Formulation and Evaluation of Baclofen Floating Tablets

Dasari Nirmala, Enjamuri Aslesha , M. Sudhakar

Department of Pharmaceutics, Malla Reddy College of Pharmacy, Maisammaguda, Dhulapally, Secunderabad -500100 Telangana State India affiliated to Osmania University.

*Corresponding Author E-mail: dasarinirmala1980@gmail.com

ABSTRACT:

The present study was carried out with an objective of formulation and evaluation of floating tablets of baclofen for prolongation of gastric residence time with a view to deliver the drug at controlled manner in gastrointestinal tract and consequently into systemic circulation. Baclofen, a centrally acting skeletal muscle relaxant, is indicated in the long-term treatment of spasticity resulting for multiple sclerosis and spinal cord injuries. Therefore baclofen floating tablets were prepared by direct compression method using 3 grades of Eudragit (Eudragit L100, Eudragit S100, and Eudragit RSPO). Fourier transform Infrared spectroscopy confirmed the absence of any drug/polymers/excipient interactions. The prepared floating tablets were evaluated for hardness, weight variation, thickness, friability, drug content uniformity, total floating time, water uptake (swelling index) and in-vitro dissolution studies. Among the 12 formulations F3 showed drug release 98.37% in pH 1.2 dissolution medium. All the formulations showed drug content ranging from 80.93 to 98.37%. Drug release rate kinetics studies shown that drug release follows Higuchi mechanism.

KEYWORDS: Floating tablets, Floatation, sustained release, baclofen, direct compression, Eudragit.

INTRODUCTION:

The oral route is increasingly being used for the delivery of therapeutic agents because the low cost of the therapy and ease of administration lead to high levels of patient compliance Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents the drug is released slowly at the desired rate from the system. After release of drug, the residual System is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration (.Shweta Arora et al) Baclofen, a centrally acting skeletal muscle relaxant, is indicated in the long-term treatment of spasticity resulting from multiple sclerosis and spinal cord injuries.

Baclofen is rapidly and extensively absorbed and eliminated. The half-life of the drug is ∼2.5 to 4 hrs in plasma. Baclofen has absorption window in upper G.I. tract, and as result display low bioavailability (Gande

). Baclofen is difficult to formulate in to sustained release dosage forms because on arrival to colon (or even before) its absorption is diminished or nonexistent, In the present investigation efforts were made to increase the residence time of baclofen at or above the absorption window through preparation of gastro retentive tablet considering the fact that it is stable under gastric condition.

MATERIALS AND METHODS:

Materials:

Baclofen obtained gift sample from Natco labs, Eudragit S-100 obtained from Merck Specialties’ Pvt Ltd (Mumbai), Eudragit L-100 obtained from SD fine chemicals( Mumbai, India) Eudragit RSPO obtained from SD fine chemicals (Mumbai, India) Sodium bicarbonate obtained from Merck Specialties Pvt Ltd (Mumbai, India), Microcrystalline cellulose obtained from Heligent pharma (Mumbai, India), Magnesium stearate obtained from SD fine chemicals (Mumbai, India). And all other chemicals used were of analytical grades.

Methods: Drug – Excipient Compatibility Studies:

Fourier Transform Infrared (FTIR) spectroscopy (P.R. Kakad et al):

The physical properties of the physical mixture were compared with those of plain drug. Samples was mixed thoroughly with 100mg potassium bromide IR powder and compacted under vacuum at a pressure of about 12 psi for 3 minutes. The resultant disc was mounted in a suitable holder in Perkin Elmer IR spectrophotometer and the IR spectrum was recorded from 3500 cm to 500 cm. The resultant spectrum was compared for any spectrum changes.

Preparation of Baclofen Floating Tablets:

All the tablet formulations were prepared by direct compression method. All excipients except magnesium stearate were accurately weighed and passed through No. 40 mesh. Calculated amount of the drug, polymer (Eudragit S-100, L-100 and RSPO) and filler microcrystalline cellulose (Avicel pH101) were mixed thoroughly. Then the powder mixture was lubricated with magnesium stearate and compressed .total weight of tablet was 200mg. the compositions of different formulations were shown table no 1

Evaluation of Baclofen floating tablets (Narang N et al):

Weight variation test:

To study the weight variation, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of deter mining the drug content uniformity. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in the following table and none deviate by more than twice the percentage. The mean and deviation were determined. The percent deviation was calculated using the following formula.

