDS. The aggregation morphology and particle size of ASD and APC-SNEDDS prepared in aqueous solutions were determined by transmission electron microscope and particle size analyzer, respectively. Stability of ASD and APC-SNEDDS in gastrointestinal luminal contents and mucosa homogenates were also explored. The differences of in situ intestinal permeability of ASD and APC-SNEDDS were compared. APC-SNEDDS reduced the aggregation size from 389?±?7?nm (ASD) to 148?±?3?nm (APC-SNEDDS). APC-SNEDDS increased the remaining drug in large intestine luminal contents from 47?±?1% (ASD) to 83?±?1% (APC-SNEDDS) during 4?h incubation. APC-SNEDDS provided an 11-fold increase in Ka value and an 11-fold increase in P_eff value compared to ASD. In summary, APC-SNEDDS improved ASD’s oral bioavailability mainly by increasing membrane permeability, destroying self-micelles and inhibiting the intestinal metabolism.     

Influence of omega fatty acids on skin permeation of a coenzyme Q10 nanoemulsion cream formulation: characterization,in silico and ex vivo determination

Objective: The aim of this study was to develop a coenzyme Q10 nanoemulsion cream, characterize and to determine the influence of omega fatty acids on the delivery of coenzyme Q10 across model skin membrane via ex vivo and in silico techniques.

Methods: Coenzyme Q10 nanoemulsion creams were prepared using natural edible oils such as linseed, evening primrose, and olive oil. Their mechanical features and ability to deliver CoQ10 across rat skin were characterized. Computational docking analysis was performed for in silico evaluation of CoQ10 and omega fatty acid interactions.

Results: Linseed, evening primrose, and olive oils each produced nano-sized emulsion creams (343.93–409.86?nm) and exhibited excellent rheological features. The computerized docking studies showed favorable interactions between CoQ10 and omega fatty acids that could improve skin permeation. The three edible-oil nanoemulsion creams displayed higher ex vivo skin permeation and drug flux compared to the liquid-paraffin control cream. The linseed oil formulation displayed the highest skin permeation (3.97?±?0.91?mg/cm²) and drug flux (0.19?±?0.05?mg/cm²/h).

Conclusion: CoQ10 loaded-linseed oil nanoemulsion cream displayed the highest skin permeation. The highest permeation showed by linseed oil nanoemulsion cream may be due to the presence of omega-3, -6, and -9 fatty acids which might serve as permeation enhancers. This indicated that the edible oil nanoemulsion creams have potential as drug vehicles that enhance CoQ10 delivery across skin.     

Novel oleic acid derivatives enhance buccal permeation of didanosine

The aim of this study was to explore the potential of novel oleic acid (OA) derivatives as buccal permeation enhancers for the delivery of didanosine (ddI). The OA derivatives, i.e. ester derivative (OA1E), the dicarboxylic acid derivative (OA1A) and the bicephalous dianionic surfactant (OA1ANa) were synthesized and their effects were compared to the parent OA. OA, OA1E, OA1A and OA1ANa at 1%?w/w all showed potential for enhancing the buccal permeability of ddI with enhancement ratio (ER) of 1.29, 1.33, 1.01 and 1.72, respectively. OA1ANa at 1%?w/w demonstrated the highest flux (80.30?±?10.37?µg?cm^?2?h), permeability coefficient (4.01?±?0.57?×?10^?3?cm?h^?1) and ER (1.72). The highest flux for ddI (144.00?±?53.54?µg?cm^?2?h) was reported with OA1ANa 2%?w/w, which displayed an ER of 3.09 more than that with ddI alone. At equivalent concentrations, OA1ANa (ER?=?3.09) had a significantly higher permeation-enhancing effect than its parent OA (ER?=?1.54). Histomorphological studies confirmed that OA1ANa at all concentrations (0.5, 2.0 and 6.0%?w/w) had no adverse effects on the mucosae. Morphological changes such as vacuoles formation and increased intercellular spaces were attributed to the buccal permeation-enhancing effect of OA1ANa. This study demonstrated the potential of novel OA derivatives as buccal permeation enhancers. OA1ANa at 2%?w/w was also identified as the optimal novel OA derivative to widen the pool of fatty acid derivatives as chemical permeation enhancers for buccal drug delivery.     

