Azza A. Mahmoud

Nanoemulsion as a potential ophthalmic delivery system for dorzolamide hydrochloride.

Dilutable nanoemulsions are potent drug delivery vehicles for ophthalmic use due to their numerous advantages as sustained effect and high ability of drug penetration into the deeper layers of the ocular structure and the aqueous humor. The aim of this article was to formulate the antiglaucoma drug dorzolamide hydrochloride as ocular nanoemulsion of high therapeutic efficacy and prolonged effect. Thirty-six systems consisting of different oils, surfactants, and cosurfactants were prepared and their pseudoternary-phase diagrams were constructed by water titration method. Seventeen dorzolamide hydrochloride nanoemulsions were prepared and evaluated for their physicochemical and drug release properties. These nanoemulsions showed acceptable physicochemical properties and exhibited slow drug release. Draize rabbit eye irritation test and histological examination were carried out for those preparations exhibiting superior properties and revealed that they were nonirritant. Biological evaluation of dorzolamide hydrochloride nanoemulsions on normotensive albino rabbits indicated that these products had higher therapeutic efficacy, faster onset of action, and prolonged effect relative to either drug solution or the market product. Formulation of dorzolamide hydrochloride in a nanoemulsion form offers, thus, a more intensive treatment of glaucoma, a decrease in the number of applications per day, and a better patient compliance compared to conventional eye drops.

Chitosan/sulfobutylether-β-cyclodextrin nanoparticles as a potential approach for ocular drug delivery

Development of efficient ocular delivery nanosystems remains a major challenge to achieve sustained therapeutic effect. The purpose of this work was to develop chitosan nanoparticles using sulfobutylether-β-cyclodextrin (SBE-β-CD) as polyanionic crosslinker and to investigate the potential of using those nanostructures as ocular drug delivery systems. Econazole nitrate (ECO) was chosen as model drug molecule. The influence of different process variables (chitosan molecular weight and the concentration of the two ionic agents) on particle size, polydispersity index, zeta potential, drug content, in vitro release and mucoadhesive properties was investigated. The results showed that the prepared nanoparticles were predominant spherical in shape having average particle diameter from 90 to 673 nm with positive zeta potential values from 22 to 33 mV and drug content values ranging from 13 to 45%. Drug release from optimized nanoparticles was controlled with approximately 50% of the original amount released over a 8h period. The release profile of nanoparticles followed a zero-order release kinetics. The optimized nanoparticles were tested for their use as ocular drug delivery systems on albino rabbits. The in vivo studies revealed that the prepared mucoadhesive nanoparticles had better ability in sustaining the antifungal effect of ECO than the ECO solution. Therefore, chitosan/SBE-β-CD nanoparticles developed showed a promising carrier for controlled delivery of drug to the eye.

Phospholipid based colloidal poloxamer-nanocubic vesicles for brain targeting via the nasal route.

In this study, new phospholipid based colloidal nanocubic vesicles encapsulating olanzapine for its brain targeting via the nasal route were developed. The nanocubic vesicles were prepared by incorporating non-ionic copolymers, poloxamer 188 or 407, in the lipid bilayer. The effect of phospholipid:poloxamer molar ratio on the physicochemical properties of the nanocubic vesicles was investigated. The in vivo behavior and brain targeting of these vesicles were evaluated in rats. TEM photographs showed that the vesicles looked spherical before adding poloxamer. However, after poloxamer incorporation, the vesicles showed a predominant cubic shape, except those containing phospholipid:poloxamer in the molar ratio 5:1 which were spherical. DSC study confirmed perturbation of the packing characteristics as well as fluidization of the lipid bilayer by the polymer with consequent formation of the nanocubic structure. The mean diameter of the vesicles was in the range of 363-645 nm. All vesicles were elastic and the elasticity was found to depend on both poloxamer type and concentration. The intranasal nanocubic vesicles were significantly more efficient in targeting olanzapine to the brain compared to the liposomal vesicles with drug targeting efficiency values of 100% and 80%, respectively, and absolute bioavailability of 37.9% and 14.9%, respectively.

Brain delivery of olanzapine by intranasal administration of transfersomal vesicles

The aim of this study was to investigate the presence of a possible direct correlation between vesicle elasticity and the amount of drug reaching the brain intranasally. Therefore, transfersomes were developed using phosphatidylcholine (PC) as the lipid matrix and sodium deoxycholate (SDC), Span® 60, Cremophor® EL, Brij® 58, and Brij® 72 as surfactants. The influence of the type of surfactant and PC-to-surfactant ratio on vesicle morphology, size, membrane elasticity, drug entrapment, and in vitro drug release was studied. The prepared transfersomes were mainly spherical in shape, with diameters ranging from 310 to 885 nm. Transfersomes containing SDC and Span 60 with optimum lipid-to-surfactant molar ratio showed suitable diameters (410 and 380 nm, respectively) and deformability indices (17.68 and 20.76 mL/sec, respectively). Values for absolute drug bioavailability in rat plasma for transfersomes containing SDC and those containing Span 60 were 24.75 and 51.35%, whereas AUC0–360min values in rat brain were 22,334.6 and 36,486.3 ng/mL/min, respectively. The present study revealed that the deformability index is a parameter having a direct relation with the amount of the drug delivered to the brain by the nasal route.

