Formulation and Evaluation of Eplerenone Matrix Tablets using Aloe Vera, Guar Gum and Povidone K-30

Purpose: In the existing work different sustained release matrix tablets of eplerenone were prepared with dried mucilage of Aloe vera, guar gum and povidone K30 by using different binder: tablet weight ratios viz. 1:20, 2:20, 3:20, 4:20 and 5:20. Method: During this process Aloe vera leaves are procured, extracted, dried and characterized to obtain Aloe vera mucilage powder. Pre-formulation studies were performed and studied for the functional groups and also compatibility studies were conducted. The formulations that were prepared using Aloe vera were named as EPA, for Guar gum as EPG, for Povidone K30 as EPP and finally combination of Aloe vera and Povidone K30 was named as EPAP. Results: From the graphs, kinetic evaluation was done and observed that the drug release is governed by diffusion mechanism and this is confirmed by r values. The regression coefficient values, clearly indicates that the drug release is governed by zero order and almost all formulations showing Fickian release. Among all the formulations that were prepared EPAP-5 is selected as best. The best formulation is compared with the marketed formulation. Conclusion: Aloe vera gel dried powder is a suitable matrix agent in formulating sustained release tablets of eplerenone. It may be useful in similar preparations of other drugs.


Introduction
Among the entire delivery systems oral route is highly preferred because of its high comfort zone that cannot be produced by other routes.In order to release the drug at specific location different types of polymers are used and they also help to show prolonged action.Many advanced technologies are available and these are making the delivery systems more suitable and advantageous when compared to the past.Controlled release oral drug delivery system is one among the advanced technologies that is most widely preferred.
(1) Eplerenone is a steroidal anti mineralcocorticoid of the spirolactone group that is used as an adjunct in the management of chronic heart failure.The recommended starting dose of eplerenone for the treatment of essential hypertension is 50 mg once daily titrated to a maximum of 50 mg twice daily.
Bharghava Bhushan Rao P et al.

June 2018
The Pharmaceutical Journal of Sri Lanka 8(1) For the treatment of heart failure, the recommended starting dose is 25 mg once daily, titrated over 4 weeks if tolerated to the target dose of 50 mg once daily.No adjustment is necessary for patients with mild to moderate hepatic impairment or for the elderly.The maximum effective dose should be limited to 100 mg daily to avoid the increased risk of hyperkalemia with higher doses.The elimination halflife is 4 to 6 hours.Absolute bioavailability 69% (100-mg oral tablet).Peak plasma concentrations usually attained within 1.5-2 hours.Hence in the present work in order to decrease the dose and to make available the drug for prolonged period matrix tablets of eplerenone are formulated.
In the present investigation various matrix tablets were prepared by wet granulation using Aloe barbadensis Miller leaf mucilage dried powder, Guar gum and Povidone K-30 as polymers in different proportions.The prepared tablets are compared with the marketed product. (2)

Extraction of mucilage from Aloe vera leaves:
1 kg of fresh leaves were carved and mixed with 1 liter of water and centrifuged at 4000 rpm for 15 minutes.Distinct, mucilaginous solution was decanted.The obtained mucilage was washed with 250 ml of Ethanol, 250 ml of water and followed by 100 ml of Acetone.725 g of mucilage was obtained by treating 1kg of leaves.(4) Bharghava Bhushan Rao P et al.

June 2018
The Pharmaceutical Journal of Sri Lanka 8(1) Purification and drying of the Aloe mucilage Purification is a crucial step during this work.The above obtained paste was mixed with trichloroacetic acid solution in 1:2 proportions.1500 ml solution was reacted with 0.1N sodium hydroxide base adding slowly until precipitation was formed.To the above recovered 725 g of precipitate 100 ml of ethyl alcohol was added, followed by washing with 50 ml acetone and 50 ml diethyl ether.The obtained paste was dried by spreading on the open slabs.700 g of powder was obtained by taking 725 g of above formed mucilage.
From the above formed powder physical and chemical properties were studied and results are shown in Table 1.This is done in order to study the melting points of the pure drug and pure polymers and also to study the changes that were produced when they are made in the form of a tablet.Heating rate of 10°C/min was maintained in nitrogen atmosphere by taking a sample of 3 mg.The results are shown in Figures 1, 2. The DSC scan of eplerenone showed a short endothermic peak at 195.2 0 C. The thermo gram with Aloe vera mucilage powder and povidone K30 showed endothermic peaks at 149 0 C, 195.2 0 C, 260 0 C respectively.(5) Bharghava Bhushan Rao P et al.

June 2018
The Pharmaceutical Journal of Sri Lanka 8( 1)

Solubility analysis
In order to confirm the solubility of the drug it was made to dissolve in different solvents and it was found that eplerenone was soluble in dichloromethane, sparingly soluble in acetone and freely soluble in dilute NaOH and KOH solutions.

