İpek Özcan

Pegylation of poly(γ-benzyl-L-glutamate) nanoparticles is efficient for avoiding mononuclear phagocyte system capture in rats.

Poly(γ-benzyl-L-glutamate) (PBLG) derivatives are synthetic polypeptides for preparing nanoparticles with well controlled surface properties. The aim of this paper was to investigate the biodistribution of pegylated PBLG in rats. For this purpose, nanoparticles were prepared by a nanoprecipitation method using mixtures of different PBLG derivates, including a pegylated derivate to avoid mononuclear phagocyte system uptake. The morphology, size distribution, and surface charge of the nanoparticles were investigated as a function of the amount of polymer employed for the preparation. Moderately polydispersed nanoparticles (polydispersity index less than 0.2) were obtained. Their size increased with polymer concentration. The zeta potential values were negative whatever the formulations. The availability of polyethylene glycol chains on the nanoparticles’ surface was confirmed by measuring the decrease in bovine serum albumin adsorption. For in vivo distribution studies, pegylated and nonpegylated nanoparticles were prepared with polymer mixtures containing PBLG-fluorescein isothiocyanate and imaged by fluorescence microscopy to measure their accumulation in liver and spleen tissues of rats after intravenous administration. Injection of stealth formulations resulted in negligible fluorescence in liver and spleen compared with nonpegylated formulations, which suggests that these nanoparticles are promising candidates as a stealth-type long-circulating drug carrier system and could be useful for active targeting of drugs while reducing systemic side effects.

Synthesis and characterization of surface‐modified PBLG nanoparticles for bone targeting: In vitro and in vivo evaluations

In this study, poly(γ-benzyl-l-glutamate) (PBLG) polypeptide derivatives were synthesized by ring-opening polymerization of amino acid N-carboxyanhydride using selected amine-terminated initiators. Alendronate, a targeting moiety that has a strong affinity for bone, was conjugated to PBLG. Monomethoxy polyethylene glycol (PEG) was used for a hydrophilic layer on the surface of the nanoparticles (NPs) to avoid reticuloendothelial system uptake. NPs were prepared by nanoprecipitation technique not only for PBLG or PBLG-PEG but also for composite polymers with different ratios. Fluorescein isothiocyanate would be attached to the NPs as a labeling agent. The size and morphology of NPs were evaluated by dynamic laser light scattering and transmission electron microscopy, and were found to be in a useful range (less than 80 nm) for bone-targeted drug delivery. In addition, the PEGylation of NPs was supported by isothermal titration calorimetry analysis. The bone-targeting potential of NPs was evaluated in vitro by calcium binding and hydroxyapatite affinity assays, and in vivo by fluorescent imaging experiments on rats. The targeted NPs showed bright fluorescent labeling in femur tissue. These results demonstrated the possibility of optimized NPs prepared with new PBLG derivatives to accumulate in bone successfully.

In vitro and in vivo evaluation of oral tablet formulations prepared with ketoconazole and hydroxypropyl-β-cyclodextrin

The objective of this study was to enhance the solubility, dissolution rate, and oral bioavailability of a very poorly water-soluble anti-fungal agent, ketoconazole (KET), by inclusion complexation with a highly-soluble cyclodextrin derivative, hydroxypropyl-β cyclodextrin (HP-β-CD). Two groups of tablets containing KET alone and KET:HP-β-CD (1:2) kneaded product (KP) including magnesium stearate and lactopress (anhydrous and spray-dried) as excipients were prepared by direct compression method. After the characterization studies, the in vitro dissolution studies of these tablets in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were carried out. To evaluate the in vivo bioavailability, the tablets were administered orally to rabbits and drug levels in serum were determined by HPLC. Tablets containing the cyclodextrin complex showed a higher in vitro dissolution rate and bioavailability compared to the tablets containing KET alone.

Comparison of PLGA and lecithin/chitosan nanoparticles for dermal targeting of betamethasone valerate.

Abstract Poly(lactide-co-glycolide) (PLGA) and lecithin/chitosan (LC) nanoparticles were prepared to evaluate the difference in the behavior upon administration on skin, for steroidal treatment. For this purpose, betamethasone-17-valerate (BMV)-loaded nanoparticles with a narrow size distribution and high entrapment efficiency were prepared. Permeation studies showed that both polymeric nanoparticles enhanced the amount of BMV in epidermis, which is the target site of topical steroidal treatment, when compared with commercial formulation. 1.58-Fold increase was determined in the epidermis concentration of BMV by LC nanoparticles with respect to PLGA nanoparticles. Nanoparticles were diluted in chitosan gel (10%, w/w) to prepare suitable formulation for topical application. Accumulation from both gel formulations were found significantly higher than commercial formulation in skin layers (p < 0.05). In addition, pharmacodynamic responses were also investigated as anti-inflammatory and skin-blanching parameters. Both formulations significantly improved these parameters although they contained 10 times less amount of BMV than commercial cream. Moreover, TEWL measurement exhibited no barrier function changes upon the application of nanoparticles on skin. Overall, both nanoparticles improved the localization of BMV within skin layers; but when compared with PLGA nanoparticles, the LC nanoparticles could be classified as a better candidate for topical delivery vehicle in the treatment of various dermatological inflammatory diseases.

