Magda A. El-Massik

Self-nanoemulsifying drug delivery systems of tamoxifen citrate: Design and optimization

Tamoxifen citrate is an antiestrogen for peroral breast cancer treatment. The drug delivery encounters problems of poor water solubility and vulnerability to enzymatic degradation in both intestine and liver. In the current study, tamoxifen citrate self-nanoemulsifying drug delivery systems (SNEDDS) were prepared in an attempt to circumvent such obstacles. Preliminary screening was carried out to select proper ingredient combinations. All surfactants screened were recognized for their bioactive aspects. Ternary phase diagrams were then constructed and an optimum system was designated. Three tamoxifen SNEDDS were then compared for optimization. The systems were assessed for robustness to dilution, globule size, cloud point, surface morphology and drug release. An optimum system composed of tamoxifen citrate (1.6%), Maisine 35-1 (16.4%), Caproyl 90 (32.8%), Cremophor RH40 (32.8%) and propylene glycol (16.4%) was selected. The system was robust to different dilution volumes and types. It possessed a mean globule size of 150 nm and a cloud point of 80 degrees C. Transmission electron microscopy demonstrated spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension, as well. Realizing drug incorporation into an optimized nano-sized SNEDD system that encompasses a bioactive surfactant, our results proposed that the prepared system could be promising to improve oral efficacy of the tamoxifen citrate.

Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles

Although sildenafil citrate (SC) is used extensively for erectile dysfunction, oral delivery of SC encounters many obstacles. Furthermore, the physicochemical characteristics of this amphoteric drug are challenging for delivery system formulation and transdermal permeation. This article concerns the assessment of the potential of nanomedicine for improving SC delivery and transdermal permeation. SC-loaded nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) were fabricated using a modified high-shear homogenization technique. Nanoparticle optimization steps included particle size analysis, entrapment efficiency (EE) determination, freeze-drying and reconstitution, differential scanning calorimetry, in vitro release, stability study and high-performance liquid chromatography analysis. Transdermal permeation of the nanocarriers compared with SC suspension across human skin was assessed using a modified Franz diffusion cell assembly. Results revealed that SLNs and NLCs could be optimized in the nanometric range (180 and 100 nm, respectively) with excellent EE (96.7% and 97.5%, respectively). Nanoparticles have significantly enhanced in vitro release and transdermal permeation of SC compared with its suspensions. Furthermore, transdermal permeation of SC exhibited higher initial release from both SLN and NLC formulations followed by controlled release, with promising implications for faster onset and longer drug duration. Nanomedicines prepared exhibited excellent physical stability for the study period. Solid nanoparticles optimized in this study successfully improved SC characteristics, paving the way for an efficient topical Viagra® product.

Development of a dissolution medium for glibenclamide

A dissolution medium for slightly soluble drugs was developed using glibenclamide as a model of such drugs. The medium consists of a hydroalcoholic surfactant solution with a relatively low alcohol and Tween 80 content buffered at pH 7.4. The composition of the medium was selected on the basis of solubility data at 37°C obtained according to a central composite experimental design. The discriminating power of the medium selected (phosphate buffer pH 7.4 containing 8.5% alcohol and 0.24% Tween 80) was assessed relative to that of phosphate buffer pH 7.4, a medium usually used for the dissolution testing of glibenclamide and borate buffer pH 9.5, a medium recently recommended by the FDA. The dissolution data obtained for two commercial brands of glibenclamide tablets indicate superiority of the proposed system as a discriminatory dissolution medium for glibenclamide tablets.

