Development and Evaluation of Oral Osmotic Tablets for Metoprolol Succinate.
P.S. Salve*
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Campus, Mahatma Fuley Shaikshanik Parisar, Amravati Road, Nagpur – 440 033 (MS)
*Corresponding Author E-mail: pramodsalve77@yahoo.com
ABSTRACT:
The sustained release drug delivery system provides essential therapeutic concentration for desired period of time. The drugs having low biological half-life are suitable candidates to be developed in the SR dosage form. Oral osmotic drug delivery is independent of pH, food condition in the stomach, agitation and other variables providing zero order drug release profile leading to predictable plasma profiles. In this study we optimized the oral osmotic tablets using metoprolol succinate having biological half -life of 2-6 hours and bioavailability of 12%. The effect of drug:osmogen ratio was studied. The core tablets were prepared using sodium chloride as osmotic agent and compressed at a weight of 250 mg using 8 mm standard biconcave punches. The dibutyl phthalate, diethyl phthalate, triethyl citrate, castor oil were used as plasticizers. The PEG 400 was used as pore former. The effect of drug osmotic agent ratio, coating thickness in terms of coating weight gain, amount of plasticizers, and amount of pore former were studies as the important variables affecting the drug release. The tablet coating was carried out using cellulose acetate with plasticizer dibutyl phthalate and pore former PEG 400. The formulation consisting of drug and osmotic agent in 1:1.5 ratio, coating weight gain of 2 %w/v, 20 %w/v dibutyl phthalate, 20 %w/v PEG 400 of cellulose acetate concentration with 2 %w/v coating weight gain has shown zero order release profile.
KEYWORDS: Sustained release, osmotic drug, metoprolol succinate, plsticizer, pore former.
INTRODUCTION:
For the successful drug therapy, it is very important to minimize compliance of the side effect or frequency of dosing. Osmotically controlled drug delivery system controls the rate of drug release for an extended period of time .It utilized the principles of osmotic pressure for drug delivery. Drug release is independent of pH, food, agitation, hydrodynamic condition and concentration of drug. It provides numerous benefits compared to immediate release dosage forms.17, 29, 34 The important technique used in this drug delivery system is laser drilling. The system consists of an osmotic core (a drug with or without an osmotic agent) which is coated with a semi permeable membrane and a delivery orifice created with a mechanical or laser drill. Due to which holes are to be formed are charged in the hopper. When the dosage form comes in contact with water, water is imbibed because of resultant osmotic pressure of the core and drug is released from the orifice at a controlled rate.17,29,34 The emphasis of this investigation is to study of variables such as osmotic pressure, polymer concentration, coating weight gain, pore former level and plasticizer type on drug release.1,3,8,9,10
Osmotic pressure gradient between inside the compartment and the external environment should be optimized to control rate of drug release. It is possible to achieve and maintain a constant osmotic pressure by maintaining a saturated solution of osmogen in the compartment. The pore formers are water soluble additives which dissolves on coming in contact with water, living behind the pores through which the drug release takes place e.g. PEG 400.The polymer is used in this system is permeable to water but inpermiable to solute e.g. cellulose acetate, cellulose ethers, eudragit etc. Thickness of membrane has marked effect on drug release from osmotic system which is inversely proportional to each other. Plasticizer can change the viscoelastic behavior. It can affect the permeability of polymer films. Different types of plasticizers will have effect on the water permeation. All this variables in this drug delivery system leads to zero order release profile after initial lag which leads to more bioavailability of drug. Because of above advantages such systems form the major segment of the drug delivery market of the drug. The effective concentration at the target site can be achieved by intermittent administration of grossly excessive doses, which in most situations often results in constantly changing, and often sub or supra therapeutic.14,16,33,34,39 The rationale for this approach is that the presence of water in gastrointestinal tract is relatively constant, at least in terms of the amount required for activation and controlled osmotically based technologies. The coating of cellulose acetate polymer is used to protect the drug from gastric enviournment of stomach with an acid resistant enteric coating and control the drug release. Hence, it was envisaged to prepare osmotically controlled tablets of metoprolol succinate having biological half-life of 2-6 hours as a model water soluble drug.
MATERIALS AND METHODS:
Metoprolol succinate was obtained as a gift sample from IPCA laboratories (India). Sodium chloride was obtained from S.D.Fine chemicals (India) and Cellulose acetate was obtained as a sample from Sun pharmaceuticals (India).All solvents and chemicals were of analytical reagent grade used as obtained.
