Formulation Development and Evaluation of Bilayer Tablets of Telmisartan for Immediate Release and Metformin Hydrochloride for Sustained Release.

Nishanth I., Elango K., Deattu N., Stephen P.

Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai-600003, Tamil Nadu.

ABSTRACT:

The aim of the study was to design bilayer tablets containing Telmisartan for immediate release and Metformin hydrochloride for sustained release. Telmisartan has the strongest binding affinity to AT1 receptor among various ARBs and also has positive effects on insulin resistance syndrome because of the partial agonistic activity towards peroxisome proliferator-activated receptor-gamma (PPARγ). Metformin is an antihyperglycemic not a hypoglycemic. Combinations of both drugs effect the treatment of hypertension in Type-II diabetes mellitus patients and improve the patient compliance. Telmisartan belongs to class II drug in BCS classification. Enhancement of solubility of Telmisartan was observed with physical mixture of drug with beta (β)-Cyclodextrin. Immediate release layers were prepared by wet granulation method using various concentration of sodium starch glycolate as superdisintegrant. SR layers were prepared by wet granulation method using swellable polymer HPMC K4 M and HPMC K100 M in different ratios. Both Immediate (L1, L2 and L3) and Sustained release (F1, F2, F3, F4 and F5) tablets were formulated and evaluated. All the values were found to be satisfactory and were within limits. From the results obtained I3 and S5 were selected and finally compressed into bilayer tablets. In vitro release studies were carried out using USP type II paddle apparatus in 0.1M HCl for first 2 hours and pH 6.8 phosphate buffer solution for next 8 hours as dissolution medium. Stability studies were carried out at 40 ± 2⁰c and 75± 5% RH for a period of three months.

KEYWORDS: Telmisartan, Metformin hydrochloride, Bilayer tablet, Wet granulation.

1. INTRODUCTION:

75% of patients with type II diabetes have a prior history of cardiovascular and hypertension. Hypertension is extremely a common situation in diabetes patients. Diabetes generally increases the risk of developing high blood pressure and other cardiovascular problems.¹

Telmisartan is chemically described as 4-[[4-Methyl-6-(1-methyl-1H-benzimidazol-2 yl)-2 propyl-1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid. It is an Angiotensin II receptor blocker (ARB) mainly used to treat high blood pressure. It suppresses the effects of angiotensin II at its receptors, thereby blocking the renin angiotensin system. Telmisartan is employed in the management of essential hypertension in diabetic patients with lower incidence of side‐effects like cough. It has a half life of 24 hours, so it prevents the surge of blood pressure in early morning. Recently, Telmisartan was found to act as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPARγ).

Telmisartan has positive effects in insulin resistance syndrome. Telmisartan may become a promising ‘cardio metabolic sartan’, that targets both diabetes and cardio vascular complications in hypertensive patients.²

Metformin hydrochloride belongs to the class of oral biguanides and it is the first line of drug to treat type II diabetes mellitus. The half-life of Metformin Hydrochloride is 5 to 6 hrs; hence it is a suitable candidate for the design of sustained release drug delivery system. Metformin is an antihyperglycemic not a hypoglycemic. It does not cause insulin release from pancreas and generally does not cause hypoglycaemia even in large doses.¹

Combination therapy has various advantages over monotherapy such as minimised dose dependent side effects and improved patient compliance. Telmisartan was formulated as an immediate release layer and Metformin hydrochloride as a sustained release layer in order to treat hypertension in diabetic patients.³

2. MATERIALS AND METHODS:

Telmisartan and Metformin hydrochloride was obtained from Abhilash chemicals, Tamil Nadu. HPMC grades were obtained from Samsung fine chemicals. Ethyl cellulose was obtained from Zhongbao chemicals. Microcrystalline cellulose was obtained from Vikaas chemicals. PVP K30 was obtained from Jiao Zuo Yuanhai Fine chemicals. All other chemicals (AR grade) were obtained from Kniss Laboratories (P) Ltd, Chennai.

Development of bilayer tablets of Telmisartan and Metformin hydrochloride was carried out in two different stages. Immediate and sustained release layers were prepared separately and optimized. After optimization of individual layers, the bilayer tablets were prepared by using the optimized formulae.