A pH-independent instantaneous release of flurbiprofen: a study of the preparation of complexes,their characterization and in vitro/in vivo evaluation

In this study, furbiprofen/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes were prepared to improve the drug dissolution and facilitate its application in hydrophilic gels. Inclusion complexes were prepared using a supercritical fluid processing and a conventional optimized co-lypholization method was employed as a reference. The entrapment efficacy and drug loading of both methods were investigated. Evaluation of drug dissolution enhancement was conducted in deionized water as well as buffer solutions of different pH. Carbopol 940 gels of both flurbiprofen and flurbiprofen/HPβCD inclusion complexes, with or without penetration enhancers, were prepared and percutaneous permeation studies were performed using rat abdominal skin samples. Formation of flurbiprofen/HPβCD inclusion complexes was confirmed by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The results obtained showed that SCF processing produced a higher EE (81.91?±?1.54%) and DL (6.96?±?0.17%) compared with OCL with values of 69.11?±?2.23% and 4.00?±?1.01%, respectively. A marked instantaneous release of flurbiprofen/HPβCD inclusion complexes prepared by SCF processing (103.04?±?2.66% cumulative release within 5?min, a 10-fold increase in comparison with flurbiprofen alone) was observed. In addition, this improvement in dissolution was shown to be pH-independent (the percentage cumulative release at pH 1.2, 4.5, 6.8 and 7.4 at 5?min was 95.19?±?1.71, 101.75?±?1.44, 105.37?±?4.58 and 96.84?±?0.56, respectively). Percutaneous permeability of flurbiprofen-in-HPβCD-in-gels could be significantly accelerated by turpentine oil and was related to the water content in the system. An in vivo pharmacokinetic study showed a 2-fold increase in C_max and a shortened T_max as well as a comparable relative bioavailability when compared with the commercial flurbiprofen Cataplasms (Zepolas^®). With their superior dissolution, these flurbiprofen/HPβCD inclusion complexes prepared by SCF processing could provide improved applications for flurbiprofen.     

Silicone adhesive,a better matrix for tolterodine patches—a research based on in vitro/in vivo studies

Objective: To design and optimize a drug-in-adhesive (DIA) type transdermal patch for tolterodine (TOL) based on acrylic and silicone matrixes.

Methods: Initial in vitro studies were conducted to optimize the formulations. Two types of adhesive matrixes, drug loading, and enhancers were evaluated on the TOL transport across rabbit skin. For in vivo studies, patches were administered to rabbit abdominal skin. Pharmacokinetic assessments were performed based on plasma level of TOL up to 28?h for acrylic patch and 52?h for silicone patch after topical application.

Results: The final formulation of acrylic adhesive type patch consisted of 10% TOL (w/w) and 5.8?×?10^?4 mol isopropyl myristate (IPM) and 2.9?×?10^?4 mol Span 80 in per unit gram (mol/g) of adhesive, while 2.5% TOL (w/w) and 2.9?×?10^?4 mol/g IPM for silicone adhesive type patch. Comparison of the pharmacokinetic parameters between two types of patches showed that the steady-state concentration of silicone type patch was 2-fold higher than that of acrylic type patch being 0.97?mg/L versus 0.49?mg/L, and the absolute bioavailability was 27.5% for silicone type patch and 6.3% for acrylic type patch, respectively. In addition, the prediction of in vivo drug level from the in vitro permeation data of silicone adhesive formulation was in good agreement with actual observed concentration data in rabbits.

Conclusion: These results indicate that the silicone type of TOL patch is an appropriate delivery system for the treatment of overactive bladder (OAB).     

