Design and Development of Simvastatin Gas Powered System for Controlled Release

 

N. G. Raghavendra Rao¹*, N. G. Srivani², C. Kistayya³

¹Department of Pharmaceutics, Sree Chaitanya Institute of Pharmaceutical Science, L.M.D. Colony, Thimmapur,  Karimnagar - 505527, Telangana, India.

²Department of Pharmaceutics, V. L. College of Pharmacy, Manik Prabhu Temple Road, Raichur - 584 101, Karnataka State, India.

³Department of Pharmaceutical Chemistry, St. Johns College of Pharmaceutical Science, Yerrakota, Yemmiganur, Kurnool, Andhra Pradesh, India

 

ABSTRACT:

Simvastatin is a Hypolipidemic used to control elevated cholesterol, or hypercholesterolemia. The primary uses of simvastatin are for the treatment of dyslipidemia and the prevention of cardiovascular disease. Gas powered Floating tablets of Simvastatin were developed by direct compression method using different grades of HPMC, Carbopol, ethyl cellulose, sodium CMC, sodium alginate, mixture of sodium bicarbonate, citric acid anhydrous as gas generating agents, Citric acid was also used as an antioxidant. The results of Pre-compressional parameters were within I.P prescribed limits. The prepared tablets were subjected to post compression analysis for the parameters such as hardness, friability, weight variation, thickness, diameter, drug content, lag time subsequently buoyancy time, and in-vitro dissolution studies. Tablets of all the formulation floated more than 12hrs. The results of in vitro buoyancy time and lag time study revealed that as the concentration of sodium bicarbonate increases there is increase in total buoyancy time and decrease in lag time. The results of dissolution study reveals that, a decrease in release rate of the drug was observed on increasing the polymer ratio and also by increasing the viscosity grades of the polymer. In all the formulations, hardness test indicated good mechanical strength, friability is less than 1%, indicated that tablets had a good mechanical resistance. DSC and FT-IR studies revealed that, there was no incompatibility of the drug with the excipients used. The stability study conducted as per the ICH guidelines and the formulations were found to be stable. From this study, it can be concluded that, the formulation retained for longer periods of time in the stomach and provides controlled release of the drug and may improved bioavailability.

 

 

INTRODUCTION:

Poor bioavailability has been recorded for some drugs formulated in sustained-release dosage forms. Their narrow absorption window, lower solubility at high pH values, or enzymatic degradation in the intestinal or colonic environments was the reason of decreased bioavailability.[1-5] For this, it has been a challenge to develop the oral controlled-release dosage form because it is difficult to keep drugs at the targeted area inside the gastrointestinal tract.[6] Gastro retentive drug delivery systems provide dosage forms with longer residence time in the stomach and sustained-release behavior, which can improve bioavailability as well as acting locally on the stomach.[7,8] Increasing gastric residence time can be achieved either by floating systems that cause buoyancy above gastric fluid,9 high-density systems that sink to the bottom of the stomach,[10] bioadhesive systems that adhere to mucosal surfaces,[11] or by expandable systems that have limited emptying through the stomach pylorus due to swelling or unfolding to a larger size.[12]

 

The floating drug delivery systems were described in the literature as early as 1968.[13] These systems are designed to have a bulk density lower than the gastric fluid so they can remain buoyant for prolonged periods of time without affecting the gastric emptying rate. [3,14,15] Floating drug delivery systems can be classified as non-effervescent systems or effervescent systems.[16] Non-effervescent floating drug delivery systems swell in gastric fluid and maintain a relative stability of shape and bulk density less than the density of the gastric fluid, which assists the floating process of these dosage forms.[17] However, effer­vescent floating drug delivery systems based on effervescent components will liberate carbon dioxide due to the acidity of the gastric fluid. Liberated gas bubbles will be entrapped in the gel layer formed by hydrocolloids that produce an upward motion of the dosage form and maintain its buoyancy.[18]

 

Simvastatin is a Hypolipidemic used to control elevated cholesterol, or hypercholesterolemia. It is a member of the Statin class of pharmaceuticals. The primary uses of simvastatin are for the treatment of dyslipidemia and the prevention of cardiovascular disease. The t1/2 for Simvastatin is 2 to 4 hrs and bioavailability is 5% and efficiency of protein binding is 95%. This research study provided useful information on preformulation and formulation optimization of the selected anti retroviral drugs as floating modules during development of controlled drug delivery systems containing various rate controlling polymers, to get the desired controlled release over a period of 12 hrs. The main objective of the present research work is formulation gas powered tablets of Simvastatin, which releases the drug at controlled rate for a long period of time in the stomach. The gas powered tablets of Simvastatin were prepared by direct compression technique using polymers like HPMC K4M, K15M and Carbopal along with gas generating agent Sodium bicarbonate.

