Preparation and Evaluation of Tramadol Hydrochloride Floating Oral Delivery System

YS Gattani*, PS Kawtikwar and DM Sakarkar

Department of Industrial Pharmacy, S. N. Institute of pharmacy, Pusad. Dist: Yavatmal 445 204

*Corresponding Author E-mail: ygattani@gmail.com

ABSTRACT

Floating drug delivery system (microsphere) promises to be a potential approach for gastric retention. The present study was designed to formulate floating microsphere of tramadol hydrochloride by using enteric polymer such as acrycoat S 100 to improve the release profile of the drug and also target it to stomach and upper intestine via gastric retention. The microspheres were prepared by non-aqueous emulsification solvent evaporation technique. A 32 factorial design was used to elucidate the effect of variable viz. amount of drug and the amount of polymer. Non-aqueous emulsification solvent evaporation technique resulted in floating microsphere with good yield and moderate entrapment. The prepared floating microsphere sizes were in the range of 241.12 ± 8.4 to 421.42 ± 12.4 µm. These floating microspheres of tramadol hydrochloride were capable of floating on simulated gastric fluid for more than 12 hour. The amount of polymer affected the particle size and drug release. As the polymer concentration increases the particle size increases and drug release decreases.

KEY WORDS Tramadol hydrochloride; floating drug delivery system; Microsphere; Acrycoat S 100

INTRODUCTION:

Floating drug delivery systems (FDDS) or hydrodynamically balanced systems (HBS) are among the several approaches that have been developed in order to increase the gastric residence time (GRT) of dosage forms1,2,3. Both single and multiple unit systems have been developed. The single-unit floating systems are more popular but have a disadvantage owing to their ‘all-or-none’ emptying process leading to high variability of the gastrointestinal transit time4,5. Still, the multiple-unit dosage forms may be better suited because they are claimed to reduce the inter subject variability in absorption and lower the probability of dose dumping6. Such a dosage form can be distributed widely throughout the gastrointestinal tract (GIT), affording the possibility of a longer lasting and more reliable release of the drug from the dosage form7.

The concept of floating microparticles can also be utilized to minimize the irritant effect of weakly acidic drugs on the stomach by avoiding direct contact with the mucosa and providing a mean of getting low dosage for prolonged period8. Tramadol hydrochloride is a well-known nonsteroidal anti-inflammatory agent requiring a high dosage for efficacy in osteoarthritis. The drug is well absorbed from the upper portion of the intestine. Therefore, a floating multiparticulate system is expected to produce a prolonged release of the drug without irritant particles lodging in the mucosa.

In the present study was focused on development of controlled released floating multiparticulate drug delivery system of tramadol hydrochloride using acrycoat S100. A 32 factorial design was employed to study two important factors viz. the amount of polymer and the amount of drug.

MATERIAL AND METHOD:

Tramadol hydrochloride (TH) was obtained as a gift sample from Win-Medicare private limited (Meerut U.P.). Acrycoat S 100 was obtained from Corel Pvt. Ltd., Ahmedabad. Acetone, isopropyl alcohol and tween 20 were obtained from Loba chemicals Mumbai. All other chemicals / reagents used were of analytical grade. A UV/Vis spectrophotometer (Shimadzu 1700pharma spec) was used for drug analysis.

Preparation of microspheres 9:

The microspheres were prepared by non-aqueous emulsification solvent evaporation method. Briefly, drug and polymer i.e. tramadol hydrochloride and acrycoat S 100 were mixed in the blend of acetone and isopropyl alcohol in the ratio as 2:1. The slurry was introduced in to 200 ml of liquid paraffin while being stirred at 1200 rpm by mechanical stirrer for 2 hrs to allow the solvent to evaporate completely and the microspheres were collected by filtration. The microspheres were washed repeatedly with petroleum ether 40 –60 oC until free from oil. The collected microspheres were dried for 1hr at room temperature and subsequently stored in desiccator over fused calcium chloride.

Factorial Design:

The levels of factors viz. the amount of drug (X1) and the amount of polymer (X2) were varied independently

each at three levels (Table 1).