2.1 Preparation of Immediate release (IR) tablets: ⁴

An accurately weighed amount of Telmisartan was incorporated into β -Cyclodextrin by physical mixing to improve the solubility. Immediate release tablets containing 40mg of Telmisartan were prepared by wet granulation technique. Drug, Lactose and starch were used as intra granular material. Tartrazine yellow and PVP K 30 were dissolved in Isopropyl alcohol. The binder solution was mixed with the powder mixture to form a damp mass. The mass was passed through sieve number # 16 and dried at 60⁰C for 30 minutes. The granules were then lubricated using starch and Magnesium stearate. Three batches (L1, L2 and L3) of immediate release tablets were prepared by varying the concentrations (2, 4 and 6%) of superdisintegrant respectively. The granules were compressed into tablets using 16 Station (D tooling) tablet compression machine with 7.93 mm concave punches.

2.2 Preparation of Sustained release (SR) tablets: ⁵

SR tablets containing 500mg of Metformin hydrochloride were prepared by wet granulation technique. Hydrophilic polymers such as HPMC K4M and HPMC K100M were used in varying concentrations and five batches (F1, F2, F3, F4 and F5) were prepared. Drug, polymers and microcrystalline cellulose were used as intra granular material. PVP K30 dissolved in Isopropyl alcohol was mixed with the above powder and the damp mass was passed through sieve number # 16. The granules were dried at 60⁰C for 30 minutes. The dried granules were then lubricated using talc and Magnesium stearate. The granules were compressed into tablets using 16 station (D tooling) tablet compression machine with 18.5 × 7 mm punches.

2.3 Preparation of final bilayer tablets: ⁵

Based on the faster disintegration time and dissolution rate, optimized formulation L3 was selected and also based on the comparative release profile, optimized formulation F4 was selected for the final bilayer tablets. The granules of the optimized layers were compressed into bilayer tablets using bilayer tablet punching machine with 27 station (D-tooling) with 18.5 × 9 mm punches.

2.4 Evaluation of Bilayer tablets: ⁶

The prepared bilayer tablets were evaluated for Uniformity of weight, thickness, hardness, friability and drug content. Uniformity of weight was performed according to the official method.⁷ The thickness of the tablets was measured using vernier caliper. Hardness of the tablets was evaluated using Monsanto Hardness tester. Friability of the tablets was determined using Roche friabilator. Drug content was estimated by simultaneous equation method⁸ by measuring the absorbance at 296 nm and 233 nm respectively using UV Visible Spectrophotometer.

2.5 In vitro Drug Release studies: ^{6, 9}

The In vitro dissolution study was carried out using USP Type II (paddle) apparatus at 100 rpm. Dissolution study was carried out using 0.1M HCl for first 2 hours and pH 6.8 Phosphate buffer solution for next 8 hours at 37±0.5⁰C. 10 ml of the sample was withdrawn at regular intervals and diluted suitably. The absorbance was measured at 296nm and 233nm using UV- Visible Spectrophotometer taking respective buffer solutions as blank. The drug release was determined by simultaneous estimation method.

2.6 Stability Studies: ¹⁰

The optimized tablets were packed finally in blisters and kept at 40±2⁰c with 75±5 % RH. The tablets were evaluated for thickness, hardness, friability, uniformity of weight, drug content and in vitro drug release.

2.7 In vitro release kinetics: ^{11, 12}

The drug release from the SR layer was subjected to various release kinetics equation to determine the drug release mechanism and the results are shown in table 4.

Zero order release equation C = K₀t

First order release equation Log C = logC₀ – Kt/2.303

Higuchi’s square root of time equation Q = Kt^1/2

Korsmeyer Peppas equation M_t/M_α = Ktⁿ

Hixson Crowell equation Q₀^1/3 – Q_t^1/3 = K_HC X t

3. RESULTS AND DISCUSSION:

The present work was carried out to develop a bilayer tablet of Metformin hydrochloride as sustained release layer using HPMC K4M and HPMC K100M and Telmisartan as immediate release layer using sodium starch glycolate as superdisintegrant. 98.74% of Telmisartan was released at the end of 30mins for the immediate release layer (L3). The release profile of Telmisartan from the immediate release layer was found to be within the limit i.e. the release of the drug not less than 85% in 30 minutes. 31.12% of Metformin was released at the end of 1^st hour, 48.99% of Metformin was released at the end of 3^rd hour and 94.76% of Metformin was released at the end of 10^th hour for the (F4) sustained release layer. So the release profile of Metformin from the sustained release layer was found to be satisfactory, where the release of the drug in 1^st, 3^rd and 10^th hour were within the limits.¹³The results demonstrated that initial burst release of immediate release layer may be due to superdisintegrant. The sustained release of Metformin Hydrochloride may be due to the polymers HPMC K4M and HPMC K100M in sustained release layer. The immediate release tablets were optimized based on the disintegration time. The faster disintegration time (2min 05secs) was observed in immediate release (L3) tablets containing 6% sodium starch glycolate as superdisintegrant (Table 1). The Sustained release layer was optimized based on the release profile as given in Indian Pharmacopoeia. The batch (F4) containing HPMC K4M and HPMC K100M in 1:3 ratio met the Pharmacopoeial specifications.¹³

Postcompression Studies of Bilayer Tablets

· All the formulations of bilayer tablets fulfilled the official requirements of uniformity of dosage units. The average percentage of deviation was less than ± 3 % (Table: 3).⁷

· The thickness, length and diameter of the bilayer tablets were uniform (Table: 3).

