A Pharmaceutical Study on Oral Self-Nanoemulsifying Delivery System of Sertraline Hydrochloride for Enhanced Dissolution and Bioavailability / Amira Mohsen Abd EL Kader ; Supervised by Mahmoud M. Ghorab, Hussein O. Ammar.

Thesis (Ph.D.)-Cairo University, faculty of pharmacy, department of pharmaceutics, 2015.

Includes bibliographical references.

Depression is a prevalent psychiatric disorder with estimates reaching as
high as 21%. For nearly 2,500 years, depression has been described as
one of the most common illness of humankind, but only recently it has
commanded major public health interest. It is manifested by a depressed
mood, loss of pleasure in daily activities, sleep disturbances, cognitive
difficulties and psychomotor disturbances.
Depression is an important global public health problem due to both its
relatively high lifetime prevalence and the significant disability that it
causes. Without treatment, depression has the tendency to assume a
chronic course, to recur, and to be associated with increasing disability
over time.
Currently, different classes of antidepressants are available, each with
specific mechanism of action. Classes of antidepressants include,
serotonin selective reuptake inhibitors, serotonin norepinephrine reuptake
inhibitors, selective norepinephrine reuptake inhibitors, serotonin
antagonist/reuptake inhibitors, tricyclic and tetracyclic antidepressants
and many others.
Sertraline HCl – a selective serotonin re-uptake inhibitor (SSRI) – is
indicated for the treatment of depression and anxiety disorders, including
obsessive-compulsive disorder, panic disorder and post-traumatic stress
disorder. It is considered suitable for the treatment of depressive
symptoms in elderly patients, including those with Alzheimer’s disease
(AD), as it has minimal anticholinergic activity and is essentially devoid
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of cardiovascular effect. Furthermore, sertraline HCl may be useful in the
management of other behavioural problems experienced by AD patients
that are likely mediated by the serotonergic system, such as anxiety,
irritability and aggression.
Sertraline is administered orally in a daily dose of 50 mg. But various
problems are associated with its oral delivery such as extensive first-pass
metabolism, gastrointestinal disturbances such as nausea, dry mouth,
diarrhea, decreased appetite etc., and ultimately its poor bioavailability
(40–45%), which required this drug to be taken in high doses in order to
maintain adequate plasma levels.
Sertraline hydrochloride is practically insoluble in water. Its
bioavailability is expected to be limited by its dissolution rate. To
overcome these problems, various formulation strategies are exploited
including the use of surfactants, lipids, permeation enhancers,
micronisation, salt formation, cyclodextrin complexation, nanoparticles
and solid dispersions.
Most of the new drug candidates in development today are sparingly
soluble and associated with poor bioavailability. In recent years, much
attention has been focused on lipid-nanoemulsion formulations with
particular emphasis on self-nanoemulsifying or self-emulsifying drug
delivery systems (SNEDDS and SEDDS) to improve oral bioavailability
of poorly water-soluble drugs.
Oral-based drug delivery system is the most common way to deliver
drugs into the blood stream. The water-soluble drugs can diffuse freely
and easily in gastrointestinal tract and they have a high bioavailability.
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However, more and more drugs being discovered nowadays with the
advances in biotechnology and pharmaceutical technology are oil-soluble.
One way to deliver oil-soluble drugs is to incorporate the drug into an
inert lipid vehicle, such as nanoemulsions, oils, surfactants, dispersions
and liposomes.
Nanoemulsions are isotropic, thermodynamically stable systems and the
droplets of nanoemulsions are of very small size. Self-nanoemulsifying
drug delivery system (SNEDDS) is a pre-mixture of drug, oil, surfactant
and cosurfactant that can be used to deliver oil-based drugs. Upon gentle
shaking and gastric juice dilution in stomach, it can form nanoemulsion
spontaneously.
Preparation of sertraline HCL formulation, presents a challenge in the
development of an oral dosage form because of its poor solubility. In
recent years, self-emulsified formulations gained more attention because
of their ability to improve aqueous solubility and bioavailablity of a
variety of drugs. SNEDDS formulations are normally prepared as liquids
and dispensed in form of soft or hard gelatin capsule filled which give
rise to some drawbacks such as interaction of the fill with the capsule
shell, risks of leakage when they are filled into hard gelatin capsules and
limited shelf-life. In recent years, there is a growing trend to formulate
solid SNEDDS by adsorbing liquid SNEDDS onto suitable solid carriers.
Such solid SNEDDS can be easily filled in capsules and overcome the
disadvantages of liquid formulations described above and on oral
administration, they readily form microemulsion in vivo; presenting the
drug in nano-sized and ‘ready to absorb’ form.

Text in English, abstracts in English & Arabic.