Nilufer Yuksel

Comparison of in vitro dissolution profiles by ANOVA-based, model-dependent and -independent methods.

In this study, the aim was to apply different comparison methods to dissolution profiles of immediate release commercial film-coated tablets of naproxen sodium in order to (1) evaluate each method in terms of easy application and usefulness and (2) identify the advantages and disadvantages of each method. Dissolution testing was conducted using the USP monograph of naproxen sodium. The applied methods for the comparison of in vitro dissolution profiles are ANOVA-based methods, model-dependent methods, and model-independent methods including difference factor, f(1), and similarity factor, f(2). All the methods appear to be applicable and useful in comparing dissolution profiles. The results show that ANOVA-based methods and model-dependent methods are more discriminative than the f-factors. f-Factors seem to be easier to apply and interpret; only one value is obtained to describe the closeness of the two dissolution profiles. However, a last point for dissolution had to be determined, since the values of the f-factors depend on this point. The application and evaluation of model-dependent methods are more complicated; these methods present an acceptable model approach to the true relationship between percent dissolved and time variables, including statistical assumptions which could be checked. Dissolution profiles can be tested for differences in both level and shape by ANOVA-based methods and these methods provide detailed information about dissolution data which can be useful also in formulation development to match release to a reference product.

Enhanced bioavailability of piroxicam using Gelucire 44/14 and labrasol: in vitro and in vivo evaluation.

Piroxicam is a non-steroidal anti-inflammatory drug that is characterized by low solubility and high permeability. The purpose of the study was to investigate the in vitro and in vivo performance of the semi-solid dispersion prepared with Gelucire 44/14 and Labrasol into hard gelatin capsules (GL) for enhancing the dissolution rate of the drug. The results were evaluated by comparing with pure piroxicam filled into hard gelatin capsules (PP) and a commercially available tablet dosage form containing a piroxicam:beta-cyclodextrin complex (CD). The in vitro dissolution testing of the dosage forms was performed in different media (simulated gastric fluid, pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). Amongst the dosage forms, GL provided at least 85% piroxicam dissolution within 30 min in each of the media, behaving like a fast-dissolving immediate release drug product. Oral bioavailability of 20 mg piroxicam in GL, CD, and PP was compared after administration of a single dose to eight healthy volunteers. Three treatments were administered in crossover fashion, separated by a washout period of 2 weeks. Piroxicam was monitored in plasma by high-performance liquid chromatography. The apparent rate of absorption of piroxicam from GL (Cmax=2.64 micrograms/ml, tmax=82.5 min) was significantly higher than that of the PP (Cmax=0.999 micrograms/ml, tmax=144 min) (P<0.05) and similar to that of CD (Cmax=2.44 micrograms/ml, tmax=120 min) (P>0.05). The relative bioavailability values as the ratios of mean total AUC for GL relative to PP and CD, were 221 and 98.6%. Piroxicam is characterized by a slow and gradual absorption via the oral route and this causes a delayed onset of therapeutic effect. Thus, plain piroxicam preparations are not indicated for analgesia. The results of the in vivo study revealed that the GL dosage form would be advantageous with regards to rapid onset of action, especially in various painful conditions where an acute analgesic effect is desired.

Characterization of niosomes prepared with various nonionic surfactants for paclitaxel oral delivery

Nonionic surfactant based vesicles (niosomes) are novel drug delivery systems formed from the self-assembly of nonionic amphiphiles in aqueous media. In the present study niosomal formulations of Paclitaxel (PCT), an antineoplastic agent, were prepared using different surfactants (Tween 20, 60, Span 20, 40, 60, Brij 76, 78, 72) by film hydration method. PCT was successfully entrapped in all of the formulations with encapsulation efficiencies ranging between 12.1 +/- 1.36% and 96.6 +/- 0.482%. Z-average sizes of the niosomes were between 229.3 and 588.2 nm. Depending on the addition of the negatively charged dicetyl phosphate to the formulations negative zeta potential values were obtained. High surface charges showed that niosomes can be suspended in water well and this is beneficial for their storage and administration. PCT released from niosomes by a diffusion controlled mechanism. The slow release observed from these formulations might be beneficial for reducing the toxic side effects of PCT. The niosome preparation method was found to be repeatable in terms of size distribution, zeta potential and % drug loading values. The efficiency of niosomes to protect PCT against gastrointestinal enzymes (trypsin, chymotrypsin, and pepsin) was also evaluated for PCT oral delivery. Among all formulations, gastrointestinal stability of PCT was well preserved with Span 40 niosomes.

