Sevgi Takka

Calcium alginate microparticles for oral administration : I : Effect of sodium alginate type on drug release and drug entrapment efficiency

The natural polymers alginate and chitosan were used for the preparation of controlled release nicardipine HCl gel microparticles. The effect of the mannuronic/guluronic acid content and the alginate viscosity on the prolonged action of the microparticles, which were prepared with different types of alginates, were investigated. The mean particle sizes and the swelling ratios of the microparticles were also determined. The in vitro release studies were carried out with a flow-through cell apparatus in different media (pH 1.2, 2.5, 4.5, 7 and 7.5 buffer solutions). The release of nicardipine was extended with the alginate gel microparticles prepared with guluronic acid rich alginate. After the determination of the most appropriate alginate type, the effect of alginate-chitosan complex formation was studied on the release pattern of drug incorporated. It was observed that the alginate-chitosan complex formation reduced the erosion of the alginate-chitosan matrix at pH 7-7.5. The release of drug from the chitosan-alginate gel microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH 1.2-4.5.

Calcium alginate microparticles for oral administration: II. Effect of formulation factors on drug release and drug entrapment efficiency.

The release rate of nicardipine HCl from various alginate microparticles was investigated. Manugel A7B618 which has a high guluronic acid content of 70% and a low polymerization degree of 60-400 was used as alginate. A 2(3) factorial design was utilized for the preparation of the alginate microparticles. The effect of drug:polymer weight ratio, CaCl2 concentration and curing time on parameters such as the time for 50% of the drug to be released (t50%) and the drug entrapment efficiency were evaluated with analysis of variance. The mean particle sizes and the swelling ratios of the microparticles were determined. The in vitro release studies were carried out with a flow-through cell apparatus at different media (pH 1.2, 2.5, 4.5, 7, 7.5 buffer solutions). Drug:polymer weight ratio and the concentration of the crosslinking agent were the influential factors on the release of NC from the alginate microparticles. The release of nicardipine was extended with alginate microparticles prepared in a ratio of 1:1 (drug:polymer weight ratio). The release of drug from alginate microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH: 1.2-4.5. However, the release was due to diffusion and erosion mechanisms at pH 7-7.5.

Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets

Anionic polymers, namely Eudragit S, Eudragit L 100-55, and sodium carboxymethylcellulose, were incorporated into hydroxypropylmethylcellulose (HPMC K100M) to modify the drug release from HPMC matrices. The effects of changing the ratio of HPMC to anionic polymers were examined in water and in media with different pH. The dissolution profiles were compared according to release rates. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate buffer.

Formulation and investigation of nicardipine HCl-alginate gel beads with factorial design-based studies.

The release rate of nicardipine HCl from various alginate gel bead formulations was investigated. The formulations were prepared by utilizing 23 factorial design. The effect of drug:polymer weight ratio, CaCl2 and sodium-alginate concentration on the time for 50% of the drug to be released (t50%) and the drug entrapment efficiency were evaluated with analysis of variance. The mean particle size and the swelling ratio of the beads were determined. The in vitro release studies were carried out by flow-through cell apparatus in different media (pH 1.2, 2.5, 4.5, 7 and 7.5 buffer solutions). Drug:polymer weight ratio and the interaction of drug:polymer weight ratio and CaCl2 concentration had a significant effect on the drug entrapment efficiency. The release of nicardipine was extended with the alginate gel beads, which were prepared in a ratio of 1:1 (drug:polymer). The release of drug from alginate gel beads took place both by diffusion through the swollen matrix and relaxation of the polymer at pH 1.2-4.5. However, the release was due to the diffusion and erosion mechanism at pH 7-7.5.

In-vitro and In-vivo Evaluation of Mesalazine–Guar Gum Matrix Tablets for Colonic Drug Delivery

The aim of this study was to develop colon-specific delivery systems for mesalazine (5-ASA) using guar gum as a carrier. A colon specific matrix tablet of mesalazine with guar gum was evaluated by in vitro and in vivo X-ray studies in humans. Two different types of guar gum were used in the experiments. Tablets were prepared by the slugging method. The physical properties of tablets were tested and in vitro release studies were performed by a flow-through cell apparatus with and without galactomannanase enzyme. The type and the amount of guar gum affected the in vitro release of drug from the matrix tablets. High viscosity guar gum, in the form of a matrix tablet was capable of protecting the drug from being released in the upper region of gastrointestinal (GI) system, i.e. stomach and small intestine. X-ray imaging technique was used to monitor the tablets throughout the GI system on 8 healthy volunteers. Barium sulphate was used as a marker in the tablets for in vivo studies. These results showed that, the matrix tablets reached the colon; not being subjected to disintegration in the upper region of the GI system in all the subjects.

