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Formulation and Development of In Situ Gelling System for Nasal Administration for Ondansetron Hydrochloride by Using Pluronic F-127

Anjan De1*, Subrata Chakraborty1, Arup Mukherjee2 and Jayanta Chattopadhyay3

1Dr. B.C. Roy College of Pharmacy & Allied Health Sciences (BCRCPAHS), Durgapur - 713206, West Bengal, India.

2Chemical Technology Dept., Calcutta University, Kolkata-700 009, West Bengal, India.

3Fresenius Kabi Oncology Ltd., Kalyani,-741235, West Bengal, India.

Corresponding Author:
Anjan De
Dr. B.C. Roy College of Pharmacy & Allied Health Sciences (BCRCPAHS)
Durgapur - 713206, West Bengal, India.

Received: 12/06/2013; Revised: 23/06/2013; Accepted: 02/07/2013

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In the recent years one of the big problems with cancer chemotherapy is cancer induced nausea and vomiting (CINV). In the treatment of CINV the use of 5HT3 receptor antagonist is most popular. One of such 5HT3 antagonist is Ondansetron Hydrochloride. But Ondansetron has a low oral bioavailability along with a patient suffering from vomiting problem it is difficult to deliver the drug through oral route. So our objective is to prepare a in situ nasal gel of the Ondansetron using PF-127 as the thermoreversible polymer. We used HPMC E15 and Chitosan as the mucoadhesive polymer to increase the nasal residence time of the formulation. To increase the permeation we used Polyethylene Glycol 400 and Propylene glycol as the permeation enhancer.


Formulation ondansetron, pluronic F-127, nasal administration


Cancer induced nausea and vomiting is one of the major side effects of the cancer chemotherapy. For the treatment of the CNIV the use 5HT3recepter antagonist is the most effective. One of such antagonist is Ondansetron hydrochloride. Ondansetron has a oral bioavailability of 60% due to the first pass metabolism. In a patient suffering from nausea & vomiting it is difficult to deliver the drug through oral route. So to bypass the oral route, we have delivered the drug through nasal route which have bioavailability tense to the I.V route due to high vascularity [1].

One of the major disadvantages to deliver drug through nasal route is the mucocilliary clearance. To avoid this problem there is so many strategies one of this is the use of the mucoadhesive polymer to increase the nasal residence time. Therefore we use mucoadhesive polymer Chitosan and hydroxy propyl methyl cellulose to increase the nasal residence time [2,3].

We used PF-127 which is a block copolymerconsisting of polyoxyethelene and polyoxypropylene unit as it has thermoreversible character due to the hydrophobic interaction in warm water. The temperature of the gelation is dependent on the concentration of the PF-127. So by adjusting the concentration of the PF-127 concentration we can prepare the insitu nasal gel with Ondansetron hydrochloride.

For better patient compliance it is desirable to deliver the drug quickly through the nasal mucosa because it is difficult to hold the gel in the nasal cavity for more than 6-7 hrs. So we have used PEG 400 and Propylene Glycol as the permeation enhancer.

Materials and Methods


Ondansetron Hydrochloride (fig 1.1) was a generous gift from Albert David Ltd, Kolkata,India. PF-127 and chitosan were provided by Albert David Ltd, HPMC E15, analytical grade from Loba Chemical Pvt. Ltd, PEG 400 and Propylene Glycol from Merck. Sodium chloride, Potassium chloride and Calcium chloride used were of analytical grade.


Figure 1: Ondansetron hydrochloride, dihydrate.


IR study

To study the possible interaction between Ondansetron hydrochloride and polymeric materials (PF-127, chitosan and hydroxylpropylmethyl cellulose E 15) of the gel formulations, infrared (IR) spectroscopy was carried out on pure substances and their physical mixtures. The IR spectra were recorded using IR Spectrophotometer (Alpha – A4 size FT-IR, BRUKER. Germany) and found compatible.