· The percentage friability ranged from 0.11 to 0.3%. All the formulations of bilayer tablet comply with the official limit.⁷

· The hardness of all the formulations of bilayer tablet ranged from 8 to 8.5 Kg/cm². The tablets can withstand stress during transport and handling.¹⁴

· The percentage drug content of the IR and SR formulations were found to be within the limit.⁷

· The results of mathematical model fitting of data obtained indicated that the release was found to be zero order, in which R² value was closer to 1. In Higuchi equation the R²value was very near to 1. So the optimized formulation follows Higuchi diffusion mechanism. The n value of Korsemeyer Peppas equation was found to be 0.555, from that it was concluded that the release followed non-Fickian transport. Swelling hydration of the polymer matrix, dissolution of the drug in the polymer matrix and diffusion of the drug through the polymer matrix and surface erosion of the matrix also plays a role in the drug release.¹⁵

Composition and post compression study of immediate release tablets:

The immediate release granules of Telmisartan (L1, L2 and L3) were prepared by wet granulation technique. Sodium starch glycolate (SSG) was used as a super disintegrant in 2%, 4% and 6% concentrations to improve dissolution of the drug. The granules were compressed by 16 station (D tooling) tablet compression machine using 7.93 mm punches. The immediate release tablets were evaluated for the following parameters and the composition of IR and the values are given in table 1.

Table 1: Composition of immediate release tablets

S.NO	INGREDIENTS	L1 (mg)	L2 (mg)	L3 (mg)
01	Telmisartan	40.0	40.0	40.0
02	β- Cyclodextrin	40.0	40.0	40.0
03	Lactose	77.4	73.6	69.8
04	Starch	20.0	20.0	20.0
05	PVP K-30	3.8	3.8	3.8
06	Isopropyl alcohol	q.s	q.s	q.s
07	Sodium starch glycolate	3.8	7.6	11.4
08	Magnesium stearate	2.0	2.0	2.0
09	Tartrazine yellow	1.0	1.0	1.0
10	Talc	2.0	2.0	2.0
Total weight (mg)		190.0	190.0	190.0
Disintegration time (min)^*		10.45 ± 0.4147	7.05 ± 0.4493	2.05 ± 0.3991
In vitro dissolution (Cumulative % drug release)^* At the end of 30 min.		77.56 ± 0.2289	78.72 ± 0.2860	98.74 ± 0.2986

* Mean ± S.D (n = 3)

Composition and post compression study of sustained release tablet:

The sustained release granules were prepared by wet granulation technique. Different polymers such as HPMC K4M and HPMC K100M used in different ratios. The tablets were compressed by 16 station (D-tooling) compression machine using 18.5mm × 7mm punches. The sustained release tablets were evaluated for the following parameters and the composition of SR and the values are given in table 2.

Table 2: Composition of sustained release tablets

S.NO	INGREDIENTS	F1(mg)	F2(mg)	F3(mg)	F4(mg)	F5(mg)
01	Metformin hydrochloride	500	500	500	500	500
02	Ethyl cellulose	24	24	24	24	24
03	HPMC K4M	200	-	150	50	100
04	HPMC K100M	-	200	50	150	100
05	Microcrystalline cellulose pH102	40	40	40	40	40
06	PVP K-30	16	16	16	16	16
07	Isopropyl alcohol	q.s	q.s	q.s	q.s	q.s
08	Magnesium stearate	10	10	10	10	10
09	Talc	10	10	10	10	10
Total weight (mg)		800	800	800	800	800
In vitro dissolution (Cumulative % drug release at the end of 1^st hr)^*		35.37 ± 0.1300	21.24 ± 0.0800	24.04 ± 0.0600	31.12 ± 0.7200	33.21 ± 0.0550
In vitro dissolution (Cumulative % drug release at the end of 3^rd hr)^*		67.54 ± 0.5100	40.61 ± 0.1600	53.91 ± 0.1700	48.99 ± 0.0800	55.56 ± 0.5000
In vitro dissolution (Cumulative % drug release at the end of 10^th hr)^*		99% drug released at the end of 6^th hr.	89.08 ± 0.6320	91.63 ± 0.2600	94.76 ± 0.1400	96.78 ± 0.0200