Cuboidal lipid polymer nanoparticles of rosuvastatin for oral delivery

The present work aimed to develop and characterize sustained release cuboidal lipid polymeric nanoparticles (LPN) of rosuvastatin calcium (ROS) by solvent emulsification-evaporation process. A three factor, two level (2³) full-factorial design was applied to study the effect of independent variables, i.e. amount of lipid, surfactant and polymer on dependent variables, i.e. percent entrapment efficiency and particle size. Optimized formulations were further studied for zeta potential, TEM, in vitro drug release and ex vivo intestinal permeability. Cuboidal nanoparticles exhibited average particle size 61.37?±?3.95?nm, entrapment efficiency 86.77?±?1.27% and zeta potential ?6.72?±?3.25?mV. Nanoparticles were lyophilized to improve physical stability and obtain free-flowing powder. Effect of type and concentration of cryoprotectant required to lyophilize nanoparticles was optimized using freeze-thaw cycles. Mannitol as cryoprotectant in concentration of 5-8% w/v was found to be optimal providing zeta potential ?20.4?±?4.63?mV. Lyophilized nanoparticles were characterized using FTIR, DSC, XRD and SEM. Absence of C=C and C–F aromatic stretch at 1548 and 1197?cm^?1, respectively, in LPN indicated coating of drug by lipid and polymer. In vitro diffusion of ROS using dialysis bag showed pH-independent sustained release of ROS from LPN in comparison to drug suspension. Intestinal permeability by non-everted gut sac model showed prolonged release of ROS from LPN owing to adhesion of polymer to mucus layer. In vivo absorption of ROS from LPN resulted in 3.95-fold increase in AUC_0–last and 7.87-fold increase in mean residence time compared to drug suspension. Furthermore modified tyloxapol-induced rat model demonstrated the potential of ROS-loaded LPN in reducing elevated lipid profile.     

Nanocarrier-based topical drug delivery for an antifungal drug

Objective: The conventional liposomal amphotericin B causes many unwanted side effects like blood disorder, nephrotoxicity, dose-dependent side effects, highly variable oral absorption and formulation-related instability. The objective of the present investigation was to develop cost-effective nanoemulsion as nanocarreir for enhanced and sustained delivery of amphotericin B into the skin.

Methods and characterizations: Different oil-in-water nanoemulsions were developed by varying the composition of hydrophilic (Tween® 80) surfactants and co-surfactant by the spontaneous titration method. The developed formulation were characterized, optimized, evaluated and compared for the skin permeation with commercial formulation (fungisome 0.01% w/w). Optimized formulations loaded with amphotericin B were screened using varied concentrations of surfactants and co-surfactants as decided by the ternary phase diagram.

Results and discussion: The maximum % transmittance obtained were 96.9?±?1.0%, 95.9?±?3.0% and 93.7?±?1.2% for the optimized formulations F-I, F-III and F-VI, respectively. These optimized nanoemulsions were subjected to thermodynamic stability study to get the most stable nanoemulsions (F-I). The results of the particle size and zeta potential value were found to be 67.32?±?0.8 nm and –3.7?±?1.2?mV for the final optimized nanoemulsion F-I supporting transparency and stable nanoemulsion for better skin permeation. The steady state transdermal flux for the formulations was observed between 5.89?±?2.06 and 18.02?±?4.3?µg/cm²/h whereas the maximum enhancement ratio were found 1.85- and 3.0-fold higher than fungisome and drug solution, respectively, for F-I. The results of the skin deposition study suggests that 231.37?±?3.6?µg/cm² drug deposited from optimized nanoemulsion F-I and 2.11-fold higher enhancement ratio as compared to fungisome. Optimized surfactants and co-surfactant combination-mediated transport of the drug through the skin was also tried and the results were shown to have facilitated drug permeation and skin perturbation (SEM).

Conclusion: The combined results suggested that amphotericin B nanoemulsion could be a better option for localized topical drug delivery and have greater potential as an effective, efficient and safe approach.     

