Oral Sustained Delivery of Rosiglitazone Maleate Floating Matrix Tablets- Formulation and In Vitro Evaluation

Rahul K Godge¹, Syed N Lateef², Mahendra A Giri², Pravin D Chaudhari, Abhijeet N Merekar¹ and Prakash N Kendre^2*

¹Pravara Rural college of Pharmacy, Pravaranagar Dist. Ahemadnagar

²Sanjivani college of Pharmaceutical Edu. and Research, Kopargaon

³Modern College of Pharmacy, Nigadi, Pune

ABSTRACT

The aim of the study was to develop and physicochemicaly characterize single unit controlled delivery system of Rosiglitazone maleate and was formulated as floating matrix tablet by direct compression method using gas generating agent (sodium bicarbonate) and various viscosity grades of hydrophilic polymers (HPMC K15M, K4M; HPC and Carbapol 934P). Formulation was optimized on the basis of buoyancy and in vitro drug release profile. Also tablets were tested for various tests like hardness, thickness, weight variation, friability, swelling index and erosion index. The tablets swelled and eroded upon contact with release medium (0.1 N HCl) at 37 ⁰C. The release rate could efficiently be modified by varying the matrix forming polymer, the use of polymer blends and the addition of water soluble or water insoluble fillers (such as dicalcium phosphate, lactose or mannitol). Fitting the in-vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.

KEYWORDS: Rosiglitazone maleate, Carbapol, HPMC, Floating matrix tablets, swelling index, buoyancy.

1. INTRODUCTION

The recent research studies and various literatures reveals that pharmaceutical dosage forms exhibiting good in vitro floating behavior show prolonged gastric residence in vivo (Ichikawa et al., 1991; Kawashima et al., 1991)². Oral route is the route most often used for administration of drugs. Tablets are the most popular oral formulations available in the market and are preferred by patients and physicians alike. In long-term therapy for the treatment of chronic disease conditions, conventional formulations are required to be administered in multiple doses and therefore have several disadvantages⁴.

The real issue in the development of oral controlled release dosage form is not just to prolong the delivery of drugs for more than 12 hrs but also to prolong the presence of dosage forms in the stomach or somewhere in the upper small intestine. Dosage forms with prolonged gastric residence time (GRT), i.e. gastro remaining or gastro retentive drug delivery system (GRDDS) will bring about new and important therapeutic options. For instance, these will significantly extend the period of time over which drugs may be released, and thus prolong dosing intervals and increase patient compliance beyond the compliance level of existing controlled release dosage forms. The effects of simultaneous presence of food and of the complex motility of the stomach are difficult to estimate. Obviously in vivo studies can provide definite proof that prolonged gastric residence is obtained^{7, 14}.

Extended-release dosage forms with prolonged residence times in the stomach are highly desirable for drugs (i) that are locally active in the stomach, (ii) that have an absorption window in the stomach or in the upper small intestine,(iii) that are unstable in the intestinal or colonic environment, and/or (iv) have low solubility at high pH values.

Table 1: Compositions of floating matrix tablet in mg:

Formulation*	HPMC K4M	HPMC K15M	HPMC K100M	HPC	HPMCK4M + Carbapol 934P**	Lactose	Mannitol	DCP
F-1	150	----	----	----	----	----	----	43
F-2	----	150	----	----	----	----	----	43
F-3	----	----	150	----	----	----	----	43
F-4	150	----	----	----	----	43	----	----
F-5	150	----	----	----	----	----	43	----
F-6	----	----	----	----	150	----	----	43
F-7	----	----	----	----	150	43	----	----
F-8	----	----	----	----	150	----	43	----
F-9	----	----	----	150	----	----	----	43
F-10	----	----	----	150	----	43	----	----
F-11	----	----	----	150	----	----	43	----

*All batches contained 15mg of drug, 15 %sodium bicarbonate, 1 % magnesium stearate and 1 % Aerosil.