Development of dorzolamide hydrochloride in situ gel nanoemulsion for ocular delivery.

Background: Several in situ gel-forming systems have been developed to prolong the precorneal residence time of a drug and to improve ocular bioavailability. Poloxamer 407 with its thermoreversible gelation and surface active properties was utilized to formulate a novel dorzolamide hydrochloride in situ gel nanoemulsion (NE) delivery system for ocular use. Objective: Improvement of both ocular bioavailability and duration of action for dorzolamide hydrochloride was the aim of this study. Methods: Physicochemical properties, in vitro drug release studies and biological evaluation of the prepared NEs were investigated. Results: The optimum formulation of in situ gel NE consisted of Triacetin (7.80%), Poloxamer 407 (13.65%), Poloxamer 188 (3.41%), Miranol C2M (4.55%), and water (70.59%). Biological evaluation of the designed dorzolamide formulation on normotensive albino rabbits indicated that this formulation had better biological performance, faster onset of action, and prolonged effect relative to either drug solution or the market product. The formula showed a superior pharmacodynamic activity compared to the in situ gel dorzolamide eye drops. This indicated the effectiveness of the in situ gel properties of poloxamer 407, besides formulating the drug in an NE form for improving the therapeutic efficacy of the drug. Conclusion: These results demonstrate the superiority of in situ gel NE to conventional ocular eye drops and in situ gels to enhance ocular drug bioavailability.

Norfloxacin-loaded collagen/chitosan scaffolds for skin reconstruction: Preparation, evaluation and in-vivo wound healing assessment.

Biomaterial scaffolds are versatile tools as drug carrier for treatment of wounds. A series of norfloxacin-loaded scaffolds were synthesized for treatment of wounds by combining collagen with two different types of chitosan using freeze-drying technique. Subsequently, scaffolds were screened in terms of morphology, water absorption and retention capacity, biodegradation, ex-vivo bioadhesive strength, in-vitro drug release biological compatibility, X-ray diffractometry, differential scanning calorimetry as well as in-vivo evaluation. The results indicate that the scaffold mechanical strength is dependent on the type of used chitosan. The prepared scaffolds contained interconnected porous architecture. The scaffolds had high water uptake and retention capacity with extended biodegradation rate. Scaffolds prepared with chitosan HCl showed superior bioadhesive strength compared to those prepared with low molecular weight chitosan. All scaffolds showed almost 100% drug release within 24h. As identified by the terahertz pulsed imaging measurements, there is single scaffold area with the same concentration. After 28 days of wound dressing with selected norfoloxacin-loaded or unloaded collagen/chitosan scaffolds in Albino rats, it was found that the tissue regeneration time was fast compared to non-treated wounds. Furthermore, the drug-loaded scaffolds showed normal structure of an intact epidermal layer as well as the underlying dermis as revealed by histopathological studies. The obtained results suggest that the investigated norfloxacin-loaded collagen/chitosan scaffold is a potential candidate for skin regeneration application.

Double-phase hydrogel for buccal delivery of tramadol

Context: Treatment of chronic pain is complicated by the evidence that abuse of prescription opioids is rising; therefore, in many cases, chronic pain remains undertreated. Tramadol is an atypical central analgesic with a mixed mechanism of action offering many advantages over conventional opioids. Objective: We exploited the nonopioid action of tramadol, by bypassing the first-pass effect, as well as multiparticulate drug delivery. Our aim was to identify optimal formulation parameters for designing polyvinyl alcohol (PVA), single and mixed dual cross-linked tramadol microspheres-loaded hydrogel with adequate bioadhesion and providing controlled drug release for buccal delivery. Methods: Microspheres characterization was done by scanning electron microscopy and infrared spectroscopy. Other investigations comprised the evaluation of yield, drug content, particle size, rheology, swelling, mucoadhesion, release, and permeation studies through biological membranes all together with testing the antinociceptive activity and its attenuation by the antagonist naloxone HCl. Results and conclusion: PVA-alginate microspheres (F3)-loaded carbopol hydrogel attained: the highest mucoadhesion time (1436.67 min ± 5.77) and mucin adsorption capacity, shear thinning thixotropic properties with adequate yield value and hysteresis area, best drug release (RE = 84.20 ± 2.07%) and permeation efficiency (PE = 65.30 ± 7.02%). Dissolution and permeation profiles were compared using similarity factor; F3-loaded carbogel had the lowest value. During in vivo study, the nonsignificant difference between the AUC of the groups receiving F3-loaded carbogel buccally with (group 5) and without (group 4) administration of naloxone, and between group 4 and the oral group, showed that the buccal route may arguably provide an alternative safer route of tramadol administration.

