Development of Capsule containing Immediate Release Tablet and Extended Release Floating Tablet for Monitoring Release of Atenolol

 

Mahesh Hari Kolhe^1,2*, Ritu Mehra Gilhotra³, Govind Sarangdhar Asane⁴

¹Research Scholar, Gyan Vihar School of Pharmacy, Suresh Gyan Vihar University,

Mahal, Jagatpura, Jaipur, Rajasthan, India- 302017.

²Department of Pharmaceutics, Pravara Rural College of Pharmacy, Pravaranagar,

Ahmednagar, Maharashtra, India – 413736.

³Principal and Dean, Gyan Vihar School of Pharmacy, Suresh Gyan Vihar University,

Mahal, Jagatpura, Jaipur, Rajasthan, India- 302017.

⁴St. John Institute of Pharmacy and Research, Palghar, Maharashtra, India- 401404.

 

ABSTRACT:

Atenolol is beta blocker absorbed through GIT use for heart diseases. Single tablets, floating tablets and sustained released formulations studied are insufficient to produce effective dose to enhance bioavailability and effectiveness. Our study is focused on development of capsule dosage form containing immediate release (IR) and floating extended release (ER) tablets for monitoring release of atenolol in single dosage form. Two different tablets for IR and ER were prepared in three different combinations (Batch). Pre-formulation and post formulation parameters found to be within acceptable limits of formulation. Release behavior of individual tablets and capsule containing two tablets were studied. Among the batches, capsules containing smaller amount of atenolol in IR and large amount of Atenolol in ER (batch II) showed impressive drug release pattern. This formulation was stable even after a month and achieved optimum release behavior of immediate release and sustained release. This study could be used for effective treatment for different heart complications and reduce toxicity due to high plasma concentration in increased dose frequency.

 

 

 

INTRODUCTION:

Atenolol is a competitive cardioselective β₁-blocker and reduces resting and exercise-induced heart rate as well as myocardial contractility¹. Atenolol reduces BP and heart rate which results in reduced myocardial work and O₂ requirement leading to improved exercise tolerance and reduced frequency and intensity of anginal attack. Atenolol is consistently absorbed when administered orally; with approximately 50 - 60% of the dose administered being absorbed.

 

After an oral dose of 100mg a mean peak serum level of 880 ng/ml was reached in approximately 3 hours. Atenolol is widely distributed throughout the body, but only a small amount of the drug reaches the brain. Atenolol is excreted unchanged, mainly through the kidneys. About 40 - 50% of a single oral dose is excreted in the urine (t_{1/2 elm} – 6 to 7hrs.) of healthy subjects. Adult dose for hypertension is 25-100mg daily as a single dose, depending on response².

 

Nathalie et al. studied Comparative pharmacokinetics of a floating multiple-unit capsule with a high-density multiple-unit capsule and an immediate-release tablet of atenolol³. The drug concentration of floating dosage form detectable in the plasma was 2 hrs. which was very late compared to immediate release form. According to these values, the floating mini tablets may have been retained longer in the stomach than the high density mini tablets. It is showed that it was not possible to increase the bioavailability of poorly absorbed drug such as atenolol using gastroretentive formulations. Atenolol absorption was delayed and the maximum plasma concentration was diminished in this studies. High viscosity water soluble polymers are often used in the design of sustained release formulation of poorly water soluble drugs^4,5. The absorption of such drugs can be increase through controlled release methods⁶.

 

The present study is hence based on monitoring poorly absorbed atenolol and maintains its desire concentration in blood through formulation of capsule containing IR tablet and ER Floating tablet of atenolol.

 

MATERIALS AND METHODS:

MATERIALS:

Atenolol requested from Kopran Limited as drug sample. Excipients used in the formulations are MCC PH -112 (Loba Chemicals), Starch 1500 (Loba chemicals), Aerosil (Himedia), Magnesium Stearate (Rajesh chemicals), Iron oxide (Loba Chemicals), Povidone K 30 (Loba Chemicals), HPMC K 100 M (Loba chemicals), Sodium Bicarbonate (Loba chemicals), and Deionized water prepared from Millipore was used. Capsule shells from Erawat Pharma Ltd.

 

METHODS:

Selection of excipients:

Excipients used for preparation of capsule containing immediate release tablet and extended release floating tablet of atenolol were selected based on literature according to role of ingredients in the formulation. Particularly, HPMC K 100 M was selected as a polymer for extended release of the drug⁷.