 

MATERIALS AND METHODS:

Simvastatin drug is procured as a gift sample from Lupin labs, Private Ltd. Pune, India. HPMC K4M procured as a gift sample from AstraZeneca Pvt Ltd Bangalore. Carbopol 934, xanthan gum (XG), hydroxyl ethyl cellulose (HEC), magnesium stearate and citric acid are purchased from Hi media laboratories Pvt. Ltd, Mumbai. India, Sodium bicarbonate, sodium alginate, lactose, mannitol and talc were purchased from S.D. Fine Chemicals. Mumbai. All other materials used were of pharmaceutical grade.

 

Drug-Excipients Compatibility Studies:

Fourier Transform Infrared Spectroscopy (FTIR): FTIR studies were carried out pure drug Simvastatin and best formulations like, FB3, FB6, FB7 and FB9. Infrared spectroscopy was performed using a Shimadzu FTIR 8300 Spectrophotometer and the spectrum was recorded in the region of 4000 to 400 cm^-1. The procedure consisted of dispersing a sample (drug and excipients, 1:1 ratio in potassium bromide (KBr) (200-400 mg) and compressing into discs by applying a pressure of 5 tons for 5 min in a hydraulic press. The pellet was placed in the light path and the spectrum was obtained.

 

Differential Scanning Colorimetry:

DSC studies were carried out pure drug Simvastatin and formulations like, FB3, FB6, FB7 and FB9. DSC scan of about 5mg, accurately weighed Simvastatin and other formulations were performed by using an automatic thermal analyzer system. (DSC60 Shimadzu Corporation, Japan) Sealed and perforated aluminium pans were used in the experiments for all the samples. Temperature calibrations were performed using indium as standard. An empty pan sealed in the same way as for the sample was used as a reference. The entire samples were run at a scanning rate of 10°C/min from 50-300°C.

 

Preparation of Simvastatin floating tablets [19-20]: All the formulations FB1 to FB10 were prepared by direct compression method. The composition of the tablets is given in Table 1. All the formulation tablets containing drug and other excipients, were prepared by weighing drug, diluents along with natural gums and passing them through sieve no 44 to break the lumps and also for proper blending of powder, to this powder blend 0.5 % of magnesium stearate and 1 % of talc were added to each and further mixed. The resultant blends were punched to 300 mg using convex-faced punches using a multi-station rotary compression machine (Rinek mini press-II MT).

 

The resultant blends were evaluated for pre-compressional parameters to find out the flow properties of powder blend. The pre-compressional parameters such as Bulk density, Tapped density, Angle of repose, Compressibility index and Hausner ratio.

 

 

Evaluation of Simvastatin floating tablets:

Weight Variation Test:

Weigh 20 tablets selected at random and calculate the average weight. Not more than two of the individual weights deviate from the average weight by more than the percentage limits. As per Indian Pharmacopoeia specification.        

 

Friability Test:

20 tablets were weighed and subjected to rotate on friability test apparatus. The drum rotated at a speed of 25 rpm for 4 minutes, then dedusted and reweighed the tablets. Percentage friability was calculated. Percentage friability of tablets less than 1% is considered acceptable.

 

Hardness Test:

The hardness of tablet was carried out by using Pfizer type hardness tester. The hardness of the tablet kg / cm² was measured.

 

Thickness Test:

Control of physical dimension of the tablets such as sizes and thickness is essential for consumer acceptance and to maintain tablet to tablet uniformity. The dimensional specifications were measured using verniar calipers. Six tablets from each batch were tested and average values were calculated. The thickness of the tablet is mostly related to the tablet hardness can be uses as initial control parameter.

 

Buoyancy lag time (BLT):

The time taken for dosage form to emerge on surface of medium is called floating lag time (FLT) or buoyancy lag time (BLT).

