A. Abd El-Bary

Improving the dissolution and bioavailability of nifedipine using solid dispersions and solubilizers.

ABSTRACT Nifedipine (NF) is a poorly water-soluble drug, of low and irregular bioavailability after oral administration. Although some reports have attempted to improve the dissolution of NF using solid dispersions and solubilizers, little literature information is available on the in vivo performance of such preparations. The aim of the present work was to improve the therapeutic efficacy of NF via incorporation into different types of carriers, and to investigate their in vitro dissolution and bioavailability in rabbits. Nifedipine solid dispersions were prepared by fusion, solvent, and freeze-drying methods with polyethylene glycol (PEG) 6000 and PEG monomethylether 5000 (PEG MME 5000). Complexation of NF with β-cyclodextrin (β-CyD) and solubilization by sodium lauryl sulfate (SLS) have also been studied. The dissolution was determined by the flow-through cell in order to maintain perfect sink conditions. The solid dispersions resulted in a significant increase in the dissolution rate as compared to pure drug. The highest NF dissolution rate was obtained from solid dispersions containing 95% PEG 6000 prepared by the solvent method. While, unexpectedly, the highest absorption in rabbits was obtained from 95% PEG 6000 prepared by the fusion method. Compared to SLS, β-CyD gave higher in vitro and in vivo values. Differential scanning calorimetry (DSC) and powder x-ray diffractometry indicated that NF in solid dispersions is homogeneously distributed, and no drug crystallized out of the system. The DSC thermograms of NF-β-CyD complex and NF/SLS solid mixture showed a decrease in the NF endothermic peak. The x-rays showed different diffraction patterns of pure NF and pure carrier, suggesting the formation of a new solid form.

Enhancement of carbamazepine dissolution : in vitro and in vivo evaluation

Abstract The absorption of carbamazepine (CBZ) is characterized by being dissolution-rate limited. Thus improvement of its dissolution characteristics may increase its rate and extent of absorption, hence its oral bioavailability. The objective of the work is to enhance the dissolution of CBZ, through utilizing different carriers [polyethylene glycols (PEG), phospholipids, and hydroxypropyl- β -cylcodextrin (HP β CD)]. The prepared systems were evaluated in vitro through dissolution testing, X-ray diffraction, and differential thermal analysis (DTA). The screened lead systems were further evaluated in vivo using the rabbit as an animal model. In vitro results showed that the dissolution of CBZ was profoundly enhanced from (1:2) CBZ/PEG 6000 solid dispersion, (10:1) CBZ/ l - α -dimyristoyl phosphatidyl glycerol coprecipitate, and (1 M:1 M) CBZ/HP β CD complex. X-Ray diffraction and DTA were used to explain any interaction and/or complexation between CBZ and the different carriers. For in vivo evaluation, a parallel design with four groups was adopted, with each group receiving the equivalent of 100 mg CBZ either as one of the three lead prepared systems suspended in water or as Tegretol® suspension, the reference standard. Serial blood samples were drawn over 24 h from the marginal ear vein, and plasma samples were analyzed for CBZ and its active metabolite, carbamazepine-10,11-epoxide, CBZE, by HPLC. The in vivo results showed that the extent of absorption of CBZ from its HP β CD complex was the highest among the systems tested. For all prepared systems, areas under the CBZE concentration–time curve were significantly higher than that resulting after Tegretol® suspension. This may be explained by the fact that CBZ is being presented from the Tegretol® suspension at a slower rate, with absorption occurring further down the intestine, thus bypassing the liver.

