Adel A. Ali

Nanotransfersomes of carvedilol for intranasal delivery: formulation, characterization and in vivo evaluation

Abstract Context: Development of carvedilol-loaded transfersomes for intranasal administration to overcome poor nasal permeability and hepatic first pass effect so as to enhance its bioavailability. Objective: The purpose of this study was to develop carvedilol-loaded transfersomes containing different edge activators (EAs) then evaluating the in vivo behavior of the optimized formula in rabbits. Methods: The vesicles were prepared by incorporating different EAs including Span 20, Span 60, Tween 20, Tween 80, and sodium deoxycholate (SDC) in the lipid bilayer and each EA was used in three different ratios with respect to phosphatidylcholine (PC) including 95:5%, 85:15%, and 75:25% w/w (PC:EA). Evaluation of transfersomes was carried out in terms of shape, size, entrapment efficiency (EE), in vitro release, ex vivo permeation, confocal laser scanning microscopy (CLSM), and stability studies. The pharmacokinetic study of the optimized formula was conducted in rabbits. Results: The mean diameter of the vesicles was in the range of 295–443 nm. Transfersomes prepared with 95:5% (w/w) (PC:EA) ratio showed highest EE% where Span 60 gave the highest values. Whereas those prepared using 85:15% w/w ratio showed highest percentages of drug release where SDC was superior to other EAs. The developed transfersomes exhibited significantly higher amounts of carvedilol permeated through nasal mucosa. CLSM of formula T14 containing SDC with 85:15% (w/w) (PC:EA) ratio revealed high permeation across the nasal mucosa. Conclusion: The nanotransfersomal vesicles were significantly more efficient in nasal delivery of carvedilol with absolute bioavailability of 63.4%.

Clozapine-carboxylic acid plasticized co-amorphous dispersions: Preparation, characterization and solution stability evaluation.

Abstract This study addressed the possibility of forming of co-amorphous systems between clozapine (CZ) and various carboxylic acid plasticizers (CAPs). The aim was to improve the solubility and oral bioavailability of clozapine. Co-amorphous dispersions were prepared using modified solvent evaporation methodology at drug/plasticizer stoichiometric ratios of 1:1, 1:1.5 and 1:2. Solid state characterization was performed using differential scanning calorimetry, X-ray diffraction and infra red spectroscopy. Highly soluble homogeneous co-amorphous dispersions were formed between clozapine and CAPs via hydrogen bonding. The co-amorphous dispersions formed with tartaric acid (1:2) showed the highest dissolution percentage (> 95 % in 20 minutes) compared to pure crystalline CZ (56 %). Highly stable solutions were obtained from co-amorphous CZ-citric and CZ-tartaric acid at 1:1.5 molar ratio. The prepared dispersions suggest the possibility of peroral or sublingual administration of highly soluble clozapine at a reduced dose with the great chance to bypass the first pass metabolism.

Optimization of propranolol HCl release kinetics from press coated sustained release tablets

Press-coated sustained release tablets offer a valuable, cheap and easy manufacture alternative to the highly expensive, multi-step manufacture and filling of coated beads. In this study, propranolol HCl press-coated tablets were prepared using hydroxylpropylmethylcellulose (HPMC) as tablet coating material together with carbopol 971P and compressol as release modifiers. The prepared formulations were optimized for zero-order release using artificial neural network program (INForm, Intelligensys Ltd, North Yorkshire, UK). Typical zero-order release kinetics with extended release profile for more than 12 h was obtained. The most important variables considered by the program in optimizing formulations were type and proportion of polymer mixture in the coat layer and distribution ratio of drug between core and coat. The key elements found were; incorporation of 31–38 % of the drug in the coat, fixing the amount of polymer in coat to be not less than 50 % of coat layer. Optimum zero-order release kinetics (linear regression r2 = 0.997 and Peppas model n value > 0.80) were obtained when 2.5–10 % carbopol and 25–42.5% compressol were incorporated into the 50 % HPMC coat layer.

