Research Article DESIGN AND DEVELOPMENT OF …...Metoprolol succinate bioahesive gastric drug...

©SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 355

International Journal of Research and Development in Pharmacy and Life Sciences Available online at http//www.ijrdpl.com

February - March, 2013, Vol. 2, No.2, pp 355-362 ISSN: 2278-0238

Research Article

DESIGN AND DEVELOPMENT OF BIOADHESIVE GASTRO RETENTIVE DRUG DELIVERY SYSTEM OF METOPROLOL SUCCINATE

Udayakumar.T1*, Chordia Mayor Ashok1, Udhumansha Ubaidulla1

Department of Pharmaceutics, C. L. Baid Metha College of pharmacy, chennai-97.

*Corresponding Author: Email: [email protected] (Received: December 18, 2012; Accepted: January 22, 2013)

ABSTRACT

The conventional dosage forms stay in the stomach for 0.5-2 hours and passes to small intestine and where it gets absorbed within 3-6 hours. Therefore difficult to adjust release retardation and stomach retention of drug for longer period of time. The present research work was attempted to formulate and evaluate the floating tablet with biphasic release of metoprolol succinate. Metoprolol succinate bioahesive gastric drug delivery system was prepared using bioadhesive polymer PEO, Hydrophylic polymer (Carbopol 71G, HPMC E15, Methacrylic acid, Pectin, Carragenan and Guargum) and gas forming agent Sodium bicarbonate. Metoprolol succinate bioahesive gastric drug delivery system was proved to be attained the effective plasma concentration higher than the Marketed formulation. This is due to retaining metoprolol succinate in the stomach (Where it absorbed more) by means of floating and bioadhesive property of the polymer. Metoprolol succinate bioahesive gastric drug delivery system using PEO and HPMC E15 polymers could be effective sustained release formulation. Keywords: Metoprolol succinate, Bioadhesive Gastro retentive delivery, Floating delivery.

INTRODUCTION

The conventional dosage forms stay in the stomach for 0.5-2

hours and passes to small intestine and where it gets

absorbed within 3-6 hours. Therefore difficult to adjust

release retardation and stomach retention of drug for

longer period of time. The concept of gastro retentive drug

delivery system came from the need to localize the drug at a

certain site in the body. When the site of drug absorption is

mainly in stomach or upper part of the small intestine, then

it is necessary to retain the dosage form at the site of

absorption, but the gastro intestinal transit is the limitation

for such type of dosage forms. Therefore gastro retentive

dosage forms are formulated to increase the gastric

residence time. The majority of drugs are preferentially

absorbed from the upper part of the small intestine hence

drug release at the site of absorption can improve

therapeutic efficacy of drug. Drugs having pH dependent

solubility ie highly soluble at low pH ( gastric pH) and

poorly soluble at high pH (intestinal pH) are the suitable

drug for the floating drug delivery. In the treatment of

Angina, Hypertension, Cardiac arrhythmias, Myocardial

infarction a loading as well as maintenance dose is required.

Therefore present research work was attempted to formulate

and evaluate the floating tablet with biphasic release. Drugs

having short biological half life, poor bioavailability and pH

dependent solubility are suitable for the development of

floating sustained release with biphasic drug delivery

system1,2.

Metoprolol succinate is a selective α-adrenergic antagonist.

The drug blocks α receptor located in the heart. The

blockade reduces the myocardial contractility and cardiac

Udayakumar T. et. al., February-March, 2013, 2(2), 355-362


output. The atreoventricular conduction time slow down and

automaticity is suppressed. Consequently blood pressure

falls. Absorbed from upper part of GI tract , useful for

Hyper tension, Angina pectoris, Cardiac

arrhythmias,Myocardial infraction,Migraine prophylaxis and

Hyperthyroidism3,4,5.

The objective of the study is to provide sustained delivery

and improve the bioavailability of metoprolol succinate

.Metoprolol succinate undergoes extensive first pass

metabolism due to degradation in colon, resulting only 38%

oral bioavailability. Since the half life of Metoprolol

succinate is 3-4 hours, multiple doses are needed. The

bioadhesive floating tablet can be retained in the

stomach as long as possible to allow for maximum

absorption, thereby improving the bioavailability and

maintained a constant plasma concentration for good

therapeutic response with improved patient compliance.6,7

MATERIALS AND METHODS

Metoprolol succinate, Cros povidone and PVP K-30 as gift

sample from Madras pharmaceuticals Pvt. Ltd Chennai,

PEO, Carbopol 71G and Methacrylic acid from Glenmark

pharmaceuticals Ltd, Nashik, HPMC E15, Sodium bi

carbonate, IPA, Lactose, Magnesium stearate and Talc from

S.D.fine chemicals, Mumbai, Pectin, Carrageenan and Guar

gum from Rolex Laboratories, Chennai and all other

materials used from C.L.Analytical Lab, Chennai.

