INTRODUCTION:
An ideal CDDS is the one which delivers the drug at a predetermined rate, locally or systemically, for a specified period of time.
The goal of a sustained release (SR) dosage form is to maintain therapeutic blood or tissue level of the drug for an extended period. This is usually accomplished by attempting to obtain zero order release from the dosage from1. The term “Controlled release” has a meaning that goes beyond the scope of sustained drug action. It also implies the predictability and reproducibility in the drug release kinetics which means that the release of drug ingredients from a controlled release drug delivery system proceeds at a rate profile that is not only predictable kinetically, but also reproducible from one unit to another2.
In the present investigation, studies were under taken to formulate and evaluate oral CRDDS of silymarin widely used in the treatment of hepatoprotective, hepatoregenerative and antihepatotoxic. It is freely soluble in methanol. It has elimination half-life of approximately 6 hours3. Based on these physico-chemical and bio-pharmaceutical properties, silymarin was selected as a drug candidate for developing CR tablet formulation.
In order to improve the absorption and its oral bioavailability, we have attempted to formulate a controlled drug delivery system using silymarin with HPMC K4M as drug and polymer respectively.
MATERIALS AND METHODS:
Materials:
Silymarin was obtained from M/s. Micro Laboratories Ltd, Hosur. HPMC K4M was purchased from Loba Chemicals Pvt. Ltd, Mumbai. All other chemicals and reagents used were of analytical grade.
Methods:
1. Preparation of CR tablets
Three formulations of CR tablets of silymarin using drug and HPMC K4M in three different ratios such as (1: 0.25, 1: 0.5 and 1: 0.75) were prepared by direct compression method. The active ingredient and other excipients of the tablet formulations are shown in the Table 1.
Silymarin and HPMC K4M with different concentrations, Sodium Lauryl Sulphate (SLS), Polyvinyl Pyrolidone (PVP K30) and Lactose were mixed together in mortar and pestle separately to get uniform mixture. The blend was passed through the sieve No: 16. The blend was then lubricated with magnesium stearate uniformly and then compressed in to tablets using tablet machine. (Rimek Mini Press-1, India).
2. Evaluation of blend:
The blend was evaluated for angle of repose, bulk density, tapped density, compressibility index and hausner ratio and the results were presented in Table 2.
Table – 1: Formulation of Silymarin Tablet
|
Ingredients (mg) |
Silymarin: HPMC K4M |
||
|
F1 1:0.25 |
F2 1:0.5 |
F3 1:0.75 |
|
|
Silymarin |
140 |
140 |
140 |
|
Hydroxy propyl methyl cellulose (HPMC K4M) |
35 |
70 |
105 |
|
Lactose monohydrate |
181 |
146 |
111 |
|
Poly Vinyl Pyrrolidone (PVP K30) |
16 |
16 |
16 |
|
Sodium lauryl sulphate (SLS) |
16 |
16 |
16 |
|
Magnesium Stearate |
12 |
12 |
12 |
Table 2: Evaluation of Blends
|
Parameters |
F1 |
F2 |
F3 |
|
Bulk density*(gm/cc) |
0.35 ± 0.07 |
0.34 ± 0.10 |
0.35 ± 0.06 |
|
Tapped density*(gm/cc) |
0.39 ± 0.03 |
0.38 ± 0.02 |
0.39 ± 0.06 |
|
Angle of repose*(θ) |
34º19’ ± 0.53 |
32º68’± 0.47 |
32º85’ ± 0.31 |
|
Compressibility index*(%) |
11.28 ± 0.51 |
11.71 ± 0.33 |
11.70 ± 0.15 |
Hausner ratio* |
1.12 ± 0.15 |
1.13 ± 0.24 |
1.13 ± 0.20 |
*All values are expressed as mean ± SD (n=3)
Angle of Repose:
Angle of repose is defined as the maximum angle possible between the surface of the pile of powder and horizontal plane4.
θ = tan-1 h/r
Where,
h = height of the pile
r = radius of the pile
Bulk Density:
Bulk density is defined as the ratio between a given weight of granules and its bulk volume5.
Weight of granules
Bulk Density =
Bulk volume
Tapped Density:
Tapped density is defined as the ratio between a given weight of granules and its tapped volume6.
Weight of granules
Tapped Density =
Tapped volume
Compressibility Index (CI) and Hausner Ratio:
It is a popular method of predicting powder or granules flow characteristics.
The compressibility index and the Hausner ratio are determined by measuring both the bulk density and tapped density of a powder or granules7.
C.I = Tapped density- Bulk density × 100
Tapped density
Hausner Ratio = Tapped density ⁄ Bulk density
3. Evaluation of Tablets:
Hardness Test:
Hardness is nothing but a force required to break a tablet across the diameter.
The hardness was tested using Monsanto Hardness tester8.
Uniformity of Weight:
Any variation in the weight of tablet (for any reason) leads to either under medication or over dose9.
% Deviation = Individual weight – Average weight ×100
Average weight
Friability Test:
It is performed to ensure the ability of tablets to withstand shock during processing, handling, transportation and packaging. It was usually measured by the use of Roche Friabilator. A maximum weight loss of not more than 1% from the initial weight tablets after 100 evolutions (25RPM) is considered generally acceptable10.