% Deviation = (Individual weight – Average weight / Average weight) × 100

Hardness:

Hardness of tablet is defined as the force applied across the diameter of the tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. For each formulation, the hardness of three tablets was determined using Monsanto hardness tester and the average is calculated and presented with deviation.

Thickness:

Tablet thickness is an important characteristic in reproducing appearance. Tablet thickness is an important characteristic in reproducing appearance. Average thickness for core and coated tablets is calculated and presented with deviation.

Friability:

It is measured of mechanical strength of tablets. Roche friabilator was used to determine the friability by following procedure. Reweighed tablets were placed in the friabilator. The tablets were rotated at 25 rpm for 4 minutes (100 rotations). At the end of test, the tablets were re weighed, loss in the weight of tablet is the measure of friability and is expressed in percentage as

% Friability = [(W1-W2) / W] × 100

Where,

W1 = Initial weight of three tablets

W2 = Weight of the three tablets after testing

Table 1: Formulation of Baclofen floating tablets

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Drug	20	20	20	20	20	20	20	20	20	20	20	20
Eudragit S-100	20	30	40	50	-	-	-	-	-	-	-	-
Eudragit L-100	-	-	-	-	20	30	40	50	-	-	-	-
Eudragit RSPO	-	-	-	-	-	-	-	-	20	30	40	50
Sodium bi carbonate	30	30	30	30	30	30	30	30	30	30	30	30
Mag. Stearate	3	3	3	3	3	3	3	3	3	3	3	3
Talc	3	3	3	3	3	3	3	3	3	3	3	3
MCC	Qs	Qs	Qs	Qs	Qs	Qs	Qs	Qs	Qs	Qs	Qs	Qs
Total wt(mg)	200	200	200	200	200	200	200	200	200	200	200	200

Drug content (Avinash Y et al ) :

Both compression-coated tablets of were tested for their drug content. Ten tablets were finely powdered quantities of the powder equivalent to one tablet weight of Baclofen were accurately weighed, transferred to a 100 ml volumetric flask containing 50 ml water and were allowed to stand to ensure complete solubility of the drug. The mixture was made up to volume with water. The solution was suitably diluted and the absorption was determined by UV –Visible spectrophotometer. The drug concentration was calculated from the calibration curve.

In vitro Buoyancy studies (Farnaz Fouladi et al):

The in vitro buoyancy was determined by floating lag time, and total floating time. (As per the method described by Rosa et al) The tablets were placed in a 100ml beaker containing 0.1N HCl. The time required for the tablet to rise to the surface and float was determined as floating lag time (FLT) and duration of time the tablet constantly floats on the dissolution medium was noted as Total Floating Time respectively (TFT).

In vitro release studies ( Shirwaikar AA et al ):

In vitro release studies of the control, and baclofen floating tablets were monitored. The release experiments were performed in a 1000-ml dissolution medium containing hydrochloric acid (pH of 1.2), kept at 37°C±0.5°C and stirred at 50 rpm, using USP dissolution apparatus II. A 5-ml sample was withdrawn through a 0.45 µm filter and replaced with another 5 ml of a suitable fresh dissolution medium at pre-selected intervals up to 11 hrs. Samples were analyzed by spectrophotometrically at 266 nm using UV-spectrophotometer.

Kinetic modeling of drug release (Dave B.S ):

The dissolution profiles of all the batches were fitted to zero order, first order, Higuchi and Peppas equations (equation 1–4 respectively).

Mt=M0+k0t 1

lnMt=lnM0+k1t 2

Mt=M0−kHt1/2 3

Mt/Mα=Knt 4

In these equations, M_t is the cumulative amount of drug released at any specified time (t), M₀ is the dose of the drug incorporated in the delivery system and M_t/M_α is a fraction of drug released at time (t). k₀, k₁, k_H and K are rate constants for zero order, first order, Higuchi and Korsmeyer model respectively, n is the release exponent.