Development,optimization, and characterization of a novel tea tree oil nanogel using response surface methodology

Purpose: To develop and optimize nanoemulsion (NE)-based emulgel (EG) formulation as a potential vehicle for topical delivery of tea tree oil (TTO).

Methodology: Central composite design was adopted for optimizing the processing conditions for NE preparation by high energy emulsification method viz. surfactant concentration, co-surfactant concentration, and stirring speed. The optimized NE was developed into emulgel (EG) using pH sensitive polymer Carbopol 940 and triethanolamine as alkalizer. The prepared EG was evaluated for its pH, viscosity, and texture parameters, ex vivo permeation at 37?°C and stability. Antimicrobial evaluation of EG in comparison to conventional gel and pure TTO was also carried out against selected microbial strains.

Results and discussion: Optimized NE had particle size and zeta potential of 16.23?±?0.411?nm and 36.11?±?1.234?mV, respectively. TEM analysis revealed the spherical shape of droplets. The pH of EG (5.57?±?0.05?) was found to be in accordance with the range of human skin pH. EG also illustrated efficient permeation (79.58?μL/cm²) and flux value (J_SS) of 7.96?μL cm²/h through skin in 10?h. Viscosity and texture parameters, firmness (9.3?±?0.08?g), spreadability (2.26?±?0.06?mJ), extrudability (61.6?±?0.05?mJ), and adhesiveness (8.66?±?0.08?g) depict its suitability for topical application. Antimicrobial evaluation of EG with same amount of TTO as conventional gel revealed broader zones of growth inhibitions against all the selected microbial strains. Moreover, EG was also found to be nonirritant (PII 0.0833). These parameters were consistent over 90 d.

Conclusion: TTO EG turned out to be a promising vehicle for the topical delivery of TTO with enhanced therapeutic efficacy.     

Intradermal and follicular delivery of adapalene liposomes

Abstract

Background: Adapalene is a widely used topical anti-acne drug; however, it has many side effects. Liposomal drug delivery can play a major role by targeting delivery to pilosebaceous units, reducing side effects and offering better patient compliance.

Objective: To prepare and evaluate adapalene-encapsulated liposomes for their physiochemical and skin permeation properties.

Methods: A liposomal formulation of adapalene was prepared by the film hydration method and characterized for shape, size, polydispersity index (PDI), encapsulation efficiency and thermal behavior by techniques such as Zetasizer®, differential scanning calorimetry and transmission electron microscopy. Stability of the liposomes was evaluated for three months at different storage conditions. In vitro skin permeation studies and confocal laser microscopy were performed to evaluate adapalene permeation in pig ear skin and hair follicles.

Results: The optimized process and formulation parameters resulted in homogeneous population of liposomes with a diameter of 86.66?±?3.5?nm in diameter and encapsulation efficiency of 97.01?±?1.84% w/w. In vitro permeation studies indicated liposomal formulation delivered more drug (6.72?±?0.83?μg/cm²) in hair follicles than gel (3.33?±?0.26?μg/cm²) and drug solution (1.62?±?0.054?μg/cm²). Drug concentration delivered to the skin layers was also enhanced compared to other two formulations. Confocal microscopy images confirmed drug penetration in the hair follicles when delivered using the liposomal formulation.

Conclusion: Adapalene was efficiently encapsulated in liposomes and led to enhanced delivery in hair follicles, the desired target site for acne.     

Design of antihistaminic transdermal films based on alginate–chitosan polyelectrolyte complexes: characterization and permeation studies

