Research Information System
Thesis Type: Doctorate
Institution Of The Thesis: Hacettepe University, Fen Bilimleri Enstitüsü, Nanoteknoloji ve Nanotıp A.B.D., Turkey
Approval Date: 2019
Thesis Language: Turkish
Student: Gülce Taşkor Önel
Supervisor: Nezire Saygılı
Abstract:
NSAIDs,
such as acetylsalicylic acid, ibuprofen, naproxen and flurbiprofen, are commonly
used commercial drugs with weakly acidic structure. These types of drugs are
well absorbed from the stomach and bowel mucosa. Treating pain by inhibiting
COX-1 and COX-2 cyclooxygenase enzymes causes stomach discomfort.
In
our study, pre-drug molecules were synthesized upon further reduction of
acidity of various NSAIDs in order to reduce this side effect. Drugs were
derivatized from the free carboxylic acid group which are the common functional
group of NSAIDs. In the synthesis step, the
carboxylic acid group of NSAIDs was converted to acyl halides. After that the
amide derivatives of NSAIDs were synthesized using amino acid ester and amino
alcohol containing amino functional group with method of nucleophilic addition
and elimination reactions. Chromatographic methods were used in purification
studies (TLC and column chromatography) of synthesized molecules. 1H-NMR, 13C-NMR, HRMS, IR analysis methods were used in chemical structure characterization
studies of prodrugs.
In
the second step, the nanosystems of some of these novel drug derivatives were
designed. Formulation of the structures of oil/water (o/w) nanoemulsion (NE)
containing NSAIDs and prodrugs were studied. It was aimed to increasing the
bioefficacy by preparing of nanoemulsions of both NSAIDs and some of the
prodrugs. When preparing nanoemulsions, NSAIDs or the derivatives were first
dissolved into oil phase. Then, by using the high pressure homogenization and the
ultrasonic emulsification methods, the oil phase was added into the aqueous
phase (o/w) and their colloidal dispersion systems with dimensions of 160-265 nm
were prepared. For the characterization
studies of nanoemulsions were taken dimension and zeta potential measurements, for
the morphologies of NE’s the TEM images were taken. In-vitro cell viability tests were performed by using cell culture
techniques for the selected prodrug. The developed naproxen derivative prodrug
was observed to be non-toxic on L929 mouse fibroblast cells at low
concentration. In addition, when we examined the cytotoxicity of nanoemulsion
of naproxen derivative prodrug, it was observed that the cell viability was
higher than empty nanoemulsion in almost all concentrations. Anti-inflammatory
and anti-oxidant tests were carried out for derivative molecules selected
within the scope of biological activity studies.
According to the results obtained, novel prodrug
molecules were synthesized by derivatization studies of NSAIDs. By converting
the acidic carboxylic acid group to the amide group, the acidity of the NSAIDs
were reduced. The nanoemulsion systems were formulated to increase the
bioavailability of NSAIDs and prodrugs.