RESULTS AND DISCUSSIONS:

Drug and excipient compatibility studies:

Fig No 1: FT-IR spectrum of baclofen:

Figure No 2: FTIR of Baclofen+polymer:

Table 2: Preformulation parameters of powder blend

Formulation Code	Angle of Repose	Bulk density (gm/ml)	Tapped density (gm/ml)	Carr’s index (%)	Hausner’s Ratio
F1	26.01	0.49±0.07	0.57±0.01	16.21±0.06	0.86±0.06
F2	24.8	0.56±0.06	0.62±0.05	16.87±0.05	0.98±0.05
F3	22.74	0.52±0.03	0.68±0.07	17.11±0.01	0.64±0.03
F4	25.33	0.54±0.04	0.64±0.08	17.67±0.08	1.12±0.04
F5	26.24	0.53±0.06	0.67±0.03	16.92±0.04	1.2±0.08
F6	26.12	0.56±0.05	0.66±0.06	17.65±0.09	1.06±0.09
F7	27.08	0.58±0.06	0.69±0.04	16.43±0.05	0.76±0.03
F8	25.12	0.48±0.05	0.57±0.02	17.97±0.02	1.15±0.09
F9	25.45	0.54±0.08	0.62±0.03	17.54±0.09	1.17±0.02
F10	25.24	0.52±0.04	0.61±0.08	17.54±0.04	1.18±0.04
F11	26.25	0.55±0.06	0.63±0.03	16.76±0.06	1.18±0.03
F12	26.28	0.54±0.05	0.64±0.06	17.43±0.03	1.16±0.07

Table 3: Post compression parameters of baclofen floating tablets:

Formulation code	Weight variation(mg) n=20	Hardness(kg/cm^2) n=5	Friability (%loss) n=6	Thickness (mm) n=5	Drug content (%)	Floating lag time (min)
F1	202.5	4.52±0.06	0.52	4.8±0.4	99.76	4.0
F2	205.4	4.27±0.08	0.54	4.9±0.6	99.45	4.2
F3	198.6	4.43±0.05	0.51	4.6±0.2	99.34	4.5
F4	200.6	4.57±0.09	0.55	4.9±0.5	99.87	4.1
F5	199.4	4.42±0.04	0.56	4.7±0.9	99.14	4.0
F6	200.7	4.28±0.01	0.45	4.5±0.3	98.56	4.4
F7	202.3	4.16±0.05	0.51	4.4±0.2	98.42	3.9
F8	201.2	4.37±0.07	0.49	4.7±0.8	99.65	4.6
F9	198.3	4.50±0.03	0.55	4.6±0.6	99.12	4.7
F10	202.1	4.23±0.09	0.54	4.9±0.4	99.56	5.1
F11	198.7	4.41±0.08	0.51	4.6±0.5	99.56	4.4
F12	202.2	4.54±0.06	0.54	4.8±0.2	99.86	4.1

In-Vitro Drug Release Studies:

Fig 3: Dissolution profile of Baclofen floating tablets (F1, F2, F3 formulations).

Fig 4: Dissolution profile of Baclofen floating tablets (F4,F5,F6)

Fig5: Dissolution profile of Baclofen floating tablets (F4, F5, F6 formulations)

Fig 6: Dissolution profile of Baclofen floating tablets (F10, F11, F12formulations).

Release kinetics data for optimised formulation (F3)

Fig 7 : Zero order release kinetics graph

Fig 8 : Higuchi release kinetics graph

Fig 9: Kors Mayer Peppas graph

Fig 10: First order release kinetics graph

DISCUSSION:

FTIR spectroscopy was used to examine the possible interactions between drug and polymers. The IR spectrum of optimized formulation was compared with the standard spectrum of baclofen. In the IR spectrum, peak at3441 Cm^-1indicates presence of NH2 stretching, peak at1736.21 cm^-1 indicates the presence of C=0 stretching, peak a1465.16t cm^-1 indicates presence of C=C bending (fig 1) for the standard spectrum of baclofen. Peak at 2785.70cm^-1 indicates the presence of NH2 stretching, Peak at1650.53 cm^-1 indicates the presence of C=0 stretching, Peak at1453.35cm^-1 of C=C bending for the optimized formulation (fig 2). These results indicate that there was no significant chemical interaction found in the FT-IR spectra of pure drug and optimized formulation. Tablet powder blend was subjected to various pre-formulation parameters. The angle of repose values indicates that the powder blend was good flow properties. The bulk density of all the formulations was found to be in the range of 0.43±0.07 to 0.58±0.06 (gm/cm3) showing that the powder was good flow properties. The tapped density of all the formulations was found to be in the range of 0.57 to 0.69 showing the powder was good flow properties. The compressibility index of all the formulations was found to be ranging between 16 to 18 which shown that the powder has good flow properties.