Drug content estimation:
Ten tablets were weighed and powdered, powder equivalent to 100mg of silymarin was dissolved in sufficient quantity of methanol and made up to 100ml with methanol. From this 10ml was pipetted out into a 100ml standard flask and made up to volume with phosphate buffer pH 7.4. The solution was diluted suitably with phosphate buffer pH 7.4 and analyzed for drug content by UV-double beam spectrophotometer at 286nm11.
IR studies:
It was used to study the interactions between the drug and polymer. The drug and polymer must be compatible to produce a stable product. Drug and polymer interactions were studied by using FTIR (Shimadzu, Japan, Model-84005) as per the method described by sharma8. IR Spectral Analysis of pure silymarin, Silymarin with highest proportion of polymer HPMC K4M (1:0.75) were carried out. The peaks and patterns produced by the pure drug were compared with the combination of polymer12.
In Vitro release studies:
The invitro release studies were carried out using USP type II dissolution apparatus at 50 rpm. The dissolution medium was 900 ml of phosphate buffer pH 7.4. It was maintained at 37° C ± 0.5°C. One tablet was placed inside the dissolution medium s and 10 ml of sample were withdrawn at 30 minutes interval up to 10 hours and replaced with same volume of medium. After suitable dilution the samples were analyzed at 286 nm using UV double beam spectrophotometer13.
Stability studies:
The formulation was tested for a period of 45 days at different temperatures of 4°C± 2°C, 27°C ± 2°C and 45°C± 2°C with 75% RH. At 15 days intervals the tablets were evaluated for the estimation of drug content and in-vitro release studies14.
RESULTS AND DISCUSSIONS:
The result of blend was presented in Table 2. The bulk density ranged from 0.34 to 0.35 and tapped density ranged from 0.38 to 0.39. The angle of repose ranged from 32°68’ to 34°19’. The compressibility index and Hausner ratio of the prepared blend ranged from 11.28 to 11.70 and 1.12 to 1.13 respectively. The results of angle of repose indicates good flow property of the blend and the value of compressibility index further showed support for the flow property.
The compressed tablets were evaluated for various physical parameters. The results are presented in Table 3. The hardness of the tablets ranging from 4.84 to 5.56 and percentage friability of all formulation within the range of 0.23% to 0.40%. The thickness ranged from 4.1mm to 4.4mm and the average percentage weight variation of 20 tablets from each formulation was within ± 5%. The drug content estimations showed values in the range of 96.87% to 102.74%, which contain good uniformity in drug content among different formulations. Here all the parameter are within the prescribed limits. So all the formulated tablets were falls within the limits.
Table – 3: Physico- Chemical Parameters of Tablets
|
Parameters |
F1 |
F2 |
F3 |
|
Hardness* (kg/cm2) |
5.56 ± 0.21 |
4.96 ± 0.26 |
4.84 ± 0.15 |
|
Friability* (%) |
0.40 ± 0.06 |
0.28 ± 0.09 |
0.23 ± 0.07 |
|
Uniformity of weight* (mg) |
396 ± 4.7 |
395 ± 4.07 |
400 ± 1.8 |
|
Drug content* (%) |
96.89 ± 0.33 |
97.64 ± 0.29 |
102.74 ± 1.10 |
|
Thickness* (mm) |
4.2 ± 0.04 |
4.2 ± 0.01 |
4.1 ± 0.05 |
* All values are expressed as mean ± SD (n=3)
Invitro release studies:
The data obtained from invitro release studies of all the three formulations was given in Fig-1. The formulations F1, F2 and F3 release 94.5%, 89.35% and 85.54% respectively at the end of 10hrs, where as the silymarin release from conventional marketed sample was (97.07%) in 4 hrs.
The percentage drug release of the formulation F1 (94.5%) was more than F2 (89.35%) and F3 (85.5%). The result revealed that the formulation F3 showed controlled release than formulation F1 and F2.
When the polymer ratio was increased, the percentage drug release of silymarin was decreased from controlled release dosage form.
The polymer concentration played a major role in drug release. At higher concentration of the polymer, the drug release was prolonged than the lower concentration of the polymer.
IR spectral analysis:
The IR studies of pure Silymarin and formulations containing highest proportion of the polymers (1:0.75) were carried out to study the interaction between the drug and polymers used.
OH stretching, CH aliphatic stretching, C=O stretching, C=C stretching, Methylenic CH2 stretching, O-H bending and aromatic vibration bending of pure silymarin and the silymarin controlled release tablets formulations containing higher proportion of the polymers were almost in the same region of wave number ranging from 3452.34cm-1 to 649.97 cm-1. The results proved that there were no significant interactions between the drug and polymers.
Stability studies:
In the stability studies there is no change in the percentage drug content and invitro release studies at different temperatures after every 15 days intervals up to 45days. From the data (not shown), the formulation was found to be stable under the mentioned conditions since there was no significant change in percentage drug content and invitro release studies.
CONCLUSION:
The present study was to formulate and evaluate controlled release silymarin tablets with the use of HPMC K4M polymer. In light of the aforementioned discussion, it could be concluded that HPMC K4M can be used as an effective controlled release polymer to retard the release of silymarin for extended period of time. This study concluded that the inherent drawbacks of conventional silymarin dosage form can be overcome by formulating it in controlled release tablets.
This formulation may overcome the problem of poor solubility and its associated problems. Since the formulation showed sufficient release for prolonged period, the dose can be reduced and possible incomplete absorption of the drug can be avoided.
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Received on 25.03.2010 Modified on 02.04.2010
Accepted on 07.04.2010 © RJPT All right reserved
Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 927-930