Nanotransfersomes-loaded thermosensitive in situ gel as a rectal delivery system of tizanidine HCl: preparation, in vitro and in vivo performance

Abstract The purpose of the current study was to develop tizanidine HCl (TIZ; a myotonolytic agent used for treatment of spasticity) loaded nanotransfersomes intended for rectal administration, aiming to bypass the hepatic first-pass metabolism. TIZ-loaded nanotransfersomes were prepared by thin-film hydration method followed by characterization for various parameters including entrapment efficiency, vesicle diameter, in vitro release and ex vivo permeation studies. Transfersomal formulation composed of phosphatidylcholine and Tween 80 at a weight ratio of (85:15) gave a satisfactory results. It exhibited encapsulation efficiency of 52.39%, mean diameter of 150.33 nm, controlled drug release over 8 h and good permeation characteristics. Optimum formula was then incorporated into Pluronic-based thermoreversible gel using hydroxypropyl methylcellulose (HPMC) as a mucoadhesive polymer. Pharmacokinetic study was performed by rectal administration of transfersomes-loaded in situ gel to rabbits and compared with oral drug solution and rectal TIZ in situ gel. The pharmacokinetic study revealed that the transfersomal formulation successively enhanced the bioavailability of TIZ by about 2.18-fold and increased t1/2 to about 10 h as compared to oral solution. It can be concluded that encapsulation of TIZ into nanotransfersomes can achieve a dual purpose of prolonged TIZ release and enhanced bioavailability and so may be considered as a promising drug delivery system for the treatment of spasticity.

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation

Objective Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière’s disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. Methods A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers. Results Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. Conclusion The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl.

Transdermal delivery of atorvastatin calcium from novel nanovesicular systems using polyethylene glycol fatty acid esters: Ameliorated effect without liver toxicity in poloxamer 407-induced hyperlipidemic rats

Context: Atorvastatin calcium (ATV), a cholesterol‐lowering agent, suffers from poor systemic availability (14%) after oral administration in addition to other side effects on the gastrointestinal tract, liver and muscle. Objective: The goal of the present investigation was to improve ATV bioavailability and overcome complications attendant with peroral administration by developing a new nanovesicular system encapsulating ATV for its delivery via the transdermal route. Methods: The vesicular systems were prepared by incorporating different polyethylene glycol fatty acid esters such as Labrasol, Cremophor EL, Gelucire 44/14 and Tween 80 as edge activators (EAs) in the lipid bilayer. The effect of the phosphatidylcholine (PC):EA molar ratio on the physicochemical properties of the vesicles was investigated. The pharmacokinetic studies of the optimized formulation were evaluated in rats. The optimized formulation was tested in poloxamer 407‐induced hyperlipidemic rats. The plasma lipid profile, activity of liver enzymes, and oxidative stress parameters were measured using commercially available kits. Results: The results revealed high ATV entrapment efficiency (EE%) ranging from 55.62 to 83.91%. The formulations that contained Labrasol showed the highest EE%. The mean diameter of the vesicles was in the range of 186–583 nm. T8 containing Gelucire 44/14 as an EA in the molar ratio of 15:1 (PC:EA) gave the smallest size and exhibited the best permeation parameters across the skin. The pharmacokinetic studies revealed that about three times statistically significant (p < 0.05) improvement in bioavailability, after transdermal administration of nanotransfersomal ATV gel compared to oral ATV suspension. The transdermal vesicular system exhibited a significant decrease in plasma total cholesterol, triglycerides and LDL cholesterol comparable to oral ATV. Additionally, it lowered the malondialdehyde levels in plasma and abolished the increase in liver enzyme activity. Conclusion: The results obtained suggest that the proposed transdermal vesicular system can serve as a promising alternative means for delivery of ATV. Graphical abstract Figure. No caption available.

Development and characterization of ketorolac tromethamine osmotic pump tablets

The aim of the present study was to prepare and evaluate elementary osmotic pump tablets (OPT) of ketorolac tromethamine (KT). Because of its high potency, short half-life and excellent water solubility it would appear to be the drug of choice for these formulations. Twenty OPT formulae were prepared and subjected to release-rate study and the release data were analyzed to determine the drug release order. Compatibility study between KT and the used excipients was carried out also scanning electron microscopy in order to elucidate the microporous nature of the tablet surfaces. The effects of an increase in weight, agitation intensity, pH and type of coating polymer on drug release from the optimal formulation (OPT-19) were studied. It was found that the optimal OPT formula was able to deliver KT at a zero-order for up to 12 h independent of both release media and agitation rates; the effect of type of coating polymer was not significant.