All the formulations has shown the Hausner^,s ratio ranging between 0 to 1.2 indicating the powder has good flow properties(table 2). The weight variation of 12 formulations was found to be in between 198.3 to 202.3 the hardness of all the formulations is in between 4.1 to 4kg/cm². The percentage drug content of all the formulations was above 98%. The floating lag time of all formulations was in between 3.9min to 5.1min.All the parameters such as weight variation, friability, hardness, thickness and drug content were found to be within limits (table2). From the dissolution curves (fig 3,4,5and 6)it was evident that the formulations prepared with different grades of Eudragit polymer were able to retard the drug release up to desired time period i.e., 10 hours. Whereas the formulations prepared with Eudragit S-100 retarded the drug release in the concentration of 40 mg showed required release pattern i.e., retarded the drug release up to 10 hours and showed maximum of 98.37 % in 10 hours (Formulation F3) with good floating lag time and floating buoyancy time. Release kinetics applied for optimized formulation (F3 formulation) r² values obtained for zero order, first order, higuchi and Peppas were found to be 0.93, 0.98, 0.99, and 0.92 respectively. The best linearity was found in Higuchi's equation plot which was 0.99 (fig 8) indicating the release of drug from matrix based on diffusion mechanism.

REFERENCES:

1. Shweta Arora, Javed Ali, Alka Ahuja, Roop K. Khar, and Sanjula Baboota. Floating Drug Delivery Systems: A Review. AAPS PharmSciTech 2005; 6 (3) E372-E389.

2. Gande and YM Rao Sustained-release effervescent floating matrix tablets of baclofen: development, optimization and in vitro-in vivo evaluation in healthy human volunteers. Daru journal of pharmaceutical sciences 2011; 19(3): 202–209.

3. P.R. Kakad1, S.B. Gondkar1, A.B. Darekar1, S.T. Darade1.Formulation and Optimization of Sustained Release Floating Matrix Tablets of Baclofen. International Journal of Drug Delivery 4 (2012) 443-454.

4. Narang N. An updated review on: floating drug delivery system (FDDS) .Int J Appl Pharm. 2011; 3(1):1–7.

5. Avinash Y Kaushik, Ajay K Tiwari, and Ajay Gaur. Role of excipients and polymeric advancements in preparation of floating drug delivery system, Int J Pharm Investing. 2015 Jan-Mar; 5(1): 1–12

6. Farnaz Fouladi and Seyed Alireza Mortazavi paration and In-vitro Evaluation of Gastroretentive Bupropion Hydrochloride Tablets Tropical Journal of Pharmaceutical Research June 2012; 11 (3): 351-359.

7. Shirwaikar AA and Srinatha A. Sustained release bilayered tablets of diltiazem hydrochloride using insoluble matrix system. Indian J Pharm Sci 2004; 66(4): 433-437.

8. Dave B.S, Amin A.F, Patel M.M, Gastroretentive drug delivery system of ranitidine hydrochloride: formulation and in-vitro evaluation, AAPS Pharm. Sci. Tech. (2004): 5(2); 1-6.

9. Asnaashari S¹, Khoei NS, Zarrintan MH, Adibkia K, Javadzadeh Y. Preparation and evaluation of novel metronidazole sustained release and floating matrix tablets. Pharm Dev Technol. 2011 Aug; 16(4):400-7.

10. Loh ZC, Elkordy AA. Formulation and evaluation of different floating tablets containing metronidazole to target stomach. Curr Drug Deliv. 2015;12(4):425-43.

Received on 22.10.2016 Accepted on 30.11.2016

© Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 2016; 6(4): 255-260.

DOI: 10.5958/2231-5659.2016.00035.7