Alaa A. Kassem

Silymarin loaded liposomes for hepatic targeting: In vitro evaluation and HepG2 drug uptake

Silymarin has hepatoprotective properties and is used in treatment of various liver diseases, but its bioavailability from oral products is very poor. In order to overcome its poor oral bioavailability we have prepared silymarin loaded hepatic targeting liposomes suitable for parenteral administration. The liposomal formulations were composed of hydrogenated soy phosphatidylcholine and cholesterol with or without distearoylphosphoethanolamine-(polyethyleneglycol)-2000 and various amounts of β-sitosterol β-D-glucoside (Sito-G) as the hepatic targeting moiety. Increasing the amount of Sito-G in the liposomes gradually decreased drug encapsulation efficiencies from ∼70% to ∼60%; still showing promising drug encapsulation efficiencies. Addition of Sito-G to non-PEGylated liposomes clearly affected their drug release profiles and plasma protein interactions, whereas no effect on these was seen for the PEGylated liposomes. Non-PEGylated liposomes with 0.17 M ratio of Sito-G exhibited the highest cellular drug uptake of 37.5% for all of the studied liposome formulations. The highest cellular drug uptake in the case of PEGylated liposomes was 18%, which was achieved with 0.17 and 0.33 M ratio of added Sito-G. The liposome formulations with the highest drug delivery efficacy in this study showed hemolytic activities around 12.7% and were stable for at least 2 months upon storage in 20 mM HEPES buffer (pH 7.4) containing 1.5% Polysorbate 80 at 4 °C and room temperature. These results suggest that the Sito-G containing liposomes prepared in this work have hepatic targeting capability and that they are promising candidates for delivering silymarin to the liver.

In Vitro Release Studies of Flurbiprofen from Different Topical Formulations

ABSTRACT The release profiles of flurbiprofen (F) from different gel and ointment formulations were studied in order to evaluate factors governing the release process. Carbopol 934P (CAB), poloxamer 407 (POL), and eudragit S100 (EUD) gel bases were used, while emulsion (EML) and polyethylene glycol (PEG) ointments were employed. The release studies were conducted using membraneless diffusion cells and lipophilic receptor medium, isopropyl myristate (IPM). The effects of gelling agent concentrations and the initial drug load on drug release were determined. Hydrogels were observed to give higher amounts of drug release than hydrophobic EUD gel and ointments, despite the lower bulk viscosity of these bases. Flurbiprofen release from CAB gels was 3.06–1.56-fold higher than from other formulations. Over a 4-hr period, the amount of F released was 492.8 and 316.0 µg/cm2 from 2% CAB and 25% POL gels, while it was 213.05, 168.61, and 160.9 µg/cm2 from EML, 40% EUD, and PEG bases, respectively. The diffusivity of F in the gel bases was an inverse function of the polymer concentrations over the range of 1–3% CAB, 20–30% POL, and 35–45% EUD gels. Drug release was increased from the bases as the initial F concentration increased over the range 0.25–1.0%, while the diffusion coefficient observed an inverse relationship. The CAB and POL gels could be the vehicles of choice for the rapid release and onset of F after topical application.

Response surface methodology for the development of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate.