The purpose of this study was to develop suitable matrix-type transdermal drug delivery systems of Ketotifen fumarate (KF) as antiasthmatic drugs. Chitosan–alginate polyelectrolyte complex (PEC) films were used as drug release regulators for KF. Antihistaminic films with variable PEC compositions were prepared using different ratios of chitosan (CTS) to sodium alginate (ALG). Propylene glycol (PG) was used as plasticizer; Tween 80 (T₈₀) and Span 20 (S₂₀) were used as permeability enhancers. Nine formulations were obtained by film casting method and characterized in terms of weight uniformity, thickness, folding endurance, moisture lost, and moisture absorption. In addition, drug release and permeation through rat abdominal skin mounted in Franz cell were investigated. All formulations were found to be suitable in terms of physicochemical characteristics, and there was no significant interaction between the used drug and polymers. It was noticed that when T₂₀ is used as permeation enhancer, a satisfactory drug release pattern was found where 99.88% of drug was released and an amount of 2.121?mg/cm² of KF was permeated after 24?h. For the optimal formulation, a permeability coefficient of 14.00?±?0.001?cm h^?1 and a latency time of 0.35?±?0.02?h were found. The in-vitro analysis showed controlled release profile which was fitted by Korsmeyer–Peppas model (R²?=?0.998). The obtained results suggested that new controlled release transdermal formulations of asthmatic drugs could be suitably designed as an alternative to the common forms.     

Synthesis and characterization of amphiphilic star-shaped copolymers based on β-cyclodextrin for micelles drug delivery

Purpose: A series of β-CD amphiphilic star-shaped copolymers with exceptional characteristics were synthesized and their potential as carriers for micelles drug delivery was investigated.

Methods: A series of amphiphilic copolymers based on β-CD were synthesized by introducing poly (acrylic acid)-co-poly(methyl methacrylate)-poly (vinyl pyrrolidone) or poly (acrylic acid)-co-poly(methyl methacrylate)-co-poly(monoacylated-β-CD)-poly (vinyl pyrrolidone) blocks to the primary hydroxyl group positions of β-CD. The micellization behavior of the copolymers, the synthesis conditions, characteristics, drug release in vitro and tissue distribution of vinpocetine (VP) micelles in vivo were investigated.

Results: Around 60 types of β-CD amphiphilic star-shaped copolymers were successfully synthesized and the critical micelle concentration ranged from 9.80?×?10^?4 to 5.24?×?10^?2g/L. The particle size, drug loading and entrapment efficiency of VP-loaded β-CD-P₄ micelles prepared with optimal formulation were about 65?nm, 21.44?±?0.14%, and 49.05?±?0.36%, respectively. The particles had good sphericity. The cumulative release rates at 72?h of VP-loaded β-CD-P₄ micelles in pH 1.0, pH 4.5, pH 6.5, or pH 7.4 media were 93%, 69%, 49%, and 43%, respectively. And, the lung targeting efficiency of VP-loaded β-CD-P₄ micelles was 8.98 times higher than that of VP injection.

Conclusion: The VP-loaded β-CD-P₄ micelles exhibited controlled-release property, pH-induced feature and lung targeting capacity compared with VP injection, suggesting that the β-CD-P₄ copolymers are an excellent candidate for micelles drug delivery.     

Dual-purpose vardenafil hydrochloride/dapoxetine hydrochloride orodispersible tablets: in vitro formulation/evaluation,stability study and in vivo comparative pharmacokinetic study in healthy human subjects

Erectile dysfunction (ED) is the most important disorder after premature ejaculation for sexual activity in men. Vardenafil hydrochloride (VH) is an oral therapy for the treatment of erectile dysfunction. VH oral disintegrating tablets (ODTs) have been prepared by freeze drying technique to improve its dissolution profile and the overall clinical performance. Dapoxetine hydrochloride (DH) was added to the best three formulae of the prepared VH ODTs to treat premature ejaculation. All the ODTs formulae were evaluated for weight variation, friability, drug content, in vitro disintegration time, wetting time, and the dissolution study. Gelatin as a matrix former with N-methylpyrrolidone as a solubilizer in VH/DH ODTs improved the dissolution rate and extent of release of VH and DH with 100% of drug being dissolved after 15?min. In vivo study results from six healthy male volunteers showed shorter T_max of VH from VH/DH ODT of 0.583?±?0.129?h and shorter T_max of DH from VH/DH ODT of 0.625?±?0.137?h and showed AUC_0–12 of VH from VH/DH ODT of 39.234?±?10.932?ng/ml^?h¹ and AUC_0–12 of DH from VH/DH ODT of 531.681?±?129.544?ng/ml^?h¹, with relative bioavailability values of 100.9 and 85%, respectively, compared to (Levitra^®) and (Priligy^®).     