 

Determination of in vitro floating lag time:

The in-vitro buoyancy was determined by floating lag time and total floating time, as per the method. In a 250 ml beaker containing buffer solution, maintained at 37 ± 0.5°C in a water bath. Their physical state was observed for 24 h. The time required for the tablet to rise to the surface and float was determined as floating lag time and total duration of time by which dosage form remain buoyant is called total floating time.

 

In-vitro dissolution studies:

The release rate of Simvastatin from floating tablet was determined by Dissolution Tester apparatus DS-8050 Lab India. The dissolution test was performed using 900ml 0.1N HCL with 1% sodium lauryl sulphate at 37°C ± 0.5⁰C. At each hour interval, aliquots of 10 ml were withdrawn from the dissolution medium and the amount was replaced with fresh medium to maintain the volume constant. The samples were filtered through a Whatman filter paper and diluted to a suitable concentration with dissolution media for the study. The absorbance of the solutions was measured at 236 nm. Cumulative percentage of drug release was calculated using an equation obtained from standard curve.

 

Determination of swelling index:

The swelling index of tablets was determined in 0.1N HCL (with 1%SLS) at 37ºC temperature. The swollen weight of the tablet was determined at predefined time intervals over a period of 5hr. The swelling index (SI) is expressed as a percentage and was calculated from the following equation.

 

Stability Studies:

Stability studies were performed on optimised formulation, prepared tablets were wrapped with aluminium foil and kept in a vial. These samples were placed in a stability chamber (Thermolab, humidity and photo stability chamber) at 40±2⁰ C and 75±5% RH according to ICH guidelines. At regular time intervals of 15, 30, 60 and 90 days tablets were analysed for drug release lag time.

 

RESULTS AND DISCUSSIONS:

Drug - Excipient compatibility studies:

FTIR Studies:

In the present study, it has been observed that there is no chemical interaction between Simvastatin and the polymers used. The FT-IR spectra of pure drug peaks are observed in the Simvastatin sample were 3546.35cm^-1(Free O-H stretch), 2929.97 cm^-1, (Methyl C-H symmetric stretch; Methylene C-H asymmetric stretch) 1697.41cm^-1 (Ester C=O stretch, associated), 1464.02cm-1 (Methylene C-H symmetric bend; Methyl C-H asymmetric bend), 1265.35 cm-1, (Lactone-C-O-C bend) 1165.04 cm^-1 (Ester –C-O-C- bend), 1072.48 cm^-1 (Secondary alcohol C-O stretch), 869.92 cm^-1(Tri substitute olefinic C-H wag) which co-relates with the peaks of standard Simvastatin sample. Similarly the IR spectrum of Simvastatin formulations FB3, FB 6, FB7 and FB9 showed characteristic absorption bands at or near that of Simvastatin absorption bands values indicating that there was no chemical and physical change in the functional groups present in Simvastatin. [Shown in Fig 1].

 

DSC Studies:

DSC study revealed that the thermogram of pure drug (Simvastatin) shows an endothermic peak at 139.16⁰C. The endothermic peak clearly establishes the fact that the melting point observed with the DSC thermogram is agreement with reported literature value. It is also confirmed that the drug used is in its pure form. These thermograms of all formulations with the polymers were also taken for this study. The study also reveals that the thermogram of pure drug and other formulations [Shown in Fig 2].  FB3, FB 6, FB7 and FB9 were shown endothermic peaks at 139.10, 138.69, 139.15, 138.26 respectively. It reveals that irrespective of the polymers used in the formulation there is negligible changes in the melting point range of formulations in comparison with the pure drug (Simvastatin). Thus the DSC thermograms study reveals that there is no any kind of interaction of the drug with different types of polymer and their excipients used during the study.

 

Evaluation of Simvastatin gas powered tablets[21, 22]:

The Gas powered tablets of Nevirapine were prepared direct compression technique.  The values of pre-compression parameters evaluated were within prescribed limits and indicated good free flowing property. The results of pre-compression parameters were given in Table 2.

