Mohamed Ahmed El-Nabarawi

Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: In vitro/in vivo evaluation

Microemulsion (ME) and poloxamer microemulsion-based gel (PMBG) were developed and optimized to enhance transport of diclofenac epolamine (DE) into the skin forming in-skin drug depot for sustained transdermal delivery of drug. D-optimal mixture experimental design was applied to optimize ME that contains maximum amount of oil, minimum globule size and optimum drug solubility. Three formulation variables; the oil phase X1 (Capryol(®)), Smix X2 (a mixture of Labrasol(®)/Transcutol(®), 1:2 w/w) and water X3 were included in the design. The systems were assessed for drug solubility, globule size and light absorbance. Following optimization, the values of formulation components (X1, X2, and X3) were 30%, 50% and 20%, respectively. The optimized ME and PMBG were assessed for pH, drug content, skin irritation, stability studies and ex vivo transport in rat skin. Contrary to PMBG and Flector(®) gel, the optimized ME showed the highest cumulative amount of DE permeated after 8h and the in vivo anti-inflammatory efficacy in rat paw edema was sustained to 12h after removal of ME applied to the skin confirming the formation of in-skin drug depot. Our results proposed that topical ME formulation, containing higher fraction of oil solubilized drug, could be promising for sustained transdermal delivery of drug.

Promising ion-sensitive in situ ocular nanoemulsion gels of terbinafine hydrochloride: Design, in vitro characterization and in vivo estimation of the ocular irritation and drug pharmacokinetics in the aqueous humor of rabbits

Terbinafine hydrochloride (T-HCl) is recommended for the management of fungal keratitis. To maintain effective aqueous humor concentrations, frequent instillation of T-HCl drops is necessary. This work aimed to develop alternative controlled-release in situ ocular drug-loaded nanoemulsion (NE) gels. Twelve pseudoternary-phase diagrams were constructed using oils (isopropyl myristate/Miglyol 812), surfactants (Tween 80/Cremophor EL), a co-surfactant (polyethylene glycol 400) and water. Eight drug-loaded (0.5%, w/v) NEs were evaluated for thermodynamic stability, morphology, droplet size and drug release in simulated tear fluid (pH 7.4). Following dispersion in gellan gum solution (0.2%, w/w), the in situ NE gels were characterized for transparency, rheological behavior, mucoadhesive force, drug release and histopathological assessment of ocular irritation. Drug pharmacokinetics of sterilized F31 [Miglyol 812, Cremophor EL: polyethylene glycol 400 (1:2) and water (5, 55 and 40%, w/w, respectively)] in situ NE gel and oily drug solution were evaluated in rabbit aqueous humor. The NEs were thermodynamically stable and have spherical droplets (<30 nm). The gels were transparent, pseudoplastic, mucoadhesive and showed more retarded zero-order drug release rates. F31 in situ NE gel showed the least ocular irritation potential and significantly (P<0.01) higher C(max), delayed T(max), prolonged mean residence time and increased bioavailability.

Transdermal drug delivery of paroxetine through lipid-vesicular formulation to augment its bioavailability

Paroxetine (PAX) is the most potent serotonin reuptake blocker antidepressant clinically available. This study is aimed to reduce the side effects accompanied with the initial high plasma concentration after oral administration of PAX and fluctuations in plasma levels and also to decrease the broad metabolism of the drug in the liver by developing and optimizing liposomal transdermal formulation of PAX in order to improve its bioavailability. PAX liposomes were prepared by reverse phase evaporation technique using lecithin phosphatidylcholine (LPC), cholesterol (CHOL) and drug in different molar ratios. The prepared liposomes were characterized for size, shape, entrapment efficiency and in vitro drug release. The studies demonstrated successful preparation of PAX liposomes. The effect of using different molar ratios of (LPC:CHOL) on entrapment efficiency and on drug release was studied. Liposomes showed percentage entrapment efficiency (%EE) of 81.22 ± 3.08% for optimized formula (F5) which composed of (LPC:CHOL, 7:7) and 20mg of PAX, with average vesicle size of 220.53 ± 0.757 nm. The selected formula F5 (7:7) was incorporated in gel bases of HPMC-E4M (2%, 4%, and 6%). The selected formula of PAX liposomal gel of HPMC-E4M (2% and 4%) were fabricated in the reservoir type of transdermal patches and evaluated through in vitro release. After that the selected formula of PAX liposomal gel transdermal patch was applied to rabbits for in vivo bioavailability study in comparison with oral administration of the marketed PAX tablet. An HPLC method was developed for the determination of PAX in plasma of rabbits after transdermal patch application and oral administration of the marketed PAX tablets of 20mg dose. The intra- and inter-day accuracy and precision were determined as relative error and relative standard deviation, respectively. The linearity was assessed in the range of 5-200 ng/ml. Pharmacokinetic parameters were determined as the C(max) of PAX liposomal transdermal patch was found to be 92.53 ng/ml at t(max) of 12h and AUC(0-48) was 2305.656 ngh/ml and AUC(0-∞) was 3852.726 ngh/ml, compared to the C(max) of 172.35 ng/ml after oral administration of the marketed PAX tablet with t(max) of 6h and AUC(0-24) was 1206.63 ngh/ml and AUC(0-∞) was 1322.878 ngh/ml. These results indicate improvement of bioavailability of the PAX after liposomal transdermal patch application and sustaining of the therapeutic effects compared to oral administration.

