الفهرس 
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Abstract
Olanzapine is a third generation atypical antipsychotic approved by the Food
and Drug Administration (FDA) in 1996. Olanzapine is used to treat
schizophrenia and delirium and significantly improves both the positive and
negative symptoms of schizophrenia compared to placebo. Olanzapine may also
reduce opioid requirements and be “opioid sparing” in cancer patients with
uncontrolled pain who also have cognitive impairment or anxiety. Olanzapine is
a good second line antiemetic for patients with nausea refractory to
butyrophenones or phenothiazines or who have extrapyramidal reactions to
usual antiemetics. Olanzapine’s activity at multiple receptors is similar to
methotrimeprazine and, as a result, has a potential role in the treatment of
nausea and vomiting refractory to standard medications.
Olanzapine is presently available as tablet, which after administration shows
extensive first-pass metabolism, with approximately 40 per cent of the dose
metabolized before reaching the systemic circulation. Therefore, orally
disintegrating wafers and intramuscular injection are available to overcome the
bioavailability problems.
Since the target site of action for olanzapine is the brain, a strategy is thereby
desirable which, not only improves the bioavailability by preventing extensive
first-pass metabolism, but also provides targeting to the receptor site and
bypasses the BBB so as to achieve the desired drug concentration at the site of
action. This would prevent availability of the drug at non-targeting sites and
reduce its side effects. A controlled release IN formulation for olanzapine
instead of conventional oral dosage form would be useful. The IN formulation
would improve patient compliance, provide brain targeting for the drug, thus
more predictable brain drug level would be achieved and thereby, reduces its
side effects. IN administration offers a practical, non-invasive and an alternative route of administration for rapid drug delivery to the brain. Direct transport of
drugs to the brain circumventing the brain barriers following IN administration
provides a unique feature and better option to target drugs to the brain.
Vesicular systems play an important role in nasal drug delivery into the
systemic circulation by overcoming limitations of the nasal route such as ciliary
clearance and breakdown by nasal peptidase enzyme. The vesicular systems as
liposomes, cubosomes, transferosomes, virosomes, discosomes and
pharcosomes are highly ordered assemblies of one or several concentric lipid
bilayers formed when certain amphiphilic building blocks are confronted with
water.
Liposomes are spherical microscopic vesicles composed of one (unilamellar)
or more (multilamellar) concentric lipid bilayers, arranged around a central
aqueous core. Liposomes have been investigated as carriers of various
pharmacologically active agents such as antineoplastic drugs, antimicrobial
drugs, chelating agents, steroids, vaccines and genetic materials via oral, ocular,
topical, transdermal and IN administration. Liposomes provide an efficient drug
delivery system because they can alter the pharmacokinetics and
pharmacodynamics of the entrapped drugs.
Cubosomes are discrete, sub-micron, nanostructured particles of
bicontinuous cubic liquid crystalline phase. For lipophilic drugs, cubosomes
have been proposed as a delivery system which may provide both a
solubilization benefit (increased drug payload) and also a means for controlled
or sustained release. Cubosomes exhibit bioadhesive properties which make
them useful for gastrointestinal, lung, nasal, oral, buccal, rectal and vaginal drug
delivery. Transfersomes are specially optimized ultradeformable (ultraflexible) lipid
supramolecular aggregates able to penetrate the mammalian skin intact. Each
transfersome consists of at least one inner aqueous compartment which is
surrounded by a lipid bilayer with specially tailored properties due to the
incorporation of “edge activators” into the vesicular membrane.
The aim of the present study was to utilize cubosomal and transfersomal
vesicles as drug carrier systems for developing a novel intranasal formulation
for olanzapine capable of targeting the drug to brain.
Chapter I: Preparation and characterization of olanzapine cubosomal
vesicles
Olanzapine cubosomes were prepared by the use of L–
–
phosphatidylcholine and each of Poloxamer 407 (Plx 407) and Poloxamer 188
(Plx 188) at different phospholipid : Plx molar ratios adopting the thin layer
evaporation technique. The influence of Plx type and L–
–phosphatidylcholine :
Plx molar ratio on cubosomal morphology, vesicle size, drug entrapment,
vesicle membrane elasticity and in-vitro drug release was studied.