Preparation of the In-situ Gel

For the preparation of the in-situ, the technique described by Schmolka et al., was used (4, 5). 1% of Ondansetron hydrochloride was dissolved in distilled water. Then propylene glycol and PEG 400 were included as permeation enhancer at 1% concentration. Muco-adhesive polymer, 1% HPMC E 15 and 0.5% Chitosan were added and stirred completely till to get the clear solution. Then the solution was kept into the refrigerator and cooled to 4?C. Then PF- 127 was added in the concentration range of 20% &15% along with a mild stirring and kept overnight at 4?C.

Physical characterization


To check the clarity of the formulation we have used the technique of visual inspection in front of the black & white background & distinguished in terms of clear & very clear which were denoted as ‘++’ & ‘+++’ respectively.


To check the pH of the formulation, a 5% solution of the prepared gel was made and the pH was checked using digital pH meter (Systronics pH System 362).

Content Uniformity

1ml of the gel in a 25 ml volumetric flask, then serial dilutions were made using distilled water to make the concentration of the solution 10mcg/ml. Then the absorbance of the final solution was examined using UV-VIS spectrophotometer (Shimadzu UV-VIS1800, Japan)(fig 1.2).


Figure 2: Standard ultraviolet absorption spectrum of Ondansetron HCl. (λmax.249nm)

Gelation Temperature [6]

To evaluate the gelation temperature, the technique proposed by Choi et al., was referred. The gel was first cooled to 4?C. Then from it, 10 ml of the gel was taken in a 20 ml beaker. After that the gel was placed on a hot plate magnetic stirrer and a magnetic bid (1x5/16 inch octagonal) was inserted into it. The gel was constant stirred at 100 rpm with an increase in temperature at 1?C /min. The temperature at which the magnetic bid stopped its rotation was noted as the gelation temperature.

Determination of Mucoadhesive Force [7]

The mucoadhesive force of the formulation was determined using goat nasal membrane. Two cylindrical plastic vials with 2cm diameter were taken. A hook was attached on one side of both the vial. The goat nasal membrane was then tied to the other side of both the vial. After that 50 micro liter of the gel was applied on one of the membrane side of one vial then the other vial was applied at the membrane side on the first. The two vials were held for 2min after that the unit was hanged from a hook and at the bottom of the system a plastic container was placed. Water was poured drop by drop into the container until the two vials got detached from each other. Then the weight of the container with water was noted along with the bottom vial from which the container was hanged.

The bioadhesive force, expressed as the detachment stress in dyne/cm2, was determined from the minimal weights that detached the tissues from the surface of each formulation using the following equation.

Detachment stress (dyne/cm2) = m x g /A,

Where, m =Weight required for detachment of two vials in grams,

g = Acceleration due to gravity [980cm/s2],

A = Area of tissue exposed

The nasal mucosa was changed for each measurement. Measurements were repeated six times for each of the gel preparations.

Viscosity Measurement [8,9,10]

The viscosities of various formulations were measured with increase in temperature by using Cone and Plate viscometer (Brookfield viscometer Model Cap 2000 +2).

In-vitro Permeation Study

In-vitro permeation study of the gel was performed with goat nasal membrane using Keshary Chein cell. The mucosa was stored in normal saline with few drops of gentamycin sulphate injection to avoid bacterial growth. After the removal of blood and bony cartilage from the mucosal membrane it was ready for use. 67 ml of the Nasal Electrolyte solution (pH 5.5) was placed in to the acceptor chamber. The temperature within the chamber was maintained at 340C by circulating hot water. Then formulation equivalent to 2mg was placed in the donor compartment & sampling was done at predetermined interval from the acceptor compartment & equal amount of fresh SNES solution was replaced. Then the absorbance was examined using UV-VIS spectrometer at 249 nm.

Results and Discussion

pH ,Clarity and Content uniformity

pH of all the formulation were found to be within 5 to 5.2 . There was no such distinct effect of the change of the formulations on the pH of the final formulations.

Again, from the clarity test it can be said that all the formulations are clear. The formulations with HPMC E15 were found to be clearer than formulations containing Chitosan. The formulations which are very clear are denoted by +++ & the formulations are clear not very clear denoted by ++.

The percentage drug content of all prepared nasal formulations were checked and found to be in the range of 97-101% (table 1.2).


Table 1: Combination of the Eight Formulations


Table 2: Clarity, pH, Content Uniformity of the Eight Formulations.