Provesicular granisetron hydrochloride buccal formulations: In vitro evaluation and preliminary investigation of in vivo performance

Granisetron hydrochloride (granisetron) is a potent antiemetic that has been proven to be effective in acute and delayed emesis in cancer chemotherapy. Granisetron suffers from reduced oral bioavailability (≈60%) due to hepatic metabolism. In this study the combined advantage of provesicular carriers and buccal drug delivery has been explored aiming to sustain effect and improve bioavailability of granisetron via development of granisetron provesicular buccoadhesive tablets with suitable quality characteristics (hardness, drug content, in vitro release pattern, exvivo bioadhesion and in vivo bioadhesion behavior). Composition of the reconstituted niosomes from different prepared provesicular carriers regarding type of surfactant used and cholesterol concentration significantly affected both entrapment efficiency (%EE) and vesicle size. Span 80 proniosome-derived niosomes exhibited higher encapsulation efficiency and smaller particle size than those derived from span 20. Also, the effect of %EE and bioadhesive polymer type on in vitro drug release and in vivo performance of buccoadhesive tablets was investigated. Based on achievement of required in vitro release pattern (20-30% at 2h, 40-65% at 6h and 80-95% at 12h), in vivo swelling behavior, and in vivo adhesion time (>14 h) granisetron formulation (F19, 1.4 mg) comprising HPMC:carbopol 974P (7:3) and maltodextrin coated with the vesicular precursors span 80 and cholesterol (9:1) was chosen for in vivo study. In vivo pharmacokinetic study revealed higher bioavailability of buccal formulation relative to conventional oral formulation of granisetron (AUC0-∞ is 89.97 and 38.18 ng h/ml for buccal and oral formulation, respectively). A significantly lower and delayed Cmax (12.09±4.47 ng/ml, at 8h) was observed after buccal application compared to conventional oral tablet (31.66±10.15 ng/ml, at 0.5 h). The prepared provesicular buccoadhesive tablet of granisetron (F19) might help bypass hepatic first-pass metabolism and improve bioavailability of granisetron with the possibility of reducing reported daily dose (2mg) and reducing dosing frequency.

Effect of fixed aqueous layer thickness of polymeric stabilizers on zeta potential and stability of aripiprazole nanosuspensions

The aim of this study was to evaluate the effect of the thickness of adsorbed polymer layer (also known as Fixed Aqueous Layer Thickness, FALT) of polymeric stabilizers on zeta potential and stability of nanoparticles in a suspension. Aripiprazole, a poorly water soluble drug was used as a model drug to evaluate rationale for increased FALT and to understand the effect of hydrophilicity and hydrophobicity of polymeric stabilizers on FALT of aripiprazole nanosuspensions. The nanosuspensions were prepared by media milling and Pluronic F68, Pluronic F127, Hydroxypropyl methylcellulose (HPMC) and Hydroxypropyl cellulose (HPC) were used as polymeric stabilizers. The particle size (immediately after preparation and after 1 week of storage at 25°C) and zeta potential of aripiprazole nanosuspensions were determined. For Pluronics, FALT was determined theoretically whereas for HPMC and HPC it was calculated as Debye Huckel parameter from the zeta potential dependence on the ionic strength. An increase in FALT resulted in reduced zeta potential. With an increase in FALT of polymers used, the stability of nanosuspensions showed improvement. Furthermore, a linear correlation was shown to exist between the FALT and length of hydrophilic chains in Pluronics.