* Mean ± S.D (n = 3)

In vitro Dissolution study of IR tablets and SR tablets:

The in vitro dissolution study of IR tablets showed that 6% concentration of SSG was found to be optimum for immediate release of Telmisartan. The 2% and 4% concentration of SSG was found to be releasing the drug slowly when compared to 6% SSG. The 6% concentration of SSG released 98.74% at the end of 30mins. Therefore formulation L3 was optimized and selected for final bilayer tablets. The in vitro dissolution study of IR tablets shown in Fig.1.

Fig. 1: In vitro Dissolution study of IR tablets of Telmisartan

Based on the in vitro dissolution studies of SR tablets, formulation (F4) containing HPMC K4M and HPMC K100M (1:3 ratio) met the IP specifications at the end of 1^st, 3^rd and 10^th hour. Thus the formulation F4 was optimized and selected for bilayer tablets. The in vitro

dissolution study of the formulated SR tablets is given in Fig.2.

Fig. 2: In vitro dissolution study of SR tablets

POST COMPRESSION STUDY OF BILAYER TABLETS

1. Optimized immediate layer of Telmisartan (L3) was prepared by wet granulation method.

2. Optimized sustained release layer of Metformin (F4) hydrochloride was prepared by wet granulation method

The granules were compressed on 27 station (D-tooling) bilayer tablet compression machine using 18.5 × 9 mm inch punches. The optimized bilayer tablets were evaluated for the following parameters and the values are given in table 3.

Table 3: Post compression study of Bilayer tablets

S.No.	Parameters	Bilayer Tablet
1	Uniformity of weight (g)^*	1.0014 ± 0.0156
2	Thickness (mm)^*	7.10 ± 0.0120
3	Diameter (mm)^*	9.34 ± 0.0630
4	Length (mm)^*	18.45 ± 0.0200
5	Hardness (kg/cm²)^*	8.32 ± 0.3600
6	Friability (%)^**	0.287 ± 0.0120
7	Drug content (simultaneous estimation method)^** i) Telmisartan (%w/w) ii) Metformin hydrochloride (%w/w)	98.36% ± 0.1400 96.42% ± 0.2700

^*Mean ± S.D (n=5), ^** Mean ± S.D (n=3).

The in vitro dissolution of drugs in bilayer tablets:

In vitro dissolution study of Telmisartan in bilayer tablets is given fig.3.

Fig. 3: In vitro Dissolution study of Telmisartan in bilayer tablets

The in vitro dissolution studies of the optimized bilayer tablets met the IP specifications at the end of 1^st, 3^rd and 10^th hour. In vitro dissolution study of Metformin in bilayer tablets is given fig.4.

Determination of drug release mechanism of optimized bilayer tablets:

· The order of release was found to be zero order, in which R² value was closer to 1 than the value of R² of the first order equation.

· In Higuchi equation the R²value was very near to 1. So it concluded that the optimized formulation follows Higuchi diffusion mechanism.

· The n value of Korsmeyer Peppas equation was found to be 0.555, from that it was concluded that the release followed non-Fickian transport.

· Swelling hydration of the polymer matrix, dissolution of the drug in the polymer matrix and diffusion of the drug through the polymer matrix and surface erosion of the matrix also plays role in the drug release. The results showed that the formulation followed zero order release.

Fig. 4: In vitro Dissolution study of Metformin hydrochloride in bilayer tablets

Photograph of final optimized Bilayer tablets shown in Fig. 5.

Fig no.5: Photograph of Bilayer tablets

4. CONCLUSION:

· Success of the in vitro drug release studies recommends the product for further in vivo studies, which may improve patient compliance.

· From the results, Bilayer tablet showed as initial burst effect to provide dose of immediate release layer Telmisartan to control the blood pressure level and the sustained release of Metformin HCl for 10 hours to control the blood glucose level. The developed formulation shows an alternative to the conventional dosage form for the treatment of hypertension in patients with type II diabetes mellitus.

· Combination of Telmisartan as an immediate release layer and Metformin HCl as a sustained release layer reduces polytherapy to monotherapy and improves the patient compliance.

· The data obtained from in vitro release study for sustained release layer were fitted to various mathematical model like zero order, first order, Higuchi model and Peppas model. The results of mathematical model fitting of data obtained indicated that, the best fit model was zero order. Thus the release of the drug from the dosage form was found to be by diffusion and non-fickian release.

