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

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.

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.

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.

 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.

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.

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).

DRUG PROFILE

DRUG NAME: fluoxetineis 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),

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.

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.

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 in-situ 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. 

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,hydroxypropylmethyl cellulose or hypromellose (HPMC).

•Ion‐activated systems: gelrite, gellan , hyaluronic acid, alginates.

• UV induced gelation• Solvent exchange induced gelation

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 poly (nisopropylacrylamide) and their drug release behaviours .

  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.

 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.

PLAN OF WORK

Preformulation studiesDetermination of solubility of fluoxetine drug Determination of partition coefficient of

drugs Melting point determination of drugsStudy drug polymer interaction. Drug-excipient compatibility study. Preparation of standard curve of fluoxetine

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 

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.

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.

VISCOSITY MEASUREMENT :The viscosity measurements were carried out by using Brookfield DV Pro-II 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.

DETERMINATION OF MUCOADHESIVE FORCE  The mucoadhesive strength of each formulation was determined by measuring 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. 

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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