λ max of eplerenone
Eplerenone was found to be maximum at 245 nm and ratio of absorptivity was calculated which was less than 3%.
Estimation of eplerenone 50 mg of eplerenone was taken and mixed with 50 ml of 6.8 pH buffer, from the above solvent 1 ml was taken (1000 µg/ml) and diluted to 10 ml in order get 100 µg/ml.Different dilutions were prepared ranging from 2.0 -20.0 µg/ml.The absorbance of the solutions was measured at 245 nm using UV-visible spectrophotometer.Standard curve was plotted by concentration versus absorbance and represented in Table 2. (7, 8)  20, 2:20, 3:20, 4:20 and 5:20.These agents were used as matrixing agents along with other ingredients.The mentioned formulations were compressed by a direct compression technique using 8 mm flat faced punches.Dissolution studies were performed and formulations with Aloe and povidone showed better release.So, combination of Aloe and povidone were selected for further studies.The compositions of formulations are shown in Tables 3, 4. ( 9)

Evaluation of matrix tablets:
The prepared tablets were studied for precompression and post-compression parameters.Pre-compression parameters results include Angle of Repose, Bulk Density and Compressibility Index (Table 5).( 10) Bharghava Bhushan Rao P et al.

June 2018
The Pharmaceutical Journal of Sri Lanka 8( 1)

Drug Release studies
In order to study the drug release, dissolution studies were performed by using USP dissolution apparatus II (paddle) with phosphate buffer pH 7.4 as the medium.The kinetic values produced from in vitro drug release profile of EPAP-1 -EPAP-5 are shown in Tables 6, 7. The in vitro drug release kinetics of the formulations was depicted from the Figures 6, 7, 8. Linear regression graphs were plotted for EPAP 1-EPAP 5 and shown in Figures 9a, 9b, 9c and 9d.Since the formulation EPAP-5 was optimized it was compared with marketed tablets and shown in Figure 10.

Discussion
Matrix tablets of eplerenone, were prepared and these were found economical since a natural matrixing agent was used during the formulation.Different formulations were prepared using Aloe vera, guar gum and povidone.Optimized formulation was selected based on the minimum drug release.
The endothermic peaks in DSC scan of eplerenone formulations with Aloe vera mucilage and povidone showed slight change in shifting towards the lower Bharghava Bhushan Rao P et al.

June 2018
The Pharmaceutical Journal of Sri Lanka 8(1) temperature.Thus these minor changes in the melting endotherm in the drug could be due to the mixing of the drug and polymers which lower the purity of each component in the mixture.The characteristic functional group peaks C-O-C, -CH, -C=C, C=O-CH3, -OH, C=O of eplerenone in the FTIR spectrums were not getting disturbed even after mixing with the polymers used indicating the suitability of the polymers used with eplerenone.
The matrix tablets that were formulated were studied for post compressional parameters and they were found within the range as per Pharmacopoeia specifications.Hardness and friability studies were performed on optimized formulation in order to study compactness and mechanical strength and they were within the acceptable range.Similarly from the uniformity content it was confirmed that the drug and polymer were mixed uniformly.
Matrix tablets of eplerenone prepared using combination of Aloe vera mucilage dried powder and povidone K-30 showed good swelling properties at first 2 hr and steady swelling in next 10 hr which indicates the uniformity of swelling of matrix tablets followed by drug release.From the drug release studies, it was clearly noticed that the increase in Aloe vera concentration decreases the drug release.Basing on the drug release kinetic studies it was found that the release was governed mainly due to diffusion and erosion mechanism as obtained from the values of regression coefficient (r) obtained from the graph.With regard to the optimized formulation EPAP-5 it was found to be a zero order release pattern.Korsmeyer Peppa's plot indicates that almost all the formulations of eplerenone with Aloe barbadensis Miller leaf mucilage powder and povidone K30 matrix tablets followed Fickian release behavior.
The formulated matrix tablets of eplerenone using Aloe and povidone were studied for their derived properties, physical and chemical properties and invitro drug release studies.Almost all the formulations showed fairly acceptable values for all the parameters evaluated.
The formulation EPAP-5 matrix tablets were found to be suitable in order to provide 12 h drug release.The drug release was compared with the marketed tablets and found to be similar.

Conclusion
The main intention of this work is to check the suitability of Aloe vera as a matrixing agent which can retard the drug release for prolonged period of time.The drug release was found to be decreased by increasing the concentration of Aloe.Aloe vera alone was tried during the formulation but when it was combined with Povidone K-30 it made a great change in the drug release pattern and also produced prolonged action.Hence not only eplerenone matrix tablets can be made with Aloe vera but also other drugs could be made into matrix tablets.

Table 1 : Physical and chemical characterization of Aloe vera mucilage dried powder Property Aloe vera powder
All values mentioned as mean ± S.D: No. of trials (n) = 3: S.D, Standard deviation