nasal drug delivery

1. FORMULATION AND EVALUATION OF FLUOXETINE HYDROCHLORIDE
DRUG AS NASAL IN SITU GEL DRUG DELIVERY SYSTEM
A
Synopsis
of Proposed Research Work for M.Pharm Project Submitted to
Chhatrapati Shahu Ji Maharaj University, Kanpur
Under the guidance of
Mr. VINOD DOHAREY
LECTURER
C.S.J.M UNIVERSITY, KANPUR
Submitted by:
VIBHA BAJPAI
M.PHARM
DEPARTMENT OF PHARMACEUTICS
[Roll No. -2563012]
Year 2013-14
University Institute of Pharmacy
Chhatrapati Shahu Ji Maharaj University, Kanpur – 208 024

2. Nasal drug delivery
 I t is also a type of mucoadhesive drug delivery
system In this ,drugs are administered through nasal
cavity by different dosage forms like solutions ,
emulsions, gel.etc
 The nasal route is an attractive alternative to drug
administrations, and provides a direct access to the
systemic circulation.

3. MERITS OF NASAL DRUG DELIVERY
SYSTEM
 A rapid onset of action is possible through nasal
route, for the administration of systemically acting
products.
 Deposition of an active compound in the nasal cavity
results in avoidance of its degradation through the
‘‘first-pass’’ metabolism.

4.  Ease of self-administration/good patient compliance
 lower doses and less side effects
 quicker onset of pharmacological activity .
 Useful for both local & systemic drug delivery.
 For CNS drugs, better site for rapid onset of action
Ex. Inhalation anesthesia.

5. Mechanism of drug absorption
 drug passes through the mucous membrane of the
nasal cavity. Mainly 2 mechanisms are involved .
 The first mechanism – it involves an aqueous route
of transport.(paracellular route)
 Second mechanism – it involves transport of drugs
through lipoidal route (transcellular process) .
 it is mainly responsible for transport of lipophilic
drugs that show rate dependency on there
lipophillicity and molecular wt of drug.

6. INTRODUCTION
GEL
 Gels are an intermediate state of matter containing
both solid and liquid components. The solid
component comprises a three dimensional network
of inter connected molecule or aggregates which
immobilizes the liquid continuous phase.

7. In-Situ Gel Delivery Systems
 In-situ gelation is a process of gel formation at the
site of application after the composition or
formulation has been applied to the site.
 it permits the drug to be delivered in a liquid form.
 The in-situ gelation
compositions comprising a
drug, a film forming polymer and a gel forming ionic
polysaccharide (such as an alginate).

8. DRUG PROFILE
 DRUG NAME: fluoxetine
 is an antidepressant of the selective serotonin
reuptake inhibitor (SSRI) class.
 Fluoxetine is approved for the treatment of:
 major depression (including pediatric depression),
 obsessive-compulsive disorder (in both adult and
pediatric populations),

9. POLYMER PROFILE
 PLURONIC F 127
 A compound which has received considerable attention is
the
polyoxyethylene
/polyoxypropylene
/
polyoxyethylene triblock co-polymer pluronic F127
(polaxomer 407) the thermo reversible gelation .
 Gels of pluronic F127 have been explored for application
in ophthalmic, topical, nasal, rectal, subcutaneous,
intraperitoneal administration.
 There are, however, inherent problems associated with
triblock copolymers is results in the presence of di block
impurities.

10. SODIUM ALGINATE
 Alginic
acid is a linear block copolymer
polysaccharide consisting of β-D mannuronic acid
(M) and α-L guluronic acid (G) residues joined by
1,4-glycosidic linkage .
 Dilute aqueous solutions of alginates form firm gels
on the addition of di and trivalent metal ions.

11. OBJECTIVES OF PROPOSED STUDY
 The aim of the present study was to minimize the
unwanted toxic effects of fluoxetinehydrochloride by
kinetic control of drug release. Reduce hepatotoxicity
when given orally.
 The objective of present research work is to improve
bioavailability by formulating thermo reversible insitu nasal gel. Formulation was developed to reduce
the mucociliary clearance by using mucoadhesive
polymer in gel, thereby increasing the contact time
with nasal mucosa and hence improving the
absorption of drug.

12. VARIOUS APPROACHES OF INSITU
GELATION
•
pH‐triggered systems : cellulose acetate
phthalate(CAP)
latex,carbopol,
polymethacrilic
acid(PMMA),
polyethylene
glycol(PEG),
pseudolatexes.
• Temperature dependent systems: : chitosan,
pluronics,tetronics,xyloglucans,hydroxypropylmethy
l cellulose or hypromellose (HPMC).

13. •Ion‐activated systems: gelrite, gellan , hyaluronic
acid, alginates.
• UV induced gelation
• Solvent exchange induced gelation

14. BRIEF LITERATURE SURVEY
 ElKamel, et al., (2006), formulated environmentally responsive
ocular gel of carteolol HCl using gelrite as polymer. After in vitro
release studies they concluded that gelrite formulation (0.4%w/w)
containing 1% drug showed significantly improved bioavailability as
compared to commercial aqueous solution.
 D. I. Ha, et al., (2006), prepared thermo‐responsive and inject
able hydrogels based on hyaluronic acid and
(nisopropylacrylamide) and their drug release behaviours .
poly
 Sultana, et al., (2006), developed ophthalmic delivery system
for perfloxacin mesylate based on in situ gel of gelrite and
evaluated for rheological characterizations, antimicrobial efficacy,
in vitro release pattern. The developed formulation showed better
therapeutic efficacy than marketed preparation.