Formulation of tablets
Metoprolol succinate extended release tablets 250mg were formulated using sodium chloride and other excipients except binding agents were taken and blended. It was granulated using PVP K-30 in isopropyl alcohol. The wet mass was passed through sieve #14 and granules obtained were dried at 45oC for 1hr.The granules were mixed with magnesium stearate and talc. The granules were evaluated for bulk density, tapped density, angle of repose and compressibility. These granules were compressed using 8mm concave punches in multi station rotary tablet punching machine. The core tablet was prepared containing different concentration of sodium chloride in formulation. The tablets were evaluated for different parameters like appearance, weight, variation, thickness, hardness, friability, drug content and in vitro release.
Coating of tablets
The core tablets were coated by using spray coating technique. The solution contains cellulose acetate 2% w/v in acetone: IPA (4:1) with PEG 400 and solution was sonicated for 30 minute to obtain a clear solution. Core tablets were placed in coating pan of filler capacity 20 g. The core tablets were coated at different levels using spray coating method and dried with the help of dryer with an inlet air temperature of 40°C. The coating condition were pan with 4 baffles, speed 30 revolutions per minutes, spray rate 1 (ml/min), spray pressure 40 (lb/in2.), drying temp 40°C.
In vitro release studies of coated tablets.
In- vitro release studies for coated tablets were done with dissolution apparatus USP II (Paddle), using buffer acetate and phosphate at pH 1.2 and 6.8 with speed of 75rpm.The volume required was 900ml. From the vessel, 10 ml of sample was withdrawn after every one hour and replaced with 10 ml respective buffer by using 10 ml of calibrated pipette and absorbance was noted at 224 nm by using UV- spectrophotometer.
Study of effect of variables on drug release
1. Effect of osmogen
2. Effect of polymer concentration
3. Effect of different coating level
4. Effect of pore former level
5. Effect of plasticizer level
Effect of different types of plasticizer
Effect of different plasticizers e.g. triethyl citrate (TEC), dibutyl phthalate (DBP), diethyl phthalate (DEP) and castor oil in-vitro drug release from coated tablets were studied. The nature of each plasticizer is shown in Table 2.
RESULTS:
Coating of tablet
The biconvex shaped coated tablets were smooth and weight gain achieved of coated tablets was found to be 2 % and 5 %. Polymer was made soft, flexible and permeability also increased by addition of plasticizer (DBP, DEP, TEC and castor oil) and microporous structure of membrane was controlled with pore former PEG 400.
In-Vitro drug release study
Uncoated and Coated tablets were then subjected to dissolution studies and effect of various factors on the drug release from coated tablet was determined.
Table 1 Effect of variables on drug release
|
Sr.no. |
Formulation code |
Osmogen (mg) |
Cellulose acetate (%w/v) |
Coating weight gain (%) |
PEG 4OO(% of polymer) |
Plasticizer (% ) |
|
1 |
F1 |
47.5 |
2 |
2 |
20 |
20 |
|
2 |
F2 |
95 |
2 |
2 |
20 |
20 |
|
3 |
F3 |
142.5 |
2 |
2 |
20 |
20 |
|
4 |
F4 |
-- |
5 |
-- |
-- |
-- |
|
5 |
F5 |
-- |
5 |
-- |
-- |
-- |
|
6 |
F6 |
-- |
5 |
-- |
-- |
-- |
|
7 |
F7 |
47.5 |
-- |
5 |
-- |
-- |
|
8 |
F8 |
95 |
-- |
5 |
-- |
-- |
|
9 |
F9 |
142.5 |
-- |
5 |
-- |
-- |
|
10 |
F10 |
-- |
-- |
-- |
-- |
50 |
|
11 |
F11 |
-- |
-- |
-- |
-- |
50 |
|
12 |
F12 |
-- |
-- |
-- |
-- |
50 |
|
13 |
F13 |
-- |
-- |
-- |
13 |
-- |
|
14 |
F14 |
-- |
-- |
-- |
14 |
-- |
|
15 |
F15 |
-- |
-- |
-- |
15 |
-- |
Table 2 Formulations with different types of plasticizer
|
Sr. No. |
Formulation code |
Plasticizer
|
Nature of plasticizer |
|
1 |
F2 |
DBP |
Hydrophobic |
|
2 |
F16 |
TEC |
Hydrophilic |
|
3 |
F17 |
DEP |
Hydrophobic |
|
4 |
F18 |
Castor oil |
Hydrophobic |
Figure 1 Cumulative percent drug release of uncoated tablets
As shown in figure 1, the drug release from batches U1, U2 and U3 were 99.17, 98.94 and 99.48 % respectively. In first hour about 80-90% drug release was observed from uncoated formulation batches and complete drug release was observed in two hours.
Effect of different factors on drug release
Effects of osmogen, polymer concentration, coating level, plasticizer level, pore former level and types of plasticizer on drug release was given below.
