INTRODUCTION:
There is no exact control over drug release in traditional dosage forms, and the supplied dose of medication reaches the systemic circulation immediately. The goal of designing oral controlled medication delivery systems should be to provide more predictable and improved drug bioavailability. Among all the methods that have been investigated for the systemic delivery of medicines via diverse pharmaceutical products of varied dose forms, the oral drug delivery system has made significant progress as the most commonly used route of drug administration1-2.
Hydrogels are hydrophilic, three-dimensional polymeric networks capable of absorbing huge quantities of water or biological fluids. The networks are made up of homopolymers or copolymers and are insoluble owing to chemical crosslink’s (tie-points, junctions), as well as physical crosslink’s such entanglements and crystallites. The latter is responsible for network structure and physical security3-4.
Finasteride is classified as a synthetic 4-azasteroid drug. It works as an enzyme inhibitor. It is used to treat anti-hyperplasia and also as an anti-baldness agent. Finasteride's mechanism of action is based on its preferential inhibition of Type II 5a-reductase via the formation of a stable complex with the enzyme. This enzyme transforms testosterone into dihydrotestosterone (DHT), a more potent androgenic hormone. Type II 5a-reductase inhibition prevents the peripheral conversion of testosterone to DHT95-6.
MATERIALS AND METHODS:
Finasteride was procured from Yarrow Chem Pvt. Ltd, Mumbai, Calcium Chloride was obtained from Rankem Chemicals Ltd. Ahmadabad and Sodium Alginate and Na CMC was obtained from S.D Fine Chem Mumbai. All other chemicals and reagents used were of analytical grade, and were used as obtained.
Standard Calibration Curve:
The standard calibration curve of Finasteride was carried out on UV spectrophotometer by using phosphate buffer of pH 7.4 as the solvent. From the solution which is now having a concentration of 100μg/ml samples of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5ml were pipette out into 10ml volumetric flasks. The volume was made up to the mark with Phosphate buffer 7.4 to get the final concentration of 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50 μg/ml respectively. The absorbance of concentration was measured at 304nm7-8.
Drug-Excipients Interaction Study9-10:
Fourier Transformation Infra-red Spectroscopy:
The study by FTIR of the drug and excipient was carried out by conventional KBr plate method in order to study the interaction of the drug and polymer so as to determine the physical as well as chemical changes that can occur during the formulation. For this the mixture of powder of excipient and pure was mixed in a ratio of 1:1 with potassium bromide and the small pellet was formed by pressing the mixture in a hydraulic press and the FT-IR was carried out in the frequency range 400-4000 cm-1.
Differential Scanning Calorimeter:
The DSC study was carried out by studying thermograms of pure drug and its physical mixture with polymers was carried out to investigate any possible interaction between the drug and the utilized polymer. The selected heating rate is from 50°C to 400°C at an increase of 20°C per minute using Differential Scanning Calorimeter.
Formulation of Hydrogel:
The Finasteride hydrogel formula was created utilizing Sodium Alginate + Na CMC as a polymer at a concentration of 2% w/v and Calcium Chloride as a cross linking agent at a concentration of 1-3% w/v. Initially, the correct weights of Finasteride, propylene glycol, and Sodium Alginate + Na CMC were used. The water was then measured and put into a beaker with a motorized stirrer. Drug was dissolved in the minimum quantity of Calcium Chloride then polymer was dissolved in the required amount of water and both the solution was mixed together followed by the remaining amount of propylene glycol. This solution is then poured onto a china dish set in an 80±2°C thermostatic water bath. The reaction was kept going for another two hours until the water gets completely evaporate from the prepared hydrogel. The hydrogel is then placed in the oven to dry. The formulation chart of hydrogel preparation is depicted in Table 2. The dried hydrogel is then wrapped in an aluminium foil and stored in a desiccator for further use11-13.
Table 1: Formulation Chart of Hydrogel
|
Batch |
Sodium Alginate +Na CMC (%w/v) |
Calcium Chloride (%w/v) |
Stirring Time (min) |
Distilled Water (ml) |
|
BB1 |
2% |
1% |
120 |
10ml |
|
BB2 |
2% |
3% |
60 |
10ml |
|
BB3 |
2% |
2% |
60 |
10ml |
|
BB4 |
2% |
2% |
120 |
10ml |
|
BB54 |
2% |
1% |
60 |
10ml |
|
BB6 |
2% |
3% |
90 |
10ml |
|
BB7 |
2% |
3% |
120 |
10ml |
|
BB8 |
2% |
3% |
90 |
10ml |
|
BB9 |
2% |
1% |
90 |
10ml |
|
BB10 |
2% |
2% |
90 |
10ml |
|
BB11 |
2% |
2% |
90 |
10ml |
Evaluation of Hydrogels:
Percent Yield:
The evaluation parameter of percentage yield calculates the amount of practical yield obtained after the experiment of a particular batch. This parameter gives the efficiency of the process involved14. In the current experiment the parameter is calculated by the following formula:
Practical Yield
Percent Yield = ------------------------- × 100
Theoretical Yield
Drug Content:
1gm of hydrogel was weighed and transferred to a beaker containing phosphate buffer pH 7.4 which was previously mounted on a mechanical stirrer. Continued the stirring for 12 hrs to dissolve the hydrogel completely in to solvent. Then obtained solution was filtered studied under double beam UV spectrophotometer at 304nm15.
