Captopril Floating Tablets- 03 Version 6653

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IJPWR VOL1 ISSUE 3 (Jun-Sep) – 2010

INTERNATIONAL JOURNAL OF PHARMA WORLD RESEARCH

(An International Quarterly Published Online Research Journal)

www.ijpwr.com E-mail:[email protected]

Title:

DEVELOPMENT OF FLOATING MATRIX TABLETS: AN APPROACH

USING NATURAL GUMS.

Sreenivasa Reddy N1*, Mahendra Kumar C B2, Rohith G3, Chandrashekhar M S1.Sindhuabraham4,

1, Department of Pharmaceutics, Government College of Pharmacy, No.2, P.Kalinga Rao road,

Subbaiah circle, Bangalore- 560027, India. E-mail: [email protected]

2 Professor and Principal, St. Mary’s College of Pharmacy, St.Francis street, Secunderabad,-5000025

3 Drugs Testing Laboratory, Palace Road, Bangalore, India.

4 MS Ramaih College of Pharmacy, MSRIT Campus, Gokul, Bangalore- 560054, India.

*Corresponding author

Sreenivasa Reddy N;

E-mail: [email protected]

http://www.ijpwr.com/

mailto:[email protected]

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ABSTRACT

In this study floating matrix tablets were prepared using Captopril as a model drug. Tablets

containing a mixture of drug along with Xanthan gum, Gum karaya, Gellan gum & Pullulan gum along

with HPMC K4M, PVP K-30, and Sodium bicarbonate were prepared by direct compression. Sodium

bicarbonate was added as a gas generating agent, produced carbon dioxide in the gastric acidic

environment which helped in maintaining the buoyancy. The prepared tablets were evaluated for

physical properties, content uniformity, hardness, friability, floating lag time and in vitro drug release.

Among the studied formulations, F9 was found to be suitable for gastric retention based on evaluation

parameters, which was considered desirable for the drugs with absorption window in upper GIT. The

linear regression analysis and model fitting showed that all these formulations followed Higuchi model,

which had a higher value of correlation coefficient (r). Stability studies of all formulations were

carried out at elevated temperature and humidity conditions of 40±2 o C/75±5% RH and a control

sample was placed at ambient conditions for 12 months. There was no significant change in buoyancy

property and drug content, indicating that the formulations are stable.

Keywords: Captopril, Pullulan Gum, sustained release, intragastric floating tablet

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INTRODUCTION

In recent years, oral dosage forms for gastric retention have drawn more and more attention for their

theoretical advantages in permitting control over the time and site of drug release.1 The real challenge

in the development of a controlled drug delivery system is not just to sustain the drug release, but also

to prolong the presence of the dosage form in the stomach or the upper small intestine until the drug is

completely released in the desired period of time.2 Gastro retentive drug delivery devices are primarily

controlled release drug delivery systems, which gets retained in the stomach for longer period of time,

thus helping in absorption of drug for the intended duration of time. This in turn improves

bioavailability, reduces drug wastage, and improves solubility of drugs that are less soluble at high pH

environment. It also helps in achieving local delivery of drug to the stomach and proximal small

intestine. Gastric retentive drug delivery devices can be useful for the spatial and temporal delivery of

many drugs.3 Many drugs categorized as once a day delivery have demonstrated to have sub optimal

absorption due to dependence on transit time of the dosage form. Therefore, a system designed for

longer gastric retention will extend the time within which drug absorption can occur in small intestine.4

Thus it has been suggested that formulation of drugs with narrow absorption window in a unique

dosage form prolongs gastric residence time and extended absorption phase. The controlled gastric

retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, flotation,

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sedimentation, expansion, modified shape systems or by the simultaneous administration of

pharmacological agents that delay gastric emptying.5

Gastric emptying of dosage forms is an extremely variable process and the ability to prolong

and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a

longer period of time than conventional dosage forms. Several difficulties are encountered in designing

controlled release systems for better absorption and enhanced bioavailability.6

Captopril, an angiotensin-converting enzyme (ACE) inhibitor, is used to treat hypertension,

congestive heart failure, and renal syndromes such as diabetic nephropathy and scleroderma, either

alone or in combination with other thiazide diuretics. The half life of Captopril is less than 3 hours and

the presence of food in the gastro intestinal tract reduce its absorption by about 30 to 40 percent.7

MATERIALS & METHODS:

MATERIALS

Captopril was received as a gift sample from Charaka Pharma(p) Ltd, Mumbai. HPMC 4K, Aerosil,

Sodium bicarbonate, Magnesium stearate, Purified talc were obtained as gift samples from Varsha

laboratories, Bangalore. Xanthan gum, Gum karaya, Pullulan gum, Gellan gum was received as gift

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samples from CP Kelco Laboratories, Germany, Emboitics Pharmaceuticals & Micro labs,

Bangalore.