 

 

Table 1: Formulations of Simvastatin Floating tablets

 

Table 2: Evaluation of Pre-Compression Parameters (FB1-FB10)

FC=Formulation code *All the values expressed as mean ± SD, n=3

 

Table 3: Evaluation of Post Compression Parameters (FB1-FB10)

FC=Formulation code, **All the values expressed as mean ±SD, n=20,

*All the values expressed as mean ±SD, n=3.

 

 

All the formulations were evaluated for various parameters like hardness of all the tablets prepared by direct compression method was maintained within the 5.4 kg/cm² to 6.8 kg/cm².

 

The friability result were found in all designed formulations in the range of 0.43 to 0.91 % to be well within the approved range (<1%). The weight variation was found in FA1-FA8 in the range 296.18-304.09 mg, where as FB1-FB10 formulations shows in the range of 296.12- 305.05 mg, the FC1-FC8 formulations shows in the range of 299.66-301.66 mg. All the tablets passed weight variation test as the average percentage weight variation was within 7.5% i.e. in the pharmacopoeial limits. The mean thickness was (n=3) almost uniform in all the formulations prepared by different methods. Thickness of tablets prepared by direct compression, the values ranged from 4.06 mm to 4.35mm. The standard deviation values indicated that all the formulations were within the range. The mean hardness test, friability, weight variation and thickness results are tabulated in Table 3.

 

 

Fig 1: IR spectra of pure drug Simvastatin and formulations FB3, FB 6, FB7 and FB9.

 

 

Fig 2: DSC Thermograms of pure drug Simvastatin and formulations FB3, FB 6, FB7

 

Water Uptake Study (Swelling Index):

Tablets composed of polymeric matrices build a gel layer around the tablets core when they come in contact with water. This gel layer governs the drug release. Kinetics of swelling is important because the gel barrier is formed with water permeation. Swelling is also a vital factor to ensure floating. To obtain floating the balance between swelling and water acceptance must be restored.[23] Results of water uptake study showed that the order of swelling in these polymers could indicate the rates at which the preparations are able to absorb water and swell. Maximum liquid uptake and swelling of polymer was achieved up to 7 hrs and then gradually decreased due to erosion.

 

The swelling of polymers used in this CGPS tablets (HPMC K4M, carbopol, sodium CMC, sodium alginate) could be determined by water uptake of the tablets. The complete swelling was achieved by the end of 7 hrs. The swelling index was in range of 77.52 ± 0.40 - 198.01 ± 0.68. The moisture uptake values are given in Table 3.

 

In-Vitro Buoyancy and Lag Time Study: Formulations from FB1, FB2, and FB8 did not float; this was due to the lower percentage of gas generating agent. The formulation FB3, FB4, FB5, FB6 floated but the lag time was more and floating time is less. For the formulations FB7, and FB9 the duration of buoyancy was more than 12 hrs, the floating capacity increased in these formulations and floated with less lag time due to high concentration of gas generating agent sodium bicarbonate induced CO₂ generation in the pressure of dissolution medium (0.1N HCL with 1% sodium lauryl sulphate). The gas generation is trapped and protected within the gel formed by hydration of the polymers, thus decreasing the density of tablet. It was observed that paddle speed affected the floating properties of tablet [24]. The tablet floated with less lag time due to high concentration of gas generating agent. However, some results revealed that, as the concentration HPMC K4M and carbopol increased, total floating time increased, this is because of increased gel strength of matrices, which prevents escape of evolved carbon dioxide from matrices, leading to decreased density of the formulations. As the density of tablets falls below 1 the tablet become buoyant.

 

The results shows that amount of HPMC K4M and carbopol increased, TFT increased due to increased matrix integrity at high amount of HPMC K4M while amount of NaHCO₃ and citric acid increases TFT decrease because NaHCO₃ and citric acid promote faster erosion of tablets. From the results of swelling index it was concluded that swelling increases as the time passes because the polymer gradually absorb water due to hydrophillicity of polymer. The outermost hydrophilic polymer hydrates and swells and a gel barrier is formed at the outer surface. As the gelatinous layer progressively dissolves and/or is dispersed, the hydration swelling release process is repeated towards new exposed surfaces, thus maintaining the integrity of the dosage form. Thus, the viscosity of the polymer had major influence on swelling process, matrix integrity, as well as floating capability, hence from the above results concluded that linear relationship exists between swelling process and viscosity of polymer. So the presence of optimum amount of Carbopol, NaHCO₃, and citric acid is important in achieving good floating time and minimum floating lag time. Incorporation of sodium bicarbonate helps to produce carbon dioxide gas which entrapped inside the hydrophilic matrices leads to increase in volume of dosage form resulting in lowering of density and dosage form starts to float. As the amount of polymer in the tablet formulation increases, the drug release rate decreases and as the concentration of gas generating agent (NaHCO₃) increases the drug release increases and at the same time floating lags time decreases.  All the results were given in Table 4 and Fig 3.