Duodenum-triggered delivery of pravastatin sodium via enteric surface-coated nanovesicular spanlastic dispersions: Development, characterization and pharmacokinetic assessments

Pravastatin sodium (PVS) is a hydrophilic HMG-CoA reductase inhibitor that is mainly absorbed from duodenum. PVS has a short elimination half-life (1-3 h), suffers from instability at gastric pH, extensive hepatic first-pass metabolism and low absolute bioavailability (18%). The current work aimed to develop enteric surface-coated spanlastic dispersions as controlled-release duodenum-triggered systems able to surmount PVS drawbacks. PVS-loaded spanlastic dispersions were prepared by ethanol-injection method using span(®) 60. Tween(®) 60 and Tween(®) 80 were explored as edge activators. As a novel approach, the fine spanlastic dispersions were surface-coated with an enteric-polymer (Eudragit(®) L100-55) via freeze-drying. The systems were evaluated, before and after enteric-coating, for particle size, zeta potential, PVS entrapment efficiency (EE%), morphology and PVS release studies. PVS pharmacokinetics from the best achieved system and an aqueous solution were estimated in rats by UPLC-MS/MS. The best achieved enteric surface-coated spanlastic dispersion (E-S6) displayed spherical nanosized vesicles (647.60 nm) possessing negative zeta potential (-6.93 mV), promising EE% (63.22%) and a biphasic drug-release pattern characterized by a retarded-release phase (0.1 N HCl, 2 h) and a controlled-release phase (pH 6.8, 10 h). The higher Cmax, delayed Tmax, prolonged MRT(0-∞), longer elimination t50% and enhanced oral bioavailability unravel E-S6 potential for oral PVS delivery.

Formulation and Evaluation of Secnidazole or Doxycycline Dento-Oral Gels

Local delivery of antibiotics has been shown to be effective in reducing periodontopathic microorganisms. The purpose of this study is to formulate gels containing secnidazole or doxycycline hydrochloride that could be used in the treatment of periodontitis by direct periodontal intrapocket administration. Different mucoadhesive polymers were used as cellulose derivatives, carbopol and eudragit. The prepared gels were evaluated for their in vitro drug release, rheological behavior, and mucoadhesive force. Increasing the concentration of each polymer increased the viscosity, mucoadhesion, and the time required for 30 and 50% release of the original mass of each drug. Gels with appropriate balance of the above-examined parameters were selected for microbiological evaluation. Microbiological studies on selected gels showed faster release of the two drugs (expressed as inhibition zones) than the commercial products of chlorhexidine gel (Elugel®) and miconazole nitrate emulgel (Miconaz®).

Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies.

Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well.

Effect of Chemical Structure on the Release of Certain Propionic Acid Derivatives from Their Dosage Forms

The aim of this study was to investigate the relationship between the chemical structure and release properties of certain drug products. Propionic acid derivatives were used as a model. These include ibuprofen (I), ketoprofen (K), tiaprofenic acid (T), flurbiprofen (F), and naproxen (N). They are all aryl derivatives of propionic acid and differ only in the aryl group. Such an aryl group may be either isobutylphenyl, benzoylphenyl, benzoylthienyl, fluorobiphenyl, or methoxynaphthyl group in I, K, T, F, and N, respectively. Three dosage forms were selected for this study: capsules, suppositories, and creams. The release of propionic acid derivatives from the capsules and suppositories decreased in the order ibuprofen > tiaprofenic acid > ketoprofen > flurbiprofen > naproxen, and for the creams the release decreased in the order ibuprofen > tiaprofenic acid > flurbiprofen > ketoprofen > naproxen. The difference in drug release in the first case was attributed to the difference in the chain length, and in the creams which are composed of two phases, the partition coefficient was found to affect the drug release. The molecular weight of the drug had no effect on the release. The drug release from different dosage forms was not affected after 1 month storage.

Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, ex vivo, bio-distribution and in vivo pharmacokinetic studies

Abstract Being one of the highly effective drugs in treatment of Alzheimer’s disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2 mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478 ± 4.94 nm) with a nearly neutral zeta potential (ZP, −8 ± 0.2 mV) and an entrapment efficiency percentage of 48 ± 6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and in vitro release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the in vivo pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels.