الفهرس 
Nasal anatomyOnly 14 pages are availabe for public view
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Abstract
There has been a great focus on intranasal drug delivery as an alternative
route for both oral and systemic routes besides its brain targeting. The high
vasculature of the nasal mucosa and the direct connection to the brain through
the olfactory bulb in the nose offer superior advantages in terms of rapid action,
non-invasiveness and brain targeting and thus improve the patient compliance.
Based on all these facts, this study focused on the development of an efficacious
intranasal formulation of the antiemetic drug dimenhydrinate. DMH is an
ethanolamine antihistamine used as an OTC drug for the prevention and
treatment of nausea, vomiting, dizziness, and vertigo associated with motion
sickness. Moreover, it is used for the prevention of postoperative and drug
induced vomiting.
The main goal of this work was to bypass the first pass metabolism
experienced by the oral delivery of the drug and to enhance its brain
bioavailability, in addition to achieving rapid drug delivery in emergency
vomiting control. For achieving these goals two approaches were attempted; the
first was to formulate an in situ mucoadhesive nasal formulation thus increasing
the residence time and the contact with the nasal mucosa for better drug
absorption, while the second approach was to entrap the drug in penetration
enhancer containing vesicles (PEVs) which are vesicular systems consisting of
one or more concentric spheres of lipid with a penetration enhancer which are
then incorporated in the in situ gelling system creating a composite system.The work in this thesis was divided into three chapters
Chapter I: Preparation and characterization of dimenhydrinate
nasal mucoadhesive in situ gelling systems
This chapter dealt with the formulation and characterization of
dimenhydrinate thermosensitive in situ gels. Using the cold method
formulations containing different concentrations of the thermosensitive
polymers P407 and P188 were prepared and the mucoadhesive sodium
hyaluronate was then incorporated. The formulations were characterized
through the following studies; gelation temperature, viscosity, in vitro drug
release and mucoadhesion. Stability of the selected dimenhydrinate in situ
forming gel stored in fridge was conducted as well.
The results of this work revealed the following:
In situ forming gels of dimenhydrinate were successfully prepared using
poloxamer polymer.
It was revealed that the use of poloxomer 407 (P407) didn’t give gel in the
physiological temperature range, and that a combination of P407 and P188
should be used.
Chitosan was not a suitable mucoadhesive agent for the prepared in situ
gelling systems of dimenhydrinate, and only hyaluronic acid was
successfully incorporated.
The physiological gelation temperature range after the addition of HA, was
only achieved at P407/ P188 ratios of (19/12) and (20/11) respectively.
The addition of the mucoadhesive HA by a concentration of 0.5% had a
significant impact on gelation temperature of in situ gelling systems while
increasing the concentration to 1% showed insignificant difference on the
former (containing 0.5% HA). Increasing the temperature from 25 ˚C to 37 ˚C caused the viscosity of the in
situ gelling systems to be significantly increased due to the gel formation,
proving the thermosensitivity of the polymer.
The variation in poloxomer composition caused non-significant increase in
viscosity of in situ gelling systems, while the addition of the mucoadhesive
agent HA generally increased the viscosity of the formulations in a
significant way.
The poloxomer based in situ gelling systems prepared provided a sustained
release of dimenhydrinate over 6 hours, with a cumulative percentage of
drug released reaching 66.28% after 6 hours.
Generally, the addition of HA led to significant increase in the mucoadhesive
force of the formulations.
The in situ forming gel formula (F27) composed of 19% P407, 12% P188
and 1% HA as mucoadhesive agent was selected for the creation of
nanocomposite in situ forming gelling system in the next chapter as it
showed gelation at the physiological temperature with acceptable viscosity
and mucoadhesion.
Chapter II: Preparation and characterization of dimenhydrinate
nanocomposite in situ forming gels.
This chapter dealt with the formulation, and characterization of
dimenhydrinate vesicles (Penetration enhancer containing vesicles). PEVs were
prepared by the reversed phase evaporation technique (REV) using different
amounts of phospholipid in the presence of the penertration enhancers labrasol
and transcutol. The prepared PEVs were characterized through the following
studies; EE%, particle size analysis, zeta potential and PDI. Stability of the
dimenhydrinate PEVs stored at fridge for three months was conducted as well.
The PEVs with optimum dimenhydrinate entrapment efficiency and acceptable particle size and PDI in the nano range were selected for further incorporation in
a thermosensitive in situ forming gelling system previously optimized in chapter
I while trying other poloxomer ratios. The prepared nanocomposite in situ
forming gels were then evaluated for their gelation temperature, viscosity, in
vitro release, mucoadhesion and the stability was conducted upon three months
storage period in terms of measuring the gelation temperature.
The results of this work revealed the following:
The dimenhydrinate loaded PEVs were successfully prepared by the
reversed phase evaporation technique (REV) using labrasol and transcutol
as penetration enhancers.
The EE% for dimenhydrinate in PEVs ranged from 78.915 ± 3.46 % to
95.35 ± 0.15%.
The EE% of DMH was not affected by the phospholipid amount; where by
scaling up the amount of phospholipid there was an insignificant variation
in EE% without certain pattern.
The particle size of the formed PEVs ranged from 59.46 ± 1.6 nm to 266.5
± 20.5 nm. It was clear that by increasing the amount of phospholipids the
particle size significantly increased.
Increasing the amount of the penetration enhancers (PEs) labrasol and
transcutol resulted in a significant decrease in the particle size.
The polydispersity index (PDI) values of the prepared PEVs were in the
range of 0.251 ± 0.07 to 0.75 ± 0.05.
Storage for three months resulted in a significant increase in particle size of
PEVs of formulae (K1-K3) and an insignificant increase in particle size of
PEVs of formulae (K4-K6).
The zeta potential of the PEVs of all the PEVs formulae has shown an
insignificant change upon storage. TEM showed the outline and the core of spherical vesicles.
Incorporating the selected DMH loaded PEVs in the selected in situ gel with
the combination of P407 and P188 at a ratio of 19% and 12% respectively
increased the gelation temperature dramatically above the physiological
required temperatures.
The DMH loaded nanocomposite in situ gelling formula (K14) with %w/v
(P407/P188) ratio of (18.5/11.5) and (K15) with %w/v (P407/P188) ratio of
(18.75/11.25) exhibited gelation temperature in the physiological range
(32.83 ± 1.04 ˚C and 35.67 ± 0.29 ˚C respectively).
The viscosity of the DMH loaded PEVs (K4) was not affected by
temperature increase from 25 ˚C to 37 ˚C while the nanocomposite in situ
gelling formula showed significant viscosity increase.
The formulae showed a satisfactory sustained drug release rates within 6
hours. The percentage of drug release from the PEVs formula (K4) ranged
from 4.94 ± 0.44% after the first 15 minutes to 46.11 ± 1.71% at the end of
the 6 hours.
The DMH loaded nanocomposite in situ gelling formula (K15) containing
poloxamer and the mucoadhesive HA after the first 15 minutes showed
percentage of drug release of 2.66 ± 1.17% and after the 6 hours the
percentage of drug release was 24.99 ± 1.89%.
The DMH loaded nanocomposite in situ gelling formula (K15) showed
higher mucoadhesiveness than the DMH loaded PEVs (K4) owing to the
presence of poloxamers and hyaluronic acid in the former.
The gelation temperature of the stored DMH loaded nanocomposite in situ
gel (K15) was 34 ± 0.5 ˚C, which lied in the physiological range.
The DMH loaded PEVs (K4) composed of 600 mg phospholipids and
penetration enhancers (labrasol and transcutol) each 1 ml in addition to 200
mg DMH and 0.5 ml PEG 400 as a solubilizer was selected as a epresentative to a drug loaded PEVs for further conduction of in vivo
experiments in the next chapter.
The DMH loaded nanocomposite in situ gel (K15) composed of 600 mg
phospholipids and penetration enhancers labrasol and transcutol each 1 ml
in addition to 200 mg DMH and 0.5 ml PEG 400 as a solubilizer added to
them (P407:P188) at ratio of (18.75:11.25) % w/v and 1% HA as a
mucoadhesive, it was selected as a representative to DMH nanocomposite in
situ gelling system for conduction of in vivo study in the next chapter
Chapter III: Pharmacodynamic Study on the selected intranasal
in situ gelling formulae of dimenhydrinate
This chapter involved the examination of the in vivo therapeutic
effectiveness of the selected formulae prepared in chapters I and II. This was
done by evaluating the ability of the selected formulae to prevent the cisplatin
induced pica effect in rats which was used as an animal model analogue to
motion sickness.
Cisplatin as a pica inducing agent increases the kaolin intake, decreases
the food and water intake and decreases the gastric emptying, resulting in an
increase in the stomach content weight. The food, water and kaolin intake were
assessed before and after cisplatin injection, the selected formulae were given
before the cisplatin in order to test the efficacy of the formulae in preventing
pica effect. After that the rats were killed by decapitation, and the gastric
content for each rat was weighed.
The work in this chapter included the following:
1. The three chosen formulae from chapters I and II to be studied for their
intranasal antiemetic response in cisplatin induced pica models in rats were
prepared.Six groups of rats were used, each group included 8 rats, and each animal
was placed in an individual cage for a three days habituation period prior to
the start of the experiment. group I acted as normal control, while group II
rats acted as cisplatin control as they were subjected to pica induction with
no prophylactic formula.
3. A thick paste of kaolin (China clay) was prepared by mixing kaolin with 1%
gum Arabic.
4. Before the cisplatin intraperitonial injection (i.p.), three groups of rats were
given the dimenhydrinate formulae intranasally; a formula for each group
and a fourth group was orally given the marketed Dramenex®.
5. The food, water and kaolin intake of the six groups were assessed for three
days before induction. The 24 hours post induction (cisplatin intraperitoneal
injection) food, water and kaolin intake were also assessed in order to test
the efficacy of the formulae in preventing pica effect.
6. After 24 hours of observation and assessment the rats were killed by
decapitation, and gastric content was weighed.
7. Autopsy samples were taken from the nose of scarified rats after volume of
50 µl containing 1 mg dimenhydrinate of the selected final two formulae of
chapters I and II were administrated in each nostril of male Wistar rats
weighing 130-150 g by 24 hours for histopathological study.
The results of this work revealed the following:
Cisplatin induced pica effect (consumption of material without nutritional
value as kaolin) when injected intraperitonially to rats.
Formulae (K4), (F27) and (K15) were administered intranasally 15 min after
the oral Dramenex® and at a lower dose. Oral Dramenex® and the intranasal
(K4), (F27) and (K15) showed general significant increase in food and water
intake and decrease in kaolin consumption and stomach content weight relative to cisplatin injection except (K4) whose decrease in the stomach
content weight was insignificant.
The DMH nanocomposite in situ gelling formula (K15) showed comparable
results to that of the marketed oral Dramenex® in reversing the cisplatin
induced actions (decrease in food and water intake, and increase in kaolin
consumption) at a lower dose of DMH and faster onset of action.
The DMH loaded PEVs formula (K4) and the DMH in situ gelling formula
(F27) were comparable to the marketed oral Dramenex® in the water intake
and kaolin consumption experiments at a lower dose of DMH and faster
onset.
In order of superiority in reversing the motion sickness simulated condition
induced by cisplatin, the formulae were arranged in the following order:
DMH nanocomposite in situ gelling formula (K15) > DMH in situ gelling
formula (F27) > DMH loaded PEVs formula (K4). This highlights the
effectiveness of the nanocomposite in situ gelling system compared to the
vesicular system.
The DMH nanocomposite in situ gelling formula (K15) and DMH in situ
gelling formula (F27) were found to be safe on nasal mucosa of rats, as
evident by the preservation of the normal histological structure of the nasal
mucosa.
These results demonstrate that the prepared DMH nanocomposite in situ
nasal gel was efficient in reversing the symptoms associated with motion
sickness compared to the oral marketed product with lower dose and faster
onset of action avoiding the limitations of the oral route. The studied
nanocomposite poloxomer in situ gel composed of the PEVs can be
considered a suitable drug carrier system for the nasal delivery of DMH.