Table 1: Variables and their levels for factorial design

Variables	Amount of drug	Amount of
(levels)	Amount of drug	polymer
Batches	X1 (g)	X2 (g)
AK1	-1 (1)	-1 (1)
AK2	-1 (1)	0 (1.5)
AK3	-1 (1)	+1 (2)
AK4	0 (2)	-1 (1)
AK5	0 (2)	0 (1.5)
AK6	0 (2)	+1 (2)
AK7	+1 (3)	-1 (1)
AK8	+1 (3)	0 (1.5)
AK9	+1 (3)	+1 (2)

EVALUATION 10, 11, 12:

Mean Particle Size:

The particle size of the microsphere was determined using optical microscope. The diameter was measured for about 50 microspheres and the average particle size determined.

Scanning Electron Microscopy (SEM):

Scanning electron microscopy (SEM) (FEI Philips-XL- 30, VNIT, Nagpur) was performed to characterize the surface of formed microspheres. Microspheres were mounted directly onto the sample stub and coated with platinum film.

Determination of percent yield and drug entrapment:

Total percentage yield of floating microspheres calculated by weighting of prepared microspheres was divided by the total amount of all the non–volatile components used for the preparation of the microspheres.

For determination of drug entrapment microspheres equivalent to 100 mg of the drug TH were taken for evaluation. The amount of drug entrapped was estimated by crushing the microspheres and extracting with aliquots of 0.1N HCl repeatedly. The extracts were transferred to a 100 ml volumetric flask and the volume was made up using 0.1 N HCl. The solution was filtered and the absorbance was measured after suitable dilution spectrophotometrically at 271nm against 0.1 N HCl as a blank. The amount of drug entrapped in the microspheres was calculated by the following formula.

% Drug entrapment = (Calculated drug concentration / Theoretical drug concentration) X 100

In-vitro evaluation of floating ability:

An in vitro floating study was carried out using simulated gastric fluid USP containing 0.02 % Tween 20 as a dispersing medium. Microspheres were spread over the surface of 500 ml dispersion medium at 37 ± 0.5o C. A paddle rotating at 100 rpm agitated the medium. Each fraction of microspheres floating on the surface and those settled down were collected at a predetermined time point. The colleted samples were weighed after drying.

% floating microsphere = (Weight of floating microspheres / Initial weight of floating microspheres) X 100.

SEM 1 SEM 2

SEM 3 SEM4

Figure 1: SEM of floating microspheres

In-vitro drug release:

A USP basket apparatus has been used to study in vitro drug release from microspheres. In the present study, drug release was studied using a modified USP XXI dissolution apparatus type I (basket mesh # 120, equals 125 µm) at 100 rpm in 0.1 mol l-1 HCl (pH 1.2) as dissolution fluids (900 ml) maintained at 37 ± 0.5 °C. Samples of 5 ml each were withdrawn at regular intervals and same quantity was replaced by fresh dissolution medium. The sample was diluted and absorbance was measured at 271 nm. The present drug was calculated taking into consideration dilution factors and the slope and constant obtained from the calibration curve.

Table 2: Evaluation parameters for various batches of tramadol HCL floating microsphere

Batch code	Drug polymer	Mean particle size a	Percent yield b	Entrapment efficiencyb	In-vitro floatability b
Batch code	ratio	(µm)	Percent yield b	Entrapment efficiencyb	(After 12 hrs)
AK1	01:01	278.42±8.4	96.01±2.4	80.24±2.1	63.00 ± 1.9
AK2	01:01.5	267.35±11.2	95.4±3.1	79.24±2.8	72.60± 1.5
AK3	01:02	241.12±8.4	92.54±2.8	73.16±3.4	69.20± 2.4
AK4	02:01	378.56±12.4	94.37±3.4	84.37±2.4	60.8 ± 1.4
AK5	02:01.5	251.37±9.6	98.57±1.8	89.14±2.2	66.80 ± 2.1
AK6	02:02	401.23±14.31	94.46±1.9	79.63±1.8	72.40± 3.2
AK7	03:01	346.74±9.4	97.08±2.4	81.34±2.5	70.2 ± 0.8
AK8	03:01.5	304.87±11.2	95.63±3.1	70.31±2.4	65.20± 2.4
AK9	03:02	421.42±12.4	96.78±2.8	75.81±1.8	68.40± 1.8

a Mean ± SD, n = 10. b Mean ± SD, n = 3.