Topical liquid crystalline gel containing lornoxicam/cyclodextrin complex

Lornoxicam is a potent analgesic non-steroidal anti-inflammatory drug that can be used topically to relieve pain and to reduce inflammation. The objectives of this study were to improve the therapeutic efficacy of lornoxicam by complexation with cyclodextrins and to formulate it in liquid crystalline gel. Lornoxicam and β-cyclodextrin (βCD) or hydroxypropyl-β-cyclodextrin (HPβCD) complexes were prepared using the kneaded method in 1:1, 1:2, 1:3 and 1:4 drug:CD molar ratios. Inclusion complexation in aqueous solution and solid state was evaluated by the ultraviolet, phase solubility diagram, differential scanning calorimetry, X-ray diffractometry and Fourier-transform infrared spectroscopy. The stoichiometry for the inclusion complex was found to be 1:2 drug:CD molar ratio as determined from Job’s plot. This result was confirmed by the in vitro dissolution studies for the prepared complexes. Among all the prepared complexes, the complex prepared with βCD in 1:2 drug:CD molar ratio showed highest improvement in drug dissolution and was chosen to be formulated in a topical preparation. For developing liquid crystalline gel, different ratios of Brij 97, glycerol and oils (liquid paraffin, isopropyl myristate and Miglyol® 812) were prepared. The formula composed of Brij 97 and glycerol in 3:1 weight ratio, 10% Miglyol® 812 and 40% water showed higher drug release compared to the other prepared gels. Moreover, this formula showed low ex vivo permeation on excised pigskin thus it could offer high topical effect with low systematic side effects. This formula showed superior anti-inflammatory activity when applied topically on rats’ skin after induction of burn compared to that of Feldene® gel.

Fast relief from migraine attacks using fast-disintegrating sublingual zolmitriptan tablets

Zolmitriptan is a potent molecule for treatment of migraine. Its current oral therapies present drawbacks such as slow onset of action, low bioavailability and large inter-subject variability. Fast disintegrating sublingual zolmitriptan tablet (FDST) using freeze-drying technique has been developed to enhance tablet disintegration and dissolution with the intention of speeding drug absorption and onset of effect, hence mitigating the effects on the gastrointestinal dysmotility that typically accompanies the migraine attack. The FDSTs were prepared using different concentrations of gelatin as binder and mannitol or L-alanine as matrix supporting/disintegration enhancing agents. The effect of formulation variables on the physicochemical and solid-state properties, as well as the dissolution behaviour of the tablets, was studied. The formulated FDSTs disintegrated within 30 s and showed significantly faster dissolution rate of zolmitriptan compared to the zolmitriptan oral tablet. Tablet containing 2% gelatin and mannitol showed acceptable weight variation, drug content and friability values. Furthermore, it had a low in-vitro and in-vivo disintegration time (11 s) and it reached 100% of drug release within 30 s. This sublingual formulation gave faster and higher zolmitriptan plasma concentration in rabbits compared to the oral zolmetriptan market product. Zolmitriptan FDST may therefore constitute an advance in the management of acute migraine attacks.

Rapid pain relief using transdermal film forming polymeric solution of ketorolac

Context: Ketorolac is one of the most potent nonsteroidal anti-inflammatory drugs and is an attractive alternative to opioids for pain management. Objective: Development and evaluation of transdermal ketorolac film forming polymeric solution. Materials and methods: Eudragits® RLPO, RSPO and E100 as well as polyvinyl pyrrolidone K30 dissolved in ethanol were used as film forming solutions. In vitro experiments were conducted to optimize formulation parameters. Different permeation enhancers were monitored for potentiality of enhancing drug permeation across excised pigskin. Results: The use of 10% oleic acid, Lauroglycol® 90 or Azone® with 5% Eudragit® RSPO, showed the highest enhancement effect on ketorolac skin permeation and showed faster analgesic effect compared to the ketorolac tablet. The formula comprising 5% Eudragit® RSPO and 10% Lauroglycol® 90 showed the greatest pharmacodynamic effect and thus was subjected to pharmacokinetic studies. The pharmacodynamic and pharmacokinetic results didn’t run paralleled to each other, as the ketorolac tablets showed higher plasma concentrations compared to the selected ketorolac transdermal formulation. This might be due to the induction of analgesia by the available ethanol in the transdermal preparation. Conclusion: Optimized transdermal ketorolac formulation showed marked ability to ensure fast and augmented analgesic effect that is an essential request in pain management.