الفهرس 
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Abstract
The main objective of this thesis is preparation and characterization of polymeric nanoparticles (PNPs) having a great potential as drug delivery systems for various types of therapeutic agents, such as anti-inflammatory, antioxidant drugs and anticancer drugs, offering many advantages concerning targeting to specific sites. PNPs will be studied as drug carriers in the pharmaceutical field due to their unique features, such as the capability to protect drugs, the versatility to control drug release and adjustable surface properties. Preparation of PNPs by the use of selected biodegradable polymers such as poly(ε-caprolactone) (PCL), poly (D, L-lactic-co-glycoic acid) (PLGA) and chitosan (CS) which are suitable for use in drug delivery due to their high biodegradability, biocompatibility permeability to wide range of drugs and non-toxicity.
In this work, two models drugs were used Vitamin C (Vit.C) and 5-Fluorouracil (5-FU). This due to Vit.C had low stability while 5-FU had major drawback is systemic toxicity arising from its non-specificity, low plasma half-life, very low bioavailability leading to the use of high doses resulting in side effects. An alternative to overcome these drawbacks improving drug bioavailability, promoting controlled drug release, and choosing for more cell selectivity is the application of polymeric nanoparticles as Vit.C and 5-FU carriers. Factors such as the type of polymers, type and ratio of various additives such as some biologically safe emulsifiers as polyvinylalcohol (PVA), and cross
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Summary and Conclusions
linkers as sodium tripolyphosphate (STPP) and the effect of the methods of preparation will be studied.
- The efficiency of the PNPs in drug encapsulation will be studied by measuring drug encapsulation efficiency (EE%), particle size and zeta potential of the PNPs using UV spectrophotometry and zeta- sizer.
- In vitro drug release profile of the drug loaded nanoparticles prepared will be investigated.
TO achieve this goal, this work is divided into three parts:
In the first part
-The preparation of Vit. C entrapped and unentrapped poly(ε-caprolactone) nanoparticles (Vit.C–PCNPs), (PCNPs), respectively, by double emulsion technique. By using emulsifier as (PVA, % 0.5) was used as emulsion stabilizer in the outer aqueous phase (W2).
- Determination of free Vit.C in the prepared Vit.C–PCNPs via UV instrument.
-The effect of several factors influencing drug encapsulation efficiency (EE%) and the particles size were investigated as the stirring time for 1st and 2nd emulsion (i.e., 5 min for 1st emulsion & 15 min for 2nd
emulsion; 15 min for 1st emulsion & 5 min for 2nd emulsion; and 5 min for 1st & 2nd emulsion) and speed of homogenization for 1st emulsion from 4000 up to 20000 rpm.
- Determination of Encapsulation efficiency of Vit.C–PCNPs shows that EE% values ranging from 44.82% up to 93.2% have a general decrease in drug EE% was observed with increasing speed of
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Summary and Conclusions
homogenization from 4000 up to 20000 rpm, whereas the increase in stirring time exhibited an increase in the EE% in case of 2nd emulsion.
- Determination of particle size of Vit.C–PCNPs shows that the increase in stirring time led to a decrease in the particle size of the prepared nanoparticles.
- Determination of zeta potential of the prepared Vit.C–PCNPs shows that the physical stability of the prepared formulations and to determine the electrophoretic mobility of Vit.C–PCNPs, Negative net surface charges were observed for all the prepared formulations and the values of zeta potential were generally found between -1.53 and -22.4 mV.
- The results showed that the optimized condition that which gives highest EE% value is 93% and lowest particle size 150 nm obtained at
stirring time 5 min for 1st emulsion & 15 min for 2nd emulsion and speed of homogenization for 1st emulsion at 20000 rpm.
-Investigation of chemical structure of Vit.C-PCNPs and PCNPs by using FTIR show that the characteristic peaks of drug were also observed were diminished or shifted when compared with pure drug peak at the same wave number but not in physical mixture, therefore confirming that the drug is interacting with polymer.
- Characterization of Vit.C–PCNPs by Differential Scanning Calorimetry and X-Ray diffraction revealed molecularly dispersed Vit.C in the nanoparticles in case of drug loaded nanoparticles.
- Characterization of Vit.C–PCNPs by Thermal gravimetric analysis shows that Vit.C–PCNPs demonstrated no decomposition peak for the drug compared to the free drug indicating enhanced stability effect for the prepared carriers.
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Summary and Conclusions
- Determination of the shape of Vit.C-PCNPs using TEM show that the nanoparticles are well identified and presented in a nearly perfect sphere to oval shape.
- The results showed that decreasing the particle size with increasing the stirring speeds of the first emulsion from 4000 to 16000 rpm, and also decreasing the particle size with increasing stirring time for the second
emulsion from 5 to 15 min .
- Determination of the morphology of the surface of the prepared
Vit.C–PCNPs and PCNPs by using SEM shows that the all nanoparticles were in spherical shape with smooth surface and unimodel size.