The purpose was to prepare, characterize, and optimize a self-nanoemulsified drug delivery system (SNEDDS) of a model lipophilic compound, all-trans-retinol acetate. As part of the optimization process, the main effects, interaction effects, and quadratic effects of the formulation ingredients were investigated. Method. A three-factor, three-level Box-Behnken design was used to explore the quadratic response surfaces and construct a second-order polynomial model in the form: Y = A + A1X1+ A2X2+ A3X3+ A4X1X2+ A5X2X3+ A6X1X3+ A7X12+ A8X22+ A9X32+ E. Amount of added oil (X1), surfactant (X2), and cosurfactant (X3) were selected as the factors. Particle size (Y1), turbidity (Y2), and cumulative amount of the active ingredient emulsified after 10 (Y3) and 30 (Y4) min were the observed variables. Response surface plots were used to demonstrate the effect of factors (X1), (X2), and (X3) on the response (Y4). Amount of added soybean oil (X1), Cremophor EL (X2), and Capmul MCM-C8 (X3) showed a significant effect on the emulsification rates, as well as on the physical properties of the resultant emulsion (particle size and turbidity). Observed and predicted values of Y4 obtained from the constructed equations were in close agreement. Response surface methodology was then used to predict the levels of factors X1, X2, and X3 under the constrained variables for an optimum response. Applied constraints were 0 < Y1 < 0.5, 1 < Y2 < 20, 60 < Y3 < 80, and 90 < Y4 < 100. The predicted values were 0.0704 µm for particle size (Y1), 18.95 NTU for turbidity (Y2), 88.88% for drug release after 10 min (Y3), and 110.7% drug release after 30 min (Y4). Two new formulations were prepared according to the predicted levels. The observed and predicted values were in close agreement.

Diacerein niosomal gel for topical delivery: development, in vitro and in vivo assessment

Abstract The purpose of this study was to load diacerein (DCR) in niosomes by applying response surface methodology and incorporate these niosomes in gel base for topical delivery. Box–Behnken design was used to investigate the effect of charge-inducing agent (X1), surfactant HLB (X2) and sonication time (X3) on the vesicle size (Y1), entrapment efficiency (Y2) and cumulative drug released (Y3). DCR niosomal formulations were prepared by thin film hydration method. The optimized formula was incorporated in different gel bases. DCR niosomal gels were evaluated for homogeneity, rheological behavior; in vitro release and pharmacodynamic activity by carrageenan-induced hind paw edema method in the rat compared with DCR commercial gel. The results revealed that the mean vesicle sizes of the prepared niosomes ranged from 7.33 to 23.72 µm and the entrapment efficiency ranged from 9.52% to 58.43% with controlled release pattern over 8 h. DCR niosomal gels exhibited pseudoplastic flow with thixotropic behavior. The pharmacodynamic activity of DCR niosomal gel in 3% HPMC showed significant, 37.66%, maximum inhibition of edema size in comparison with 20.83% for the commercial gel (p < 0.05). These results recommended the incorporation of DCR niosomes in 3% HPMC for topical application as a potent anti-inflammatory drug for the treatment of osteoarthritis.

Salbutamol sulfate suppositories: influence of formulation on physical parameters and stability.

Purpose. To prepare and evaluate a suppository dosage form of salbutamol sulfate. The prepared formulae with and without different concentrations of gels were tested for hardness, melting time, content uniformity, and drug release. The stability of some of the selected formulae was assessed. Methods. Salbutamol sulfate was formulated as a rectal suppository with emulsifying fatty bases (suppocire and witepsol) and water-soluble bases (PEG) adopting the molding from a melt technique. Physical characteristics and dissolution profiles of the prepared formulations were determined as the responses. The effects of adding gels, methyl cellulose (MC), and Eudispert (Eud) and their concentrations (1, 3, and 6%) on these responses were also investigated. Formulations showing high rank order were scaled up for shelf-life stability study for one year. Results. The results showed that all the investigated formulae have acceptable physical characteristics with respect to hardness, melting time (except F7), and uniformity of drug content. The amount of drug dissolved in 100 min of dissolution time was inversely affected by the melting point of the fatty base. The release from PEG bases was found to be molecular weight dependent. Addition of 1% MC or Eud gel increased the release from all the investigated formulae. Increasing gel concentration to 3% then to 6% showed different effects on the release. The degradation of salbutamol sulfate in the investigated formulae was found to be a first-order reaction. Conclusions. Rectal suppository of salbutamol sulfate could be prepared as an alternative to the oral dosage form to circumvent the first-pass metabolism.