Gelation Temperature

The gelation temperature is one of the important phenomena of this formulation. The in-situ gelling of the formulation was designed to occur near to the nasal temperature. The gelation temperature of the various formulations varied greatly with the combinations of the formulations (table 1.3). We have studied them differently.


Table 3: Gelation temperature, Mucoadhesive force of eight formulations.

First the effects of PF-127 concentration were studied on the gelation temperature. The formulations with 20% of PF- 127 showed gelation temperature within the range of 32 – 29?C. But the formulations with 15% of PF- 127 showed gelation at higher temperature from graph.

Again, while studying the different formulations with same PF-127 concentration, we saw that the formulation with HPMC E15 as mucoadhesive polymer showed higher gelation temperatures than the formulations with Chitosan as mucoadhesive polymer in both the higher and lower PF127 containing gel. That means the gels with 20% PF-127 BF1, BF2 has higher gelation temperature than BF 3, BF4. Similarly, the gels with 15% PF-127, BF5, BF6 shows higher gelation temperature than BF 7, BF8 (fig 1.3).


Figure 3: Effect of PF 127concentration on gelation temperature.

Now, if the formulations were evaluated with respect to the permeation enhancer. We see that formulation with same PF- 127 concentration , same mucoadhesive polymer containing PEG 400 shows slightly lower gelation temperature than the formulation containing propylene glycol as permeation enhancer. That means BF1 shows gelation temperature lower than BF2, similarly gelation temperature of BF3 is lower than the gelation temperature of BF4, gelation temperature of BF5 is less than gelation temperature of BF 6 and gelation temperature of BF 7 is lower than that of BF 8.

Mucoadhesive Force

Mucoadhesive force is required to increase the nasal residence time of the gel. So mucoadhesive force is also an important parameter for the nasal gel. The formulation should have an optimum mucoadhesive force to provide optimum resistance to the mucocilliary clearance of the gel. The formulations have a distinct effect on the mucoadhesive force of the gel. The mucoadhesive polymer itself is not only the mucoadhesive force provider. There is a distinct effect of the PF- 127 on the mucoadhesive force. Not great but the permeations enhancers also have effect on the mucoadhesive force of the gel (Table 1.3).

If studying in respect to the PF- 127 concentration, it was found that the first 4 formulations BF1, BF2, BF3, and BF4 with 20% PF-127 showed quite higher mucoadhesive force than the formulations with 15% PF127 i.e., BF5, BF6, BF7, BF8( fig 1.6). Again, in both case of the 15% and 20% PF 127 containing gel, it has seen that between the formulations with same amount of PF-127 the formulations with Chitosan as mucoadhesive polymer shows higher mucoadhesive force than the formulations with HPMC E15 as mucoadhesive polymer.


Figure 4: Effect of the Mucoadhesive polymer on Gelation Temperature.


Figure 5: Effect of the permeation Enhancer on Gelation Temperature


Figure 6: Effect of the PF-127 concentration on Mucoadhesive force.

While studying the effect of the permeation enhancer, we have seen that the formulations with same amount of PF-127 and same adhesive polymer the formulation containing PEG 400 as permeation enhancer show lower mucoadhesive force than the formulations with propylene glycol as the permeation enhancer (fig 1.7 & 1.8).


Figure 7: Effect of the Mucoadhesive polymer & Permeation Enhancer on the Mucoadhesive force of the formulations contain 20% PF-127.


Figure 8: Repalce


The viscosity of the formulations remains lower up to a certain temperature then a sudden rise in the viscosity occurred with the increase in the temperature (fig 1.9).

From R2 value we can state all the formulations show highest linearity to the Korsmeyer-Peppas Model (table 1.5) & from the n value it was seen that the drug is diffused from the formulations following non-fickian diffusion mechanism (table 1.6).


Table 5: Regression co-efficient of the Model Equations on the In-vitro diffusion kinetics.


Table 6: Table of ‘n’ values of Korsmeyer-Peppas model.

