الفهرس 
General IntroductionOnly 14 pages are availabe for public view
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Abstract
اThe main target of novel drug delivery systems is maintaining constant and
effective drug level in the body, decreasing the side-effects and it also localizes
the drug action by targeting the drug delivery using drug nanocarriers. Vesicular
systems are among the most commonly used systems to achieve such purpose.
The dermal penetration enhancement of active constituents is highly correlated to
the need for efficient therapies for local as well as systemic drug delivery. The
interest in enhancing the dermal penetration is driven by the poor oral absorption,
severe adverse effects, and frequent dosing associated with many drugs. As an
alternative route of administration, the skin provides a new chance for overcoming
these problems. However, the opportunity of delivering active ingredients by the
dermal route becomes limited due to the formidable barrier characteristics of the
stratum corneum. Therefore, many attempts have been focused on implementing
techniques and formulating many preparations to augment the permeation of
drugs through the stratum corneum as the development of new classes of elastic
lipid vesicles called penetration enhancer nanovesicles. The use of nanocarriers
such as penetration enhancer nanovesicles and proniosomal gels are examples of
formulation techniques that have shown to enhance the dermal delivery of drugs.
Penetration enhancer containing vesicles can be described as vesicular systems
that are mainly constituted from phospholipids with the addition of penetration
enhancer. The incorporation of penetration enhancer can play a vital role in the
ease of the penetration of the active drug molecules into the skin. It can execute its
action through versatile mechanisms either to fluidize the different skin
compartments or to disrupt the highly organized lamellar compartments through
interacting with intracellular lipids. Proniosomal gel preparations can be defined
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as semisolid liquid crystal products of non-ionic Surfactants. In addition, they
contain cholesterol and lecithin in lower concentrations. They can be formulated
by dissolving the surfactant in a minimum amount of the organic solvent and the
aqueous phase. These structures are considered to be liquid crystalline compact
noisomal hybrids that can be transformed into niosomes in situ after hydration.
Proniosomal gels are considered to be the selective vesicular system optimum for
the delivery of many medications through transdermal route due to the penetration
enhancing effect of the added surfactant.
Levofloxacin is third-generation member of fluoroquinolones with potent
antibacterial effects and broad spectrum of activity against different types of
bacterial strains making it the first choice for the treatment of many complicated
infectious diseases. Levofloxacin can treat effectively respiratory tract infections
and it can effectively be used in attacking resistant strains causing complicated
urinary tract infections. It exerts its antibacterial effect through inhibition of the
DNA GYRASE and DNA IV topoisomerase resulting in a lethal effect for the
cells.
Drug delivery systems are simply defined as formulations that allow the
introduction of a drug in the body to improve the efficacy and safety of this
substance. Thus, the main aim of the thesis was to formulate and evaluate
biocompatible nanocarrier systems for dermal drug delivery such as penetration
enhancer nanovesicles and proniosomal gels. These forms were prepared with the
use of levofloxacin to increase its therapeutic effect and to increase the patient
compliance with minimum side effects.
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To fulfill this aim, the work in the thesis was divided into two chapters:
Chapter I: Preparation and characterization of penetration enhancer
containing vesicles loaded with levofloxacin.
Penetration enhancer nanovesicles loaded with levofloxacin were prepared
using the film hydration method. Five different hydrophilic and lipophilic
penetration enhancers were selected and used to formulate levofloxacin-loaded
penetration enhancer containing vesicles. All of them contained levofloxacin and
were prepared using the selected penetration enhancers: polyethylene glycol,
propylene glycol, limonene, transcutol and the use of cineole. The prepared
penetration enhancer nanovesicles were characterized in the terms of the particle
size, polydisperity index, zeta potential ,entrapment efficiency ,in vitro release,
and ex vivo permeation studies.
from the obtained results, it was found that:
1. L1-LV penetration enhancer nanovesicles displayed the smallest particle
size among the other formulations. The addition of lipophilic penetration
enhancers (cineole and limonene) by higher concentrations led to significant size
enlargement. This might be due to the liposomal aggregation and fusion induced
by penetration enhancer incorporation.
Polyethylene glycol, propylene glycol and cineole penetration enhancer
nanovesicles exhibited the same behavior, in which by the initial increase of
penetration enhancer, the particle size increased. Then by, increasing the
concentration of the penetration enhancer , the particle size decreased. Transcutol
showed the opposite behavior. The versatile characteristics of the incorporated
penetration enhancers could readily affect the particle size of the nanovesicles
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depending on the manner or the mode of the interaction of the penetration
enhancer with the phospholipid bilayer.
2. Most of the entrapment efficiency percentage results of penetration enhancer
nanovesicles showed biphasic behavior. It showed a large burst effect by adding
penetration enhancer concentration, followed by decreased entrapment efficiency
percentage values through a further increase of the penetration enhancer
concentration. In others, it showed the reverse behavior. For the cineole and
limonene penetration enhancer nanovesicles, the increase in entrapment efficiency
percent results could be attributed to the hydrophobic nature of these penetration
enhancers where they could boost the hydrophobicity of the lipid bilayer.
Limonene penetration enhancer nanovesicles showed higher entrapment
efficiency results than cineole penetration enhancer nanovesicles. This could be
ascribed to the lipophillicity of the terpenes that was evident from the log P values
for both terpens. Higher entrapment efficiency was obtained for levofloxacin with
the addition of the hydrophilic penetration enhancers as polyethylene glycol,
acting as co-solvents led to the enhancement of drug solubility in the aqueous core
of the penetration enhancer nanovesicles. PEG3-LV penetration enhancer
nanovesicles displayed the highest entrapment efficiency. For the transcutol
penetration enhancer nanovesicles loaded with levofloxacin, they showed low
entrapment efficiency percent if compared to other tested penetration enhancer
due to the difference in the physicochemical characteritics of levofloxacin and
transcutol. As a consequence of that, the solubility of the drug in the penetration
enhancer /aqueous phase was very limited as transcutol is hydrophilic surfactant
that has the tendency to be dissolved in the aqueous core of the vesicles rather to
be incorporated into the bilayered membrane.
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3. The penetration enhancer concentration used had great effect on drug
release. The addition of the hydrophilic penetration enhancers had a more
significant impact on the drug release due to the increased hydrophilicity of the
prepared vesicles thus enabling more levofloxacin release into the aqueous buffer.
T3-LV penetration enhancer nanovesicles displayed the highest release percent.
The results were shown to be in an increasing order in case of transcutol
penetration enhancer nanovesicles, in contrast to other penetration enhancer
nanovesicles.
Most of the formulations showed a biphasic behaviour as in case of limonene
and propylene penetration enhancer nanovesicles, by the initial increase of the
penetration enhancer, the release rate was increased. Then, the release rate was
decreased by further increase of the penetration enhancer concentration. Cineole
and polyethylene glycol penetration enhancer nanovesicles showed opposite
behaviour.
4. It was found that maximum drug permeated and deposited in the skin was
for transcutol penetration enhancer nanovesicles in comparison to propylene
glycol penetration enhancer nanovesicles. This might be attributed to the presence
of trancutol that makes the vesicles able to permeate the skin and their interaction
with the lipids of the stratum corneum. Where, it could be described as a
fluidizing effect on the stratum corneum, making the permeation for the vesicles
easier and more loaded and deposited in the dermis.
Chapter II: Preparation and characterization of proniosomal gel loaded
with levofloxacin.
The coacervation phase separation system is the most prevalent utilized
strategy for the preparation of proniosomal gels. Distinctive amounts of the
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surfactants, lecithin, and cholesterol were incorporated in the formulations to
discover their impact on the entrapment efficiency, in vitro release rate, and exvivo
permeation characteristics of the prepared proniosomal gels. The prepared
proniosomal gels loaded with levofloxacin were characterizied in terms of the
particle size, polydisperity index, zeta potential, entrapment efficiency, in vitro
release ,and ex vivo permeation.
from the obtained results, it was found that:
1. Among gel formulations, tween 80 had the largest vesicle size, whereas span
20 proniosomal gel formulation had the smallest vesicle size. It could be
attributed to the difference in the entrapment efficiency values. Where, the
entrapment efficiency of tween 80 was lower than that for span 20. It has been
proposed that, in general, vesicle size is dependent upon the alkyl chain length of
the surfactant, whereby a longer alkyl chain leads to a larger vesicle size.
2. The entrapment efficiency of proniosomal gels prepared with spans was
observed to be high in comparison to the proniosomes prepared from various
types of tween.
This can be attributed to the following reasons :
-The highly lipophilic segment of the drug was intercalated totally inside the
lipid bilayer lead to an increase in the entrapment efficiency.
-The alkyl chain length , phase transition temperatures and the HLB estimation
of the surfactant majorly affected the permeability of proniosomal gels.
3. Span 20 proniosomal gels exhibited the highest encapsulation efficiency in
comparison to others prepared by tweens.
4. It was clear that incorporating the drug molecules into proniosomal gels
resulted in a sustainable drug release.
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5. Span 80 exhibited a higher percentage of drug permeation and deposition
across various skin layers after 6 hours if compared to tween 80. Where, it might
be attributed to being the less lipophilic nature of the tween compared to span.
Therefore, it could be concluded that penetration enhancer nanovesicles and
proniosomal gels loaded with levofloxacin are promising carriers for dermal drug
delivery to enhance the bioavaibility and increase patient compliance.