PREPARATION OF FLOATING MATRIX TABLETS

The ingredients were passed through a 80 mesh sieve. The required quantities of Xanthan gum, Gum

karaya, Pullulan gum, Gellan gum, HPMC 4K, PVP-K30, Di calcium phosphate and Sodium

bicarbonate were blended together in a suitable mixer. Captopril was added to the above and the

mixing continued. Magnesium stearate,Talc & Aerosil were finally added and the blend was then

compressed in to tablets by using a 5 mm punch rotary tablet Minipress machine (Rimek RSB-4, ,

Cadmach, Ahmedabad, India). Table 1 gives the details of the various formulations.

Table 1: Composition of floating matrix tablets of Captopril

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9

Captopril 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5

Xanthan Gum 75 50 - - 50 - - - -

Gum Karaya 25 25 25 25 50 50 25 25 50

Gellan Gum - - 75 50 - 50 - - -

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Pullulan Gum - - - - - - 75 50 50

Aerosil 20 20 20 20 20 20 20 20 20

HPMC 4K 50 50 50 50 50 50 50 50 50

PVP K-30 20 20 20 20 20 20 20 20 20

Di Calcium Phosphate 14.5 39.5 14.5 39.5 14.5 14.5 14.5 39.5 14.5

Sodium bicarbonate 30 30 30 30 30 30 30 30 30

Magnesium Stearate 1 1 1 1 1 1 1 1 1

Purified Talc 2 2 2 2 2 2 2 2 2

Total 250 250 250 250 250 250 250 250 250

*All the quantities expressed are in terms of milligrams

EVALUATION OF PHYSICAL PROPERTIES OF FLOATING MATRIX TABLETS:

Hardness: The crushing strength of the tablets was measured using Monsanto hardness tester. Three

tablets from each formulation were tested randomly and average reading noted.

Friability: The friability of a sample of 20 tablets was measured using ROCHE Friabilator (Electro

lab) 20 previously weighed tablets were rotated at 25 RPM for 4 minutes. The weight loss of the tablets

before and after measurement was calculated using the following formula:

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Percentage friability = Initial weight – Final weight x 100

Initial weight

Thickness: The thickness of the tablets was measured using screw gauge meter.

Weight Uniformity: The test was carried in conformity with the official method described in I.P.

Twenty tablets from each formulatiions were selected randomly after compression, weighed

individually and average weight was determined. None of the tablets deviated from the average weight

by more than 5%.

Assay of drug content: Ten tablets were randomly sampled from each formulation batch, finely

powdered and individually estimated for the drug content after suitable dilution, using UV-VIS

Spectrophotometer (UV1601, Shimadzu) at 212 nm.5,8,9

In vitro buoyancy study: The in vitro buoyancy was carried out by determining floating lag time .The

tablets were placed in a 100 ml glass beaker containing 0.1N HCl. The time required for the matrix

tablet to rise from bottom to the surface of the glass beaker and float on surface was determined. Total

floating time was measured as buoyancy lag time during in vitro dissolution studies.5,10

Curve Fitting analysis: Mathematical models, zero-order, first-order, Higuchi & Peppas were applied

to analyze the release rate mechanism and pattern11

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In vitro drug release study: In vitro drug release studies for all the formulations were carried out

using tablet dissolution USP II type (paddle method). The dissolution media used was 0.1N HCl,

maintained at 37±0.5°C and the media was rotated at 50 rpm. Aliquots were withdrawn at different

time intervals, filtered and analyzed spectrophotometrically at 212nm for cumulative drug release. The

dissolution studies were conducted in triplicate and the mean values were plotted against time. The

duration of floatation was also noted for each of the formulations.5,8

Stability Studies: The tablets were stored in an aluminum foil and subjected to elevated temperature

and humidity conditions of 40±2°C/75±5% RH and a control sample was placed at an ambient

condition. The samples were withdrawn once a month for 12 months and evaluated for active drug

content, in vitro buoyancy and drug release profile. The results showed that the drug content did not

differ from initial drug content by not more than 3%, indicates formulations are stable.

RESULTS AND DISCUSSION:

The weight variation and thickness of all the floating matrix tablets were determined and found to

comply with the standards of Indian pharmacopoeia. The hardness of all the formulations were in the

range of 4.0±0.02 to4.5±0.002 kg/cm 2. The percentage friability of all the formulations were ranged

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between 0.41±0.02% to 0.59±0.3% (n = 20). The duration of in vitro buoyancy was carried out and the

studies of all the formulations revealed the rate of floating as follows:

F9>F8>F5>F3>F7>F6>F2>F4>F1. Table 2 gives the Floating lag time and total floating time values

of all the formulations. Figure 1 gives the details of the buoyancy test of Formulation F9.

Table 2: Floating lag time and total floating time values for formulations F1- F9.

FormulationFloating lagtime (min)

Total floatingtime (hrs)

F1 12 >24

F2 8 >14

F3 7 >14

F4 10 >14

F5 8 >24

F6 9 >14

F7 9 >12

F8 4 >10

F9 3 >24

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Figure 1: Floating properties of gastro retentive Captopril matrix tablets ( Formulation F9)

(A)at 0 hour,(B) at 30 minutes,(C) after 1 hour, (D)3 hours, (E)5 hours & (F) 8 hours;

Figure (A) at 0 hour Figure (B) at 30 minutes

Figure (C). at 1 hour Figure (D). at 3rd hour

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Figure (E) at 5th hour Figure (F) at 8th hour

Formulations were designed as per the Table 1 at various concentrations of Xanthan, Karaya gum,

Gellan gum & Pullulan gum. Formulation F1, F2, F3, F4, F7 & F8 contained same amount of Karaya

gum and varying the other polymer in two different concentrations (1:2 &1:3), where as F5,F6 &F9

contain equal amount of Gum karaya and other polymers(1:1).By comparing the values of In vitro

dissolution studies(Fig 2) the highest drug release was shown by F7 i.e.99.67% with in 5 hours. After

carrying out in vitro studies all the nine formulations, it was concluded that the formulations having

Pullulan gum along with Gum karaya in the ratio 3:1 as polymer matrix exhibits better release of drug

(Table3).

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Table 3: % Cumulative drug release for formulations F1-F9

Sl.No. Formulation% Cumulative Drug Release

1 hr 2 hr 3 hr 4 hr 5 hr 6 hr 7 hr 8 hr

1 F1 35.73 47.25 50.00 59.68 60.48 63.23 63.91 73.02

2 F2 37.97 45.53 52.74 64.26 70.79 77.14 90.03 98.62

3 F3 46.33 57.41 67.70 70.20 75.97 77.84 79.87 88.76

4 F4 44.67 58.41 64.94 76.97 78.35 82.81 91.23 97.59

5 F5 35.22 46.04 53.26 54.12 72.33 84.87 93.12 93.98

6 F6 45.36 62.02 68.38 78.35 82.13 93.12 95.87 97.07

7 F7 50.98 77.86 91.14 98.42 99.67 -- -- --

8 F8 32.98 43.29 55.67 64.26 70.79 77.14 90.03 98.62

9 F9 23.19 28.00 39.69 60.30 72.33 75.42 84.53 92.09

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Figure 2: Drug release profile of Captopril floating matrix tablets for formulations F1-F9

% cdr

Time in hours

The variation in the concentration of polymers may affect the drug release pattern . Theoretically

speaking, this behavior is expected one, since a more amount of polymer will always delays the release.

However when the release of F7 is compared with F1 (figure 01), it was found that F1 has shown

decrease in the release marginally with 73.02 % at 8th Hour against F7 with 97.07% (with in 5 hours).

0

20

40

60

80

100

120

0 2 4 6 8 10

F1

F2

F3

F4

F5

F6

F7

F8

F9

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The drug release behavior of different formulations follows the order

F1<F3<F9<F5<F6<F4<F8<F2<F7.

Above studies revealed that formulation F7 releases the drug at better rate than any other

formulations, this can be attributed to the hydrophilic nature of polymer and pores formed by the

release of CO2.

Whereas Formulations F5, F6 & F9 which contains Gum karaya with Xanthan gum, Gellan gum &

Pullulan gum in the ratio 1:1 have shown 93.98%, 97.07% & 92.09% drug release respectively. The

drug release retardation of F5, F6 & F9 follows the order F9<F5<F6.

In the present work, the drug incorporated is basic in nature and the presence of sodium bicarbonate

makes the polymer soluble to some extent. But, the dissolved polymer also imparts pH changes as it is

acidic in nature. Hence the complex nature of these developments might have lead to the initial slow

release of the drug. By using gum karaya constant in the formulations along with other polymers

which can influence the rate of drug release by retardation to get deserved gastro retentive floating

matrix tablets.

Hence, if the polymer does not modulate the matrix pH, an increase in matrix porosity due to the

dissolution of the polymer is the predominating factor due to which we may see enhancement using

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insoluble fillers and retardation using soluble fillers. Hence, by replacing a portion of the highly

soluble filler with less soluble polymer, a lowering in matrix porosity will be seen and the converse is

true for insoluble fillers. Release Kinetics study carried out by fitting the results obtained for zero

order, first order, Higuchi and Korsemeyer Peppas models and results are compared in table no.4.

Table 4: Zero order & first order kinetics for formulations F1-F9

FormulationCode

Zero Order First Order Higuchi Model Korsemeyermodel(n values)

F1 0.9728 0.7787 0.9731 0.967

F2 0.9678 0.7231 0.9713 0.878

F3 0.9881 0.9569 0.9701 1.578

F4 0.9875 0.9255 0.9660 0.901

F5 0.9902 0.9618 0.9745 1.122

F6 0.9924 0.9123 0.9881 1.577

F7 0.9878 0.8976 0.9887 1.062

F8 0.9975 0.8657 0.9891 1.189

F9 0.9831 0.8745 0.9674 1.554

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For all the 9 formulations, the stability studies were carried out at elevated temperature and humidity

conditions of 40±2°C/75±5% RH and control sample was placed at an ambient condition for a period

of 12 months and it was found that there was no change in buoyancy property of all the 9 formulations.

The drug content was obtained once a month up to 12 months showed that the drug content did not

differ not more than 5% from initial drug content, indicating that the formulations are stable.

CONCLUSION

Formulation F9 gave better controlled drug release and floating properties in comparison to the other

formulations. This formulation took 3 minutes to become buoyant. The gastro retentive floating drug

delivery is a promising approach to achieve in vitro buoyancy and thereby longer gastric retention time

for weakly basic drug by using gel-forming as well as low density polymers like xanthan ,gum karaya,

gellan gum, pullulan gum, HPMC K4M and gas-generating agent sodium bicarbonate. These results

are encouraging because the longer gastric residence time is an important factor which influences the

bioavailability of the drugs included in the prolonged/controlled release dosage forms.

ACKNOWLEDGEMENTS:

I specially thank all the pharmaceutical manufacturers who provided the drug, polymers and

excepients as gift samples for my research work. My sincere thanks to Dr.B.R.Jagashetty, Drugs

Controller for the State of Karnataka, Director, Health & family welfare services, Government of

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Karnataka, and Dr. S. Shashidhara., Principal, Government College of Pharmacy, Bangalore for their

necessary permission & kind support for my research work.

REFERENCES:

1. Patel A Modasiya M Shah D, V Patel, “Development and in vitro floating behavior of verapamil

HCL intragastric floating tablets”. AAPS PharmSciTech, Vol 10, 310-315, 2009.

2. S.T Prajapati, D.M Patela, “Gastric floating matrix tablets: Design and optimization using

combination of polymers”. Acta Pharm, Vol 58, 221-229, 2008.

3. A Shweta , J Ali , Ahuja , K.K Roop, B sanjula, “Floating drug delivery system- A review”,

Journal of Controlled Release, 112-116, 2005.

4. P.LBardonner, V Falvre, W.J Pagh, J.C Piffaretti, F Falso, “Gastro retentive dosage forms:

Overview and special case of Helicobacter pyroli”, Journal of Controlled Release, Vol.111,1-18, 2006.

5. Samip S Shah, Sridhar J Pandia, Maheash K Waghulade, “Development and investigation of gastro

retentive dosage form of weekly basic drug”, Asian Journal of Pharmaceutics, Vol 4, 11-16, 2010.

6. G Rohith, B.K Sridhar, A Srinath, “Floating drug delivery of a locally acting H2 antagonist. An

approach using an in situ gelling liquid formulation”, Acta pharm, Vol.59, 345-354, 2009.

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7. www.drugbank.com

8. Indian Pharmacopeia; Captopril tablets monograph; 2007. P.849-850

9. British Pharmacopoeia. Captopril tablets monograph; 2008 P.379-380/2490

10. M Rosa, H Zia , T Rhodes, “ Dosing and testing In vitro of a bioadhesive and a floating drug

delivery system for oral application”, International Journal of Pharmaceutics , Vol 105,65-70, 1994.

11. Reddy KR, Mutalik S, Reddy S, once-daily sustained release matrix tablets of Nicorandil ;

Formulation and In vitro evaluation. AAPS Pharm Sci Tech 2003; 4:61

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Captopril Floating Tablets- 03 Version 6653