Effect of osmogen
Figure 2 Effect of osmotic agent on drug release in formulation with 2% coating weight gain
Figure 3 Effect of osmogen on drug release in formulation with 5 % coating weight gain
The effect of osmogen on release of metoprolol succinate was studied in two formulation batches i.e. F1 to F3 and F7 to F9 with coating weight gain of 2 and 5% as shown in figure 2and 3 respectively.
Effect of polymer concentration
Figure 4 Effect of polymer concentration on drug release in formulation containing drug: osmogen in 1: 0.5 ratio
Figure 5 Effect of polymer concentration on drug release in formulations containing drug: osmogen in 1:1ratio
Figure 6 Effect of polymer concentration on drug release in formulations containing drug: osmogen in 1:1.5 ratio
The effect of polymer concentration on release of metoprilol succinate was studied in three formulations contain drug: osmogen ratio i.e. 1:0.5 (F1 and F4), 1:1 (F2 and F5) and 1:1.5 (F3 and F6) with coating weight gain of 2 and 5% as shown in figure 4,5 and 6 respectively.
Effect of coating level
.
Figure 7 Effect of coating level on drug release in formulations containing drug: osmogen in 1:0.5 ratio
Figure 8 Effect of coating level on drug release in formulations containing drug: osmogen in 1: 1 ratio
Figure 9 Effect of coating level on drug release in formulations containing drug: osmogen in 1:1.5 ratio
The effect of coating level on release of metoprilol succinate was studied in three formulations contain drug: osmogen ratio i.e. 1:0.5 (F1 and F7), 1:1 (F2 and F8) and 1:1.5 (F3 and F9) with coating weight gain of 2 and 5% as shown in figure 7,8 and 9 respectively.
Effect of pore former level
Figure 10 Effect of pore former on drug release in formulations containing drug: osmogen in 1:0.5 ratio
Figure 11 Effect of pore former on drug release in formulations containing drug: osmogen in 1:1 ratio
Figure 12 Effect of pore former on drug release in formulations containing drug: osmogen in 1:1.5 ratio
The effect of pore former on release of metoprilol succinate was studied in three formulations contain drug: osmogen ratio i.e. 1:0.5 (F1 and F13), 1:1 (F2 and F14) and 1:1.5 (F3 and F15) with coating weight gain of 20 and 50% as shown in figure 10,11 and 12 respectively.
Effect of plasticizer level
Figure 13 Effect of plasticizer level on drug release in formulations containing Drug:osmogen in 1:0.5 ratio
Figure 14 Effect of plasticizer level on drug release in containing drug: osmogen in 1: 1 ratio
Figure 15 Effect of plasticizer level on drug release in formulations containing drug: osmogen in 1:1.5 ratio
The effect of plasticizer level on release of metoprilol succinate was studied in three formulations contain drug: osmogen ratio i.e. 1:0.5 (F1 and F10), 1:1 (F2 and F11) and 1:1.5 (F3 and F12) with coating weight gain of 20 and 50% as shown in figure 13,14 and 15 respectively.
Effect of different types of plasticizers
The effect of different types of plasticizer on release of metoprilol succinate is shown in figure 16.
Figure 16.Effect of different types of plasticizer on drug release
DISCUSSION:
Effect of osmogen
From figures 2 and 3, it was observed that formulation batches F1, F2, F3, F7, F8, and F9 release the drug 40.38, 67.21, 89.94, 3.58, 32.41 and 49.28% in 12 hours respectively. The release of drug was increased with increase in drug: osmogen ratio i.e. 1:0.5 (F1 and F7), 1:1 (F2 and F8) and 1:1.5 (F3 and F9).
It was observed that with increased in concentration of sodium chloride, the release of drug was increased. The release of batch F7 containing 1:0.5 drug osmotic agent ratio was 3.52% due to low development of osmotic pressure inside the compartment and that of formulation batches F8 and F9 containing drug : osmotic agent ratio 1:1 and 1:1.5, release were 32.41 and 49.28 % respectively.
As the water gets imbibed inside the membrane the core tablets get saturated and the osmotic pressure was developed. The release of the drug was increased with increase in drug: osmogen ratio i.e.1:0.5(F1 and f7), 1:1(F2 and F8) and 1:1.5.Thus, it was revealed that with increase in osmogen level, drug release was increased.
