Rehab N. Shamma

In vitro and in vivo evaluation of nimesulide lyophilized orally disintegrating tablets

Development of a lyophilized orally disintegrating tablet (ODT) that enhanced the in vitro dissolution and in vivo absorption of nimesulide (NM), a drug with poor solubility and poor bioavailability, is presented. The ODTs were prepared by freeze-drying an aqueous dispersion of NM containing a matrix former, a sugar alcohol, and a collapse protectant. In addition, different disintegration accelerators were tested. The influence of formulation parameters on the disintegration time and in vitro dissolution of NM from ODTs along with other tablet characteristics was investigated. Results obtained from disintegration and dissolution studies showed that lyophilized ODTs disintegrated within few seconds and showed significantly faster dissolution rate of NM compared to the plain powder drug and NM in commercially available immediate release tablet Sulide. The ODTs were also examined using differential scanning calorimetry, X-ray diffraction, and scanning electron microscope. Stability results, after 12-month storage of selected ODTs at 25 degrees C and 60% relative humidity, were satisfactory. The extent of absorption of NM from a selected ODT when compared to an conventional immediate release tablet as a reference after administration of 100mg oral dose of NM was determined in healthy subjects using a randomized crossover design. In this study, the rate of absorption of NM from ODT was faster than that from the reference tablet, had a significantly higher (p=0.012) peak plasma concentration, and shortened time to C(max) by 1h (p=0.029). The extent of absorption expressed by AUC was 62% larger when compared to the commercially available tablet.

Follicular delivery of spironolactone via nanostructured lipid carriers for management of alopecia

Spironolactone (SL) is a US Food and Drug Administration-approved drug for the treatment of hypertension and various edematous conditions. SL has gained a lot of attention for treating androgenic alopecia due to its potent antiandrogenic properties. Recently, there has been growing interest for follicular targeting of drug molecules for treatment of hair and scalp disorders using nanocolloidal lipid-based delivery systems to minimize unnecessary systemic side effects associated with oral drug administration. Accordingly, the objective of this study is to improve SL efficiency and safety in treating alopecia through the preparation of colloidal nanostructured lipid carriers (NLCs) for follicular drug delivery. SL-loaded NLCs were prepared by an emulsion solvent diffusion and evaporation method using 23 full factorial design. All of the prepared formulations were spherical in shape with nanometric size range (215.6–834.3 nm) and entrapment efficiency >74%. Differential scanning calorimetry thermograms and X-ray diffractograms revealed that SL exists in amorphous form within the NLC matrices. The drug release behavior from the NLCs displayed an initial burst release phase followed by sustained release of SL. Confocal laser scanning microscopy confirmed the potential of delivering the fluorolabeled NLCs within the follicles, suggesting the possibility of using SL-loaded NLCs for localized delivery of SL into the scalp hair follicles.

Design and optimization of surfactant-based nanovesicles for ocular delivery of Clotrimazole

Abstract The objective of this study was to develop an efficient ocular nanovesicular carrier providing a controlled delivery of Clotrimazole (CLT); a water insoluble antifungal drug. The nanovesicular carriers were formulated using Span 60 with one of the following edge activators (EA): Tween 80 (TW80), sodium cholate (SC) or sodium deoxycholate (SDC). A 32 full factorial design was used to study the effect of two independent variables, namely, the type of EA and the ratio of Span 60 to EA. The effects of these parameters on the mean particle size, entrapment efficiency (EE) and zeta potential (ZP) were investigated as dependent variables. Then, optimization was performed producing the best optimized formulation composed of SDC as an EA at the ratio of 90:10 (Span 60:EA) with an average diameter of 479.60 nm, EE of 87.92% and ZP of −33.7 mV. The optimized nanovesicular carriers appeared as spherical unilamillar vesicles with CLT in an amorphous state as evidenced by the differential scanning calorimetry study. The antifungal activity against Candida albicans compared to niosomal formulation as well as the CLT suspension was determined. CLT-loaded nanovesicular carriers displayed sustained antifungal effect over 12 h. The AUC of the optimized formulation was 3.09 times more than that of drug suspension with no sign of irritation after testing for ocular tolerance. Therefore, the present study showed the feasibility of using non-ionic surfactant nanovesicles as carrier systems for prolonged ocular delivery of CLT.