Formulation and in vitro evaluation of a thermoreversible mucoadhesive nasal gel of itopride hydrochloride

Itopride hydrochloride (ITO HCl) is a prokinetic agent, used in the treatment of gastrointestinal motility disorders. The aim of the study was to develop stable mucoadhesive thermoreversible nasal gel to avoid first pass effect. ITO HCl was incorporated into the blends of thermoreversible polymers like poloxamer 407 and various mucoadhesive polymers in different concentrations to increase the contact of the formulations with nasal mucosa. The compatibility between the drug and the suggested polymers was studied by Fourier transform infrared and differential scanning calorimetry (DSC). The formulations were evaluated for clarity, pH, gelation temperature, mucoadhesive strength, gel strength, viscosity, and drug content. In addition, the in vitro drug release and the dissolution efficiency (DE)% were measured. The optimized formulations that showed the highest dissolution efficiency% (DE%) in saline phosphate buffer of pH 6.4 at 35?±?0.5?°C were chosen for stability testing at temperatures of 4?±?2 and 25?±?2?°C/60?±?5% RH. It was found that F1 and F17 that contain 18% w/v poloxamer 407 and 0.5% w/v of hydroxypropylmethyl cellulose K4M or methyl cellulose (MC), respectively, showed higher stability results as indicated by their higher t₉₀ values (days).     

Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14

The aim of the present study was to develop a novel semi-solid self-microemulsifying drug delivery system (SMEDDS) using Gelucire^® 44/14 as oil with strong solid character to improve the oral bioavailability of poorly soluble drug valsartan. The solubility of valsartan in various excipients was determined, the pseudo-ternary phase diagram was constructed in order to screen the optimal excipients, and DSC analysis was performed to evaluate the melting point of SMEDDS. The optimal drug-loaded SMEDDS formulation was consisted of 30% Gelucire^® 44/14 (oil), 40% Solutol^® HS 15 (surfactant), and 30% Transcutol^® P (cosurfactant) (w/w) with 80?mg valsartan/g excipients. The average droplet sizes of the optimized blank and drug-loaded SMEDDS formulations were 26.20?±?1.43 and 33.34?±?2.15?nm, and the melting points of them were 35.6 and 36.8?°C, respectively. The in vitro dissolution rate of optimal semi-solid SMEDDS was increased compared with commercial capsules, resulting in the 2.72-fold and 2.97-fold enhancement of C_max and AUC_0–t after oral administration in rats, respectively. These results indicated that the novel semi-solid SMEDDS formulation could potentially improve the oral bioavailability of valsartan, and the semi-solid SMEDDS was a desirable system than the traditional liquid SMEDDS because it was convenient for preparation, storage and transportation due to semi-solid state at room temperature and melted state at body temperature.     

Modulated release of 5-fluorouracil from pH-sensitive and colon targeted pellets: An industrially feasible approach

Pellets, reliant on pH-sensitivity and time-dependency for drug delivery, provide one of the most versatile opportunities for targeting colon. 5-Fluorouracil (5-FU) loaded pellets were prepared by extrusion-spheronization using Avicel^® PH101 as a spheronization aid and hydroxypropylmethylcellulose K4M (HPMC K4M) solution as a binder. A 3² full factorial design was employed to optimize spheronization speed and time. Obtained pellets were evaluated for flow properties, pellet size, roundness and aspect ratio. Optimized batch was coated in a bottom-spray fluidized bed processor (FBP) with an inner coat of sustained release polymer Eudragit NE30D and an outer coat of pH-sensitive polymer Eudragit FS30D. The coating levels were statistically optimized and in vitro drug release was monitored by changing pH media method. Optimized system with 15% inner and outer coating levels revealed t_50% (time required for 50% drug release) to be about 9?h while almost complete drug was released in 24?h (98.71?±?1.33%) with highest dissolution efficiency (DE_24h) of 58.71%. The optimization model was validated; the predicted and experimental/actual values for validation batch (M1) were in close tolerance and the standard error (SE) was also small. Drug release was also studied at pH 7.4. Scanning electron microscopy (SEM) demonstrated average coating thickness to be 32.50?±?3.0 µm. Hence, the present study provides constructive results for colon targeting of 5-FU pellets with industrially feasible processes.     