** HPMC K4M and Carbapol 934P blend was taken in 3:1 ratio respectively.

Table 2: Properties of the compressed tablets:

Formulation	Thickness *	Drug Content (%)*	Friability (%)	Hardness (kg/cm^2)*
F-1	2.78± 0.025	98.19 ± 1.5	0.34	5.4 ± 0.7
F-2	2.95 ± 0.03	98.21 ± 1.3	0.35	5.5± 0.1
F-3	2.93± 0.01	96.9 ± 1.9	0.39	5.5 ± 0.1
F-4	2.84 ± 0.03	98.3 ± 0 .8	0.43	5.5 ± 0.1
F-5	2.85 ± 0.04	98.4 ± 1.1	0.76	5.5 ± 0.2
F-6	2.90 ± 0.0264	97.04 ± 1.2	0.35	5.9 ± 0.3
F-7	2.96 ± 0.025	98.01 ± 1.6	0.27	5.4 ± 0.6
F-8	2.90 ± 0.0173	97.03 ± 1.3	0.43	5.5 ± 0.1
F-9	2.92 ±0.0152	98.97 ± 1.3	0.35	5.5 ± 0.3
F-10	2.92 ± 0.0264	98.10 ± 1.7	0.35	5.5 ± 0.4
F-11	2.92±.0264	98.33 ± 1.19	0.19	5.6 ± 0.3

* All the values are expressed as mean ± SE, n = 3

Table 3: Floating Lag Time:

Formulation	Floating lag time (min)*
	pH 1.2	pH 2.0	pH 3.0
F-1	<1.0	<4.0	>4.0
F-2	<1.0	<4.0	>4.0
F-3	<1.0	<4.0	>4.0
F-4	<1.0	<4.0	>4.0
F-5	<1.0	<4.0	>4.0
F-6	>1.0	<4.0	>4.0
F-7	>1.0	<4.0	>4.0
F-8	>1.0	<4.0	>4.0
F-9	<1.0	<4.0	>4.0
F-10	<1.0	<4.0	>4.0
F-11	<1.0	<4.0	>4.0

Each sample was analyzed in triplicate (n = 3)

In addition, as the total gastrointestinal transit time of dosage forms is increased by prolonging the gastric residence time, these systems can also be used as sustained release devices with a reduced frequency of administration and, therefore, improved patient compliance .Recent approaches to increase the gastric residence time of drug delivery systems include (i) bioadhesive devices (ii) systems that rapidly increase in size upon swallowing and (iii) low density devices that float on the gastric contents ^3,5,8,10.

2. MATERIALS AND METHODS:

2.1 Materials:

Rosiglitazone maleate was obtained as a gift sample (Cipla pharmaceutical Ltd., Kurkum MIDC, Pune), Other polymers and chemicals such as HPMC K4M, K15M (Colorcon Asia Ltd., Goa, India), Carbapol 934P, colloidal silicon dioxide (Aerosil), magnesium stearate, sodium bicarbonate (New Life Pharmaceuticals, Pune,India). Remaining all the materials were obtained commercially and used as such.

2.2Fabrication of floating matrix tablets ⁶:

Tablets containing Rosiglitazone maleate as a pure drug were prepared by direct compression method. The respective powders (drug, polymers, and fillers) and optional additives, compositions listed in Table No.1 were blended thoroughly with a mortar and pestle and finally mixed with magnesium stearate and colloidal silicon dioxide as a lubricant and glidant respectively. Tablets of 250 mg each were compressed by using multiple-punch tabletting machine (Cadmach, Ahmedabad) with constant weight, thickness, diameter (10 mm) and hardness ( approximately 5 Kg/cm² unless otherwise stated) using beveled flat-faced punches.

Hardness was measured by using Monsanto hardness tester and diameter and thickness was measured by digital vernier caliper.

2.3 Characterization of tablets: ⁶

The properties of the compressed matrix tablets, such as hardness, friability, weight variation and content uniformity were determined by using reported procedure. Hardness was measured by using Monsanto hardness tester and friability was measured by Roche friability testing apparatus. Weight variation and uniformity of drug content were performed according to I.P.procedures.Content uniformity was determined by weighing 10 tablets individually.

2.4 Floating behavior of the tablets: ^11,15

In vitro buoyancy study of the tablets (n=3) was determined using USP (type II) dissolution apparatus containing 900 ml of 0.1 N HCl (pH 1.2 at 37 ⁰C) at 100 rpm. The time (min) taken by the tablet to reach the top from the bottom of the container (floating lag time), and the time for which the tablet constantly floats on the surface of the medium (duration of floating), was measured.

