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Öğe Design of an orally disintegrating tablet formulation containing metoprolol tartrate in the context of quality by design approach(Marmara University Press, 2021) Yeğen, Gizem; Aksu, Buket; Cevher, ErdalOrally Disintegrating Tablets (ODTs) are solid dosage forms that rapidly disintegrate or dissolve to release the drug upon contact with saliva in the mouth. As these tablets require special attention during formulation design, it is necessary to use advanced control and formulation design techniques to increase the quality. Quality by Design (QbD) was defined as an approach including better scientific understanding of critical process and product attributes, designing controls and tests based on scientific understanding limits during development stage and used to work in an environment for continuous improvement of information obtained during the product lifecycle. The aim of the study was to develop an ODT formulation containing Metoprolol tartrate with appropriate features via QbD approach with the help of artificial intelligence programs to enlight the multivariate relations between critical parameters and quality attributes of on final product and to obtain an optimum formulation. Physical and chemical tests were conducted on tablets prepared by direct compression according to the designated formulation and process variables. Then, experimental data was evaluated with modeling programs use artificial intelligence technique, FormRules V3.32 to understand the relationship between independent input variables and the critical quality attributes; later with INForm V5.1 for optimization. The optimized formula was prepared and according to test results tablets shows compliance with the pharmacopoeia limits. The adoption of QbD approach and usage of artificial intelligence programs has increased the efficiency of the formulation development process with better understanding of the product and process.Öğe Development of chitosan-pullulan composite nanoparticles for nasal delivery of vaccines: In vivo studies(Taylor & Francis Ltd, 2015) Cevher, Erdal; Salomon, Stefan K.; Somavarapu, Satyanarayana; Brocchini, Steve; Alpar, H. OyaHere, we aimed at developing chitosan/pullulan composite nanoparticles and testing their potential as novel systems for the nasal delivery of diphtheria toxoid (DT). All the chitosan derivatives [N-trimethyl (TMC), chloride and glutamate] and carboxymethyl pullulan (CMP) were synthesised and antigen-loaded composites were prepared by polyion complexation of chitosan and pullulan derivatives (particle size: 239-405 nm; surface charge: +18 and +27 mV). Their immunological effects after intranasal administration to mice were compared to intramuscular route. Composite nanoparticles induced higher levels of IgG responses than particles formed with chitosan derivative and antigen. Nasally administered TMC-pullulan composites showed higher DT serum IgG titre when compared with the other composites. Co-encapsulation of CpG ODN within TMC-CMP-DT nanoparticles resulted in a balanced Th-1/Th-2 response. TMC/pullulan composite nanoparticles also induced highest cytokine levels compared to those of chitosan salts. These findings demonstrated that TMC-CMP-DT composite nanoparticles are promising delivery system for nasal vaccination.Öğe Development of chitosan-pullulan composite nanoparticles for nasal delivery of vaccines: Optimisation and cellular studies(Taylor & Francis Ltd, 2015) Cevher, Erdal; Salomon, Stefan K.; Makrakis, Apostolos; Li, Xiong Wei; Brocchini, Steve; Alpar, H. OyaNasal immunisation with nanoparticles has already shown promising results. In this study, nanoparticle composites carrying BSA for nasal vaccination prepared using electrostatic interaction process between polycation N-trimethyl chitosan chloride (TMC), chitosan glutamate (CG), chitosan chloride (CCl) and polyanion carboxymethyl pullulan (CMP). A mass ratio of 2:1 for TMC-CMP combination produced stable nanocarriers. For CCl-CMP and CG-CMP formulations needed a mass ratio of 3:1. Loading efficiency was >90% for all formulations. Nanoparticles' size ranged from 207 to 603 nm. The surface charge of the complexes varied between +14 and +33 mV. SDS-PAGE integrity of the model antigen was also demonstrated. MTT studies showed that nanoparticle composites were less toxic to Calu-3 cells than the particles of cationic polymers alone. FITC-BSA loaded nanoparticles efficiently taken up by J774A.1 macrophages as confirmed by confocal microscopy highlighting the potential of these novel nanoparticulate carriers' use for nasal vaccination.