- Studying of drug release profiles of Vit.C from the best formulation of the prepared Vit.C-PCNPs the results showed that the highest release is encountered at stirring time 5 min for 1st emulsion & 15 min for 2nd
emulsion and speed of homogenization for 1st emulsion at 20000 rpm.
In the second part
- Preparation of 5-Fluorouracil entrapped and unentrapped chitosan nanoparticles (5-FU-CSNPs), CSNPs, respectively, based on the ionic gelation method by using STPP as crosslinker.
- The nanoparticles were collected and separated from the free drug in the nanoparticulate suspension by means of centrifuge at 6000 rpm and at room temperature for 45 minutes.
- Determination of free 5-FU in the prepared 5-FU–CSNPs via UV instrument.
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- Several factors influencing the size of particles and drug encapsulation efficiency (EE %) were investigated as the molecular weights of chitosan and of CS: STPP mass ratio.
- Determination of Encapsulation efficiency of the prepared 5-FU–
CSNPs shows that EE% values ranging from 1.69% up to 36.33% have a general decrease in drug (EE%) was observed with increasing the concentration of CS from 3 up to 5 mg/ml.
- Investigation of chemical structure of 5-FU-CSNPs by using FTIR show that the characteristic peaks of drug were also observed were diminished or shifted when compared with pure drug peak at same wave number but not in physical mixture, therefore confirming that the drug is interacting with polymer.
- Characterization 5-FU-CSNPs techniques including XRD and DSC verified that the successful molecularly dispersed drug in the nanoparticles in case of drug loaded nanoparticles.
- TGA studies in case of 5-FU–CSNPs demonstrated no decomposition peak for the drug compared to the free drug indicating enhanced stability effect for the prepared carriers.
- Determination of the shape of 5-FU-CSNPs using TEM the nanoparticles are presented in spherical shape.
- The results showed that by decreasing the particles size with decreasing the ratio of CS: STPP.
-Studying of drug release profiles of pure 5-FU and 5-FU from the best selected formulation of the prepared 5-FU-CSNPs the results showed that pure 5-FU reached 82.58% after 24 h compared to 12.01–19.53% for 5-FU-CSNPs formulations, in addition to a higher percentage of
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drug release is observed in the low molecular weight chitosan at molar mass ratio CS: STPP (5:1).
In the third part
-The preparation of 5- Fluorouracil entrapped and untrapped PLGA nanoparticles (5-FU-PLGNPs), (PLGNPs), respectively, by using double emulsion technique.
- The nanoparticles were collected and separated from the free drug in the nanoparticulate suspension by means of centrifuge at 6000 rpm and at room temperature for 45 minutes.
- Determination of free 5-FU in the prepared 5-FU-PLGNPs via UV instrument.
- the effect of stabilizer (PVA) content on the properties of the prepared emulsions were studied by using different stabilizer PVA concentrations (0.5%, 1% and 3%) for 2nd emulsion influencing EE%, and the size of particles were investigated.
- Determination of EE% of the prepared 5-FU–CSNPs shows that EE% values ranging from 14.4% up to 34.4% have a general decrease in drug (EE%) was observed with increasing the concentration of Stabilizer (PVA) from 0.5 up to 3mg/ml.
- Characterization 5-FU-PLGNPs techniques including XRD and DSC verified that DSC study revealed molecularly dispersed 5-FU in the nanoparticles in case of drug loaded nanoparticles.
-The results showed that by decreasing the particles size with increasing the stabilizer concentrations of the second emulsion from 0.5 % to 3%, keeping drug conc. (10 mg/ml), polymer and stirring time at 5 min for first emulsion and 15 min for second emulsion as in case of F
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0.5, where exhibited a particle size recorded 355.4 nm at PVA concentration 0.5% whereas in case of F3 at PVA concentration (3%), the particles size was reduced to 211nm.
- Investigation of chemical structure of 5-FU-PLGNPs by FTIR show that the characteristic peaks of 5-FU-PLGNPs were also observed were diminished or shifted when compared with pure drug peak at same wave number, therefore confirming that the drug is interacting with polymer.
- Determination of zeta potential of the prepared 5-FU–PLGNPs shows that the physical stability of the prepared formulations and to determine the electrophoretic mobility of 5-FU–PLGNPs, Negative net surface charges were observed for all the prepared formulations and the values of zeta potential were generally found between -4.87 and -8.31mV.
- Determination of the shape and diameter of 5-FU-PLGNPs using TEM show that the nanoparticles are presented in spherical shape.
Generally, the obtained results from the present work would help in understanding the influence of various formulation parameters in the double emulsion method, leading to the preparation of an efficient formulation for nanoparticulate of appropriate characteristics with the highest encapsulation efficiency and the lowest particle size for successful delivery of Vit.C, 5-FU and similar hydrophilic drugs.