Table 4: Swelling characteristics:

Formulation	Time (Hr.)	Swelling Index
F-1	2	1.03
	4	1.77
	8	3.43
	10	3.58
F-2	2	1.02
	4	1.84
	8	3.39
	10	3.58
F-3	2	1.07
	4	1.78
	8	3.44
	10	3.58
F-4	2	1.01
	4	2.13
	8	3.35
	10	3.59
F-5	2	0.88
	4	2.46
	8	2.96
	10	3.3
F-6	2	0.99
	4	1.79
	8	2.49
	10	3.46
F-7	2	1.01
	4	1.78
	8	2.80
	10	3.40
F-8	2	1.03
	4	1.82
	8	2.88
	10	3.40
F-9	2	1.04
	4	1.84
	8	2.90
	10	3.44
F-10	2	1.09
	4	1.82
	8	2.42
	10	3.17
F-11	2	1.15
	4	2.03
	8	2.51
	10	3.33

2.5 Determination of swelling and erosion behavior: ¹³

The swelling and eroding behavior of matrix tablet was determined, reported by Al-Taani and Tashoush. Matrix tablet was introduced into the dissolution apparatus containing 900 ml of 0.1 N HCl

(PH 1.2 at 37 ⁰C) at 100 rpm. The tablets were removed using a small basket and swollen weight of each tablet was determined. To determine matrix erosion, swollen tablets were placed in a vacuum oven at 40 ⁰C and after48 hours tablets were removed and weighed. Swelling (%) and erosion (%) was calculated according to the following formula, where S is the weight of the matrix tablet after swelling; R is the weight of the eroded matrix tablet; and T is the initial weight of the matrix tablet:

Swelling Index = S − T / T

% Erosion = (T – R) / T ×100.

2.6 Accelerated stability testing: ^16-18

The stability studies were carried out on optimized formulations. The formulations were stored at 40± 2⁰C/75 ± 5 % RH (% relative humidity) for one month. After interval of 7, 15 and 30 days samples were withdrawn and retested for drug content, floating lag time and drug hardness.

Kinetic treatment for floating matrix tablet formulations:

Fig. (a): Formulation-1

Fig. (b): Formulation-2

Fig. (c): Formulation-3

2.7 In vitro drug release studies: ^{6, 12}

Dissolution tests were conducted in triplicate for all batches in a USP (type-II) dissolution rate test apparatus (type II) The release studies were performed by using 900 ml of 0.1 N HCl (pH 1.2 at 37 ⁰C) at 100 rpm. Five milliliters aliquots were withdrawn at specific time intervals and drug content was determined by UV-visible spectrophotometer (simatzu-1650 PC) at 318.5 nm. The release studies were conducted in triplicate.

2.8 Kinetic analysis of the dissolution data: ^1,9,19

In order to study the exact mechanism of drug release from the matrix floating tablets, the release data were fitted to zero-order, first-order and higuichi equation. These models fail to explain drug release mechanism due to swelling (upon hydration in contact with dissolution medium) along with gradual erosion of the matrix. Therefore, the dissolution data was also fitted to the well-known exponential equation (Korsmeyer equation), which is often used to describe the drug release behavior from polymeric systems:

Log (M _t / M _f) = Log k + n Log t

Where, M_t is the amount of drug release at time t; M _f is the amount of drug release after infinite time’s is a release constant incorporating structural and geometric characteristics of the tablet; and n is the diffusion exponent indicative of the mechanism of the drug release.

Fig. (d): Formulation-4

Fig. (e): Formulation-5

Fig. (f): Formulation-6

Fig. (g): Formulation-7

In order to make sure the release exponent for different batches of floating matrix tablets, the log value of % drug dissolved was plotted against log time for each batch according to the Equation. Value of n = 0.45 indicates Fickian (Case I) release ;> 0.45 but <0.89 for non-fickian (anomalous) release; and >0.89 indicates super case II type of release. Case II generally refers to the erosion of the polymeric chain and anomalous

Fig. (h): ormulation-8

Fig. (i): Formulation-9

Fig. (j): Formulation-10

Fig. (k): Formulation-11

transport (non-fickian) refers to a combination of both diffusion and erosion controlled-drug release. Mean dissolution time (MDT) was calculated from dissolution data using the following equation (Mockel and Lippold):MDT = (n / n + 1). K – 1 / n Where, n =release exponent and k = release rate constant.