 

Physical compatibility study of the atenolol with Excipients:

Compatibility study of active ingredient was carried out with excipients under stressed conditions of 60^oC for 6 hours and 80°C for 30 minutes⁸. This aided in ruling out apparently incompatible excipients. Binary mixture of the drug and the excipients were prepared according to formula in 1:1 ratio.

 

Table 1: Selection of excipients based on their functions in formulation

Sr.	Excipients for IR Tablet		Excipients for ER Floating Tablet
	Excipient	Function	Excipient	Function
1.	MCC PH -112	Diluent	Povidone K 30	Binder
2.	Starch 1500	Disintegrant and Binder	NaHCO3	Gas Generating Agent
3.	Aerosil	Glidant	HPMC K 100 M	ER Polymer
4.	Mg Stearate	Lubricant	Mg Stearate	Lubricant
5.	Iron oxide	Colour	P/Water q.s	Vehicle

 

Table 2: Composition of various ingredients for preparation of atenolol IR tablets.

Sr.	Excipient	Quantity
		Batch I	Batch II	Batch III
1.	Atenolol	25 mg	12.5 mg	37.5 mg
2.	MCC PH -112	25 mg	12.5 mg	37.5 mg
3.	Starch 1500	7 mg	3.5 mg	10.5 mg
4.	Aerosil	1.5 mg	0.75 mg	2.25 mg
5.	Mg Stearate	1.495 mg	0.75 mg	2.245 mg
6.	Iron oxide	0.005 mg	0.0025 mg	0.0075 mg
	Total weight	60 mg	30 mg	90 mg

 

Table 3. Composition of various ingredients for preparation of atenolol ER floating tablets.

Sr.	Excipient	Quantity
		Batch I	Batch II	Batch III
1.	Atenolol	25 mg	37.5 mg	12.5 mg
2.	Povidone K 30	3.5 mg	5.25 mg	1.75 mg
3.	NaHCo3	13 mg	19.5 mg	6.5 mg
4.	HPMC K 100 M	17 mg	25.5 mg	8.5 mg
5.	Mg Stearate	1.5 mg	2.25 mg	0.75 mg
6.	Purified Water	q.s.	q.s.	q.s.
	Total weight	60 mg	90 mg	30 mg

 

Preparation of Immediate release tablet of atenolol:

Immediate release (IR) tablets are prepared by direct compression method. Drug and all excipients were sifted, sieved through sieve number 30. Equivalent quantities sufficient for hundred tablets including three batches were taken for the formulation. Representatively, Atenolol and MCC PH -112 were accurately weighed as given in the formula (table 2) for three different batches and mixed together in a glass mortar. Starch 1500 and aerosil were mixed together separately in glass mortar and added in drug mixture and properly mixed. Sifted and sieved magnesium stearate was added to the above mixture and again mixed properly together for 5 minutes. This powder mixture was put under physical characterization (bulk and tapped density) and compressed separately according to batches using 5 mm round punch.

 

Preparation of Extended Release floating tablet of atenolol:

Extended Release (ER) atenolol tablet was prepared by using ingredients given in table 3 for three different batches separately. Drug and all excipients were sifted, sieved through sieve number 30. Equivalent quantities sufficient for hundred tablets were taken for the formulation. Representatively, Atenolol, Sodium bicarbonate and HPMC K 100 M was taken and mixed in glass mortar. Separately povidone K 30 was dissolved in purified water under stirring to get clear solution in a beaker and added in to the mortar containing drug mixture with continuous stirring for preparation of granules. The wetted mass was passed through sieve no. 18 to prepare granules. Granules were dried in the oven at 50⁰C for 1 hour. Dried granules were sifted manually through sieve number 20 and mixed with previously sifted, sieved through number 40 sieve and weighed magnesium stearate in polythene bag for 5 minutes. Properly lubricated granules were compressed separately according to batch size as given in table 3 using 5 mm round punch. Tablets were studied for physical characterization.

 

Preparation of capsule containing IR and ER tablets.:

Hard gelatin capsules of size 00 were procured and stored in proper environmental conditions. During preparation of capsule containing combination of atenolol tablets, capsule body was filled with immediate released tablet of atenolol followed by extended release tablet of atenolol. Cap of the capsule was fitted properly. Three different formulation batches were prepared. Batch I, batch II and batch III as given in table 2 and table 3 were prepared and filled in capsule shells accordingly. Each batch of 50 capsules was prepared following same method and was evaluated.

 

RESULTS:

Micromeritic properties:

The micromeritic properties of granules like bulk density, angle of repose, tapped density; compressibility index and Hausner’s ratio were evaluated to check the flow properties of granules⁹.

