- Corresponding Author:
- A. V. Bhalerao*
Padm. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-411 018, India
E-mail: [email protected]
Ondansetron is a serotonin receptor antagonist used in the management of nausea and vomiting that is associated with cancer chemotherapy. There is a need for intranasal delivery due to poor bioavailability of drug because of first pass effect. The objective of this study was to develop an intranasal delivery system of ondansetron hydrochloride using thermo-sensitive polymer PF127 and mucoadhesive polymer hydroxypropylcellulose. Due to increase in bioadhesive polymer concentration, there was increase in bioadhesion strength, at the same time there was decrease in the spredability. An in vitro diffusion study revealed that viscosity of the vehicle has an influence on drug. The release of ondansetron hydrochloride from the gel matrix showed diffusion- controlled.
Ondansetron hydrochloride, in situ Gel, intranasal delivery system, bioadhesive polymer
Ondansetron hydrochloride is a serotonin (5HT3) receptor antagonist used in the management of nausea and vomiting that is associated with cancer chemotherapy. There is a need for intranasal delivery due to poor bioavailability of drug because of first pass effect . The objective of this study was to develop an intranasal delivery system of ondansetron hydrochloride using thermo sensitive polymer PF127 and mucoadhesive polymer.
Materials and Methods
Lutrol F127 (PF127 and hydroxypropylcellulose (Klucel LF) was procured from Signet Chemicals Mumbai. Ondansetron hydrochloride was received as a gift sample from Dr. Reddy?s Lab Hyderabad.
Nasal formulations consisting of aqueous gels of PF127 containing 18% (w/v) of polymer were prepared using the method described by Schmolka . Composition was given in Table 1. The prepared formulations were evaluated for appearance, clarity, pH, gelation temperature, spredability, bioadhesion strength, viscosity, drug content and diffusion study. Gelation temperature (TG) was measured by visual inspection using a modifi cation of Miller and Donavan technique . Rheological studies were performed using a Brookfield digital CAP 2000+ viscometer to determine viscosity. Spreadability in terms of flow ability of various mucoadhesive thermoreversible gels was determined . The bioadhesive potential of each formulation was determined by measuring the weight required to detach the formulation from nasal mucosal tissue using a method described by Yong et al. .
|Poloxamer 407 (mg)||900||900||900||900||900|
|Propylene glycol (ml)||0.9||0.9||0.9||0.9||0.9|
|Sodium metabisulphite (mg)||12.5||12.5||12.5||12.5||12.5|
|Benzalkonium chloride (mg)||1||1||1||1||1|
|Distilled water q.s.||5ml||5ml||5ml||5ml||5ml|
Table 1: The Formulae for the Preparation of In Situ Nasal Gels with Varying Concentration of Hydroxylpropylcellulose
In vitro release studies were carried out in the following manner
A glass cup with a cross-sectional area of 7.5 cmnd and adhesive tape, and inverted under the surface of 500 ml of simulated nasal fl uid of pH 5.5 at 35±0.5° in USP XXIII Type I Dissolution Test Apparatus with a speed of 50 rpm. Five millilitres of aliquots were withdrawn at specifi ed time intervals and immediately replaced with fresh dissolution medium . The drug content in the withdrawn samples was determined spectrophotometrically at 310 nm using a UV/Vis spectrophotometer and simulated nasal electrolyte solution as a blank.
Results and Discussion
All gels were glassy clear in appearance. Gel pH was in the range of 5.3 to 5.6 which was in the range of pH at the absorption site (4.5-6.5). In the preliminary studies, the minimum concentration of PF127 that formed gel below 340 was found to be 18% wt/vol. The plain formulation (F1) without bioadhesive polymer has minimum bioadhesion 529.2 dyne/cm2 but maximum spredability and 88.2% drug release after 8 h. In all formulations 0.2% w/v bioadhesive polymer showed maximum spredability while 0.7% w/v showed minimum spredability (Table 2). There was drastic increase in viscosity at gelation temperature (Table 3, fi g. 1). It was observed that the concentration of bioadhesive polymer increased from 0.2% to 0.7% showed retardation of ondansetron hydrochloride release from 75.2% to 54.9% (fi g. 2).
|Formulation||Appearance||pH||Gelation||Drug content||Bioadhesive Strength||Spredability in|
|Temperature (°)||(%)||(dyne/cm2)||distance (cm)|
Table 2: Chracteristics of all Formulations
|Formulation||Viscosity at||Viscosity at||Gelling point|
|250 in cP||350 in cP||by graph (0)|
Table 3: Viscosity of Nasal Formulation at different Temperatures
Figure 1: Viscosity of gels containing various concentrations of
Viscosity measurements at different temperatiures were made for gels containing various concentrations of HPC (hydroxypropylcellulose), (─◆─) F5 0.7% HPC, (─■─)F4 0.5% HPC, (─▲─) F3 0.3% HPC, (─■─) F2 0.2% HPC and F1 plain.
Various solubilizers were tried during preformulation study. Propylene glycol and Transcutol were selected as solubilizers for further study. Poloxamer 407 gives gelation temperature in nasal temperature range 280 to 350 in 18% w/v concentration. Addition of bioadhesive polymer from 0.2% to 0.7% further lowered the gelation temperature from 340 to 290. Gelation temperatures obtained using two different methods (visual inspection and rheological method) did not vary more than ±10. The gelation temperature lowering effect of bioadhesive polymer might have caused in part by the increased viscosity after dissolution of mucosadhesive polymer. The pH values of all formulations were found in the range of 5.3 to 5.6. Formulation should posses? mild acidic pH for activation of lysozyme (A natural antibacterial enzyme important for controlling nasal microbial count which becomes inactive at alkaline pH). The pKa of ondansetron hydrochloride is 7.4; so drug present in solubilised form in pH range 5 to 6.5 (ondansetron hydrochloride precipitate above 6.8). It was observed that the concentration of bioadhesive polymer increased from 0.2% to 0.7% showed retardation of ondansetron hydrochloride release, probable mechanism for such retardation of release may be reduction in number and dimensions of the channels in gel structure by increased viscosity of the formulation. From the study it can be concluded that the nasal in situ gels can be formulated of ondansetron hydrochloride using PF127 and bioadhesive polymer.
We would like to thank Dr. Reddy?s Lab. and Signet Chemicals for supplying drug and polymer samples respectively.
- Cho E, Gwak H, Chun I. Formulation and evaluation of ondansetron nasal delivery systems. Int J Pharm 2008;349:101-7.
- Schmolka IR. Artifi cial skin: Preparation and properties of Pluronic F-127 gels for treatment of burns. J Biomed Mater Res 1972;6:571-82.
- Miller SC, Donovan MD. Effect of poloxamer 407 gels on the miotic activity of pilocarpine nitrate in rabbits. Int J Pharm 1982;5:142-52.
- Shinde JV, Mali KR, Dias RJ, Havaldar VD, Mahajan NS. In situ Mucoadhesive nasal gels of metaclopramide hydrochloride: preformulation & formulation studies. J Pham Res 2008;1:88-96.
- Yong CS, Choi JS, Quan QZ, Rhee JD, Kim CK. Effect of sodium chloride on gelation temperature, gel strength and bioadhesive force of poloxamer gels containing diclofenac sodium. Int J Pharm 2001;226:195-205.
- Zaki NM, Awad GA, Mortada ND, AbdelHady SS. Enhanced bioavailability of metaclopromide HCl by intranasal administration of a mucoadhesive in situ gel with modulated rheological and mucociliary transport properties. Eur J Pharm Sci 2007;32:296-307.