Procedure for preparation of Metoprolol succinate BGRDDS

tablets

The granules were prepared as per Master formula (Table-

1). 100 tablets of each formulation 18 formulations were

made .The drug Metoprolol succinate, Bioadhesive polymer

PEO, Hydrophylic polymer (Carbopol 71G, HPMC E15,

Methacrylic acid, Pectin, Carragenan and Guargum),

Sodiumbicarbonate and Crospovidone, were passed 40

sieve separately and blended. Added binding solution

containing PVP K-30 in Iso propyl alcohol till to get uniform

granules. The wet mass passed through mesh 16 and dried

at 500c for 30 minutes to get moisture content less than 1%.

Lubricated the dried granules with Magnesium stearate and

talc. The lubricated granules compressed on cadmach tablet

punch machine for all formulations. Physical characteristics of

tablets like Thickness, Diameter, Hardness test14, Friability

test14, weight variation test14, Buoyancy Lag time15 and

Dimension stability15 represented in Table-2.

Drug content determination

Weighed a quantity equivalent of the powder 0.12 gram by

crushing 20 tablets of Metoprolol succinate, transfer to 100

ml volumetric flask added 75 ml of 95% Ethanol mixed and

filtered. Diluted 5 ml of the filtrate to 50 ml with 95%

Ethanol measuring absorbance at275 nm.

Buoyancy Lag time

The floating time and buoyancy Lag time were determined in

USP apparatus 11 in acid environment 0.1 N Hcl at 370c .

The time required to raise to the surface of the medium

was determined as buoyancy Lag time and the duration of

which tablet floats on the surface of the medium was noted

as the duration of buoyancy represented in Table 2 and in

Fig 2.

Dimensional stability

The dimensional stability studied using USP dissolution

apparatus11 using dissolution medium 0.1 N Hcl volume

being 900 ml at 370c with 50 rpm and observed visually

that are represented in Table 2 and in Fig4.

Invitro dissolution of BGRDDS tablets

The rate and order of drug release from the tablet in order

to confirm extend of use of the formulation by using USP

dissolution apparatus-1 Electro Lab TDT-08L Mumbai. The

dissolution medium was 0.1 N Hcl at pH1.2, 900ml with

rpm50 at 370c. The studies were carried out for 24 hours by

withdrawing samples of 5 ml at interval of 15 minutes, 30

minutes,1 hour, 2hrs,3hrs,4hrs,6hrs,8hrs,10hrs,12hrs and 24

hrs. The dissolution medium was replenished with fresh

medium and analysed using SHIMADZU UV-1601 Japan uv

spectrophotometer at 275 nm.

Biomucoadhesive study

The mucoadhesive property of the formulation apart from

floating property could be very important for gastro

retentive drug delivery8. All formulations containing different

bio-muco adhesive polymer in different concentrations were

used to adhere in the stomach. Only the Formulations F3, F6,

F12 and F15 passed invitro evaluation comparable with

Marketed formulation were subjected .By using a modified

balance the left and right arm of the balance were attached

with tablets of a formulation and weights which are in equal



Table: 1 Composition of Bioadhesive Gastroretentive Floating Tablet

Formulations F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 F17 F18

Metoprolol succinate

25

25

25

25

25

25

25

25

25

25

25

25

25

25

25

25

25

25

Carbopol 71G

75

25

12.5

- - - - - - - - - - - - - - -

HPMC E15 - - -

75

62.5

50 - - - - - - - - - - - -

Methacrylic acid - - - - - -

75

25

12.5

- - - - - - - - -

Pectin - - - -- - -- - - - 75 50 37.5

- - - - - -

Carragennan - - - - - - - - - - - -

75

37.5

25 - - -

Guargum - - - - - - - - - - - - - - -

75 50 25

PEO 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25

Sod. bicarbonate

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

Cross povidone

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

PVPK 30

10

10

10

10

10

10

10

10

10

10

10

10

10

10

10

10

10

10

Talc q.s qs q.s qs q.s qs q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s

Mg. stearate

q.s

qs

q.s

qs

q.s

qs

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

Lactose 25 75

87.5

25 37.5

50 25 75 87.5

25 50 62.5

25 62.5

75 25 50 75

Fig1: FTIR spectra for drug and polymer interaction study



weight. Left side arm to make the tablet to contact with

stomach tissue this already contains few ml of 0.1 N Hcl. The

tip of the stomach tissue was to contact with tablet and

maintained at 370c to mimic invivo conditions. In this goat

stomach tissues were taken from freshly slaughtered animals

and kept in ice cold buffer condition. Then slowly the number

of weights added on right side arm till the tablet came

out from the goat stomach tissues which are represented in

Table3.