Table 4: Floating ability of  FB1- FB10 Formulation.

FC=Formulation code

 

Fig 3: Plot of Floating Lag time values of Simvastatin formulations (FB1-FB10)

 

 

Table 5: In-vitro Drug Release Studies of FB1-FB10 formulations

FC=Formulation code, All values are expressed as mean ± SD, n=3,

 

In-vitro drug release studies of simvastatin formulations:

The release rate of Simvastatin from floating tablet was determined by Dissolution Tester apparatus DS-8050 Lab India. The dissolution test was performed using 900ml 0.1N HCL with 1% sodium lauryl sulphate at 37°C± 0.5^oC. The drug release from the formulations FB1-FB10 was found to be76.01, 94.034, 88.51, 82.32, 76.36, 99.28, 74.38, and 70.51% in 12 hrs. Among all the formulations FB7 formulation shows the drug release around 99.28% within 12 hrs. From the in-vitro drug release study it is found to be as the concentration of the polymer increases the drug release decreases. The dissolution profiles of all the formulations are shown in Table 5 and Fig 4-5.

 

From results the formulation containing large concentration of high viscosity polymers induced formation of strong viscous gel layer that leads to decreased water diffusion into the tablet which results in decrease drug release.

 

In-vitro drug release kinetic studies:

The dissolution profiles of all the batches were fitted to zero-order, by plotting cumulative amount of drug release versus time, first-order by plotting log cumulative percentage of drug remaining versus time, Higuchi, by plotting cumulative percentage of release versus square root of time, Korsmeyer-Peppas equation models by plotting log cumulative percentage of drug released versus log time.

 

Fig 4:  In-vitro drug release profiles of Simvastatin formulation FB1-FB5:

 

Fig 5:  In-vitro drug release profiles of Simvastatin formulation FB6-FB10

 

A result shown in Table 6 reveals that all formulations follow zero order kinetics as correlation coefficient (r²) values are higher than that of first order release kinetics. The calculated n values from power law equation for drug release profiles were between 0.870-0.997 with a correlation coefficient (r²) values >0.94, suggest that drug release mechanism from Simvastatin Floating  tablets followed non-Fickian  (anomalous) transport mechanism.

 

The Table 7 shows the parameters of the tablets after stability study. The promising formulations were subjected to short term stability study. The best formulations were selected.  After three month the tablets were again analyzed for the hardness, drug content uniformity and floating time. No significant changes in other parameters were observed in the tablets prepared with different technique of all formulations was within the acceptable limits.

Table 6: In-vitro Drug release kinetics of FB1-FB10 Formulation

FC=Formulation code

 

Table 7: Stability study data

FC=Formulation code

 

 

CONCLUSION:

From the present study, it can be concluded that, the formulation retained for longer periods of time in the stomach (spatial control) and provides controlled release of the drug. Hence, controlled gas powered system tablets retained for longer periods of time in the stomach which may leads to improve the therapeutic effect of the drug by increasing its bioavailability.

 

REFERENCES:

1.     Hoffman A. Pharmacodynamic aspects of sustained release prepara­tions. Adv Drug Deliv Rev. 1998;33:185–199.

2.     Baumgartner S, Kristl J, Vrecer F, Vodopivec P, Zorko B. Optimisation of floating matrix tablets and evaluation of their gastric residence time. Int J Pharm. 2000;195:125–135.

3.     Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J Control Release. 2000;63(3):235–259.

4.     Streubel A, Siepmann J, Bodmeier R. Drug delivery to the upper small intestine window using gastroretentive technologies. Curr Opin Pharmacol. 2006;6:501–508.