Öğe The efficacy of sustained-release chitosan microspheres containing recombinant human parathyroid hormone on MRONJ(Sociedade Brasileira De Pesquisa Odontologica, 2019) Taysi, Aysegul Erten; Cevher, Erdal; Sessevmez, Melike; Olgac, Vakur; Taysi, Nuri Mert; Atalay, BerkemTreatment of patients with bisphosphonate usage is a significant concern for oral surgeons because it interferes with jaw bone turnover and regeneration. In case of adverse effects manifesting related to bisphosphonate use, oral surgeons are usually treating and keep the patient's symptoms under control. In this study, we aimed to investigate a new treatment protocol for medication-related osteonecrosis of the jaw (MRONJ). This treatment protocol consisted of administering human parathyroid hormone (hPTH) loaded chitosan microspheres which were prepared by ionotropic gelation method or/and the prepared microspheres were suspended in a poloxamer gel. After in-vitro optimization studies, the efficacy of the chosen formulations was evaluated in-vivo studies. Zoledronic acid was administered daily to forty-eight adult female Sprague-Dawley rats, divided into four experimental groups, at a daily concentration of 0.11 mg/kg over three weeks to induce the MRONJ model. At the end of this period, maxillary left molar teeth were extracted. In the first group, the subjects received no treatment. In the negative control group, poloxamer hydrogel containing empty microspheres were immediately applied to the soft tissues surrounding the extraction socket. The treatment group-1 was treated with local injections of poloxamer hydrogel containing hPTH. The treatment group-2 was treated with a single local injection of poloxamer hydrogel containing hPTH-loaded chitosan microspheres. Both treatment groups received a total of 7 mu g of hPTH at the end of the treatment protocol. Our study demonstrates successful attenuation of MRONJ through a local drug delivery system combined with hPTH, as opposed to previously attempted treatment strategies.Öğe Induction of humoral and cell-mediated immunity in mice by chitosan-curdlan composite nanoparticles administered intranasally and subcutaneously(Editions de Sante, 2023) Sessevmez, Melike; Sinani, Genada; Okyar, Alper; Alpar, Hazire Oya; Cevher, ErdalInfectious diseases seriously threaten human life. The need for novel delivery systems and adjuvants suitable to be used in clinic for antigens remains a challenge. Among various attempts that have been made to provide optimum immune responses for protein antigens with poor immunogenicity, polymeric nanoparticles offer great opportunities. In this study, carboxymethyl curdlan (CMC) as a polyanionic polymer and chitosan chloride (CC) and N-trimethyl chitosan (TMC) as polycationic polymers were synthesised in-house and composite nanoparticles (CC-CMC-BSA and TMC-CMC-BSA) loaded with bovine serum albumin (BSA) as a model antigen were prepared via polyelectrolyte complexation and reported here for the first time. Nanoparticles with an average size ranging from 153 nm to 615 nm, positive surface charge (from +24 mV to +55 mV) and encapsulation efficiency as high as 90% were obtained depending on the concentration of polymers in the formulation. The nanoparticles showed good physical stability for three months and low toxicity in Calu-3 and A549 cells. Furthermore, SDS integrity of antigen was maintained. In vivo studies in mice indicated that nasal and subcutaneous administration of composite nanoparticles could provide long-term humoral and cellular immunity as determined by serum antibody titres (IgG, IgG1, IgG2a) and cytokine (IL-2, IL-4, IL-6, IL-10 and IFN-γ) levels. Elevated sIgA levels after nasal administration of the nanoparticles showed that mucosal immunity was successfully stimulated. These findings suggest that chitosan-curdlan composite nanoparticles show optimum properties to be used as nanovaccine for nasal immunisation of protein antigens.Öğe Modified chitosan-based nanoadjuvants enhance immunogenicity of protein antigens after mucosal vaccination(Elsevier, 2019) Sinani, Genada; Sessevmez, Melike; Gök, M. Koray; Özgümüş, Saadet; Alpar, H. Oya; Cevher, ErdalNasal vaccination is considered to be an effective and convenient way of increasing immune responses both systemically and locally. Although various nanovaccine carriers have been introduced as potential immune adjuvants, further improvements are still needed before they can be taken to clinical usage. Chitosan-based nanovaccine carriers are one of the most widely studied adjuvants, owing to the ability of chitosan to open tight junctions between nasal epithelial cells and enhance particle uptake as well as its inherent immune activating role. In present study, bovine serum albumin (BSA) loaded nanoparticles were prepared using novel aminated (aChi) and aminated plus thiolated chitosan (atChi) polymers, to further enhance mucoadhesiveness and adjuvanticity of the vaccine system by improving electrostatic interactions of polymers with negatively charged glycoproteins. Nanocarriers with optimum size and surface charge, high encapsulation efficiency of model antigen and good stability were developed. Negligible toxicity was observed in Calu-3 and A549 cell lines. In vivo studies, revealed high levels of systemic antibodies (IgG, IgG(1) and IgG(2a)) throughout the study and presence of sIgA in vaginal washes showed that common mucosal system was successfully stimulated. Cytokine levels indicated a mixed Th1/Th2 immune response. A shift towards cellular immune responses was observed after nasal immunisation with antigen loaded nanoparticle formulations. These nanoparticles exhibit great potential for nasal application of vaccines.