Table 5: Erosion characteristics:

Formulations	Time in hrs. (% Erosion)
	0	2	4	6	8	10	12	16	20
F-1	0	14.4	19.6	26.0	30.8	39.6	44.4	55.6	68.4
F-2	0	11.6	18.8	24.8	31.6	37.6	45.2	56.4	69.6
F-3	0	13.2	19.2	25.6	29.2	38.0	46.8	58.1	68.8
F-4	0	11.2	18.0	26.0	29.6	39.6	48.4	57.6	69.2
F-5	0	12.0	19.6	24.8	31.6	38.4	50.4	56.4	68.4
F-6	0	7.4	12.4	20.8	24.8	29.6	38.0	44.4	50.8
F-7	0	8.4	13.2	18.6	25..2	29.0	36.4	43.6	56.4
F-8	0	9.2	15.6	19.6	26.4	30.8	40.4	42.0	57.6
F-9	0	12.8	20.4	26.8	30.8	36.4	45.2	56.8	68.8
F-10	0	11.6	21.2	24.4	31.6	38.4	45.6	56.8	67.6
F-11	0	10.8	19.8	28.4	30.0	38.0	44.4	55.6	66.8

Table 6: Average percentage drug release data:

Sr. No.

Avg. % drug release

F-1

F-2

F-3

F-4

F-5

F-6

F-7

F-8

F-9

F-10

F-11

1

1 hr

14.52 ± 0.29

15.52 ± 0.29

14.55 ± 0.27

14.60 ± 0.13

15.11 ± 0.54

12.81 ± 0.29

13.01 ± 0.37

14.28 ± 0.65

13.15 ± 0.47

15.58 ± 0.47

13.88 ± 0.46

2

2 hrs

18.13 ± 0.38

19.13 ± 0.38

19.17 ± 0.41

19.13 ± 0.38

19.83 ± 0.51

15.85 ± 0.26

16.01 ± 0.47

19.28 ± 0.85

16.69 ± 0.51

19.87 ± 0.95

17.81 ± 0.35

3

4 hrs

30.93 ± 0.34

31.93 ± 0.34

30.95 ± 0.31

30.93 ± 0.34

32.03 ± 0.34

27.28 ± 0.18

26.98 ± 0.57

27.33 ± 0.86

30.15 ± 0.43

31.56 ± 0.66

30.14 ± 0.38

4

6 hrs

36.48 ± 0.46

34.33 ± 0.46

37.44 ± 0.48

38.48 ± 0.46

39.00 ± 0.34

34.90 ± 0.46

36.30 ± 0.69

32.46 ± 0.77

36.47 ± 0.61

38.92 ± 0.48

37.10 ± 0.48

5

8 hrs

47.29 ± 0.30

48.01 ± 0.30

48.21 ± 0.32

48.29 ± 0.30

49.09 ± 0.72

41.79 ± 0.06

42.07 ± 0.87

39.88 ± 0.48

46.66 ± 0.43

49.29 ± 0.68

46.51 ± 0.43

6

10 hrs

54.21 ± 0.27

53.23 ± 0.27

52.24 ± 0.29

54.21 ± 0.27

55.68 ± 0.65

46.41 ± 0.04

45.17 ± 0.48

42.11 ± 0.37

54.16 ± 0.27

55.74 ± 0.57

54.82 ± 0.46

7

12 hrs

63.69 ± 0.13

64.50 ± 0.13

65.65 ± 0.17

61.60 ± 0.13

64.38 ± 0.35

51.11 ± 0.89

53.15 ± 0.52

49.73 ± 0.86

62.43 ± 0.44

65.55 ± 1.85

62.45 ± 0.34

8

14 hrs

72.43 ± 0.29

73.63 ± 0.29

71.70 ± 0.39

72.73 ± 0.30

73.32 ± 0.30

58.12 ± 0.93

57.23 ± 0.68

59.38 ± 0.75

70.83 ± 0.66

74.00 ± 0.66

72.58 ± 1.00

9

16 hrs

82.66 ± 0.15

81.56 ± 0.12

83.64 ± 0.17

82.66 ± 0.15

83.20 ± 0.16

66.98 ± 0.44

69.59 ± 0.59

71.63 ± 0.44

80.19 ± 0.97

83.77 ± 1.00

81.20 ± 0.57

10

18 hrs

94.86 ± 0.69

93.76 ± 0.69

94.81 ± 0.71

94.85 ± 0.69

85.92 ± 0.43

79.63 ± 0.49

81.43 ± 0.63

83.25 ± 0.45

85.80 ± 0.23

86.01 ± 0.35

86.06 ± 0.27

11

20 hrs

97.13 ± 0.22

97.09 ± 0.49

96.78 ± 0.31

97.05 ± 0.38

96.81 ± 0.32

91.59 ± 0.84

93.12 ± 0.98

93.8 ± 0.69

96.42 ± 0.44

96.52 ± 0.48

96.09 ± 0.20

Each sample was analyzed in triplicate (n = 3)