Formulation design and optimization of novel soft glycerosomes for enhanced topical delivery of celecoxib and cupferron by Box–Behnken statistical design

Background: The present study describes glycerosomes (vesicles composed of phospholipids, glycerol and water) as a novel drug delivery system for topical application of celecoxib (CLX) and cupferron (CUP) compound.

Aim: The goal of this research was to design topical soft innovative vesicles loaded with CLX or CUP for enhancing the efficacy and avoiding systemic toxicity of CLX and CUP.

Methods: CLX and CUP loaded glycerosomes were prepared by hydrating phospholipid-cholesterol films with glycerol aqueous solutions (20–40%, v/v). Box–Behnken design, using Design-Expert® software, was the optimum choice to statistically optimize formulation variables. Three independent variables were evaluated: phospholipid concentration (X₁), glycerol percent (X₂) and tween 80 concentration (X₃). The glycerosomes particle size (Y₁), encapsulation efficiency percent (Y₂: EE %) and drug release (Y₃) were selected as dependent variables. The anti-inflammatory effect of CLX and CUP glycerosomal gel was evaluated by carrageenan-induced rat paw edema method followed by histopathological studies.

Results: The optimized formulations (CLX2* and CUP1*) showed spherical morphology under transmission electron microscopy, optimum particle size of 195.4?±?3.67?nm, 301.2?±?1.75?nm, high EE of 89.66?±?1.73%, 93.56?±?2.87%, high drug release of 47.08?±?3.37%, 37.60?±?1.89% and high cumulative amount of drug permeated in 8?h of 900.18?±?50.24, 527.99?±?34.90?µg.cm^?2 through hairless rat skin, respectively. They also achieved significant remarkable paw edema inhibition in comparison with the control group (p? Conclusion: Finally, the administration of CLX2* and CUP1* loaded glycerosomal gel onto the skin resulted in marked reduction of edema, congestive capillary and inflammatory cells and this approach may be of value in the treatment of different inflammatory disorders.     

In vitro percutaneous absorption enhancement of granisetron by chemical penetration enhancers

Granisetron (GRN), a potent antiemetic agent, is frequently used to prevent nausea and vomiting induced by cancer cytotoxic chemotherapy and radiation therapy.

Objective: As part of our efforts to further modify the physicochemical properties of this market drug, with the ultimate goal to formulate a better dosage form for GRN, this work was carried out to improve its permeability in vitro.

Methods: The permeation behavior of GRN in isopropyl myristate (IPM) was investigated across excised rabbit abdominal skin and the enhancing activities of three novel O-acylmenthol derivatives synthesized in our laboratory as well as five well-known chemical enhancers were evaluated.

Results: It was found that the steady-state flux of granisetron free base (GRN-B) was about 26-fold higher than that of granisetron hydrochloride (GRN-H). The novel enhancer, 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP), was observed to provide the most significant enhancement for the absorption of GRN-B. When incorporated in the donor solution with the optimal enhancer M-HEP, the steady-state flux of GRN-B increased from (196.44?±?12.03) μg·cm^?2·h^?1 to (1044.95?±?71.99) μg·cm^?2·h^?1 (P?<?0.01).

Conclusion: These findings indicated that the application of chemical enhancers was an effective approach to increase the percutaneous absorption of GRN in vitro.     