 

The micromeritic properties of granules were evaluated to check the flow properties. Bulk density, angle of repose, tapped density and Hausner’s ratio was carried out. All the study was carried out in triplicate and result was given in average ± Standard Deviation (SD). The bulk density was found to be in the ranged from 0.75 to 0.85 (Table 4).  The compressibility index was less than 10. Hausner’s ratio was ranged from 1.08 ± 0.022 to 1.06 ± 0.032. Angle of repose was recorded for the granules was not beyond 19 and 22 for IR and ER granules respectively.

 

Table 4. Micromeritic properties of the formulation batches

Sr.	Properties	Granules for IR tablet	Granules for ER tablet
1.	Bulk density	0.75±0.008	0.82±0.016
2.	Tap density	0.81±0.016	0.87±0.028
3.	Compressibility index	7.75±1.97	6.38±2.89
4.	Hausner’s ratio	1.08±0.022	1.06±0.032
5.	Angle of repose	19.66±1.24	22±2.44

 

Hardness and Friability test:

Hardness of the tablets was carried out using hardness tester. Average of six Friability of the tablets was determined by using USP friability test apparatus. Pre- weighed sample of tablets was placed in the friability tester, which was then operated for 25 revolutions for 4 min, tablets were dedusted and reweighed. The friability of the tablets was calculated using the formula, the percent of fractions to weight difference to initial weight. Friability of the formulations was determined as the percentage of weight loss of 10 tablets in EF 2, Electrolab, India friabilator¹⁰. Hardness of tablets was obtained in between 5.00 and 7.7 for IR and ER tablets. The friability of the formulation was 0.17 ± 0.12 % and 0.18 ± 0.07 % respectively for IR and ER tablets. Results are shown in table 5.

 

Floating characteristics of extended release (ER) tablet:

Floating characteristics of the tablets were determined using USP dissolution 8 station paddle apparatus (Electrolab EDT-08Lx, Mumbai, India.) under sink conditions. 900 ml of 0.1 N HCl (pH 1.2) was used as medium and temperature of which was maintained to 37 ⁰C throughout the study. The time between the introduction of tablet and its buoyancy (in vitro buoyancy study) on the gastric fluid required for the tablet to float on the gastric fluid (floating lag time) and the time during which dosage forms remain buoyant (floatation duration) were measured. The matrix integrity of the test tablets was observed visually during study^11-13.

 

Drug content:

Ten capsules were weighed and content (tables) were separated. Powder equivalent to the average weight of the tablet from each tablet was weighed accurately and transferred separately into a 100 ml volumetric flask and dissolved in a suitable quantity of methanol. The solutions were made up to the mark and mixed well. A portion of sample was filtered and analyzed by a spectrophotometer (Shimadzu UV1700, Japan) at 225 nm. ¹⁴. Drug content of capsules of three batches were determined. It was found that the drug content of batch I, batch II and batch III capsules were 97.82±1.13 %, 97.82±1.13 % respectively.

 

 

Table 5. Post granulation parameter study

Sr.	Properties	Granules for IR tablet			Granules for ER tablet
		Batch I	Batch II	Batch III	Batch I	Batch II	Batch III
1.	Weight uniformity	57±0.4	28±0.4	86±0.5	56±0.5	85±0.4	28±0.5
2.	Hardness	5.24±0.054	5±0.3	5.4±0.4	7.21±0.241	7.7±0.2	7±0.4
3.	Friability	0.17 ± 0.12 %	0.19±0.2 %	0.21±0.2 %	0.18 ± 0.07 %	0.21±0.15%	0.19±0.3 %
4.	Disintegration time (in seconds)	29±1.01	32±1.55	41±1.70	-	-	-
5.	Floating lag time	-	-	-	2.6 min.	2.3 min.	2.8 min
6.	Floating duration	-	-	-	5.2 hrs.	5.3 hrs.	5.1 hrs.

 

 

Drug release:

Dissolution studies of two tablets of the capsule were conducted in triplicate in a USP dissolution 8 station paddle apparatus (Electrolab EDT-08Lx, Mumbai, India.). The dissolution medium was 900ml 0.1N HCl (pH 1.2) at 37⁰C±0.5⁰C with a stirring speed of 100 RPM. At predetermined time intervals, five ml samples were withdrawn and sink conditions maintained. The samples were analyzed for drug release by measuring the absorbance at 225nm using spectrophotometric method (Shimadzu UV, 1700, Japan). Mean percent cumulative drug release was plotted against time of release¹⁵. The drug release data was analyzed to study release kinetics using zero order, first order, Korsemeyer- Peppas and Higuchi equations¹⁶.