Table 7: Kinetic treatment for floating matrix tablet formulations:

Formulation	Zero Order Plot	First Order Plot	Korsmeyer- Peppas Plots	Matrix Plots	Hix. Crow. Plots	Best Fit Model
	Regression coefficient (R^2)	Regression coefficient (R^2)	Regression coefficient (R^2)	Regression coefficient (R^2)	Regression coefficient (R^2)
F-1	0.9817	0.9066	0.9936	0.9711	0.9667	Peppas
F-2	0.9817	0.9066	0.9936	0.9719	0.6971	Peppas
F-3	0.9813	0.9119	0.9936	0.9714	0.9684	Peppas
F-4	0.9720	0.9219	0.9949	0.9807	0.9773	Peppas
F-5	0.9728	0.9149	0.9954	0.9799	0.9749	Peppas
F-6	0.9657	0.9464	0.9944	0.9880	0.9843	Peppas
F-7	0.9681	0.9524	0.9943	0.9822	0.9867	Peppas
F-8	0.9645	0.9649	0.9942	0.9842	0.9904	Peppas
F-9	0.9832	0.9105	0.9949	0.9725	0.9718	Peppas
F-10	0.9722	0.9240	0.9940	0.9799	0.9782	Peppas
F-11	0.9811	0.9220	0.9948	0.9742	0.9765	Peppas

3. RESULTS AND DISCUSSION:

In the present study, HPMC K4M, K15M, K 100M, HPC & Carbapol 934P which are commonly used in hydrophilic matrix drug delivery systems, have been employed to formulate floating sustained release tablets of Rosiglitazone maleate. Formulation with Carbapol retards the release of the drug because of its cross-linked polymeric nature with high molecular weight (~2 × 106 Da.) and viscosity and when contacted with water it would swell and hold the water inside its microgel network.

Evaluated data demonstrates again that the incorporation of Carbapol 934P has negative effect on the floating behavior of the delivery system. This can be explained by the moisture isotherm of Carbapol 943P which illustrates that Carbapol 934P has a much higher moisture absorption curve compared to cellulose based HPMC and HPC. The moisture gain for Carbapol 943P is significantly higher compared to moisture gain of HPMC (55% weight gain for Carbapol 934P verses ~ 33%for HPMC at RH of 95%). This results in a dramatic increase in the density of the GFDDS which in turn, shows a corresponding decrease in the floating capacity of GFDDS. After accelerated stability testing it was found that irrespective of concentration of polymer, these formulations are able to retain their stability for one month.¹⁸

In the present studies of dissolution given in the Table No.6 formulation of the batches 1,2,3,4 and 5 were shown the release of drug 63.69%, 64.5%, 65.65%, 61.60% and 64.38 at the end of 12 hours and 97.13%, 97.09%, 96.78%, 97.05% and 96.81% of drug at the end of 20 hours, respectively.

Further the result of dissolution studies of formulation batches 4, 6 and 7 composed of HPMC K4M and Carbapol 934P combination with different fillers showing release of drug 51.11%, 53.15%, 49.73% at the end of 12 hours and 91.59%, 93.12%, 93.88% at the end of 20 hours, respectively.

In further dissolution studies of formulations 9, 10 and 11 composed of HPC along with different fillers released the drug 62.43%, 65.55% and 62.45% at the end of 12 hours and 96.42%, 96.52 and 96.09% at the end of 20 hours, respectively.

3. CONCLUSION:

Overall, this study concludes that from all formulations, formulation 1 shown the highest release (best formulation) followed by 2, 3, 4, 5, 9, 10, 11, 6, 7, and 8 at the end of twenty hours. There was not significant difference in all the formulation batches despite different molecular sizes of polymers, the release of the drug was delayed to same extent, except the formulations with Carbapol 934P which was also observed by some other investigators where Carbapol 934P was found to compromise the release and floating property of GFDDS.¹⁸ Also there was no significant difference in the release of the drug with the different types of fillers. Fitting the in-vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.

4. ACKNOWLEDGEMENT:

The author would like to sincerely gratitude to the New Life Pharmaceuticals, Pune, India.Colorcon Asia Ltd., Goa, India, Dr.Reddy’s Laboratories, Hyderabad, India for providing all requirements for this project work. Also very thankful to all those who have help directly or indirectly to carry out the research work successfully.

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Received on 11.09.2009

Accepted on 10.11.2009

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Research Journal of Pharmaceutical Dosage Forms and Technology. 1(3): Nov. – Dec. 2009, 257-262