In vitro and in vivo effects of morin on the intestinal absorption and pharmacokinetics of olmesartan medoxomil solid dispersions

Abstract

Purpose: In-situ evaluation to corroborate morin effects on the intestinal absorption and pharmacokinetic behavior of freeze-dried OLM-loaded solid dispersions with Caco-2 and in-vivo studies

Methods: Intestinal transport and absorption studies were examined by Caco-2 permeability, in-situ single pass perfusion and closed-loop models along with in-vivo pharmacokinetic studies to evaluate and confirm the effect of P-gp-mediated activity of morin. We evaluated the intestinal membrane damage in the presence of morin by measuring the release of protein and lactate dehydrogenase (LDH) followed by using qualitative and quantitative morphometric analysis to describe the surface characteristics of intestinal epithelium.

Results: Morin showed the highest P_eff value 13.8?±?0.34?×?10^?6?cm/s in jejunum than ileum (p?<?.01) at 100?µM with absorption enhancement of 1.31-fold together with enhanced (p?<?.01) secretory transport of 6.27?±?0.27?×?10?^?6?cm/s in Caco-2 monolayer cells. Our findings noticed 2.37 (in-situ); 2.39 (in-vivo) and 1.43 (in-situ); 1.36 (in-vivo) fold increase in AUC_0–t with elevated C_max and shortened T_max for freeze-dried solid dispersion in the presence of morin as compared to pure OLM and freeze-dried solid dispersions without morin, respectively.

Conclusions: Our study demonstrated that increased solubilization through freeze-dried OLM-loaded solid dispersion together with efflux inhibition improved intestinal permeability to one system that might lead to novel solubilization and efflux pump inhibition as a novel alternative potential to increase oral absorption and bioavailability of OLM.     

A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis,characterization, cytotoxicity,and pharmacokinetic evaluation

In the current study, retinoic acid (RA) was conjugated to Pluronic F127 (PF127) through an esterification process. Mixed micelles were formed with tocopheryl polyethylene glycol 1000 (TPGS) for co-delivery of paclitaxel (PTX) and RA to the cancer cells. Mixed micelles of RA-PF127 and TPGS in different weight ratios (10:0, 7:3, 5:5, 3:7, 0:10 w/w) were prepared and physicochemical properties including, particle size, zeta potential, critical micelle concentration (CMC), drug loading content, entrapment efficiency, drug release, cellular uptake and in vitro cytotoxicity, were investigated in details. Furthermore, the pharmacokinetics of PTX-loaded optimized mixed micelles were evaluated in Sprague-Dawley rats and compared with Stragen^® (PTX in Cremophor EL^®). Particle sizes and zeta potentials of the drug-loaded micelles were in the range of 102.6–223.5?nm and ?5.3 to ?9.6?mV, respectively. The 7:3 and 5:5 micellar combinations had lower CMC values (0.034–0.042?mg/mL) than 0:10 (0.124?mg/mL). The entrapment efficiencies of 10:0, 7:3, and 5:5 were 53.4?±?9.3%, 61.3?±?0.5%, and 78.7?±?1.66%, respectively. The release rates of PTX from 7:3 and 5:5 mixed micelles were significantly slower than other formulations. Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded mixed micelles compared to free PTX. The V_d and t_1/2ß of PTX-loaded RA-PF127/TPGS (7:3) were increased by 2.61- and 1.27-fold, respectively, while the plasma area under the curve (AUC) of the micelles was 2.03-fold lower than those of Stragen^®. Therefore, these novel mixed micelles could be effectively used for delivery of PTX and RA to the cancer cells. Moreover, TPGS as part of micelle composition could enhance the therapeutic effect of PTX and reduce side effects.     

Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis

A series of co-engineered macrolide–mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital^? inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200?mg of 50:50?w/w AZ: mannitol had 57.6%?±?7.6% delivery efficiency with a fine particle fraction (≤6.8?µm) of the emitted aerosol cloud being 80.4%?±?1.1%, with minimal throat deposition (5.3?±?0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide–mannitol therapy may provide a means of treating bronchiectasis.