REVERSED PHASE LIQUID CHROMATOGRAPHIC DETERMINATION OF VINPOCETINE IN HUMAN PLASMA AND ITS PHARMACOKINETIC APPLICATION

ABSTRACT A simple, rapid specific and reliable high performance liquid chromatographic assay of vinpocetine in human plasma has been developed. Reversed phase chromatography was conducted using a mobile phase of methanol : water (80 : 20 v/v), containing 0.1% triethylamine, pH 7, adjusted with glacial acetic acid. The flow rate was 2 mL/min, UV detection at 274 nm. The drug after extraction from plasma was chromatographed using a C18 reversed–phase column. The average recoveries of vinpocetine from spiked plasma in the concentration range from (0.01–0.1) µg/mL was 91.83% and the coefficient of variation was 3.03%. Regression analysis for the calibration plot for plasma standards obtained on three different days for the drug concentrations between (0.01–0.1) µg/mL indicated excellent linearity (r>0.999) and the coefficient of variation of the slopes of the three lines was <2%. Analysis of variance of the data showed no detectable difference in the slopes of the three standard plots (F = 3.2, P>0.01). The high correlation coefficients and the similarities in the slopes are good indication of the excellent reproducibility and linearity of the proposed method. The proposed method was applied to study the bioequivalence of a commercial product of vinpocetine using as reference standard the innovator drug product. The study was conducted on using two tablets (2 × 5 mg) of each of the commercial product and the reference standard in a two way open randomized crossover design involving twenty four volunteers. The criteria used to assess bioequivalence of the products were AUC (0–∞), C max, t max, t 1/2 and K. The obtained values for these parameters were 519.8 ± 8.2 ng h/mL, 64.3 ± 1.6 ng/mL, 1.5 h, 2.09 ± 0.27 h and 0.34 ± 0.04 h−1 for product A whereas, for product B they were, 514.6 ± 10.7 ng h/mL, 63.5 ± 1.3 ng/mL, 1.5 h, 2.2 ± 0.35 h and 0.32 ± 0.04 h−1 respectively.

REVERSED PHASE LIQUID CHROMATOGRAPHIC DETERMINATION OF MELOXICAM IN HUMAN PLASMA AND ITS PHARMACOKINETIC APPLICATION

A simple, rapid, specific and reliable high performance liquid chromatographic assay of meloxicam in human plasma has been developed. Reversed phase chromatography was conducted using a mobile phase of methanol:phosphate buffer (60:40) V/V, pH 3.2, adjusted with phosphoric acid, UV detection at 346 nm. The drug after extraction from plasma was chromatographed using a C18 reversed phase analytical column. The average recoveries of Meloxicam from spiked plasma in the concentration range from (0.04–0.8) μg/ml was 93.33% and their respective CV was 2.86%. Regression analysis for the calibration plot for plasma standards obtained on three different days for the drug concentrations between (0.04–0.8)μg/ml indicated excellent linearity (r > 0.9996) and the coefficient of variation of the slopes of the three lines was < 2%. Analysis of variance of the data showed no detectable difference in the slopes of the three standard plots (F = 2.9, P > 0.01). The high correlation coefficients and the similarities in the slopes are good indication of the excellent reproducibility and linearity of the proposed method. The proposed method was applied to study the bioequivalence of a commercial product of meloxicam using as reference standard the innovator drug product. The study was conducted on using two tablets (2 × 7.5 mg) of each of the commercial product and the reference standard in a two-way open randomized crossover design involving twelve volunteers. The criteria used to assess bioequivalance of the two products were AUC(0 − ∞), Cmax, Tmax, t1/2 and K. The obtained values for these parameters were 4.225 ug.hr/ml, 0.711 ug/ml, 2.5 hour, 1.827 hour and 0.364 hr−1 for product A. Whereas for product B they were, 4.18 ug.hr/ml, 0.683 ug/ml, 2.5 hour, 0.407 hour and 0.303 hour−1.

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%.