Infrared Spectroscopy (IR):

Fourier- transform infrared (FT-IR) spectra were obtained on Shimadzu FTIR 8400S, Nagpur. The pellets were prepared on KBr press. In order to confirm that the microsphere process involves only the physical entrapment of drug and no interaction between drug and polymer takes place. The infrared (IR) spectra of pure drug, blank microsphere and TH loaded microsphere were obtained from the solid state and structural chemistry unit. The spectra were recorded over the wave number range of 4000 to 600 cm-1.

were selected. Beyond 4 % w/v concentration it was difficult to disperse the polymer solution in liquid paraffin. Hence the levels of amount of polymer were selected at 1, 1.5 and 2 grams per 50 ml of solution.

The SEM photographs showed that the fabricated microspheres were spherical with a smooth surface and exhibited a range of sizes within each batch (Figure1). The prepared floating microsphere of TH showed good yield and moderate entrapment. The microspheres floated for prolonged time (>12 hour) surface of the dissolution medium without any apparent gelation (Table 2).

Figure 2: In-vitro release of tramadol HCL from acrycoat S 100 floating microsphere (Bars represent mean ± SD; n =3, codes in Table 2).

RESULT AND DISCUSSION:

Floating microspheres of tramadol hydrochloride prepared by the non-aqueous emulsification solvent evaporation technique using acrycoat S 100 as a rate- controlling polymer. The floating microsphere obtained had particle size between 241.12 ± 8.4 to 421.42 ± 12.4 µm. the mean particle size data indicate that the amount of polymer affected the particle size. An increase in amount of polymer amount of polymer resulted in an increase in viscosity, which in turn resulted in increased particle size.

Drug polymer ratio affected particle size and release characteristics of the drug. (Table2). A batch with 1 % w/v acrycoat S 100 was prepared but it showed significant coalescence of dispersed phase. Therefore 2 % w/v and 3 % w/v concentration of acrycoat S 100

Figure 3: IR spectra of drug (Top) and drug polymer complex (below)

In-vitro release data showed that highest released was obtained for batch having a drug polymer ratio of 2:1.5 (AK5) that gave the highest release of 98.92 % in12 hours as shown in Figure 2.

In order to study the interaction between the drug and polymer IR studies were performed. The IR data of tramadol indicated the presence of characteristic peaks at 2929 cm-1, 3307 cm-1, 1640 cm-1 and 1242 cm-1 as shown in Figure 3. The IR spectra of blank acrycoat S 100 microspheres were taken and it showed a band at 3470 cm-1. From the IR spectra of pure drug (TH), blank floating microsphere and microsphere loaded with TH it was found that microsphere process involves only physical entrapment between drug and polymer there was no interaction between drug and polymer takes place as shown in Figure-3.

CONCLUSION:

The non-aqueous emulsification solvent evaporation technique resulted in floating microsphere with good yield, moderate entrapment and well in-vitro floatability. Both variables viz. amount of drug and amount of polymer affected the mean particle size and drug release. Use of factorial approach helped in understanding the effect of variables in better way. IR studies indicated that there was no interaction between the drug and polymer and the microsphere process involved only physical entrapment of drug.

Thus floating microsphere of tramadol hydrochloride using acrycoat S 100 may be employed to obtain extended release and overcome the gastrointestinal problems encountered with the drug. Future study may done for optimization using other techniques for obtaining TH loaded acrycoat S 100 floating microsphere.

ACKNOWLEDGEMENT:

Authors are thankful to Win-Medicare pvt. Ltd. (Meerut U.P.) for providing the gift sample of Tramadol hydrochloride.

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Received on 15.05.2008 Modified on 10.07.2008

Research J. Pharm. and Tech. 1(3): July-Sept.. 2008;Page 171-174