In- Vitro drug permeation Study

The in- vitro drug permeation study of the various formulations are studied using Goat Nasal Membrane, collected from the local slaughter house approved by the Municipal Corporation, Durgapur, W.B. Cumulative % release of drug from 8 formulations at 5 hr is tabulated in Table – 1.4. The formulations containing 15 % PF-127 showed higher % release at 5 hr than the formulations containing 20% PF-127. Further, from the values of the permeability co-efficient (table 1.4) it has been observed that the formulations with same concentration of PF-127 & mucoadhesive polymer containing propylene glycol as permeation enhancer showed higher values of permeability co-efficient than the formulation containing PEG400 as the permeation enhancer.


Table 4: In-Vitro Percentage Cumulative Permeation ,Flux & Permeability co-efficient of Ondansetron Hydrochloride through Goat Nasal Membrane from the formulations containing 20 % & 15 % of PF-127 at 5 hr.respectively.


pH , Clarity & content uniformity

The pH of the formulations was maintained within the range of 5 - 5.2 to activate the lysozyme in the nasal secretions, which is responsible for destroying certain microbes at acidic pH. Under alkaline pH lysozyme is inactive and nasal tissue is susceptible to microbial infection.

Again all the formulation remained clear & content uniformity remained within 97-101%. This signified that the polymer along with the drug was homogeneously mixed with water to from clear solution.

Gelation Temperature

The increase in the PF 127 concentration resulted in decrease of gelation temperature. This is because of the strengthening of the lattice structure of the PF 127 in the solution at higher concentration which are become closely packed as a result higher number and volume occupied by micelles at low temperature to form the gel [11].

The lower gelation temperature of the Chitosan containg formulations than the HPMC E15 containing formulation is because Chitosan has greater ability to increase viscosity & to produce more extensive intermolecular hydrogen bonding to produce a close alignment in the gel structure.

Again,the increased gelation temperature of the Propylene glycol containing formulation than the PEG 400 containing formulation is because of more distortion of the lattice structure of the gel by Propylene glycol than PEG 400. So the gel is formed at slightly higher temperature.

Mucoadhesive Force

The mucoadhesiveness of the gel is due to the formation of the hydrogen bonding between the gel and the mucus membrane.

The increase in PF-127 concentration increases the mucoadhesive strength of the gel. This is because as the concentration is increased more compact lattice structure is produced as well as density is increased. For that reason more no of mucoadhesive polymer remains within a fixed volume of gel to produce more hydrogen bonding than the low PF-127 containing gel.

Again, the higher mucoadhesive force of Chitosan than HPMC E15 is because of its ability to form more condensed hydrogen bonding than HPMC E15 which provides higher mucoadhesive force to the formulations.

The mucoadhesive force reducing effect of the Propylene glycol than PEG 400 is due to increased formation of the mixed micelle by Propylene glycol than PEG 400.


The viscosity of the formulation remains low up to a certain temperature. This is because the formulation remains in liquid state up to that temperature. Then with the increase with temperature the formulation change into gel. As a result the viscosity of the formulation gets increased.

Release Study

The release of the formulation is evaluated at 32? C. As a result the formulation containing 15% PF-127 remains liquid in that temperature. But the formulation containing 20% PF-127 transfer to gel in that temperature. As a result release is retread for the formulation containing 20% PF-127 due to the close matrix structure of the gel. [12]

Again, from the permeability co-efficient values it is clear that propylene glycol provides higher % release across the nasal membrane than the PEG 400 that proves the better permeation enhancing effect of the propylene glycol than PEG 400.

Analysis of the Release Mechanism

From the R2 value it is clear that all the formulation shows release by following Korsmeyer-Peppas Model and from the ‘n’ value we see that the release followed the Non-Fickian release mechanism. That means here the release is occurred by diffusion as well polymeric chain erosion.


Ondansetron hydrochloride was successfully formulated as an in-situ gelling system using HPMC E15 and chitosan. The formulated system provided a sustained release of the drug over a 5- hour period in-vitro and the developed formulations showed marked increase in permeation rate. The nasal residence time has significantly improved, and this can be viewed as viable alternative to conventional nasal drops. The ease of administration coupled with its ability to provide sustained release could probably result in less frequent administration, thus enhancing better patient compliance.


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