Design of polyethylene glycol-polyethylenimine nanocomplexes as non-viral carriers: mir-150 delivery to chronic myeloid leukemia cells

MicroRNAs (miRNAs) are acknowledged as indispensable regulators relevant in many biological processes, and they have been pioneered as therapeutic targets for curing disease. miRNAs are single‐stranded, small (19–22 nt) regulatory non‐coding RNAs whose deregulation of expression triggers human cancers, including leukemias, mainly through dysregulation of expression of leukemia genes. miRNAs can function as tumour suppressors (suppressing malignant potential) or oncogenes (activating malignant potential) like actors of complex diseases. To address the issue of overcoming instability and low transfection efficiency in vitro, the polyethylene glycol–polyethyleneimine (PEG–PEI) nanoparticle was used as non‐viral vector carrier for miR‐150 transfection, which is downregulated in chronic myeloid leukemia. PEG–PEI [PEG(550)3‐g‐PEI(1800)]/miRNA nanocomplexes were synthesised and characterised by particle size distribution (PSD), polydispersity index (PDI) and zeta potential, surface charge, their cytotoxicity, and transfection efficiency. Interaction with human leukemia cells (K‐562 and KU812) and control cells NCI‐BL2347 with them has been investigated. The transfection efficiency of PEG–PEI/miRNA at N/P 26 rose 6.7‐fold above the control by qRT‐PCR. The size of homogenous nanocomplexes (PBI < 0.5) was 160.8 ± 11 nm. The data indicate that PEG–PEI may be an encouraging non‐viral carrier for altering miRNA expression in the treatment of chronic myeloid leukemia, with many advantages such as relatively high miRNA transfection efficiency and low cytotoxicity.

The Absorption of 99mTc-alendronate Given by Rectal Route in Rabbits

Alendronate sodium (ALD) is a bisphosphonate medication used in the treatment and prevention of osteoporosis. Absorption of ALD as oral formulation is very poor (0.5%–1%). Its bioavailability can decrease with food effect. It has some gastrointestinal adverse effects such as gastritis, gastric ulcer, and esophagitis. The aim of this study was to develop a rectal formulation of ALD as an alternative to oral route and to investigate the absorption of it by using gamma scintigraphy. For this reason, ALD was labeled with Technetium-99m (99mTc) by direct method. The radiochemical characterization of the 99mTc-ALD was carried out by paper chromatography, thin layer chromatography, and electrophoresis methods. The labeling efficiency of 99mTc-ALD was found 99% without significant changes until 6 h postlabeling at room temperature. The rectal suppositories containing 99mTc-ALD were prepared by fusion method using polyethylene glycol (PEG) 1500. The 99mTc-labeled ALD suppositories were administrated to rabbits by rectal route. Serial scintigrams over all bodies of the rabbits were obtained at different time intervals using a gamma camera. We found that the rectal absorption of 99mTc-ALD from suppository formulation was possible. According to our results, this formulation of ALD can be suggested for the therapy of osteoporosis as an alternative route.

The Preparation and Evaluation of Sustained Release Suppositories Containing Ketoprofen and Eudragit RL 100 by Using Factorial Design

The preparation of ketoprofen (KP) sustained release (SR) suppositories was designed according to the 32 × 21 factorial design as three different KP:Eudragit RL 100 ratios (1:0.5, 1:1, 1:2), three particle sizes of prepared granules (250–500, 500–710, and 710–1000 μm) and two different PEG 400:PEG 6000 ratios (40:60, 50:50). The conventional KP suppositories were also prepared by using Witepsol H 15, Massa Estarinum B, Cremao and the mixture of PEG 400:PEG 6000. The dissolution studies of suppositories prepared were carried out according to the USP XXIII basket method in the phosphate buffer (pH = 7.2) at 50 rpm, and it was shown that the dissolution time was sustained up to 8 hours. According to the results of the factorial design, the most important independent variable on t50 and t80 was drug:polymer ratios. The log of partition coefficient of KP was determined as 1.46, showing the high affinity to the oily phase. n exponent and kinetic studies were conducted to explain diffusion mechanism, and it is understood that if the inert KP:Eudragit RL 100 ratio is increased in the particles, the Fickian difusion dominates and the best kinetic turns to Higuchi from the Hixson-Crowell. There is neither crystalline form of KP nor degradation product in the suppositories detected with the differential scanning calorimetry (DSC) studies. In addition to these studies, antiinflammatory activity of SR suppositories also determined that it was significantly extended according to the conventional suppositories.

Evaluation of in vitro release and skin irritation of benzoyl peroxide-containing products

Abstract Benzoyl peroxide (BPO) has been known as a highly effective topical agent in acne vulgaris therapy for a long time. It induces an irritant dermatitis with erythema and scaling. Therefore, the aim of this study was to formulate BPO containing w/o/w multiple emulsion and gel formulations with and without chitosan microparticles to decrease skin irritation and to compare the release profiles through cellulose acetate, cellophane membranes and excised rat skin. A commercial preparation was also used and the similarities between commercial and experimental formulations were assessed by difference factor (f). The release results indicated that gel base exhibited a higher drug release than the other experimental formulations (p

Innovative topical formulations for treatment of dermatitis.

The treatment of dermatitis with conventional dosage forms (ointment, cream, lotion etc.) has many concerns due to side effects especially in long-term therapy. Recent studies focused on strategies to optimize the potency of formulation while minimizing side effects. Several attempts have been made to increase the safety of treatment, including special vehicles (nanoparticle, liposome, patch etc.), combined therapy and new synthesized agents. This review provides major innovations and advances of new approaches for dermatitis treatment based on the published articles and patent applications.