Alendronate PLGA microspheres with high loading efficiency for dental applications

Purpose: Alendronate sodium, used systemically as a bone protective agent, proved to also be effective locally in various dental bone applications. Development of alendronate-loaded microspheres with high loading efficiency for such applications would be greatly challenged by the hydrophilicity and low MW of the drug. The aim of this study was to incorporate alendronate sodium, into poly (lactide-co-glycolide) (PLGA) microspheres (MS) with high loading efficiency. Methods: Three multiple emulsion methods: water-in-oil-in-water (W/O/W), water-in-oil-in-oil (W/O1/O2) and solid-in-oil-in-oil (S/O1/O2) were tested. In addition to entrapment efficiency, MS were characterized for surface morphology, particle size, in vitro drug release and in vitro degradation of the polymer matrix. Alendronate microspheres with maximum drug loading and good overall in vitro performance were obtained using the W/O1/O2 emulsion technique. Results: Drug release from the microspheres exhibited a triphasic release pattern over a period of 13 days, the last fast release phase being associated with more rapid degradation of the PLGA matrix. Conclusions: Biocompatible, biodegradable PLGA microspheres incorporating alendronate sodium with high loading efficiency obtained in this study may offer promise as a delivery system for bisphosphonates in dental and probably other clinical applications.

Sildenafil citrate nanoemulsion vs. self-nanoemulsifying delivery systems: rational development and transdermal permeation

Sildenafil citrate (SC) is the first choice drug for erectile dysfunction. Nevertheless, drug oral delivery is hampered by some obstacles including first pass metabolism, numerous side effects, relatively short duration and long onset of action. Furthermore, drug delivery formulation and transdermal application of SC is challenged by its amphoteric nature, low oil and water solubility, pH-dependent characteristics and poor membrane permeability. In this paper, relevance of nanomedicine to improve SC characteristics and transdermal permeation was assessed. SC-loaded self-nanoemulsifying drug delivery system (SNEDDS) and nanoemulsions have been developed and appraised. Both nanocarriers encompassed the bioactive excipient, Cremophor RH40® as a surfactant. The nanocarriers encompassed an oil blend of Caproyl 90® and Maisine 35-1® and propylene glycol as a co-surfactant. Nanocarrier assessment was based on solubility studies, robustness to dilution, globule size analysis, cloud point measurement, transmission electron microscopy and in-vitro dialysis. Transdermal permeation study of nanocarriers and drug suspensions via human skin was performed using modified Franz diffusion assembly. SC-SNEDD system was robust to dilution in different media and folds of dilution, maintaining its nano-metric range. SC-nanoemulsion exhibited spherical shaped globules 70 nm in size. Cloud points of all dispersions formed were higher enough than 37°C. In-vitro release from both nanocarriers was significantly higher than drug suspension. Nanoemulsion elaborated could significantly enhance transdermal permeation of SC with higher initial permeation and prolonged release. Paradoxically, SC-SNEDDS exhibited scanty transdermal permeation that could be attributed to low water content of stratum corneum. Nanoemulsion and SNEDDS elaborated exhibited promising in-vitro characteristics for oral sildenafil citrate delivery whereas nanoemulsion elaborated was promising for SC transdermal permeation, as well.

Towards a universal dissolution medium for carbamazepine.

ABSTRACT The aim of this study was to develop a dissolution medium for assessment of various carbamazepine (CBZ) formulations with different strengths. The design of a system inhibiting transformation of the anhydrous CBZ (CBZ A) to the dihydrate form (CBZ D), with minimum surface-active properties and suitable sink was investigated. The effect of pH, different concentrations of sodium lauryl sulphate (SLS), polyvinylpyrrolidone (PVP), and methyl cellulose (MC) on dissolution rate, solubility, dissolution solubility, and polymorphic transformation of CBZ was assessed. Solution-mediated transformation of CBZ A into CBZ D was monitored using optical microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. Results showed that different strengths (100, 200, 400 mg) of the same CBZ tablet formulation exhibited different dissolution patterns, in 1% SLS (USP system). Such differences were reduced in 0.5% SLS solution which provided sufficient sink for up to 200 mg CBZ. It was also shown that solubility of CBZ A could not be detected in the media under study (water, SGF, SIF, and SLS solutions) due to its rapid transformation into CBZ D. The use of 3% PVP solution protected CBZ A from conversion for 75 min, while 0.01% MC completely inhibited the transformation up to 24 h. Therefore, a medium consisting of 0.5% SLS and 0.01% MC was selected. The medium provided: a) protection against transformation of CBZ A to CBZ D, b) increased solubility of CBZ A (204 mg % compared to 128 mg % of CBZ D in 0.5% SLS), c) suitable sink for up to 400 mg CBZ and d) overlapping dissolution profiles of various strengths of the same CBZ formulation. The suggested system may be a step in the way of solving CBZ dissolution problems that forced the USP to specify two similar dissolution tests with two different limits for conventional 200 mg CBZ tablets.