Selection and evaluation of best formulation

The formulation F6 passed physical characteristics such as

Tablet size, Hardness, Friability, Weight variation, Drug

content and Dissolution profile and also showed good

buoyancy Lag time(0sec) and duration of floating (24hours)

Table 2. Physical parameters of metoprolol gastric retentive tablets Formulations Thickness

in mm Diameter

in mm Hardness in Kg/cm2

Friability in % W/W

Weight variation in

mg ±SD

Buoyancy lag time in

sec

Duration of buoyancy

in hour

Dimensional stability at 24

hour F1 4.85 8.02 7.5 0.120 198.5±0.09 0 24 +++ F2 4.84 8.01 7.3 0.128 199.2±0.12 0 24 ++ F3 4.87 8.04 7.8 0.098 201.4±0.08 0 24 ++ F4 4.85 8.00 7.2 0.219 200.5±0.27 0 24 +++ F5 4.89 8.04 7.6 0.154 197.3±0.18 0 24 ++ F6 4.86 8.05 7.1 0.135 202.4±0.31 0 24 ++ F7 4.82 8.03 7.0 0.178 202.2±0.22 0 24 - F8 4.84 8.03 7.2 0.089 201.8±0.07 0 24 ++ F9 4.85 8.01 7.8 0.081 197.9±0.43 0 18 ++ F10 4.87 8.06 7.9 0.084 199.3±0.39 0 24 +++ F11 4.89 8.02 7.8 0.093 199.2±0.21 0 24 - F12 4.88 8.05 7.2 0.142 203.8±0.53 0 24 ++ F13 4.87 8.01 7.5 0.169 201.7±0.43 0 24 ++ F14 4.82 8.05 7.7 0.162 197.5±0.26 0 24 ++ F15 4.86 8.03 7.4 0.151 204.4±0.37 0 24 + F16 4.85 8.02 7.3 0.206 198.5±0.49 0 24 +++ F17 4.87 8.04 7.5 0.153 196.9±0.35 0 16 ++ F18 4.83 8.04 7.6 0.119 202.7±0.09 0 24 -

Fig 2: Picture Representation of various Stages of Floating Tablets



with constant rate of release drug in more sustained manner

than the Marketed formulation. Formulation F6 having more

biodhesiveness. Hence BGRDDS F6 was chosen as the best

formulation and the formulation shows good reproducibility

results.

Drug polymer interaction study of selected formulation

BGRDDS

Metoprolol succinate –polymer discs were prepared by

pressing Metoprolol succinate and HPMC E15 with potassium

bromide and the spectra between 4000 cm-1 to 500 cm-1

was obtained under the operational conditions. The

absorption maxima obtained correspond in position and

relative intensity to reference spectrum and it is shown in

Fig1.

Determination of Swelling Index

Swelling index of tablet was determined in 900 ml 0.1 N Hcl

pH1.2 using USP dissolution Apparatus type11with 50 rpm

at 37 ± 0.50c throughout the study. After a selected time

interval the tablet was withdrawn blotted to remove excess

water and weighed (Fig 3).

W t --- W o

Swelling Index= -----------------------------------

W0

Where W0= Initial weight of tablet

Wt =Weight of tablet at time‘t’

Method development for EX-VIVO Mucoadhesion

measurement

The goat mucosa fixed to a paddle with cyanoacrylate glue.

Tablet under test put in the mucosa with minimum force. The

paddle was rotated for 24 hours 50 rpm in 900ml 0.1N Hcl

at 37 ± 0.50c. The tablet was observed visually for 24 hours

at 1 hour interval.

Stability studies

According to ICH and WHO guidelines selected best

formulation BGRDDS F6 was sealed in aluminium packaging

coated inside with polyethylene kept in humidity chamber

maintaining at 450c and 75% RH for 3 months. At the end of

studies , samples analysed for Drug content, Invitro

dissolution , Floating behaviour, Bioadhesive property ,

Dimensional stability and other physicochemical properties.

In vitro Kinetic analysis

The invitro drug release data explored for type of release

mechanism. The coefficient of correlation each of the kinetics

was calculated and represented in Table4.

Invivo bioavailability study

The selected best formulation BGRDDS of F6 containing

Metoprolol succinate subjected to invivo studies and

compared with Marketed formulation. 6 male albino rabbits

were weighed 1 kg with age of 12 months and divided into

2 groups of each. Each group was subjected to a single dose

randomized parallel design study. The animals housed

individually under environmental conditions 23 ± 20c,

55±5%RH, 12 hours Light/Dark cycle. The rabbit fasted

over night allow free access to tap water only. The test

sample and marketed formulations administered to rabbits

by gastric intubation method9. 0.5 ml of blood samples were

withdrawn from the marginal vein of rabbit at various time

intervals. The plasma samples were separated by

Centrifugation, drug extracted assayed for Metoprolol

succinateby HPLC.

Determination of Metoprolol succinate in plasma by HPLC

Plasma samples were deproteinised. Drug extracted using

Methanol, 0.001%W/V of Metoprolol succinate solution as a

standard .Chromatographic procedure was carried out using

C18 ODS (Octa Decyl Saline) hypersil stainless steel column

as stationary phase. Mobile phase prepared by dissolving

3.9 gram of ammonium acetate in 810 ml of water add 2 ml

triethylene and10 ml glacial acetic acid and 3 ml phosphoric

acid and 146 ml of acetonitrile.The flow rate of Mobile

phase was 20µl detected at wavelength 275 nm.

Metoprolol succinate plasma concentration was calculated

from the sample.

RESULTS AND DISCUSSIONS

The prepared granules Bulk density 0.210-0.424 gm/ml,

Tapped density 0.367-0.485gm/ml, Carr’s index 8.38-

13.63%, Hausers ratio 0.83-1.400 and Angle of repose

20.03-28.610.The Thickness of tablets ranges from 4.82-

4.89 mm and the Diameter of the tablets ranges from 8.00-

8.06 mm. The Hardness of the tablets were 7-7.9kg/cm2

optimum for controlled release. The Friability 0.081-

0.219w/w passes as per IP limit should not be more than 1%

w/w. The Weight uniformity of tablets were within IP limit ±

7.5.The Buoyancy Lag time for all formulations were 0 sec.



The duration of buoyancy for all formulations were upto 24

hours except F9 and F17 showed 18 and 16 hours

respectively. So these formulations were failed and rejected

for further evaluation. It is important to maintain physical

integrity of the tablet upto 24 hours in case of once daily

formulations. The formulations F7, F11and F18 were lost

their necessary physical integrity at 24 hours. Remaining

formulations showed excellent and were subjected for further

evaluation studies. The drug content of formulations F1-F18

were 99.12-99.72%. From the results of invitro dissolution

formulations F3,F6,F12 and F15 were shown the release

97.12± 0.77, 98.94 ± 0.39, 97.51 ± 0.35, 97.25± 0.55

% as compared to Marketed formulation (98.47 ± 0.68) at

24th hour. Formulation F6 found to be attained the

percentage release is more Sustained manner than Marketed

formulation. In Bio-mucoadhesive study formulation F6 had

more biomucoadhesiveness when compared to all other

formulations F3, F12 and F15.

The swelling behavior of formulation F6 containing HPMC

E15 and PEO showed that swelling is increased upto 10

hours it decreased swelling in first 10 hours water is

absorbed by the polymer (HPMC is Hydrophilic polymer

which is attributed to its structure) and weight gain by the

tablet is seen. When water ingress from outer side to the

tablet core the outer gel layer starts to erode. This erosion

of polymer dominated over water sorption after 10 hours.

Hence the reduction in tablet weight occurs after 10 hours

because of erosion of matrix.

Ex-vivo mucoadhesion measurement formulation F6 were

found to remain attached to the mucosa for 24 hours along

with maintaining tablet integrity.This difference of gel

strength and integrity on swelling between PEO and HPMC

E15 could be attributed to chemical structure of the

polymers. Combination of PEO and HPMC E15 were studied

for Mucoadhesion. The mucoadhesion is enhanced by using

combination of polymers in appropriate proportions. When

PEO and HPMC were used in combination, hydrogen

bonding may occur between ether oxygen of PEO and

hydrogen of hydroxy groups of HPMC.

From the invivo bioavailability study the result and graph

was found to be that BGRDDS of F6 Showing AUC0-t 206

µgm-hr/ml was higher than the Marketed product AUC0-t

193 µgm-hr/ml. The test formulation attained higher

concentration (cmax) of 14.9µgm/ml than the Marketed

product (cmax) 14.5 µgm/ml at 24 hours respectively. It

remains in the stomach for 24 hours which may be due to

bioadhesiveness. As the swelling continues, the core and outer

swelling get diminished and size reduction along with slight

modulation in structure at 24 hour indicates structural

integrity retaining capacity of the developed formulation in

stomach for 24 hours.

Short term stability shows there was no change in

physicochemical and physical properties. (Buoyancy,

Dimensional stability and Bioadhesiveness) as well in drug

release profile even after storage at 450c and 75% RH for

three months. So there was no degradation of physical

Table 3. Biomucoadhesive study of selected formulations

Batch code Weight in gm RAS Force F in GST gm/m/s

Detachment force in GST gm/ m/s/mm2

F3 2.350 0.023 0.112 F6 3.250 0.031 0.150 F12 2.150 0.021 0.102 F15 1.800 0.017 0.086

Force F= m(mass)xg (acceleration due to gravity), RAS = Right arm side, GST= Goat stomach tissue

Table 4. Results of Kinetics of optimized formulation

Formulation Correlation coefficient R2 Order of release Zero order First order Higuchi matrix Korsemeyer

peppas Hixson crowell

F6 0.908 0.921 0.994 0.996 0.990



properties and change in the matrix system of the

formulation.

CONCLUSIONS

Metoprolol succinate tablets were prepared by various

Mucoadhesive Hydrophilic and Hydrophobic polymers such

as PEO, HPMC E15, Carbopol 71G, Methacrylic acid, Pectin,

Carragennan and Guargum. PEO is used as common for all

formulations (F1-F18). Floating tablet contains sodium bi

carbonate as a gas generating agent. Cross povidone

swelling agent which also used in floating sustained release

tablets as a drug release modifier due to its capillary

mechanism. Metoprolol succinate BGRDDS F6 was proved to

Fig 3: The Swelling of the formulation F6 at the end of 24th hour

Fig 4: Picture Representation Coding for Dimensional Stability



be attained the effective plasma concentration higher than

the Marketed formulation. This is due to retaining Metoprolol

succinate in the stomach (Where it absorbed more) by means

of Floating, Swellable, Bioadhesive Property of the polymer

PEO and HPMC E15 in BGRDDS F6. Hence it was concluded

that combination of High viscosity polymer PEO and low

viscosity polymer HPMC E15 consider being promising

polymer for Gastro Retentive Drug Delivery Systems. The

selected best formulation F6 followed Korsmeyer –peppas

kinetics and the release Mechanism was found to be

anomalous type, controlled by diffusion through swollen

matrix. So Metoprolol succinate as a BGRDDS using PEO

and HPMC E15 polymers will be a effective sustained

release formulation.

REFERENCES

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3. Rekhi GS,Nellore RV, Hussain AS,Tillman LG.Development of Metoprolol tartrate extended release matrix tablet. J.Controlled release 1198;50;247-256.

4. Chavanpatil M, Jain P; Chaudhary S, Shar S, Vavia P, Novel sustained release swellable and bioadhesive gastro retentive drug delivery system for Ofloxacin.Int.J.Pharm.2006,316;89-92.

5. Qi H,Chen W, Huang C, Li L.Development of Polaxamer analogs/Carbopol based in situ gelling and Mucoadhesive ophthalmic delivery system for Puerarin.Int.J.Pharm..2007, 337;178-187.

6. Srivastava AK,NarayanRao D,Wadhwa R.S. and Mishra B. Oral sustained delivery of Atenolol from floating matrix tablets formulation and invitro evaluation. Drug Dev Ind Pharm 2005; 31:367-374.

7. Rahman Z, Ali M,Khar R. Design and evaluation of bilayer floating tablets of Captopril. Acta pharm.2006;56;49-57.

8. Jain KS, Agarwal GP,Jain NK.A novel Calcium silicate microsphere of Repaglinide; Invivo Investigation. J.Control release; 2006; 113; 111-116.

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Research Article DESIGN AND DEVELOPMENT OF …...Metoprolol succinate bioahesive gastric drug...

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