Interaction between nicardipine hydrochloride and polymeric microspheres for a controlled release system

The microspheres containing nicardipine hydrochloride (NCH) were prepared by the solvent evaporation method using acrylic polymers, Eudragit RS and L. The results of the release experiments with microspheres proposed that there should exist an interaction between NCH and the acrylic polymers. The mechanism of this interaction was investigated by differential scanning calorimetry (DSC) and powder X-ray diffractometry (XRD). These analysis indicated that NCH and polymers interact at the molecular level, possibly NCH forming a solid solution with polymers. Furthermore, the formulations ended with a solid solution between NCH and acrylic polymers and their blends made possible the preparation of controlled release microspheres to retard and to enhance drug release rate at pH 1.2 and 7.5, respectively.

Investigation of triacetin effect on indomethacin release from poly(methyl methacrylate) microspheres: Evaluation of interactions using FT-IR and NMR spectroscopies

The purpose of this study was to form indomethacin (IND)-loaded poly(methyl methacrylate) (PMMA) microspheres having an extended drug release profile over a period of 24h. Microspheres were prepared by solvent evaporation method using sucrose stearate as a droplet stabilizer. When PMMA was used alone for the preparation of microspheres, only 44% of IND could be released at the end of 8h. Triacetin was added to PMMA, as a minor phase, and the obtained microspheres showed a high yield process with recovery of 89.82% and incorporation efficiency of 102.3%. A desired release profile lasting 24h was achieved. Differential scanning calorimetry (DSC) analysis showed that IND was found to be in an amorphous state in the microspheres. Fourier transform infrared (FT-IR) and nuclear magnetic resonance ((1)H NMR) spectra suggested that there might be a hydrogen bond present between the IND hydroxyl group and PMMA. No interaction between triacetin and IND or PMMA as the formation of secondary bonds was observed. The release enhancement of IND from microspheres was attributed to the physical plasticization effect of triacetin on PMMA and, to some extent, the amorphous state of the drug.

Preparation of polymeric microspheres by the solvent evaporation method using sucrose stearate as a droplet stabilizer

Polymeric microspheres containing nicardipine hydrochloride (HCl) as a reference drug were prepared with the acrylic polymers Eudragit RS and L by the solvent evaporation method. Different concentrations of sucrose stearate as a droplet stabilizer were used. Sucrose stearate affected the diffusion rate of the solvent from the preliminary emulsion droplets to the outer phase for the formation of microspheres. Increasing concentrations of sucrose stearate in the formulations caused increasing porosity on the surface of the microspheres. However, a correlation between the concentrations of sucrose stearate and diameters of microspheres could not be assessed. From this point of view, during processing, applied stirring rate was important.

Preparation and characterization of poly(D,L-lactic-co-glycolic Acid) microspheres containing flurbiprofen sodium.

This study aimed to prepare biodegradable microspheres containing flurbiprofen sodium, a nonsteroidal anti-inflammatory drug (NSAID), as the drug delivery system to the periodontal pocket. Microspheres were prepared from biodegradable copolymers of poly (D,L-lactic-co-glycolic acid) (PLGA) using solvent evaporation method. The effects of the different copolymers and amounts of polyvinyl alcohol (PVA) as a dispersing agent on characteristics of the microspheres were evaluated. Although there was no correlation between microsphere size and amount of PVA, an optimum PVA concentration was essential to achieve narrower size distributions of microspheres. As the concentration of PVA increased, the drug loading of the microspheres increased. The effect of PVA on drug loading was found to be statistically significant for those microspheres prepared from PLGA 50:50 (p < 0.05). Regarding copolymer composition, PLGA 85:15 provided higher drug loading into the microspheres than PLGA 50:50 (p < 0.05). The recoveries of microspheres (60–80%) were affected neither by different PVA concentrations nor by copolymer compositions (p > 0.05). According to the first-order release rate constants of the microspheres, the microspheres of PLGA 50:50 released the drug at the highest rate consistently, with the highest hydrophilicity of this copolymer.