 

Table 6. Drug release kinetic study of batch II using different kinetic models

Parameter	Zero order	First order	Higuchi	Hixon- Crowell	Korsemeyer Peppas
Equation	y = 8.5758x + 0.4933	y = -0.0867x + 2.1295	y = 8.5758x + 0.4933	y= -0.2266x +4.8707	y = 0.0674x + 1.2857
R2 (Coefficient)	R² = 0.9697	R² = 0.8872	R² = 0.9697	R2=0.991	R² = 0.9942
‘n’ Value	8.5758	-0.0867	8.5758	0.2266	0.0674

 

 

Figure 1: Drug release pattern of IR tablets

 

 

Figure 2: Drug release pattern of ER tablets

 

 

Figure 3: Drug release pattern of capsule containing IR and ER tablets

 

Stability Study:

To assess the drug and formulation stability, stability studies were carried out according to ICH guidelines¹⁷. The tablets were filled in hard gelatin capsule size 00 and stored in air tight glass container. Samples were placed in stability chamber (Thermolab, India) under accelerated storage conditions (45 ±2⁰C, 75 ± 5% RH) for 3 months. At the end of studies, samples were evaluated for weight uniformity, hardness, friability and drug content.

 

Table 7. Stability study of Batch II formulation after one-month storage

Sr.	Properties	Granules for IR tablet	Granules for ER tablet
1.	Weight uniformity	57±0.4	56±0.5
2.	Hardness	5.24±0.054	7.21±0.241
3.	Friability	0.17 ± 0.12 %	0.18 ± 0.07 %
4.	Disintegration time	29±1.01	-
5.	Drug content of capsule	97.82±1.13 %

 

DISCUSSION:

Atenolol is use for management of heart disease taken orally from tablet dosage form at the dose of 25mg to 100 mg per tablet¹. Other forms of tablets were succeeded little due to release behavior of the drug including pellets and mini floating tablets unable to attained plasma concentration in therapeutic level³. Development of new combination of tablets incorporated in capsule dosage form is studied in this work. A capsule containing two tablets having different release behavior was design, one immediate release and another with extended release floating behavior. Selection of excipients was done from previous work^7,18 as shown in table 1. HPMC K 100 M would extend release whereas NaHCO₃ able to float the tablets. All excipients showed physical compatibility with atenolol which we used for preparation of tablets.

 

Two different tablets each of 30 mg, 60 mg, and 90 mg content for IR and ER behavior was prepared and added into the capsule which will contain total dose of 50 mg atenolol in three different batches (table 2 and 3). Batch I (60mg IR and 60mg ER tablet), batch II (30mg IR and 90mg ER tablet) and batch III (90mg IR and 30mg ER tablet) were formulated in capsules. Granules used for the study showed micromeritic properties within acceptable limit and has good to excellent flow property, compressibility index and Hausner’s ratio¹⁹. Hardness was obtained in between 5.0 to 7.7. Friability for all tablets were within limit as per official reference. Floating property of ER formulation and disintegration of IR tablets was obtained satisfactorily. Release pattern of IR and ER formulations were individually shown in figure 1 and figure 2 respectively. Immediate release formulation showed about 90% release in half an hour and about 96% release in one hour in vitro. This behavior was expected in this first tablet which could release desired concentration of atenolol in GIT. This would achieve initial effective plasma drug level (Onset of action) in the blood. According to previous study on atenolol tablets, which is critical to achieve later concentration in sustained manner, was achieved by second extended release tablets. ER tablets showed rise in concentration after one hour and release for up to eight hours. Sharp rise in release rate after three hours which is more that 30% cumulative release in batch II formulation. Capsules of Batch II containing 30mg IR and 90 mg ER tablets showed release kinetics satisfactorily as per Korsemeyer Peppas model where R² value was 0.9942 and 0.0674 showed as n value. In this study 12.5mg atenolol was allowed to release by IR tablets which would act as booster for ER tablets and release about 10mg drug within an hour. This is proportionally effective dose followed by release from ER tablets containing 37.5mg drug, which would maintain effective dose in the blood. Study of combine release from capsule dosage form as shown in figure 3; clearly give an idea about release pattern. The release is extended and controlled in batch II formulation. The formulation was stable after one month shown by weight variation, hardness, friability and drug content. This novel trial of formulation for atenolol which would be more effective for its dose dependent treatment of heart diseases. This way we could achieve effective treatment for different heart complications and reduce toxicity due to high plasma concentration when increased frequency of dose in some conditions of heart problems.

 

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Received on 27.04.2020            Modified on 19.06.2020

Accepted on 31.07.2020         © RJPT All right reserved