Eczacılık Fakültesi / Faculty of Pharmacy
Permanent URI for this collectionhttps://hdl.handle.net/11727/5700
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Item Ritonavir Nanosuspensions Prepared By Microfluidization With Enhanced Solubility And Desirable Immunological Properties(2022) Karakucuk, Alptug; Canpinar, Hande; Celebi, Nevin; https://orcid.org/0000-0002-6402-5042; 35924723The objective of this study was to develop ritonavir (RTV) nanosuspensions (NSs) by microfluidization method. Particle size (PS) measurements were performed by photon correlation spectroscopy. Amorphous properties of the particles were evaluated by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The dissolution studies were conducted in fed state simulated intestinal fluid (FeSSIF) medium. The flow cytometry was utilized to determine the lymphocyte sub-groups and immune response of NSs. RTV NSs were obtained with 400-500 nm PS. The crystal properties of RTV remain unchanged. The solubility of NS was enhanced five times. 57% and 18% of RTV were dissolved in FeSSIF medium for NSs and coarse powder. According to immunological studies, the prepared NSs did not significantly alter the ratio of CD4(+)/CD8(+). Therefore, NSs may be a beneficial approach for the oral administration of RTV.Item Cyclodextrin-Based Nanogel Of Flurbiprofen For Dermal Application: In Vitro Studies And In Vivo Skin Irritation Evaluation(2022) Oktay, Ayse Nur; Celebi, Nevin; Ilbasmis-Tamer, Sibel; Kaplanog, Guelnur TakeThe aim of this study was to develop and characterize flurbiprofen (FB)-loaded cyclodextrin (CD) based nanogel formulations for dermal application. Nanogels were produced via emulsification solvent evaporation and then incorporated into a hydroxypropyl methyl cellulose (HPMC) gel. The visual examination, pH, viscosity, dynamic rheological measurements and drug content analysis of nanogels were assessed. In vitro and ex vivo permeation, stability, and skin irritation were performed. pH of the FB-loaded nanogel and the nanogels in HPMC were 10.6 +/- 0.1 and 7.5 +/- 0.1 (neutral) respectively. The highest and lowest viscosities were observed in FB-loaded nanogels and in FB-free nanogels in HPMC, respectively. The tangent delta and storage modulus values of FB-loaded nanogel in HPMC were higher than those of FB-loaded nanogel. FB from nanogels in HPMC was 100% by 48 h. The final nanogel formulation was physically and chemically stable over 12 months. Skin irritation test showed no skin irritation or cellular infiltration on the histological level. In vitro and ex vivo permeation showed that the nanogels could be effective and stable formulations, especially in the dermal application of a hydro-phobic molecule.Item Oral self-nanoemulsifying formulation of GLP-1 agonist peptide exendin-4: development, characterization and permeability assesment on Caco-2 cell monolayer(2021) Celebi, Nevin; Tekeli, Merve Celik; Aktas, Yesim; https://orcid.org/0000-0002-6402-5042; https://orcid.org/0000-0002-5234-8434; 33398527; AAL-6931-2021The objective of this study was to prepare a stable self-nanoemulsifying formulation of exendin-4, which is an antidiabetic peptide. As exendin-4 is commercially available only in subcutaneous form, several attempts have been made to discover an effective oral formulation. Self-nanoemulsifying drug delivery systems are known to be suitable carriers for the oral administration of peptide drugs. Various ratios of oil, surfactant, and co-surfactant mixtures were used to determine the area in the pseudoternary phase diagram for clear nanoemulsion. The Design of Experiment approach was used for the optimization of the formulation. Blank self-nanoemulsifying formulations containing ethyl oleate as oil phase, Cremophor EL(R), and Labrasol(R) as surfactant, absolute ethanol, and propylene glycol as co-solvent in various proportions were approximately 18-50 nm, 0.08-0.204 and - 3 to - 23 mV in droplet size, polydispersity