Results obtained can be summarized as follows:
1. Olanzapine cubosomes could be prepared by the use of L–
–
phosphatidylcholine and Plx 407 or 188 at phospholipid : Plx molar ratios of
100:1, 40:1, 20:1 and 10:1 adopting the thin layer evaporation technique.
2. TEM photographs showed the typical cubic shape of olanzapine cubosomes.
3. Olanzapine cubosomes prepared by the use of Plx 188 were smaller in size
than those prepared using Plx 407.
4. Cubosomes containing Plx 407 had, generally, high drug entrapment
efficiency compared to those containing Plx 188 5. Cubosomes containing phospholipid : Plx 188 in the molar ratios 20:1 and
10:1 were characterized by having high elasticity.
6. Cubosomes prepared by the use of Plx 407 or Plx 188 at the same
phospholipid : Plx molar ratio had more or less similar values for RE.
7. The cubosomal formulation containing phospholipid : Plx 188 in the molar
ratio 10:1 was characterized by having the highest vesicle membrane
elasticity in addition to having reasonable values for vesicle size, drug
entrapment efficiency and drug release efficiency.
8. DSC studies for the above formulation confirmed incorporation of
olanzapine inside the lipid bilayers of the vesicles.
On the basis of the above results, the olanzapine cubosomal formulation
containing phospholipid : Plx 188 in the molar ratio 10:1 was selected for the
biological studies.
Chapter II: Preparation and characterization of olanzapine transfersomal
and liposomal vesicles
Transfersomal vesicles were prepared by the use of L–
–
phosphatidylcholine and different edge activators (SDC, Span® 60, Cremophor®
EL, Brij® 58 and Brij® 72) at different phospholipid :edge activator molar ratios
adopting the thin layer evaporation technique. Olanzapine liposomal vesicles
were prepared using L–
–phosphatidylcholine adopting also the same
technique. The influence of edge activator type and L–
–phosphatidylcholine :
edge activator molar ratio on transfersomal morphology, vesicle size, drug
entrapment, vesicle membrane elasticity and in-vitro drug release was studied.
Results obtained can be summarized as follows: 1. Olanzapine vesicles could be prepared by the use of L–
–
phosphatidylcholine with each of the edge activators SDC, Span® 60,
Cremophor® EL and Brij® 72 at phospholipid : edge activator molar ratios of
100:1, 40:1, 20:1, 10:1 and 5:1 and with Brij® 58 at a molar ratio of 5:1
adopting the thin layer evaporation technique.
2. TEM photographs showed a predominant spherical shape for all examined
vesicles, except formulations containing phospholipid : Brij® 58 at molar
ratios of 100:1, 20:1 and 10 :1 which showed a dendritic shape.
3. Diameters of olanzapine vesicles ranged from 310 to 885 nm and differed
according to the edge activator type in the order of Cremophor® El > Brij®
72 > SDC > Span® 60.
4. Olanzapine entrapment efficiency for the prepared vesicles ranged from
55.17 to 75.59 % ; it differed according to the edge activator type and its
concentration.
5. L–
–phosphatidylcholine together with SDC or Span® 60 were capable to
form olanzapine transfersomal vesicles with high deformability at
phospholipid : edge activator molar ratios of 40:1, 20:1 and 10:1 for SDC
and of 10:1 and 5:1 for Span® 60.
6. Olanzapine transfersomal vesicles prepared by the use of SDC or
Cremophor® El at the phospholipid : edge activator molar ratios of 10:1 and
5:1 as well as those prepared using Span® 60 at a molar ratio of 5:1 were
characterized by having the highest values for drug release efficiency.
7. Olanzapine transfersomal vesicles containing L–
–phosphatidylcholine and
SDC or Span® 60 at the phospholipid : edge activator molar ratio 10:1 were
characterized by having the highest elasticity in addition to having
reasonable values for vesicle size, drug entrapment efficiency and drug
release efficiency.
8. DSC studies for the above transfersomal vesicles as well as for the liposomal
ones confirmed incorporation of olanzapine inside the lipid bilayers of these
vesicles.