· The stability studies indicated that the bilayer tablets are stable and does not show any significant changes.

5. ACKNOWLEDGEMENT:

I express my sincere thanks and respectful regards to my Professor and Head, my Guide, My staff members and my friends for their continuous guidance, supportive suggestion, innovative ideas, help and encouragement have always propelled me to perform better. It is my privilege and honour to extend my profound gratitude and express my indebtedness to Mr. M.D. Varadharajan, Managing Director, Kniss Laboratories (P) Ltd., Chennai, for his enduring support. He has been generous with providing facilities to carry out this work.

6. REFERENCES:

1. Tripathi KD. Antihypertensive agents. In Essential of Medical Pharmacology. Jaypee Brothers Medical Publishers (P) Ltd, New Delhi. 2008; 6th ed: p. 488.

2. Sho-ichi Yamagishi. Telmisartan, its potential therapeutic implications in cardio metabolic disorders. Recent Patents on Cardiovascular Drug Discovery 1; 2006: 79-83.

3. Fred J Sandelln. Compression Tablets by Wet Granulation. In Pharmaceutical dosage forms: Tablets. Edited by Herbert A Lieberman, Leon Lachman and Joseph B Schwartz. Marcel Dekker, New York. 1989; 2nd ed: pp. 179-81.

4. Parikh B.N. et al. Formulation, optimization and evaluation of immediate release tablet of telmisartan. Journal of global Pharma Technology, 2(2); 2010:79- 84.

5. Kotta Kranthi Kumar, et al. Design, development and characterization of sustained release of Meftromin and Gliclazide bilayered tablets. International Journal of Biopharmaceutics. 1(2); 2010: 67-71.

6. Durga Prasad Pattanayak and Subash C Dinda. Bilayer tablet formulation of Metformin Hydrochloride and Glimepiride. A novel approach to improve therapeutic efficacy. International Journal of Drug Discovery and Herbal Research. 1(1); 2011:1-4.

7. Indian Pharmacopoeia: Ministry of Health and Family Welfare. Government of India, The Indian Pharmacopoeia commission, Ghaziabad. 2010.

8. Beckett A. H. and Stenlake J. B. Ultra violet- visible absorption spectroscopy. In Practical Pharmaceutical Chemistry, CBS publishers, New Delhi. 4(2); 2005:275-325.

9. Hirpara K. P. et al. UV-Spectrophotometric Determination for Simultaneous Estimation of Amlodipine Besylate and Telmisartan in Combination. Journal of Pharmaceutical Science and bioscientific Research. 2012; 2(3):133-137.

10. Dinesh Kumar P et al. Formulation and characterization of bilayer Floating tablets of Ranitidine. Rasayan J chem. 3(2); 2010:368-74.

11. Sunil Kumar, et al. ‘Formulation and evaluation of extended release Metformin tablets’. Journal of Chemical and Pharmaceutical Research, 3(4); 2010: 861-865.

12. Asaduzzaman, Md. et al. Development of sustain release matrix tablet of ranolazine based on Methocel K4M CR: in vitro drug release and kinetic approach. Journal of Applied Pharmaceutical Science, 01 (08); 2011: 131-136.

13. Indian Pharmacopoeia: Ministry of Health and Family Welfare. Government of India, The Indian Pharmacopoeia commission, Ghaziabad. Vol. I-III ; 2010: 2186-2188, 1657-1660.

14. Nithin Kumar P, Elango K, Devi Damayanthi R and Vignesh Babu S. Formulation and evaluation of bilayer tablets of losartan potassium for immediate release and metformin hydrochloride for sustained release’. IJPI’s Journal of Pharmaceutics and Cosmetology. 2(8); 2012: 37-42.

15. Harris Shoaib M. et al. Evaluation of drug release kinetics from Ibuprofen matrix tablets using HPMC. Pak J Pharm Sci 19(2); 2006:119-24.

16. Salma Banu SK and Venkateswara Rao T. Design and Development of Sustained Release Bilayered Tablets of Glipizide Research. Journal of Pharmaceutical Dosage Forms and Technology. 4 (1); 2012 :24 - 31

Received on 02.04.2013

Modified on 11.04.2013

Accepted on 30.04.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(3): May- June, 2013, 139-144

Formulation	Zero order	First order	Higuchi	Korsemeyer & Peppas		Hixson Crowell
Optimized bilayer	R²	R²	R²	R²	n	R²
Optimized bilayer	0.9495	0.9152	0.9879	0.906	0.555	0.9491