index, and zeta potential, respectively. When all formulations were compared by statistical analysis, five of them with smaller droplet sizes were selected for further studies. The physical stability test was performed for 1 month at 5 degrees C +/- 3 degrees C and 25 degrees C +/- 2 degrees C/60% RH +/- 5% RH storage conditions. As a result of the characterization and physical stability test results, ethyl oleate: Cremophor EL(R):absolute ethanol (30:52.5:17.5) formulation and four formulations containing ethyl oleate: Cremophor EL(R):Labrasol(R):propylene glycol:absolute ethanol at varying concentrations were considered for peptide encapsulation efficiency. Formulation having the highest encapsulation efficiency of exendin-4 containing ethyl oleate: Cremophor EL(R):Labrasol(R):propylene glycole:absolute ethanol (15:42.5:21.25:15.94:5.31) was selected for in vitro Caco-2 intestinal permeability study. The permeabiliy coefficient was increased by 1.5-folds by exendin-4-loaded self-nanoemulsifying formulation as compared to the exendin-4 solution. It can be concluded that intestinal permeability has been improved by self-nanoemulsifying formulation.Item Editorial, Special Issue BBBB(2021) Celebi, Nevin; Sahin, Selma; 33571635; AAL-6931-2021Item In Vitro Caco-2 Cell Permeability Studies of Ziprasidone Hydrochloride Monohydrate Nanocrystals(2021) Karakucuk, Alptug; Tashan, Emine; Ozturk, Naile; Celebi, Nevin; 0000-0002-6402-5042; 33902264Objectives: The current study focused on the evaluation of the cytotoxic effect and permeability of ziprasidone hydrochloride monohydrate (ZHM) nanocrystals on Caco-2 cells. Materials and Methods: ZHM nanocrystals were prepared by the microfluidization method in the presence of polyvinylpyrrolidone as a stabilizer. Particle size (PS), particle size distribution (PDI), and zeta potential (ZP) values were measured in characterization studies. In vitro cytotoxic effects of ZHM nanocrystals were investigated using the 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Caco-2 transport studies were conducted with formulations of ZHM coarse powder and nanocrystals. Results: Nanocrystals were obtained with 400-600 nm PS, 0.1-0.4 PDI, and >20 mV ZP values. The cell viability remained 100% for all sample groups. The permeability value of ZHM nanocrystals through Caco-2 cells increased 2.3-fold in comparison with ZHM coarse powder. Cumulative drug transport also increased at the end of the sampling period. Conclusion: Nanocrystal technology helps to increase the permeability of drug particles by increasing the saturation solubility.Item Evaluation of the hypoglycemic effect of exendin-4's new oral self-nanoemulsifying system in rats(2021) Celik Tekeli, Merve; Celebi, Nevin; Tekeli, M. Yasin; Aktas, Yesim; 33197556The objective of this study is to develop a new self-nanoemulsifying system containing exendin-4 with or without enzyme inhibitor chymostatin and to evaluate the effects of oral administration of exendin-4 and exendin-4/chymostatin loaded self nanoemulsifying system on plasma exendin-4, plasma insulin, blood glucose levels and to compare with the oral and subcutaneous administration of exendin-4 in non-diabetic and streptozotocin-induced type 2 diabetic rats. Exendin-4 and exendin-4/chymostatin loaded self-nanoemulsifying system containing ethyl oleate as the oil phase, Cremophor EL (R)/Labrasol (R) as the surfactants and propylene glycol as the co-solvent were prepared. The mean droplet size, polydispersity index, zeta potential and viscosity of exendin-4 loaded self-nanoemulsifying system were found as 24.28 +/- 0.43 nm, 0.17 +/- 0.01, -1.28 +/- 3.61 mV, 79.60 +/- 3.30 m.Pas, respectively. The mean droplet size, polydispersity index, zeta potential and viscosity of exendin-4/chymostatin loaded self-nanoemulsifying system were found as 20.25 +/- 0.35 nm, 0.11 +/- 0.02, -1.85 +/- 2.49 mV, 100.02 +/- 7.65 m.Pas, respectively according to our previous study. In the present