Controlled Crystallization of Chlorpropamide from Surfactant and Polymer Solutions

AbstractChlorpropamide crystals were prepared by recrystallization technique from alcoholic solution of Polysorbate 80, Polyethylene Glycol and Polyvinyl-pyrrolidone. Marked enhancement in the dissolution rate of the formed crystals was observed. The enhancement was found to be a function of molecular weight of the polymer used Thus the percentage drug dissoluted after three hours at 10% polymer concentration was found to be 37, 41 and 55% for Polyvinylpyrrolidone K30 K64 and K90 respectively, and 27, 31, 32% for Polyethylene Glycol 4000, 6000, and 20000 respectively. This may be due to possible solubilization effect of the surfactant and polymers. Also solution of the polymer may produce an ultrafine crystals of the drug, mainly due to the difficulty of growth of the crystals in highly viscous medium of the polymer. Infrared study revealed that no polymorphic change or complex formation had occurred.

Radioiodinated acebutolol as a new highly selective radiotracer for myocardial perfusion imaging

Acebutolol was successfully labeled with (125) I via direct electrophilic substitution reaction. Radioiodinated acebutolol was prepared with a maximum radiochemical yield of 96.5 ± 0.3% and in vitro stability up to 72 h. The in vivo biological distribution of radioiodinated acebutolol showed high heart uptake of 37.8 ± 0.14% injected activity/g organ with low lungs and liver uptakes at 5 min post-injection. In vivo receptor blocking study was carried out in mice to evaluate its selectivity to heart. Radioiodinated acebutolol showed fast heart accumulation with high heart/liver ratio, which provides the ability for fast myocardial imaging with significant decrease in the radiation hazards risk on patients. So, radioiodinated acebutolol could be displayed as a radiotracer drug of choice in case of emergency patients for myocardial perfusion imaging.

Formulation and Characterization of Nystatinloaded Nanostructured Lipid Carriers for Topical Delivery against Cutaneous Candidiasis.

Aims: The objective of the current study was to formulate nystatin (Nyst) into nanostructured lipid carriers (NLCs) to enhance its antifungal activity. Place and Duration of Study: Department of pharmaceutical technology, national research centre, Egypt, between mars 2011 to april 2013 Methodology: Nyst loaded NLCs (NYST-NLCs) were prepared by the hot homogenization and ultrasonication method followed by evaluation of its topical effect on Original Research Article British Journal of Pharmaceutical Research, 4(4): 490-512, 2014 491 the cutaneous candidiasis. The prepared Nyst-NLCs were characterized for entrapment efficiency, particle size, zeta potential, morphology (transmission electron microscopy), thermal characterisation (differential scanning calorimetry) and in vitro drug release. The study design involves the investigation of the effect of three independent variables namely liquid lipid type (Miglyol 812 and Squalene), liquid lipid concentration (30 and 50%) and Nyst concentration (0.125 and 0.25%). A stability study for 6 months was performed. A microbiological study was conducted in male rats infected with Candida albicans. Results: NLC dispersions were spherical in shape with particle size ranging from 68.06±6.56 to 141.8±3.33 nm. The entrapment efficiencies ranged from 45.50±2.34 to 92.73±0.33% with zeta potential ranging from -26.2 to -39.2 mV. The stability studies done for 6 months indicated that Nyst-NLCs were stable for more than 6 monthes.the microbiological studies showed A least number of colonies forming units (cfu/ml) were recorded for the selected Nyst-NLCs compared to the drug solution and the Nystatin® cream present in the market. Conclusion: It can be fulfilled from this work that NLCs represent promising carrier for topical delivery of Nyst offering good physical stability, high entrapment efficiency and controlled drug release. Nyst-NLCs are a good candidate for cutaneous treatment of fungal infection.

SOLID LIPID NANOPARTICLES FOR TOPICAL DELIVERY OF MELOXICAM: DEVELOPMENT AND IN VITRO CHARACTERIZATION

Isolated NPCs are able to proliferate in response to basic fibroblast growth factor and when the culture conditions are altered means addition of BDNF and NT-3, they differentiate into several phenotypes of neurons. Fabricated PCL with 10% sucrose and 10% PEG 4000 scaffold shown good proliferation rate upto 14 days while PCL with 5% sucrose shown to promote good cells attachement and survival rate more than 21 days this may be due to pore size & pore number.

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.