Transfersomal lyophilized gel of buspirone HCl: formulation, evaluation and statistical optimization

Abstract Context: Buspirone HCl has very low oral bioavailability (4%) due to deactivation by extensive first pass effect. It also has very limited transdermal permeation due to its high hydrophilicity. Objective: The aim of this study was to increase the transdermal permeation of buspirone HCl utilizing a stable dosage form. Methods: Transfersomes were prepared using Tween-80 as a flexibility imparting agent to the vesicular walls. Oleic acid and/or ethanol, with different percentages, were utilized as a permeation enhancer. Formulations were characterized by analyzing particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release and ex vivo drug permeation. Factorial design (32) was planned for the optimization of formulations using Design-Expert® software. Lyophilized transfersomal gel of the optimized formulation was prepared using hydroxypropyl methylcellulose (HPMC) K100, carboxymethyl cellulose or sodium alginate with or without mannitol as a cryoprotectant. Physical characterization of the transfersomes and the lyophilized gel were carried out using transmission and scanning electron microscopy, respectively. Results: The optimized formulation (T7), containing 35% oleic acid, had the highest desirability value (0.658) with high ex vivo drug flux (43.40 µg/h/cm2) through rat skin when compared with the aqueous drug solution and formula T1 (without oleic acid). The T7 transfersomal gel containing HPMC K100 (G2) had the highest desirability value (0.640) among the lyophilized gel formulations with decreased ex vivo drug flux (38.98 µg/h/cm2) in comparison with the original transfersomal formula (T7). Conclusions: Lyophilized transfersomal gel containing oleic acid was considered as a promising transdermal delivery system for hydrophilic drugs.

Development and optimization of a multiple-unit controlled release formulation of a freely water soluble drug for once-daily administration

A controlled release resinate beads of betahistine diHCl (BHCl), a short half-life freely water soluble drug, was developed to allow once-daily administration to improve patient compliance and eliminate the risk of intolerance of the drug. BHCl-resin complex was subsequently coated with Eudragit RS100. A 2(4) full factorial design was employed for optimization and to explore the effect of Eudragit RS100 concentration in the coating solution (X(1)), the coating percentage (X(2)), the speed of rotation (X(3)) and the concentration of plasticizer (PEG 400) (X(4)) on the release rate of the drug from the microcapsules. The extent of coating (Y(1)), and the percentage drug released at given times (Y(2), Y(3) and Y(4)) were selected as dependent variables. The optimization process was performed for X(1), X(2), X(3) and X(4) using target ranges of these responses determined based on target release model deduced form zero-order dissolution profile of BHCl for once-daily administration. The levels of X(1), X(2), X(3) and X(4) of optimized BHCl microcapsules are 14.42%, 50.63%, 1495rpm and 9.94%, respectively. The calculated value of f(2) for the optimized BHCl microcapsules filled into hard gelatin capsules was 67.03 indicating that the dissolution profiles of the optimized formulation is comparable to that of the target release model. It could be concluded that a promising once-daily extended-release microcapsules of the highly water soluble drug, BHCl, was successfully designed.

Trans-nasal zolmitriptan novasomes: in-vitro preparation, optimization and in-vivo evaluation of brain targeting efficiency