study, we focused on long-term physical stability studies, pharmacokinetic studies and pharmacodynamic studies of prepared self-nanoemulsifying systems. According to the long-term physical stability data, exendin-4 and exendin-4/chymostatin loaded self-nanoemulsifying systems were found stable both at 5 degrees C +/- 3 degrees C and at 25 degrees C +/- 60% RH for 12 months. Exendin-4 and exendin-4/chymostatin loaded self-nanoemulsifying systems increased AUC and C-max values in non-diabetic rats compared to the oral exendin-4 solution. In diabetic rats, exendin-4/chymostatin loaded self nanoemulsifying systems increased C-max values compared to the exendin-4 solution. Exendin-4/chymostatin loaded self-nanoemulsifying system decreased inter-subject variability compared to commercial Byetta (R). At 30th minute after administration of exendin-4 loaded self-nanoemulsifying system, exendin-4/chymostatin loaded self nanoemulsifying system and Byetta (R), blood glucose levels decreased to 23%, 25%, 29%, respectively. It has been shown that pharmacodynamic response is close to Byetta (R) with exendin-4/chymostatin self-nanoemulsifying system oral administration. In conclusion, a self nanoemulsifying system was found to be a suitable carrier system, and the combination with enzyme inhibitor chymostatin is thought to be promising for oral delivery of exendin-4.Item Enhanced Dermal Delivery of Flurbiprofen Nanosuspension Based Gel: Development and Ex Vivo Permeation, Pharmacokinetic Evaluations(2021) Oktay, Ayse Nur; Ilbasmis Tamer, Sibel; Uludag, Orhan; Celebi, Nevin; 34086139Purpose The objective of this study was to optimize the Flurbiprofen (FB) nanosuspension (NS) based gel and to investigate the in vitro release, ex vivo permeation, the plasma concentration-time profile and pharmacokinetic parameters. Methods FB-NSs were developed using the wet milling process with the Design of Experiment (DoE) approach. The optimum FB-NS was characterized on the basis of SEM, DSC, XRPD, solubility and permeation studies. The dermal gel was prepared by incorporating FB-NS into HPMC gel. Then the in-vitro release, ex vivo permeation studies were performed, and pharmacokinetic studies were evaluated on rats. Results The particle size, polydispersity index and zeta potential values of optimum NS were determined as 237.7 +/- 6.8 nm, 0.133 +/- 0.030 and - 30.4 +/- 0.7 mV, respectively. By means of the surfactant content and nanosized particles of the nanosuspension, the solubility of FB was increased about 7-fold. The percentage permeated amount of FB from FB-NS gel (8.40%) was also found to be higher than the physical mixture (5.25%) and coarse suspension (reference) (2.08%) gels. The pharmacokinetic studies showed that the C-max of FB-NS gel was 2.5 times higher than the reference gel, while AUC(0-24) was 2.96 times higher. Conclusion FB-NSs were successfully prepared with a wet milling method and optimized with the DoE approach. The optimized FB nanosuspension gel provided better permeation and pharmacokinetic performance compared to FB coarse suspension gel.Item Etodolac nanosuspension based gel for enhanced dermal delivery: in vitro and in vivo evaluation(2021) Celebi, Nevin; 0000-0002-6402-5042; 33752553Aim The objective of this study was to develop dermal nanosuspension (NS) based gel formulation of etodolac (ETD). Methods Etodolac nanosuspension (ETD-NS) was prepared by wet milling method and dispersed in hydroxypropyl methylcellulose (NS-HPMC) or hydroxyethyl cellulose (NS-HEC) gels. Rheologic and mechanical properties were investigated. In vitro and ex vivo permeability studies were performed. Topical anti-inflammatory and analgesic activity were evaluated in regard to carrageenan-induced inflammatory paw oedema and radiant heat tail-flick method, respectively. Results The ETD-NS with approximately 190 nm particle size (PS), 0.16 polydispersity index (PDI), and -15 mV zeta potential (ZP) values were obtained. The