Preparation and In-Vitro Evaluation of Prolonged Release Tablets of Pheniramine Aminosalicylate

AbstractProlonged release tablets of pheniramine aminosalicylate were prepared from co-precipitates of the drug in different types of Eudragit. The hardness of the tablet had a pronounced effect on the release rate of the drug. Tablets (500 mg, hardness 13 kg) and 375 mg tablets (hardness 6.5 kg) prepared from the co-precipitates containing 15% of the drug in Eudragit L 100, and 20% of the drug in Eudragit S 100 respectively, showed release rate patterns that were in agreement with Lang primary requirements for drug release from sustained release tablets.Tablets (500 mg) prepared from the co-precipitates containing 15% of the drug in Eudragit L 100 or Eudragit S 100 and 375 mg tablets containing 20% of the drug in Eudragit S 100 showed release rate patterns that were best described by Higuchi equation, indicating that a diffusion controlled mechanism was mainly operative.

Assessment of a hydroalcoholic surfactant solution as a medium for the dissolution testing of phenytoin

Abstract A buffered hydroalcoholic surfactant solution has been developed as a dissolution medium for phenytoin based on a statistically designed solubility study. A compromise between acceptable composition (relatively low additive concentrations and physiologically relevant pH), sufficient phenytoin solubility at a pH lower than the drugs pKa (8.3) and potential discrimination power was considered in the design. The medium selected was a pH 6.8 phosphate buffer containing 12% alcohol and 0.4% Tween 80. Both phenytoin and phenytoin sodium bulk powder dissolved at a higher rate in the test medium relative to water (the USP medium for phenytoin sodium capsules). The medium proved sensitive to dissolution differences between phenytoin sodium samples with different content of the acid form. A linear relationship was obtained between the acid content and percent dissolution at 30 min for these samples. Further, the test medium could detect the reduction in dissolution of a phenytoin sodium sample subjected to storage conditions (1 month at 40°C and 75% R.H.) allowing partial conversion to the acid form. From a practical standpoint, these findings may be useful in assessing the in vitro performance of both phenytoin and phenytoin sodium formulations and their dissolution stability.

A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: Preparation, characterization and in vivo evaluation

ABSTRACT This work aimed at designing efficient safe delivery system for intranasal (IN) brain targeting of the water soluble anti‐ migraine drug Almotriptan malate (ALM). Solid lipid nanoparticles (SLNs) were prepared by w/o/w double emulsion‐solvent evaporation method. Selection of the optimized SLNs formula was based on evaluating particle size (PS), poly dispersity index (PDI) and entrapment efficiency (%EE). Optimized formula exhibited acceptable ranges; PS of 207.9nm, PDI of 0.41 and %EE of 50.81%. Poloxamer 407 (Plx) at different concentrations (16%, 18%, 20% w/v), with different mucoadhesive polymers (Carbopol‐974P, Na alginate, Na‐CMC) were evaluated for gelling time and temperature, pH and mucoadhesion. The chosen mucoadhesive in‐situ gel formula; 18% Plx 407 based‐0.75%w/v Na‐CMC, showed acceptable results, so that the optimized SLNs formula was further dispersed in it and evaluated for in vitro release, stability, in vivo and pharmacokinetics studies. Biomarkers’ evaluation and histopathological examination were also investigated. Results revealed rapid ALM brain delivery of the optimized formula; Brain/blood ratios at 10min. for NF (SLNs based IN in‐situ gel), ND (Free ALM IN in situ gel) and ALM i.v. (ALM IV solution) were 0.89, 0.19 and 0.31, respectively. Toxicological results confirmed the safety of NF for nasal administration. The achieved out comings are encouraging for further clinical trials of the developed system in humans in future research.