L-Karnitin Yüklü Polimerik ve Lipit Bazlı Nanopartiküler Sistemlerin Hazırlanması ve İn-Vitro Değerlendirilmesi
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L-carnitine has attracted attention in the treatment of important problems of era such as obesity, diabetes and regional slimming in recent years due to its metabolic effects that increase fat loss and muscle building in metabolism. L-carnitine, whose main function is the transfer of long chain fatty acids to mitochondria for beta oxidation, is supplied to the body from two sources, both exogenous and endogenous. The most important sources of L-carnitine taken from food are red meat and dairy products. The increase in artificial feeding and mass production in the food sector causes the amount of L-carnitine taken into the body to be insufficient therefore obesity rates are increasing. For that reason, L-carnitine is often taken as a supplement by athletes and people who want to lose weight. However, based on its low bioavailability (14-18%), short half-life (30-60 minutes) and inability to be stored in the body L-carnitine, frequent dosing is required for its effective treatment. In addition, L-canitine has defined impurities in the European and American Pharmacopoeia Monographs. Since frequent and high dose administration of L-carnitine known to have impurities, may increase the toxic and side effects so the development of its controlled release systems is become a very important issue. The future of nanoparticular drug delivery systems as controlled release systems depend on metabolic level evaluation of the effects on cell as well as clarification of nanoparticle structure and targeting mechanism. Nanoliposomes which have lipid bilayers similar to cell membranes, have the ability to increase the penetration of the active substance. Due to their increased stability, controlled release properties, polymeric nanoparticles are the most commonly used efficient and reliable systems among the nanocarrier systems. For this purpose, L-carnitine loaded nanoliposome and PLGA nanoparticle formulations have prepared, formulations characterization (particle size (PS), polydispersity Index (PDI), zeta potential (ZP), morphology (SEM), percentage of encapsulation efficiency (EE%), molecular structure/thermal properties clarification (FTIR/ATR, TGA)) and stability studies have made within the scope of the thesis. For L-carnitine encapsulated nanoliposome (Lipo-carnitine) and L-carnitine encapsulated PLGA nanoparticle (Nano-carnitine) formulations; PS values are 97.88±2.96 nm and 250.90±6.15 nm; PDI values are 0.35±0.01 and 0.22±0.03; ZP values are 6.36±0.54 mV and -32.80±2.26 mV; EE% values are 14.26±3.52 and 21.93±4.17, respectively. Comparative in-vitro release studies of Lipo-carnitine, Nano-carnitine formulations and free solution of L-carnitine at the same concentration have performed by dialysis membrane method. While control solution (free L-carnitine) have terminated 90% of the concentration at the end of the 1st hour with immediate release; Lipo-carnitine and Nano-carnitine formulations have showed a delayed controlled release profile which has obtained from 2, 4, 6, 8 and 12 hours release points, after the immediate release effect observed at the end of the 1st hour (59.90% and 65.19%, respectively). Kinetic models (zero, first, Higuchi, Hixson Crowell) have applied to the release profiles, determination coefficients (r2) were found 0.8539 and 0.9167 respectively, and both formulations have found to be compatible with the “First Order” kinetic model. Following release studies, the effectiveness of formulations have evaluated by metabolomic studies and pathway analyzes on cardiac fibroblast cells in-vitro conditions. The number of mitochondria in cardiac fibroblasts is high due to the energy demand. Thus, L-carnitine plays a critical role in the metabolism of these cells, which derive most of their energy from fatty acid oxidation. Metabolites which are the components of intracellular metabolism, have dedected and their levels have quantified by snaphots in metabolomic studies. By comparing the results obtained from metabolomic studies, the effects of free L-carnitine and L-carnitine loaded nano-systems on amino acid, carbohydrate and lipid metabolisms have evaluated. In parallel with prolonged release of L-carnitine, the Lipo-carnitine and Nano-carnitine formulations have found to be effective on amino acid, carbohydrate and lipid metabolisms. Nano-carnitine has found to be the most effective formulation for increasing amino acid levels with polar side chains. Nano-carnitine formulation has found to be more effective compared to control and Lipo-carnitine groups, at citric acid, aconitic acid, succinic acid, fumaric acid, malic acid, oxaloacetic acid levels which are belong to tricarboxylic acid cycle (TCA). When a TCA component called α-ketoglutarate is present in the sufficient amount, it turns into glutamate and acts on the metabolic pathways of ornithine, arginine and proline aminoacids. For the level of α-ketoglutarate, a significant (p <0.05) decrease in the normalized peak area of Lipo-carnitine has observed (-1.321 ± 0.20) compared to all other groups. When the effects of saturated fatty acids and unsaturated fatty acids have examined separately, Lipo-carnitine has found to be more effective than free L-carnitine and Nano-carnitine. As a result, nano-systems have prepared by prolonging the half-life of L-carnitine with long-term effect, reducing the side effects due to prevention of frequent use and increasing patient compliance, resulting in a more effective metabolomic profile change compared to the free L-carnitine group. Thus, innovative nano formulations have developed as an alternative to conventional preparations available on the market that enable cells to use substances effectively in metabolic functions instead of storing them when presence of excess amount in the media.