Effect of polymer concentration
From figures 4, 5 and 6, it was observed that formulation batches F1, F2, F3, F4, F5 and F6 release the drug 40.38, 67.21, 89.94, 1.96, 4.47 and 9.69% in 12 hours respectively. The Drug release from formulation batches F4, F5 and F6 were 1.96, 4.47 and 9.96% respectively .The release of drug from batches containing 5% cellulose acetate concentration has retarded and lag time was increased. The lag time of batches F4, F5 and F6 were 12, 12 and 9 hours and that of batches F1, F2 and F3 were 5, 6 and 5 hours respectively
Due low permeability of coating polymer as coating polymer concentration was 5% compared to formulation batches F1, F2 and F3 containing 2% polymer concentration, the releases were 40.83, 67.21 and 89.94% respectively. The drug release was lowered in the batches containing 5% of cellulose acetate. Due to this lag time was enhanced. Thus, with increase in polymer concentration the release rate was decreased as permeability through polymer film was decreased.
Effect of coating thickness
From figures 7, 8 and 9, it was observed that formulation batches F1, F2, F3, F7, F8, and F9 release the drug 40.38, 67.21, 89.94, 3.58, 32.41 and 49.28% in 12 hours respectively. The drug release from formulation batch F7 was 3.52% compared with formulation batch F1, the release was 40.83%. The release rate was decreased with increased in coating level due to increase in thickness of coating polymer and decrease in permeability of polymer.
The drug release was decreased as coating level increased i.e. from 2% weight gain to 5% weight gain. The lag time of batches F1, F2 and F3 were 5, 6 and 5 hours and that of batches F7, F8 and F9 were 12, 7 and 8 hours respectively. Thus the lag time was increased with increase in coating level and drug release was retarded.
It was observed from batches F1to F3 and F7 to F9 that when coating level was increased, drug level was decreased; it leads to increase in lag time. The thickness of coating layer was increased with increase in coating weight gain so the permeability of coating polymer was decreased. So it was concluded that as coating level was increased the drug release was increased.
Effect of pore former concentration
From figures 10, 11 and 12, it was observed that formulation batches F1, F2, F3, F13, F14, and F15 release the drug 40.38, 67.21, 89.94, 61.39, 83.60 and 97.87% in 12 hours respectively. The drug release from batches F1, F2 and F3 (20% PEG 400) were less as compared to batches F13, F14 and F15 (50% PEG 400) respectively.
The release of Formulation batch F1 containing 20% PEG 400 was 40.83 compared with formulation batch F13 containing 50% PEG400, the release was 61.39%. So it was observed that the drug release was increased with increased in pore former level. the lag time of batches F1, F2 and F3 were 5, 6 and 5 hours compared to formulation batches F13, F14 and F15 were 5, 5 and 3 hours respectively. The lag time of drug release was decreased as pore former level was increased. Firstly at low concentration of pore former, the release was by osmosis and as concentration increases the release was by osmosis and diffusion.
Effect of plasticizer level
From figures 13, 14 and 15, it was observed that formulation batches F1, F2, F3, F10, F11, and F12 release the drug 40.38, 67.21, 89.94, 55.63, 70.19 and 94.44% in 12 hours respectively. The release rate of drug was increased with increase in plasticizer concentration. The drug release from formulation batch F1 was 40.83% compared with formulation batch F10, the release was 55.63%.
As the drug release from batches F1, F2 and F3 (20% DBP) was less as compared to batches F10, F11 and F12 (50% DBP) respectively. The lag time of batches F1, F2 and F3 were 5, 6 and 5 hours and that of batches F10, F11 and F12 were 5, 3 and 3 hours respectively. Thus lag time was decreased with plasticizer concentration was increased.
Effect of types of plastisizers
From figures 16, it was observed that formulation batches F2, F16, F17, and F18 release the drug 67.21, 88.70, 78.38 and 78.28% in 12 hours respectively. The release of drug from formulation containing hydrophilic plasticizer TEC was 88.70% compared with formulation containing hydrophobic plasticizers DBP, DEP and castor oil, the release were 67.21, 78.38 and 75.28% respectively. Plasticizer affects the properties of polymer i.e. flexibility, brittleness, permeability. Permeability of polymer improved with the addition of plasticizer. Plasticizer increases permeability of cellulose acetate as it lowers its glass transition temperature. It was observed that the release of drug from batch containing hydrophilic plasticizer (TEC) was increased compared with formulation batches containing hydrophobic plasticizer (castor oil, TEC and DEP). The release rate of drug was increased with increase in concentration of the plasticizer .The release rate was increased with hydrophilic plasticizer than hydrophobic plasticizer. Incorporation of 20% DBP, 20% PEG 400 0f cellulose acetate concentration with 2% coating weight gain and drug: osmotic agent ratio 1:1.5 show optimized batch with zero order release. Dissolution profiles of optimized formulation batches F3, F12, F15, F17 and F18 followed zero order models for release kinetics.
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Received on 15.09.2011 Modified on 20.09.2011
Accepted on 03.10.2011 © RJPT All right reserved
Research J. Pharm. and Tech. 4(12): Dec. 2011; Page 1797-1804