On the basis of the above findings, the olanzapine transfersomal vesicles
containing L–
–phosphatidylcholine and each of SDC and Span® 60 at the
phospholipid : edge activator molar ratio 10:1 as well as the liposomal vesicles
were selected for the biological studies.
Chapter III: Biological studies on olanzapine vesicles
In this chapter, biological investigations including pharmacokinetic studies,
brain drug targeting efficiency-determinations and histopathological
examinations, on Wister albino rats, were performed for the following selected
IN olanzapine vesicular formulations:
1. Olanzapine cubosomal formulation containing L–
–phosphatidylcholine :
Plx 188 in the molar ratio 10:1.
2. Olanzapine transfersomal formulation containing L–
–
phosphatidylcholine : SDC in the molar ratio 10:1.
3. Olanzapine transfersomal formulation containing L–
–
phosphatidylcholine : Span® 60 in the molar ratio 10:1.
4. Olanzapine liposomal formulation.
Results obtained can be summarized as follows:
1. Maximum olanzapine concentration in rat plasma varied in the order of IV
drug solution > transfersomes containing SDC > cubosomes > transfersomes
containing Span® 60 > liposomes.
2. Olanzapine concentration in rat plasma reached its maximum value 10 min
following administration of the IV solution, the cubosomal formulation and the transfersomal formulation containing SDC. For the transfersomal
formulation containing Span® 60 and the liposomal formulation, drug
concentration attained its maximum value after 30 and 5 min, respectively.
3. Maximum olanzapine concentration in rat brain followed the order of IV
solution > transfersomes containing Span® 60 > cubosomes > transfersomes
containing SDC > liposomes.
4. Maximum olanzapine concentration in rat brain was achieved 30 min
following IV and transfersomal vesicle administration. For the cubosomal
and liposomal vesicles, the maximum drug concentration was reached after
60 and 10 min, respectively.
5. The AUC0-360min for olanzapine in rat plasma varied in the order: IV solution
> transfersomes containing Span® 60 > cubosomes > transfersomes
containing SDC > liposomes.
5.1. The values of absolute drug bioavailability
100
( )
( )
0 360min
0 360min x
AUC IV
AUC IN
− for the cubosomal and transfersomal
vesicles were higher than that for the liposomes. Among the cubosomal
and transfersomal vesicles, the AB-value varied as follows: transfersomes
containing Span® 60 > cubosomes > transfersomes containing SDC.
5.2. The relative drug bioavailability
[ ( ) AUC ( )] 100 0 360min 0-360min AUC cubosomes or transfersomes liposomes x − varied in
the order of transfersomes containing Span® 60 > cubosomes >
transfersomes containing SDC. The values of AUC0-360min for these
vesicles are 3.5, 2.5 and 1.5 times, respectively higher than that for the
liposomes.
6. Both olanzapine cubosomal formulation and the transfersomal formulation
containing Span® 60 possessed the highest values for AUC0-360min in rat brain, while the liposomal one had the lowest value. The transfersomal
formulation containing SDC had an intermediate value.
7. The olanzapine transfersomal formulation containing Span® 60 was
characterized by having high values for t½ and MRT in rat plasma.
8. Values of MRT for olanzapine in rat brain following IV injection as well as
cubosomal and transfersomal IN administration were higher than that of the
liposomal vesicles.
9. Olanzapine cubosomal vesicles as well as the transfersomal vesicles
containing SDC possessed the highest efficiency for targeting the drug to rat
brain.
10. The main drug transport pathway to rat brain for the cubosomes and the
transfersomes containing SDC was the systemic circulation, while for the
transfersomes containing Span® 60 and the liposomes, the drug transport
was via both systemic and olfactory routes.
11. Histophathological examinations revealed that none of the severe signs such
as appearance of necrosis, sloughing of epithelial cells or haemorrhage was
detected in any of the tested rats.
On the basis of the present study, it can be concluded that both cubosomal
and transfersomal vesicles can be considered as suitable drug carrier systems for
nasal delivery of olanzapine. These systems provide brain drug targeting, thus
more predictable brain drug levels with consequent reduction of olanzapine side
effects would be achieved.