Öğe Nasal vaccination with poly(beta-amino ester)-poly(D,L-lactide-co-lycolide) hybrid nanoparticles(Elsevier Science Bv, 2017) Sinani, Genada; Sessevmez, Melike; Gök, M. Koray; Özgümüş, Saadet; Okyar, Alper; Alpar, H. Oya; Cevher, ErdalMucosal vaccination stimulates both mucosal and systemic immunity. However, mucosal applications of vaccine antigens in their free form generally result in poor systemic immune responses and need adjuvantation. In this study, bovine serum albumin loaded, new hybridised poly(beta-amino ester)-poly( D, Llactide-co-glycolide) nanoparticles were prepared by double emulsion-solvent evaporation method, characterised and evaluated in vivo as nasal vaccine carriers. Cationic spherical particles with a mean size of 240 nm, good physical stability and high encapsulation efficiency were obtained. Protein structure was not affected throughout preparation and minimal toxicity was shown in Calu-3 and A549 cells. Nasal vaccination with these nanoparticles revealed markedly higher humoral immune responses compared with free antigen following intranasal and subcutaneous immunisation. Mucosal immune response was also stimulated and cytokine titres indicated that Th1 and Th2 pathways were successfully activated. This study shows that the formulated hybrid nanoparticles can be a promising carrier for nasal immunisation of poor antigenic proteins. (C) 2017 Elsevier B.V. All rights reserved.Öğe Oral tablet formulations containing cyclodextrin complexes of poorly water soluble cefdinir to enhance its bioavailability(Elsevier, 2020) Morina, Deniz; Sessevmez, Melike; Sinani, Genada; Mulazimoğlu, Lutfiye; Cevher, ErdalCefdinir (CFD) is an oral cephalosporin antibiotic commonly used in the treatment of community-acquired infections. The oral bioavailability of CFD is limited due to its poor aqueous solubility. Cyclodextrins (CyDs) and their chemically modified derivatives are used in the pharmaceutical field to form inclusion complexes with drug molecules to improve their aqueous solubility as well as stability and to prevent side effects. In this study, CFD was complexed with CyDs such as beta-cyclodextrin (beta-CyD), gamma-cyclodextrin (gamma-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and sulphobutyl ether 7-beta-cyclodextrin (SBE7-beta-CyD) to increase its aqueous solubility and to reduce its side effects without decreasing the antimicrobial activity. Phase solubility studies were performed and the stability constant of the CFD:CyD inclusion complexes was determined. The solubility of CFD was increased after complexation with CyDs as indicated by phase solubility studies, in the order beta-CD < HP-beta-CyD < gamma-CyD < SBE7-beta-CyD, a result that depends on the conditions of complexation formation. Complex formation between CFD and CyDs was evaluated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and powder x-ray diffractometry (PXRD) studies. The antimicrobial activity of the complexes against Staphylococcus aureus and Escherichia coli strains were evaluated and the strains showed higher susceptibility to CFD:HP-beta-CyD complex. Oral tablet formulations were fabricated using Avicel (R) PH 102 or Ludipress (R) as direct compression agent and magnesium stearate as lubricant. Using CFD:HP-beta-CyD complex in tablets significantly improved the dissolution rate of the drug when compared with that of formulation containing CFD alone.Öğe Polymeric-Micelle-Based delivery systems for nucleic acids(2023) Sinani, Genada; Durgun, Meltem Ezgi; Cevher, Erdal; Özsoy, YıldızNucleic acids can modulate gene expression specifically. They are increasingly being utilized and show huge potential for the prevention or treatment of various diseases. However, the clinical translation of nucleic acids faces many challenges due to their rapid clearance after administration, low stability in physiological fluids and limited cellular uptake, which is associated with an inability to reach the intracellular target site and poor efficacy. For many years, tremendous efforts have been made to design appropriate delivery systems that enable the safe and effective delivery of nucleic acids at the target site to achieve high therapeutic outcomes. Among the different delivery platforms investigated, polymeric micelles have emerged as suitable delivery vehicles due to the versatility of their structures and the possibility to tailor their composition for overcoming extracellular and intracellular barriers, thus enhancing therapeutic efficacy. Many strategies, such as the addition of stimuli-sensitive groups or specific ligands, can be used to facilitate the delivery of various nucleic acids and improve targeting and accumulation at the site of action while protecting nucleic acids from degradation and promoting their cellular uptake. Furthermore, polymeric micelles can be used to deliver both chemotherapeutic drugs and nucleic acid therapeutics simultaneously to achieve synergistic combination treatment. This review focuses on the design approaches and current developments in polymeric micelles for the delivery of nucleic acids. The different preparation methods and characteristic features of polymeric micelles are covered. The current state of the art of polymeric micelles as carriers for nucleic acids is discussed while highlighting the delivery challenges of nucleic acids and how to overcome them and how to improve the safety and efficacy of nucleic acids after local or systemic administration.