15.  Harish, N.M., et al., (2009), developed in situ
gel of clotrimazole for oral candidiasis using
pH‐triggered system containing carbopol 934P
(0.2‐1.4% w/v) and ion‐triggered system using
gellen gum (0.1‐0.75% w/v) along with HPMC E50
LV. Formulations were evaluated for gelling
capacity, viscosity, gel strength, bio‐adhesive
forces, spread ability, microbiological studies and
in vitro release. The optimized formulation was
able to release the drug up to 6 h. The formulation
containing gellen gum showed better sustained
release compared to carbopol based gels.

16. PLAN OF WORK
 Preformulation studies
 Determination of solubility of fluoxetine drug
 Determination of partition coefficient of drugs
 Melting point determination of drugs
 Study drug polymer interaction.
 Drug-excipient compatibility study
 . Preparation of standard curve of fluoxetine

17. 
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Preparation of in situ nasal gel
Evaluation of in situ nasal gel
In vitro evaluation of in situ gel.
Evaluation of Gelation study
pH of the gels
Content uniformity
Rheological studies
Gel strength determination
Determination of Mucoadhesive Strength
Drug release study
Permeation study
Stability studies

18. EVALUATION OF GELS
 CLARITY :The clarity of various formulations was
determined by visual inspection under black and
white background.
 pH OF FORMULATION: One ml quantity of each
formulation was transferred to a beaker and diluted
by using distilled water to make 25ml. pH of the
resulting solution was determined using digital pH
meter.

19.  DRUG CONTENT :One ml of formulation was taken in 10ml
volumetric flask, diluted with distilled water and volume adjusted
to 10ml. One ml quantity from this solution was again diluted
with 10ml of distilled water. Finally the absorbance of prepared
solution was measured at 261 nm by using UV visible
spectrophotometer.
 MEASUREMENT
OF GELATION TEMPERATURE:
Gelation Temperature, defined as the temperature at which the
liquid phase makes the transition to a gel, determined by using
method described by Miller and Donovan technique. A 2ml
aliquot of gel was transferred to a test tube, immersed in a water
bath. The temperature of water bath was increased slowly and left
to equilibrate for 5min at each new setting. The sample was then
examined for gelation, which was said to have occurred when the
meniscus would no longer move upon tilting the test tube to 900.

20.  VISCOSITY
MEASUREMENT
:The
viscosity
measurements were carried out by using Brookfield DV ProII model with spindle No.62.The instrument was equipped
with the temperature control unit and the sample were
equilibrated for 10 min before the measurement. The
viscosity was measured against increasing shear rate.
Measurement was taken at 40c and 340 c respectively
 GEL STRENGTH DETERMINATION :A sample of 50g
of the nasal gel was put in a 100 ml graduated cylinder and
gelled in a thermostatically controlled water bath at 37°C. A
weight of 35 g was placed onto the gelled solution. The gel
strength, which is an indication for the viscosity of the nasal
gel at physiological temperature, was determined by the
time in seconds required by the weight to penetrate 5 cm
into the gel.

21.  DETERMINATION OF MUCOADHESIVE FORCE
 The mucoadhesive strength of each formulation was determined by measuring
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the force required to detach the formulation from goat nasal mucosal tissue by
using a modified chemical balance. A section of nasal mucosa was cut from the
goat’s nasal cavity and mucosal side was instantly fixed into each glass vial using
a rubber band. The vials with nasal mucosa were stored at 37°C for 5 minutes.
Then next vial with a section of mucosa was connected to the balance in inverted
position while first vial was placed on a height adjustable pan. Fixed amount of
sample of each formulation were placed onto the nasal mucosa of first vial. Then
the height of second vial was adjusted so that mucosal surfaces of both vials come
in intimate contact. Two minutes contact time was given to ensure intimate
contact between tissues and the sample. Weight was increased in the pan until
vials got detached. The bioadhesive force, expressed as the detachment stress in
dyne/cm2, was determined from the minimal weights that detached the tissues
from the surface for each formulation using the following equation.
Detachment stress (dyne/cm2) = m x g /A
Where, m =Weight required for detachment of two vials in gm
g = Acceleration due to gravity [980cm/s2]
A = Area of tissue exposed
The nasal mucosa was changed for each measurement.

22.  IN-VITRO RELEASE STUDIES:Drug release from in situ gel was
carried by nasal diffusion cell, using cellophane membrane (mol.wt.12,
000-14,000) with permeation area of 0.8cm2. 60ml of phosphate buffer
pH 6.4 was placed in the acceptor chamber and gel containing drug
equivalent to 10mg was placed in donor chamber. At predetermined time
points, 1ml sample was withdrawn from the acceptor compartment with
continuously replacing by fresh buffer, (pH 6.4 phosphate buffer) for a
period of 5 h. The samples were suitably diluted and measured
spectrophotometrically at 261 nm. The concentration of drug was
determined from a previously constructed calibration curve.
 IN –VITRO PERMEATION STUDY:
Fresh nasal tissue is require from nasal cavity of sheep . Tissue was
inserted in the nasal diffusion cell with permeation area of 0.8 cm2. Gel
containing drug equivalent to 10mg was kept in donor compartment. At
predetermined time point sampling was done. Blank samples (without
drug) were run simultaneously throughout the experiment. Amount of
drug permeated was determined by UV spectrophotometer at261 nm.

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26. Thank you