1. INTRODUCTION

Medicated chewing gum is solid, single dose preparation with a base consisting mainly of gum that is intended to be chewed but not swallowed. They contain one or more active substance which are released by chewing and are intended to be used for local treatment of mouth disease or systemic delivery after absorption through the buccal mucosa.¹The first patent for the production of chewing gum was filed in 1869 and was issued to Mr. W. F. Sample in Ohio under U.S. Patent No. 98,304².The drugs thereby gains direct access to the systemic circulation via the Jugular vein and avoid drug transports and first pass metabolism in the gastrointestinal tract and in the liver, thus, the bioavailability may increase³.

The factorial design is a technique that allows identification of factors involved in a process and assesses their relative importance. In addition, any interaction between factors chosen can be identified. Construction of a factorial design involves the selection of parameters and the choice of responses.⁴

2. FACTORIAL DESIGN FOR MEDICATED CHEWING GUM:

In the present study nine batches of formulations were prepared and studied. The melting method was used to formulate Ambroxol hydrochloride medicated chewing gum. Two variables were selected for the formulations in which first was concentration of elastomer and other was concentration of softener. Each batch of the formulation contains different concentration of gum base (elastomer) and softener.

Statistical models are extensively used in diversified areas to strengthen the art of the drug formulation. The response surface method (with 3 level factorial design & quadratic model) was employed to study the effect of selected parameters. The concentration of elastomer (polyvinyl acetate) {X₁} and concentration of softener (glycerol) {X₂} were selected as independent variables while the in-vitro release of drug {Y₁} and hardness of chewing gum{Y₂} were chosen as the dependent variable at present investigation^4,5. The experimental design with the corresponding formulation is outlined in (Table 1).

The statistical model: Yi = b₀+ b₁X₁+ b₂X₂+ b₁₂X₁X₂+ b₁X₁²+b₂X₂²

Where Yi is the level of response variable is the regression coefficient; X₁ and X₂ stands for the main effect; X₁X₂ is the interaction between the main effect, and X₁²and X₂²are quadratic terms of independent variables

Table 1: Experimental Design for Formulations

Formulation of Ambroxol HCl MCG by 3² Factorial Design
FORMULATION	X1	X2
F1	-1	-1
F2	-1	0
F3	-1	+1
F4	0	-1
F5	0	0
F6	0	+1
F7	+1	-1
F8	+1	0
F9	+1	+1

Table 2: Processing parameters for all formulations

Variables and their levels used in formulation of Medicated chewing gum
Variables	Levels
Variables	Low (-1)	Medium (0)	High (+1)
Conc. of elastomer (PVA) (X1)	20%	30%	40%
Conc. of softener (Glycerol) (X2)	3%	6%	9%

3. RESULTS OF FORMULATION DESIGN:

The response surface method (with 3 level factorial design and quadratic model) was employed to study the effect of selected parameters. Quadratic equations for quantitative effect of independent variables and mathematical models developed for all the dependent variables using statistical analysis software are shown in Table 3 and 4.

Table 3: Quadratic equations for quantitative effect of independent variables on the responses

Hardness=+4.683+0.686X₁-1.8116X₂-0.062X₁X₂-.040X₁²+0.145X₂²

Drug release=+96.71-3.443X₁+2.398X₂+0.502X₁X₂-3.950X₁²-1.145X₂²

The multiple regression analysis performed revealed that both the formulation variables analyzed had a significant influence on response parameter. The ANOVA demonstrates that the model was significant for Hardness and %drug release.

Table 4 : Analysis of variation (ANOVA) for dependent variables

Analysis of variance for( Hardness) R^2* = 0.9956
Source	SS*	DF*	MS*	F-value*	P-value
Model	22.58	5	4.52	137.08	0.0010
Residual	0.099	3	0.033
Total	22.68	8
Analysis of variance for(% Drug release) R² = 0.9371
Source	SS*	DF*	MS*	F-value*	P-value
Model	140.49	5	28.10	8.93	0.0506
Residual	9.43	3	3.14
Total	149.92	8

SS*- Sum of squares, DF*- Degrees of freedom, MS*- Mean of squares, F*- Fischer’s P*- Probability, R^2*- Correlation coefficient

R² value for hardness and %drug release are 0.9956 and 0.9371 respectively, indicating good correlation between dependent and independent variables. The main effect of X₁and X₂ represents the average result of changing one variable at a time from low level to its high level.

The interaction terms X₁X₂, X₁² and X₂² shows how the responses changes when two variables are simultaneously changed. The negative sign on coefficient indicate negative effect on hardness and %drug release, while positive sign on coefficient indicate positive effect on hardness and %drug release.The coefficient for X₁(concentration of elastomer) lead negative effect on % drug release which means higher the concentration of elastomer, lower the drug release.

Table 5 : Experimental runs and observed responses for 3² factorial design (Design experts 8.0.1)

Batch code	X₁	X₂	Hardness (Kg)	%Drug release
F1	-1.00	-1.00	5.73±0.10535	93.51
F2	-1.00	0.00	4.16±0.10016	95.31
F3	-1.00	+1.00	2.27±0.10148	97.50
F4	0.00	-1.00	6.74±0.11269	92.35
F5	0.00	0.00	4.56±0.10408	98.74
F6	0.00	+1.00	3.04±0.10583	96.75
F7	+1.00	-1.00	7.37±0.10148	85.74
F8	+1.00	0.00	5.25±0.10066	88.18
F9	+1.00	+1.00	3.66±0.11015	91.74

Figure 1: Response surface plot for Hardness

Figure 2: Response surface plot for % drug release

4. CONCLUSION:

In the present study, Medicated Chewing Gum of Ambroxol hydrochloride was successfully formulated by the conventional/melting method. Full factorial design was employed in formulating the MCG by changing the concentration of elastomer and concentration of softener as a independent variables. So it is concluded that formulation of medicated chewing gum of ambroxol hydrochloride containing concentration of elastomer (X₁) at 0 level and concentration of softener (X₂) at 0 level i.e. formulation F5can be taken as an ideal or optimized formulation. Study suggested that varying the concentration of gum base in the formulation, the drug release can be controlled. In-vitro drug release and hardness (chewability) were selected as dependent variables. Hardness of formulation F5 and F2 were almost similar but formulation F5 showed better drug release. So formulation F5 was selected as best optimized formulation.

5. REFERENCES:

1. European Pharmacopoeia, Strasbourg: European Directorate For the Quality of Medicines. Chewing Gum: Medicated, 5^th Edition, 2004.

2. Elias Ronald J, Chewing gum product and composition and process for the preparation thereof, U.S. Patent 1986, 4,588,592

3. Jacobsen J, Christrup L L, Jensen N H (2004), Medicated Chewing Gum: Pros and Cons. Am J Drug Delivery-2(2):75-88

4. Bolton, S., 1990. Factorial design. In: Swarbrick, J. (Ed.), Pharmaceutical Statistics. Practical and Clinical Applications,2nd Ed., Drugs and the Pharmaceutical Sciences, vol. 44. Marcel Dekker, New York, pp. 308–337.

Received on 15.06.2013 Accepted on 20.07.2013

Asian J. Pharm. Res. 3(3): July-Sept. 2013; Page 118-120