5.     Nayak AK, Maji R, Das B. Gastroretentive drug delivery systems: a review. Asian J Pharm Clin Res. 2010;3:2–10.

6.     Lee TW, Robinson JR. Controlled release drug delivery systems. In: Gennaro AR, editor. The Science and Practice of Pharmacy. Vol I. 20th ed. Remington: Mack Publishing Company; 2000:1676–1693.

7.     Kagan L, Lapidot N, Afargan M, et al. Gastroretentive accordion pill: enhancement of riboflavin bioavailability in humans. J Control Release. 2006;113:208–215.

8.     Murphy CS, Pillay V, Choonara YE, Du Toit LC. Gastroretentive drug delivery systems: current developments in novel system design and evaluation. Curr Drug Deliv. 2009;6:451–460.

9.     Xiaoqiang X, Minjie S, Feng Z, Yiqiao H. Floating matrix dosage form for phenoporlamine hydrochloride based on gas forming agent: in vitro and in vivo evaluation in healthy volunteers. Int J Pharm. 2006;310:139–145.

10.  Hwang SJ, Park H, Park K. Gastric retentive drug-delivery systems. Crit Rev Ther Drug Carrier Syst. 1998;15(3):243–284.

11.  Chavanpatil MD, Jain P, Chaudhari S, Shear R, Vavia RR. Novel sus­tained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin. Int J Pharm. 2006;316(1–2):86–92.

12.  Deshpande AA, Shah NH, Rhodes CT, Malick W. Development of a novel controlled release system for gastric retention. Pharm Res. 1997;14:815–819.

13.  Davis DW. Method of swallowing a pill. US Patent. 1968;3(418):999.

14.  Rouge N, Buri P, Doelker E. Drug absorption sites in the gastroin­testinal tract and dosage forms for site-specific delivery. Int J Pharm. 1996;136:117–139.

15.  Brahma N, Kwon HK. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J Controlled Release. 2000;63:235–259.

16.  Seth PR, Tossounian J. The hydrodynamically balanced system, a novel drug delivery system for oral use. Drug Dev Ind Pharm. 1984;10:313–339.

17.  Hilton AK, Deasy PB. In vitro and in vivo evaluation of an oral sustained-release floating dosage form of amoxycillin trihydrate. Int J Pharm. 1992;86(1):79–88.

18.  Rubinstein A, Friend DR. Specific delivery to the gastrointestinal tract. In: Domb AJ, editor. Polymeric Site-Specific Pharmacotherapy. Chichester: Wiley; 1994:282–283.

19.  Raghavendra Rao NG, Vijaya Kumar G, Akhlaaq Ahmad. Formulation and Evaluation of Gas Powered System of captopril tablets. American Journal of Pharmacy and Health Resaerch. AJPHR: Vol 3/Issue 9/Sept 2015: 40 - 56.

20.  Raghavendra Rao NG, Vijaya Kumar G, Priyanka V. Design And Development of Niveripine Gas powered systems for controlled release. Asian Journal of Biochemical and Pharmaceutical Research. AJBPR. Vol 5/Issue 3/ 2015:146 -  157.

21.  Raghavendra Rao NG, Sunil Firangi, Keyur Patel. Formulation And In-Vitro Evaluation Of Zidovudine Gastroretentive Floating Drug Delivery System For Prolong Release. International Journal of Current Biomedical and Pharmaceutical Research. IJCBPR:2011; 1(4):226-233.

22.  Raghavendra Rao NG, Sunil Firangi, Keyur Patel. Formulation and Evaluation Of Gastroretentive Effervescent Floating Drug Delivery System Of Zidovudine. American Journal of Pharma Tech Research. AJPTR: Feb: 2012; 2(1):513-529.

23.  Raghavendra Rao NG, Shrishail Ghurghure. Formulation and Evaluation of Zidovudine Controlled Release Gas Powered System Using hydrophilic Polymer. International Research Journal of Pharmacy. IRJP 2 (3), March-2011:86-94.

24.  Raghavendra Rao NG, Harsh A Panchal, Pentewar Ram. Formulation And In-Vitro Evaluation Gastroretentive Drug Delivery System Of Cefixime For Prolong Release. Der Pharmacia Sinica, 2011, 2 (2):236-248.

 

 

 

Accepted on 08.08.2016           © RJPT All right reserved

Research J. Pharm. and Tech 2016; 9(11): 1962-1970.