Development and Characterization of Mixed Niosomes for Oral Delivery Using Candesartan Cilexetil as a Model Poorly Water-Soluble Drug

The aim of this study was to prepare candesartan cilexetil-loaded niosomes and mixed niosomes to enhance the aqueous solubility of the drug, thus improving its oral bioavailability. The formulations were prepared using various types and combinations of surfactants, copolymers, and charge-inducing agents. The candesartan cilexetil entrapment efficiency, particle size, and zeta potential of these niosomes varied within the range of 99.06 ± 1.74 to 36.26 ± 2.78, 157.3 ± 3.3 to 658.3 ± 12.7 nm, and −14.7 ± 2.8 to −44.5 ± 1.5 mV, respectively. The in vitro drug release from niosomes was improved after niosomal entrapment compared to pure candesartan cilexetil. The sedimentation behavior study and formulation stability tests against bile salt revealed that mixed niosomes prepared by combining Span 60 and Pluronic P85 demonstrated better stability. The differential scanning calorimetry analysis showed the conversion of crystal structure of candesartan cilexetil to the soluble amorphous form after niosomal encapsulation which induced the drug release. Consequently, oral drug delivery by Span 60/Pluronic P85-mixed niosomes seems feasible due to enhanced drug release and stability.

Effect of different dispersing agents on the characteristics of Eudragit microspheres prepared by a solvent evaporation method.

Eudragit RS microspheres containing verapamil HCl for oral use were prepared using three different dispersing agents: aluminium tristearate, magnesium stearate and sucrose stearate, by a solvent evaporation method. The effects of the type and concentration of the dispersing agents and the inner phase polymer concentration on the size and T63.2% (the time at which 63.2% of the drug is released) of microspheres were determined by multiple linear regression analysis. The morphology of microspheres was characterized by scanning electron microscopy. The surface of microspheres prepared with sucrose stearate was smoother and non-porous and the drug release from these microspheres was the fastest. When aluminium tristearate or magnesium stearate were used as dispersing agents, the particle size of microspheres became smaller. Increasing amounts of these two dispersing agents led to the accumulation of their free particles onto the surfaces of the microspheres. The drug release from the microspheres was slower than that of the microspheres from sucrose stearate depending on their hydrophobic structures. According to the results of the multiple linear regression analysis among the dispersing agents used, aluminium tristearate showed the best correlation between the examined input (dispersing agent and polymer concentrations) and output (T63.2% and particle size) variables.

Niosomes encapsulating paclitaxel for oral bioavailability enhancement: preparation, characterization, pharmacokinetics and biodistribution

Abstract In this study, niosome formulations were prepared and evaluated for their effects on improving the oral bioavailability of paclitaxel (PCT). Niosomes were prepared from Span 40 and coated with bioadhesive carbopol polymers. The niosomes encapsulated 98.7% ± 0.8 of the initially added PCT and their size ranged from 133 ± 6 nm to 320 ± 6 nm. The stability of Carbopol 974P coated niosomes in bile salts was better than uncoated niosomes. Extended release of PCT was observed. After oral administration of formulations to Wistar rats, higher drug plasma concentrations were observed for niosomes comparing to PCT suspension. The high PCT accumulation in intestine and liver obtained after Carbopol 974P coated niosomes administration indicated their potential regarding effective treatment of localized carcinomas in intestine and liver. The relative bioavailability of PCT was increased 3.8- and 1.4-fold by uncoated and Carbopol 974P coated niosomes emphasizing the ability of niosomes on improving the oral bioavailability of PCT.