Preparation and characterization of mosapride citrate inclusion complexes with natural and synthetic cyclodextrins

The aim of this work was to investigate the inclusion complexes between mosapride citrate and SBE7β-CD in comparison with the natural β-CD to enhance its bioavailability by improving the solubility and dissolution rate. The complexation efficiency value of SBE7β-CD was higher than that for β-CD. Solid binary systems of mosapride citrate with CDs were prepared by physical mixing, kneading and freeze-drying techniques at molar ratio of 1:1(drug:CD). Physicochemical characterization of the prepared systems was studied using X-ray diffractometry, differential scanning calorimetry, Fourier-transform infrared spectroscopy and scanning electron microscopy (SEM). Amorphous drug was detectable to large extent in inclusion complexes prepared using the freeze-drying technique. From the dissolution study of different inclusion complexes in simulated saliva solution (pH 6.8), we could concluded that irrespective of the preparation technique, the systems prepared using SBE7β-CD showed better performance than the corresponding ones prepared using β-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the SBE7β-CD

Formulation and optimization of tenoxicam orodispersible tablets by solid deposition technique

Tenoxicam is a poorly water-soluble NSAID drug and dissolution plays an important role in its absorption, so the present investigation was to develop and characterize orodispersible tablets of tenoxicam using solid deposition technique on superdisintegrants in order to improve its dissolution and aqueous solubility to facilitate faster onset of action. The super-disintegrants used were crospovidone, cross-carmellose sodium, sodium starch glycolate and pregelatinised maize starch in ratios of 1:1, 1:2 and 1:4 (w/w) drug:carrier. Drug excipients compatibility study was carried out using DSC, IR spectroscopy and SEM photography. General characterization of the prepared tablets was performed, in addition to wetting time, in vitro disintegration time and in vitro dissolution studies. The formula containing cross-carmellose sodium as a carrier in a ratio of 1:2 showed highest dissolution rate and shortest disintegration time. It was subjected to stability stress testing and drug concentration was detected by stability indicating HPLC assay method and in conclusion, the results of this work suggest that stable rapid release tenoxicam orodispersible tablets can be developed by solid deposition method.

Nanosized soy phytosome-based thermogel as topical anti-obesity formulation: an approach for acceptable level of evidence of an effective novel herbal weight loss product

Purpose Herbal supplements are currently available as a safer alternative to manage obesity, which has become a rising problem over the recent years. Many chemical drugs on the market are designed to prevent or manage obesity but high cost, low efficacy, and multiple side effects limit its use. Nano lipo-vesicles phytosomal thermogel of Soybean, Glycine max (L.) Merrill, was formulated and evaluated in an attempt to investigate its anti-obesity action on body weight gain, adipose tissue size, and lipid profile data. Methods Three different techniques were used to prepare phytosome formulations including solvent evaporation, cosolvency, and salting out. The optimized phytosome formulation was then selected using Design Expert® (version 7.0.0) depending on the highest entrapment efficiency, minimum particle size (PS), and maximum drug release within 2 hours as responses for further evaluation. The successful phytosome complex formation was investigated by means of Fourier-transform infrared spec troscopy and determination of PS and zeta potential. Phytosome vesicles’ shape was evaluated using transmission electron microscope to ensure its spherical shape. After characterization of the optimized phytosome formulation, it was incorporated into a thermogel formulation. The obtained phytosomal thermogel formulation was evaluated for its clarity, homogeneity, pH, and gel transformation temperature besides rheology behavior and permeation study. An in vivo study was done to investigate the anti-weight-gain effect of soy phytosomal ther mogel. Results EE was found to be >99% for all formulations, PS ranging from 51.66–650.67 while drug release was found to be (77.61–99.78) in range. FTIR and TEM results confirmed the formation of phytosome complex. In vivo study showed a marked reduction in body weight, adipose tissue weight and lipid profile. Conclusion Concisely, soy phytosomal thermogel was found to have a local anti-obesity effect on the abdomen of experimental male albino rats with a slight systemic effect on the lipid profile data.