Abstract Migraine attack is a troublesome physiological condition associated with throbbing, intense headache, in one half of the head. Zolmitriptan is a potent second-generation triptan, prescribed for patients with migraine attacks, with or without an aura, and cluster headaches. The absolute bioavailability of zolmitriptan is about 40% for oral administration; due to hepatic first metabolism. Nasal administration would circumvent the pre-systemic metabolism thus increasing the bioavailability of zolmitriptan. In addition, due to the presence of microvilli and high vasculature, the absorption is expected to be faster compared to oral route. However, the bioavailability of nasal administered drugs is particularly restricted by poor membrane penetration. Thus, the aim of this work is to explore the potential of novel nanovesicular fatty acid enriched structures (novasomes) for effective and enhanced nasal delivery of zolmitriptan and investigate their nose to brain targeting potential. Novasomes were prepared using nonionic surfactant, cholesterol in addition to a free fatty acid. A 23 full factorial design was adopted to study the influence of the type of surfactant, type of free fatty acid and ratio between the free fatty acid and the surfactant on novasomes properties. The particle size, entrapment efficiency, polydispersity index, zeta potential and % zolmitriptan released after 2 h were selected as dependent variables. Novasomes were further optimized using Design Expert® software (version 7; Stat-Ease Inc., Minneapolis, MN), and an optimized formulation composed of Span® 80:Cholesterol:stearic acid (in the ratio 1:1:1) was selected. This formulation showed zolmitriptan entrapment of 92.94%, particle size of 149.9 nm, zeta potential of −55.57 mV, and released 48.43% zolmitriptan after 2 h. The optimized formulation was further examined using transmission electron microscope, which revealed non-aggregating multi-lamellar nanovesicles with narrow size distribution. DSC, XRD examination of the optimized formulation confirmed that the drug have been homogeneously dispersed throughout the novasomes in an amorphous state. In-vivo bio-distribution studies of 99mTc radio-labeled intranasal zolmitriptan loaded novasomes were done on mice, the pharmacokinetic parameters were compared with those following administration of intravenous 99mTc-zolmitriptan solution. Results revealed the great enhancement in zolmitriptan targeting to the brain, with drug targeting potential of about 99% following intranasal administration of novasomes compared with the intravenous drug solution. Zolmitriptan loaded novasomes administered via the nasal route may therefore constitute an advance in the management of acute migraine attacks.

Novel self-assembled nano-tubular mixed micelles of Pluronics P123, Pluronic F127 and phosphatidylcholine for oral delivery of nimodipine: In vitro characterization, ex vivo transport and in vivo pharmacokinetic studies

Subarachnoid hemorrhage (SAH) is a major cause of death in patients suffering from stroke. Nimodipine (NM) is the only FDA-approved drug for treating SAH-induced vasospasm. However, NM suffers from poor oral bioavailability (5-13%) due to its low aqueous solubility, extensive first pass metabolism and short elimination half-life (1-2h). The objective of this study was to develop NM-loaded Pluronic/phosphatidylcholine/polysorbate 80 mixed micelles (PPPMM) that can solubilize NM in aqueous media even after dilution, prolong its circulation time, improve its bioavailability and eventually help in targeting it to the brain tissue. PPPMM formulations were prepared using the thin film hydration technique, and evaluated for drug payload, solubilization efficiency (SE), micellar size, zeta potential, transmission electron microscopy (TEM) and ex vivo transport through rat intestine. The selected NM-loaded PPPMM, containing PC to Pluronics(®) molar ratio of 75:25, showed a drug payload, SE, micellar size and zeta potential of 1.06 ± 0.03 mg/mL, 99.2 ± 2.01%, 571.5 ± 11.87 nm and -31.2 ± 0.06 mv, respectively. The selected formulation had a much larger hydrophobic core volume for solubilization of NM and exhibited the highest NM transport. TEM micrographs illustrated the formation of highly flexible nano-tubular mixed micelles (NTMM). The in vivo pharmacokinetic study showed greater bioavailability of NM in plasma (232%) and brain (208%) of rats from NM-loaded PPPMM compared to that of the drug solution due to the efficiency of flexible NTMM to enhance absorption of NM from the intestinal mucosa. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NTMM could be promising to improve oral and parenteral delivery of NM.