Controlled-Release Frusemide Microcapsules: Preformulation Studies

AbstractMicroencapsulation of plain frusemide or its solid-dispersion with PEG 6000 was achieved by phase-separation coacervation. Formulations showed reasonable in-vitro dissolution behaviour were assessed for their absorption rates by LD50 testing in mice. Toxicity studies showed close agreement between the increase in lethal dose and the decrease in dissolution rate and revealed that the formulation containing frusemide as fused mixture with PEG 6000 and microencapsulated with polystyrene, in frusemide-PEG 6000-polystyrene weight ratio of 2:2:1, was the formula of choice for prolonging the absorption, hence, the action of frusemide.

Phenylpropanolamine HCl Microcapsules: Preparation and release studies

AbstractMicrocapsules of phenylpropanolamine HCL were prepared by three techniques, viz. coacervation-phase separation, air suspension, and pan coating, using different polymers and/or waxes as wall-forming materials.Formulations showed reasonable dissolution behaviour, viz. microcapsules prepared by air suspension with polymer level of 20% polyvinyl acetate copolymer (PVAC) associated with 40% carnauba wax (II) and microcapsules prepared by pan coating with polymer level of 25% RodopaceR (III), were evaluated for their absorption rates by demonstrating their toxicities compared to pure grug (I) by the LD50 method. Toxicity assessment showed close agreement between the increase in lethal dose and the decrease in dissolution rate and revealed that Formula III has more prolonged action than Formulae II and I.

Preparation and Evaluation of Directly-Compressed Indomethacin, Indomethacin Sodium and Indomethacin Meglumine Tablets

AbstractA formula containing Compactrol, Ac-Di-Sol, Aerosil 200 and talc was used to prepare directly-compressed tablets of indomethacin and its sodium and meglumine salts. The prepared tablets were evaluated for uniformity of weight and thickness, hardness, friability and content uniformity. Each batch was then divided into two, one was coated with an opaque non-enteric film coat and evaluated for coat thickness uniformity. The dissolution rates of the uncoated and coated tablets and the effect of shelf-storage, at room temperature for 11 months, on drug contents were also studied. Indomethacin meglumine tablets showed the least relative standard deviation of weight and thickness. They exhibited acceptable uniformity of content and coat thickness, and the highest hardness-friability ratio. Also exhibited, uncoated and coated, the best in-vitro release of its drug contents and the maximal stability.

Influence of Aging on the Physical Characteristics of Ampicillin Suppositories

AbstractThis part of study of in-vitro and in-vivo release of ampicillin suppositories details the effect of aging on release of both anhydrous ampicillin and ampicillin sodium from suppositories of different formulations. It also details the effect of aging on some of the physical characteristics of these suppositories. The prepared suppositories were stored in a refregirato at 4°c and tested fresh and at 80,145 and 240 days old. All the tested suppositories disintegrate within a resonable time (6 -9 min.) and showed nearly no change in the disintegration time after storage for 240 days. Also, aging had no effect on the dissolution time of polyethylene glycol. Aging caused no discoloration or crystal growth of the medicament on the surface of suppositories. Aging had an obvious effect on hardness and decreased the release rate of both anhydrous ampicillin and ampicillin sodium from all the tested suppositories.

Release Studies of Neomycin From Different Ophthalmic Ointment Bases

AbstractThe release of neomycin from ten different ointment bases for possible ophthalmic use was monitored using a microbiological agar plate method. An obvious difference in antibiotic release from the various bases was observed. The effect of benzalkonium chloride, as preservative, on the antimicrobial activity of neomycin was studied and found to be dependent on the base used. From the whole set of results for release and stability, after shelf storage for 24 months, Bases No. 9 (containing castor oil, hydrogenated castor oil and cetyl alcohol) and No. 10 (containing liquid paraffin, hard paraffin, glyceryl monostearate and wool fat) were found to be the bases of choice for neomycin ophthalmic ointments.