Bile salt-reinforced alginate-chitosan beads

A polymeric delayed release protein delivery system was investigated with albumin as the model drug. The polysaccharide chitosan was reacted with sodium alginate in the presence of calcium chloride to form beads with a polyelectrolyte. In this study, attempts were made to extend albumin release in the phosphate buffer at pH 6.8 from the alginate-chitosan beads by reinforcing the matrix with bile salts. Sodium taurocholate was able to prevent albumin release at pH 1.2, protecting the protein from the acidic environment and extending the total albumin release at pH 6.8. This effect was explained by an interaction between the permanent negatively charged sulfonic acid of sodium taurocholate with the amino groups of chitosan. Mild formulation conditions, high bovine serum albumin (BSA) entrapment efficiency, and resistance to gastrointestinal release seem to be synergic and promising factors toward the development of an oral protein delivery form.

Gemcitabine hydrochloride-loaded liposomes and nanoparticles: comparison of encapsulation efficiency, drug release, particle size, and cytotoxicity

Abstract The aim of this study is to formulate and compare the physicochemical properties of negatively charged liposomes and poly(lactide-co-glycolide) (PLGA) nanoparticles loaded with gemcitabine hydrochloride. The influence of the formulation variables on the liposome and nanoparticle properties on particle size, zeta potential, encapsulation efficiency, and drug release was evaluated. Although the PEGylated nanoparticles and PEGylated liposomes were of the same size (∼200 nm), the encapsulation efficiency was 1.4 times higher for PEGylated liposomes than for PEGylated nanoparticles. The optimized formulation of PEGylated liposomes and PEGylated nanoparticles had 26.1 ± 0.18 and 18.8 ± 1.52% encapsulation efficiency, respectively. The release of drug from the PEGylated liposomes and PEGylated nanoparticles exhibited a biphasic pattern that was characterized by a fast initial release during the first 2 h followed by a slower continuous release. Transmission electron microscopy (TEM) images identified separate circular structures of the liposomes and nanoparticles. The in vitro cytotoxicity of the optimized formulations was assessed in MCF-7 and MDA-MB-231 cells, and the results showed that the cytotoxicity effect of the gemcitabine hydrochloride-loaded liposomes and nanoparticles was more than commercial product Gemko® and gemcitabine hydrochloride solution.

Development and characterization of gemcitabine hydrochloride loaded lipid polymer hybrid nanoparticles (LPHNs) using central composite design

ABSTRACT Lipid polymer hybrid nanoparticles (LPHNs) combine the characteristics and beneficial properties of both polymeric nanoparticles and liposomes. The objective of this study was to design and optimize gemcitabine hydrochloride loaded LPHNs based on the central composite design approach. PLGA 50:50/PLGA 65:35 mass ratio (w/w), soya phosphatidylcholine (SPC)/polymer mass ratio (%, w/w) and amount of DSPE‐PEG were chosen as the investigated independent variables. The LPHNs were prepared with modified double emulsion solvent evaporation method and characterized by testing their particle size, encapsulation efficiency, and cumulative release. The composition of optimal formulation was determined as 1,5 (w/w) PLGA 50:50/PLGA 65:35 mass ratio, 30% (w/w) SPC/polymer mass ratio and 15mg DSPE‐PEG. The results showed that the optimal formulation gemcitabine hydrochloride loaded LPHNs had encapsulation efficiency of 45,2%, particle size of 237nm and cumulative release of 62,3% at the end of 24h. The morphology of LPHNs was found to be spherical by transmission electron microscopy (TEM) observation. Stability studies showed that LPHNs were physically stable until 12months at 4°C and 9months at 25°C/60% RH. The results suggest that the LPHNs can be an effective drug delivery system for hydrophilic active pharmaceutical ingredient.

Development and in vitro evaluation of pH-independent release matrix tablet of weakly acidic drug valsartan using quality by design tools

Abstract The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a ‘One factor at a time (OFAT)’ approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools.