Formulation and Evaluation of Floating Drug Delivery Systems of Famotidine Tablets

 

Y. Indira Muzib* and Malleswari. K

Department of Pharmaceutics, Institute of Pharmaceutical Technology, Sri Padmavathi Mahila University, Tirupathi.

*Corresponding Author E-mail: yindira2002@rediffmail.com

 

ABSTRACT:

Famotidine has been the most widely used drug for the treatment of peptic ulcer for many decades. The present investigation concerns the formulation and evaluation of floating tablets of famotidine which after oral administration, to prolong the gastric residence time, increase drug bioavailability and target the gastric ulcer. A floating drug delivery system was developed using hydroxy propyl methyl cellulose K100M, carbopol 940P and gas-forming agent sodium bicarbonate. The prepared tablets were evaluated in terms of their pre compression parameters, physical characteristics, invitro release, duration of buoyancy, buoyancy lag time. The prepared tablets exhibit satisfactory physical characteristics. All formulations show good in vitro buoyancy. The formulations were optimized for the different viscosity grades of hydroxy propyl methyl cellulose K100M, carbopol 940P its concentration and combinations. The results of the invitro release studies show that the formulations remain buoyant for more than 8 hrs. The formulations were subjected to various kinetic release investigations and it was found that the mechanism of drug release was from polymeric relaxation. Optimized formulation (F7) showed no significant change in physical appearance, drug content, total buoyancy time and optimized formulation stable at 40°±2°C RH for three months. Finally the tablet formulations found to be economical and may overcome the draw backs associated with the drug during its absorption.

 

KEYWORDS: Famotidine, floating drug delivery systems, In vitro   buoyancy.

 


INTRODUCTION:

The oral route of drug administration is the most convenient and commonly used method of drug delivery. However, this route has several physiological problems including an unpredictable gastric emptying rate that varies from person to person, a brief gastrointestinal transit time (8-12hr), and the existence of an absorption window in the upper small intestine for several drugs1,2. These difficulties have prompted research to design a drug delivery system which can stay in the stomach for prolonged and predictable period3,4. Attempts are being made to develop a controlled drug delivery system, which can provide therapeutically effective plasma drug concentration for a longer period, thereby reducing the dosing frequency and minimizing fluctuations in plasma drug concentration at steady-state by delivering the drug in a controlled and reproducible manner5.

 

Different methodologies have been reported in the literature to increase the gastric retention of drugs, like intra-gastric floating system, extendable or expandable and super porous biodegradable hydrogel systems6, mucoadhesive systems7, high-density systems8, Highly swellable hydrocolloids and light mineral oils9-13, The floating drug delivery systems result in longer lasting intra-gastric buoyancy which may not only provide a sustained site of specific therapeutic action but also may lead to a reduction in side effects and better patient compliance14. Drugs that act locally in the stomach e.g,antacids and misoprostol, drugs that degrade in the colon e.g. ranitidine HCl and metronidazole are suitable drug candidates for controlled release gastroretention.

 

Famotidine is a histamine H2-receptor antagonist. It is widely prescribed in gastric ulcers, Zollinger- Ellison syndrome and gastro esophageal reflux disease. In the management of benign gastric and duodenal ulceration the dose is 40 mg daily by mouth at bed time, for 6 to 12weeks; where gastro esophageal reflux disease is associated with esophageal ulceration, the recommended dosage is 40 mg twice daily for a similar period. For the short term symptomatic relief of heartburn or non-ulcer dyspepsia a dose of 10 mg up to twice daily is suggested. In Zollinger-Ellision syndrome the initial dose by mouth is 20mg every 6 hours, increased as necessary dose up to 80 mg daily have been employed15. The low bioavailability (40-45%), short biological half life (2.5-4.0 hours) favors in formulation of sustained release formulation. This approach also reduces the unwanted side effects of the drug, the tablet remain buoyant for a long period on the gastric contents, exhibiting a prolonged gastric residence time, resulting in sustained drug release and consistent blood levels of drug. Local delivery of famotidine also increases the stomach wall receptor site bioavailability and reduces acid secretion.

 

Based on the mechanism of buoyancy, two distinct different techniques i.e., non effervescent and effervescent systems have been used in the development of floating drug delivery systems in development of FDDS16. Floating drug delivery systems based on effervescent system uses matrices prepared with swellable polymers and effervescent compounds e.g. sodium bicarbonate. In non-effervescent FDDS, the drug mixes with a gel forming hydrocolloid, which swells in contact with gastric fluid after oral administration to maintain a relatively stable shape and a bulk density of less than unity within the outer gelatinous barrier. The air entrapped by the swollen polymer confers buoyancy on these dosage forms17.

 

In this present investigation floating drug delivery systems of famotidine were developed using effervescent approach using hydroxy propyl methyl cellulose (HPMC K100M) has been reported to enhance the sustained release property. Carbopol 940P is used as release modifying agent. NaHCO3 used as an effervescent agent to make the formulation buoyant for long time PVPK30 helped in granulation process, magnesium stearate and talc were used as lubricant and glidant, respectively.

 

MATERIALS AND METHODS:

Materials:

Famotidine was received as a gift sample from Vasava Pharma Private Limited, Hyderabad, Hydroxypropyl methylcellulose K100M (HPMC K100M) was obtained as gift sample from matrix Pvt. Ltd, Hyderabad, India. Polyvinyl pyrrolidine K-30 (PVP K-30), Lactose, talc, magnesium sterate was procured from Merck (India) Ltd., Mumbai. All other ingredients, reagents and solvents were of analytical grade.

 

Methods:

Preparation of Floating Tablets of Famotidine:

The ingredients were weighed accurately and mixed thoroughly. Granulation was done with a solution of PVP K-30 in sufficient isopropyl alcohol. The granules (40 mesh) were dried in conventional hot air oven at 45°C. Drying of the granules was stopped when the sample taken from the oven reached a loss on drying (LOD) value of 0.5 to 1.5% as measured by a moisture balance at 1050C. The dried granules were seived through 40/60 mesh, lubricated with magnesium sterate (2% W/W) and purified talc (1% W/W) and then compressed on a single punch tablet machine. The tablets were round and flat hardness of the tablet kept constant. Ten formulations were prepared and coded them from F1 to F10. The details of composition of each formulation is given in Table 1.

Evaluation of famotidine Granules:

The flow properties of granules (before compression) were characterized in terms of angle of repose, tapped density, bulk density, Carr’s index and Hausner ratio.

 

Physical evaluation of famotidine floating tablets:

Two tablets from each formulation were randomly selected and organoleptic properties such as colour, odour, taste, and shape were evaluated. Thickness and diameter of ten tablets were measured using vernier calipers. The prepared floating tablets were evaluated for uniformity of weight, hardness with Monsanto tester, friability test with Roche type friabilitor.

 

Drug Content:

The drug content in each formulation was determined by triturating 20 tablets and powder equivalent to average weight added  in 100ml of 0.1 N HCl followed  by stirring  for 30 minutes. The solution was filtered through 0.45µ membrane filter, diluted suitably and the absorbance of resultant solution was measured spectrophotometrically at 265 nm using 0.1N hydrochloric acid as blank.

 

In vitro buoyancy studies:

The in vitro buoyancy was determined by floating lag time. The tablets were placed in a 100-mL beaker containing 0.1N HCL. The time required to raise to the surface and float was determined as floating lag time.

 

In vitro dissolution studies:

The release rate of famotidine from floating tablets was determined using United States Pharmacopeia (USP) Dissolution testing Apparatus 2 (paddle method). The dissolution testing was performed using 900 ml of 0.1N hydrochloric acid, at 37± 0.5 C and 50 rpm. A sample (5ml) of the solution was withdrawn from the dissolution apparatus hourly and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45µ membrane filter and diluted to a suitable concentration with 0.1N hydrochloric acid. Absorbance of these solutions was measured at 265 nm using a UV/Visible spectrophotometer. The percentage drug release was plotted against time to determine the release profile.

 

Figure:1 In vitro dissolution studies for famotidine GFDDS


RESULTS:

Table: 1 Composition of different floating tablet formulations of famotidine

Ingredients

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

Famotidine

40

40

40

40

40

40

40

40

40

40

HPMC K 100 M

5

10

15

20

25

30

35

25

50

-

Carbopol 940P

5

5

5

10

15

20

15

25

-

50

Sodium bi carbonate

5

5

5

5

5

5

5

5

5

5

Citric acid

50

50

50

50

50

50

50

50

50

50

Lactose

123

118

103

103

103

98

88

88

88

88

Magnesium stearate

4

4

4

4

4

4

4

4

4

4

talc

8

8

8

8

8

8

8

8

8

8

 

Table: 2 Physical properties of Granules

S. no

Granules

Angle of repose*(Ѳ)

Bulk density ×103 kg/m3

Tapped density×103kg/m3

Carrs index(ic)

1

F1

28.83 ± 0.21

0.527

0.594

0.112

2

F2

28.61 ± 0.24

0.529

0.61

0.138

3

F3

28.02 ± 0.52

0.534

0.612

0.118

4

F4

28.48 ± 0.43

0.541

0.63

0.124

5

F5

29.88 ± 0.27

0.536

0.632

0.152

6

F6

29.64 ± 0.26

0.524

0.62

0.098

7

F7

28.92 ± 0.38

0.525

0.628

0.085

8

F8

28.85 ± 0.32

0.533

0.634

0.111

9

F9

28.37 ± 0.29

0.538

0.641

0.98

10

F10

28.31 ± 0.22

0.539

0.643

0.128

 

Table: 3 Results of post compression properties of Famotidine floating tablet:

Formulation

Thickness

Hardness

Friability

Drug content (%)

Weight variation (mg)

Code

(mm)

(kg/cm2)

(%)

F1

3.846

4.50 ± 1.2

0.68

98.20 ± 0.98

249.91 ± 1.2

F2

3.845

4.25 ± 0.99

0.54

98.53 ± 1.26

250.95 ± 1.4

F3

3.843

4.05 ± 0.23

0.57

99.12 ± 0.97

249.38 ± 1.2

F4

3.851

4.50 ± 0.18

0.63

99.70 ± 0.81

250.19 ± 0.23

F5

3.85

4.50 ± 0.21

0.72

99.41 ± 0.97

250.36 ± 1.21

F6

3.855

4.25 ± 0.24

0.68

99.59 ± 0.99

250.30 ± 1.32

F7

3.856

4.50 ± 0.22

0.66

99.12 ± 0.98

249.38 ± 1.42

F8

3.845

4.50 ± 0.48

0.78

98.82 ± 1.54

249.64 ± 1.99

F9

3.849

4.25 ± 0.31

0.91

98.53 ± 0.48

250.98 ± 1.36

F10

3.85

4.50 ± 0.23

0.63

98.72 ± 0.81

250.84 ± 1.48

 

 

 

 

 

 

 

 

 

 

 

 

 

Table:4 Results of In vitro buoyancy study of famotidine floating tablets

Formulation

Buoyancy Lag Time*

Duration of Buoyancy

T50(min)

F1

240 ± 8.5

60 (1 hr)

< 30±0.54

F2

175 ±7.09

90 (1.5 hr)

< 30±0.26

F3

160 ± 5.66

180 (3 hr)

30±0.87

F4

50 ± 0.6

> 480 (8 hr)

240±1.35

F5

25 ± 0.27

> 480 (8 hr)

240±0.14

F6

12 ± 0.27

> 480 (8 hr)

270±0.20

F7

55 ± 0.47

> 480 (8 hr)

240±1.69

F8

77 ± 0.2

> 480 (8 hr)

270±2.54

F9

18 ± 0.47

> 480 (8 hr)

300±1.35

F10

37 ± 0.47

> 480 (8 hr)

>480

 

Table:5 Kinetics of In vitro release of famotidine floating tablets

Formulation

Zero order(k0)

Zero order(r2)

First order(k1)

First order(r2)

Higuchi

Korsemayer –peppas (R)

Hixson

F1

7.94

0.885

0.082

0.678

0.921

0.578

0.678

F2

4.7

0.818

0.172

0.712

0.914

0.678

0.654

F3

11.6

0.836

0.234

0.673

0.933

0.568

0.643

F4

6.38

0.971

0.283

0.645

0.924

0.798

0.645

F5

6.02

0.987

0.276

0.665

0.965

0.796

0.567

F6

6.25

0.989

0.280

0.789

0.973

0.788

0.654

F7

8.71

0.948

0.320

0.793

0.902

0.765

0.675

F8

5.93

0.97

0.274

0.789

0.961

0.799

0.678

F9

5.9

0.904

0.276

0.678

0.904

0.766

0.698

F10

3.94

0.929

0.241

0.689

0.8

0.765

0.654


DISCUSSION:

The floating drug delivery systems of famotidine were prepared by effervescent technique using methocel (K 100M), sodium bicarbonate and PVP K-30. The effect of various formulation factors such as concentrations of swelling polymer on floating properties and drug release kinetics were studied to optimize the formulation. All the formulations compiled with compendia standards for uniformity of weight. The hardness of all formulations was found to be in the range of 4.25±0.23 to 4.50±1.2 kg/cm2, the drug content was estimated in the prepared GFDDS was found to less than ±5% variation of the stated amount of famotidine. The percent weight loss in the friability test was found to be less than 1% for all the formulations. Thus GFDDS made with two different polymers were found to of good quality fulfilling all the official and other requirement of floatable tablets. The flow properties of the granules blend were improved in all the formulations as compared to pure drug.

 

GFDDS formulated alone with HPMC K100M and carbopol 940P and combination HPMC K100M carbopol 940P. Hydration of polymers HPMC K100M and carbopol 940P results when formulations come in contact with dissolution fluid. It forms the gel structure which traps the gas generated by NaHCO3 and protected within the gel formed by hydration of polymer, thus decreasing the density of tablet below 1 and tablet becomes buoyant.

 

In the formulations F1-F8 contained HPMC K100M and Carbopol 940P in concentration of (2%, 4%, 6%, 8%, 10%, 12%, 14%) w/w of dose were selected Table-1. As concentration of HPMC K100M F1 to F7 increases, the lag time decreases. The tablet with low proportions of HPMC K100M increase the floating lag time compared to other formulations.  F10 formulation prepared with Carbopol 940P showed higher the lag time compared to HPMC K100M containing F9 formulation, because HPMC K100M has low viscosity, Compared to the carbopol 940P (Table-4).

 

Initially a burst release was observed in the GFDDS prepared from the two polymers. The slow rate of hydration and the presence of effervescent agent might be the reason for this. It is well known factor that the rate of hydration of polymer of hydrophilic matrix system during dissolution is having profound that in the rate of drug release. Generally, in hydrophilic matrix tablets, the initial burst release observed due to two factors. First the surface area of the polymers is not large enough to cover the drug release. Secondly if the polymers does not hydrate quickly, the surface barrier cannot formed immediately, which may cause a large portion of drug to be released during the initial phase of release profile. Thus, the surface area as well as hydration of polymer can play an important role in drug release from matrix tablets, especially at the beginning of release profile. Although the release rate mainly depends on the proportion of polymer, the entrapped gas within the hydro gel also influenced the rate of drug release from the GFDDS.

Decrease in dissolution rates were obtained for the two polymers by increasing the concentration HPMC of polymer. The increase in polymer content with the constant amount of drug results in decreased release rate of drug due to formulation of a matrix of low porosity and high tortuosity, which would presumably allow high gel strength and slow diffusion and erosion. The effect of polymer content on the dissolution rate of drug from hydrophilic matrices is predominant. Hence, changing the content of polymer in the tablets can modify the drug release.

 

The data of dissolution profiles of GFDDS of famotidine were shown in the figure 1. It was observed that as the concentration of polymer increases, the release was controlled. The results of invitro dissolution studies for famotidine GFDDS with HPMC K100 M and carbopol 940P shown in figure 1. The result showed that famotidine released from the GFDDS i.e. 97.86% within 1hr from F1, 98.06% within 1.5hrs from F2, 96.38% within 3 hrs from F3. 62%, 61%, 81.59%, 61.30%, 60.5%, 47.67% where as extended release was observed with F4, F5, F6, F7, F8, F9, F10 respectively.

 

The formulation F1 to F3 produced quicker drug release since these formulations contain low concentration of polymer fail to protect the drug from immediate release. F4- F10 produced higher drug release initially and thereafter sustained release up to 8 hrs. Sustained releases of these formulations were due to higher proportions of polymer content. The formulation F9, showed higher drug release which contains (20% w/w) HPMC K100M compared to the formulation F10 containing (20% w/w) carbopol 940P.

 

Drug release kinetics:

The drug release profiles of different GFDDS were fitted to various drug release kinetic models18-20 and the results were shown in Table-5 The values obtained of correlation coefficient ‘r’ values obtained by fitting the data to four popular release models were given in Table-5. The drug release from GFDDS prepared from HPMC K100M and carbopol 940P followed by  zero order plots(fig-1) were found to be fairly linear as indicated by their high regression values (r2=0.914 to 0.989). To confirm the exact mechanism of drug release from the tablets, the data were fitted according to Higuchi, Korsemeyer’s equation. Regression analysis was performed and regression value r2 were 0.909 to 0.973 for different formula. The contribution of drug diffusion to drug release was further confirmed by subjecting dissolution data to higuchi model. It was found that diffusion governs the drug release because the ‘r’ values were very close to 1. It can be concluded that the drug release is predominantly governed by diffusion. T50 values as function of polymer content in the GFDDS were shown in the Table- 4, it is clearly evident that the increase in the polymer content in GFDDS decrease the dissolution rate of drug.

 

CONCLUSIONS:

The effervescent-based floating drug delivery was a promising approach to achieve in vitro buoyancy. The addition of gel-forming polymers HPMC K100M, carbopol 940P and gas-generating agent sodium bicarbonate was essential to achieve in vitro buoyancy. The drug release from the tablets was sufficiently sustained and non-fickian transport of the drug from tablets was confirmed.

 

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Received on 03.04.2010       Modified on 30.04.2010

Accepted on 31.05.2010      © RJPT All right reserved

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1109-1113