Development and optimization of lyophilized orally disintegrating tablets using factorial design

The aim of this study was to evaluate the use of maltodextrin as a sugar-matrix former along with several cellulosic binders in the preparation of freeze—dried orally disintegrating tablets (ODT). The ODT was prepared by freeze—drying an aqueous dispersion of nimesulide (NM) containing maltodextrin and a cellulosic binder. The influence of formulation parameters on the in vitro/in vivo disintegration time and in vitro dissolution of NM from ODTs along with other tablet characteristics was investigated using full factorial design. The optimized ODT contained 5% w/v maltodextrin DE 29, 2% w/v Methocel®E15, and 5% w/v NM, disintegrated in less than 10 s and showed more than 70% of NM in ODTs dissolved within 2 min, compared to only 1.52% of NM plain drug and 7.25% of NM in immediate release commercial tablet. Crystalline state evaluation of NM in the optimized ODT was conducted through differential scanning calorimetry, and X-ray powder diffraction. The study suggests that the optimized ODT formulation developed in this work may be an alternative to conventional formulations of NM inconvenient to the patients such as intramuscular or rectal administration.

Design of freeze-dried Soluplus/polyvinyl alcohol-based film for the oral delivery of an insoluble drug for the pediatric use

Abstract Spironolactone (SL) is a poorly water-soluble drug. Being poorly soluble affects its dissolution rate which in turn affects its oral bioavailability. This work aimed to prepare freeze-dried SL-Soluplus®/polyvinyl alcohol (PVA) oral thin film in an attempt to enhance the drug solubility on one hand and at the same time prepare a solid dosage form convenient for the pediatric use. SL-Soluplus®/PVA films were prepared using polyethylene glycol 400 (PEG 400) as a plasticizer applying the solvent-casting technique. The prepared films were evaluated for their thickness, tensile strength, and in vitro dissolution studies. Box–Behnken design (17 runs) was applied to optimize the effects of the formulation variables on the film properties. The optimized film formulation was freeze-dried after casting so as to enhance the drug dissolution. Moreover, the optimized freeze-dried film was re-characterized in vitro and evaluated in vivo in human volunteers to investigate its palatability and satisfaction. The results showed that the optimized formulation composed of 10% polymer concentration containing Soluplus®:PVA (0.33:0.66) and plasticized with 30% PEG 400 possessed the highest desirability value (0.836). Freeze-drying of the optimized formulation succeeded to improve SL in vitro dissolution due to the preparation of a more porous film compared to the non-freeze-dried one. In vivo evaluation of the optimized freeze-dried film showed high satisfaction among the participating volunteers concerning the ease of administration and sensation thereafter, where all the film specimens dissolved without the need for water and no film residues remained in the mouth following film dissolution. In conclusion, freeze-dried Soluplus®/PVA-based oral thin film proved to be a successful carrier for the oral delivery of insoluble drugs like SL for pediatrics.

Tri/tetra-block co-polymeric nanocarriers as a potential ocular delivery system of lornoxicam: in-vitro characterization, and in-vivo estimation of corneal permeation.

Polymeric micelles that can deliver drug to intended sites of the eye have attracted much scientific attention recently. The aim of this study was to evaluate the aqueous-based formulation of drug-loaded polymeric micelles that hold significant promise for ophthalmic drug delivery. This study investigated the synergistic performance of mixed polymeric micelles made of linear and branched poly(ethylene oxide)-poly(propylene oxide) for the more effective encapsulation of lornoxicam (LX) as a hydrophobic model drug. The co-micellization process of 10% binary systems combining different weight ratios of the highly hydrophilic poloxamers; Synperonic(®) PE/P84, and Synperonic(®) PE/F127 and the hydrophobic poloxamine counterpart (Tetronic(®) T701) was investigated by means of photon correlation spectroscopy and cloud point. The drug-loaded micelles were tested for their solubilizing capacity towards LX. Results showed a sharp solubility increase from 0.0318 mg/mL up to more than 2.34 mg/mL, representing about 73-fold increase. Optimized formulation was selected to achieve maximum drug solubilizing power and clarity with lowest possible particle size, and was characterized by (1)HNMR analysis which revealed complete encapsulation of the drug within the micelles. Further investigations by histopathological and confocal laser studies revealed the non-irritant nature and good corneal penetrating power of the proposed nano-formulation.