Drug content can be determined by using formula:
Practical Value
Drug Content (%) = ------------------------- × 100
Theoretical
Value
Swelling Index:
The swelling index of hydrogel was determined by placing the weighed hydrogel in the basket. For first 2 hrs the dissolution medium was 0.1N HCl then followed by phosphate buffer pH 7.4 for further study, at 37şC± 0.5şC. Hydrogel samples were withdrawn at a time interval of 30 min, blotted with tissue paper to remove the excess water and weighed on the analytical balance16. Swelling index was calculated by using the following formula:
Weight of swollen hydrogel – Weight of dry hydrogel
Swelling Index (%) = ------------------------------------------ × 100
Weight of dry hydrogel
In vitro Dissolution Studies:
In vitro dissolution tests were conducted in triplicate for all formulations in a USP type II dissolution test apparatus. The dissolution medium used was 900ml 0.1N HCl for 2hr, followed by phosphate buffer of pH 7.4 at 370C±0.50C. The speed of rotation was maintained to 50 RPM. The prepared hydrogel were tied in the dialysis membrane which was previously soaked in the phosphate buffer of pH 7.4. The dialysis membrane was then tied on both the ends so that the hydrogel remains in the center of the membrane. 5ml of sample were withdrawn at regular interval of time and 5ml of dissolution medium was replaced by freshly prepared medium in order to maintain the sink condition. The withdrawn samples were filtered through Whatman filter paper and diluted to 10 ml with the same dissolution medium. The absorbance of resultant samples of all intervals was measured at 304nm using double beam UV- spectrophotometer17-19.
Scanning Electron Microscopy:
SEM was used to evaluate the surface morphology of the cross linked hydrogel produced with three different doses of citric acid: 1%, 2%, and 3%. The samples were strewn onto double-sided tape, sputter-coated with platinum, and inspected under a 10 kV microscope20.
Release Kinetic Studies:
The analysis of drug release from swellable hydrogel requires a flexible model capable of identifying the contribution to overall kinetics. To determine the kinetic modeling of drug release, the dissolution profiles of all batches were fitted to different models such as zero-order, first order, Korsmeyer Peppas, and Higuchi21-22.
Stability Study:
The need of stability testing is to test the product and also to provide evidence on how the quality of a drug substance or drug product varies with time underneath the influence of assorted environmental factors like temperature, light, humidity, and allows suggested storage conditions, re-test periods and shelf lives to be established23-24.In the present study, stability studies were carried out at Room Temperature at 25°C±2°C/ 60% RH ± 5% RH and Accelerated testing at 40°C±2°C /75% RH±5% RH for 3 months for the optimized formulation. The optimized formulation was analyzed for the swelling ratio, % drug content, % drug release and t75.
RESULTS AND DISCUSSIONS:
Standard Calibration Curve:
The results of standard calibration curve revealed that it follows the beers lamberts law as the equation obtained was linear with the values of y =0.014x + 0.005 and the regression value of R2 = 0.999.
Figure 1: Standard Calibration Curve of Finasteride
Drug –Excipient Interaction Study:
The results from FTIR of pure Finasteride represented the following band characteristics at 3309cm-1 of Free O-H stretching vibration, 1458, 1504, 1597cm-1 exhibited benzene skeleton vibrations, and 995cm-1 represented bending vibration of C=C-H, the typical transolefinic band. The results of FTIR were compared with the standard and it was found that the pure drug was having the same peaks as that of the standard which confirmed that the drug was pure and the optimized formulation was then matched with the peaks of pure drug and it was seen that there was no new formation, disappearance, mismatching of peaks.
Thermal Study:
The DSC study of pure drug shows the melting point of 267.24oC which indicates its purity and the optimized formulation reveals the melting point of 281.56oC. From the thermal study of the pure drug and the optimized formulation revealed that the drug was pure and when mixed with the excipients it shows a slight difference in the melting point which was not a significant difference in the temperature and therefore it was concluded that the drug was pure and it shows less physical or chemical interaction with the excipients.