work of bioadhesion values of NS-HEC and NS-HPMC gels were 0.229 mJ/cm(2) for both gels. Dermal permeation of ETD from NS-HEC gel (7.18%) was found significantly higher than the NS-HPMC gel (4.56%). Enhanced anti-inflammatory and analgesic activity of NS-HEC gels were observed in comparison with micronised ETD. Conclusions ETD-NS based gel formulation is promising for topical delivery of ETD.Item Development of Cyclosporine A Nanosuspension: Cytotoxicity and Permeability on Caco-2 Cell Lines(2021) Celebi, Nevin; 34931593Cyclosporine A is a calcineurin inhibitor and is usually used as an immunosuppressant medication. The main purpose of this study is to develop nanosuspension of polypeptide cyclosporine A by using the wet milling method for oral administration. Cell culture studies were also performed with human intestinal Caco-2 cell lines. Hydroxypropyl methylcellulose and sodium dodecyl sulfate were used as stabilizers in nanosuspension. In vitro characterization studies such as Fourier-transform infrared analysis and morphological imaging with scanning electron microscopy have been carried out with obtained cyclosporine A nanosuspension. The particle size, particle size distribution, and zeta potential values of the nanosuspension were measured approximately 400 nm, 0.4, and -25 mV, respectively. The solubility of cyclosporine A was increased 4.5 times in nanosuspension compared to the coarse cyclosporine A powder. As a result of cytotoxicity studies conducted with different concentrations, it was decided to conduct permeability studies at a dose equivalent to 150 mu g/mL cyclosporine A. Permeation studies have shown that the nanosuspension increases cyclosporine A transport by 5 and 1.5 times, respectively, compared to coarse powder and commercial product.Item Preparation and in vitro/in vivo evaluation of flurbiprofen nanosuspension-based gel for dermal application(2020) Oktay, Ayse Nur; Ilbasmis-Tamer, Sibel; Han, Sevtap; Uludag, Orhan; Celebi, Nevin; 32937211; AAL-6931-2021Flurbiprofen (FB) is an analgesic and anti-inflammatory drug, but its low water solubility (BCS Class II) limits its dermal bioavailability. The aim of this study is to develop a FB nanosuspension (NS) based gel and to evaluate its analgesic and anti-inflammatory activities in rats. FB-NS was produced by the wet milling method with Plantacare 2000 (R), as stabilizer. The FB-NS was then incorporated in different carrier gels such as hydroxypropyl methyl cellulose (HPMC), polycarbophil, oleogel, and chitosan. To select the optimum gel type, visual examinations, pH and rheological property measurements, texture profile analysis, in vitro release and ex vivo permeation studies were performed. Following these tests, the analgesic and anti-inflammatory activities of the optimum NS based gel were evaluated using the tail flick and carrageenan-induced paw edema methods consecutively. The NS was successfully prepared with the wet milling method, and the PS, PDI and ZP values were found to be 237.7 +/- 6.8 nm, 0.133 +/- 0.030, and -30.4 +/- 0.7 mV; respectively. Among the NS-based gels, HPMC gel showed more suitable rheological and mechanical properties, also the percentage of permeated FB and the flux value observed for HPMC gel were higher for HPMC than for the other gels. Thus, HPMC gel was selected as a carrier gel for in vivo pharmacodynamics studies. The anti-inflammatory activity of FB-NS HPMC gel was higher than that of the physical mixture gel and that of the coarse suspension gel. Results of our analgesic activity studies showed that, in the 180th min of FB nanosuspension treatment, the latency time was significantly prolonged compared to that of the control group (p<0.05). As a conclusion, while nanosuspensions increased the in vivo pharmacodynamics effect of FB by means of nanosized particles and a large surface area, the HPMC gel as a carrier prolonged the contact time of NSs with skin and eased the dermal application.