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IntRJPharmSci
Research article
Formulation and Evaluation of Metformin HCl Floating Tablet using Pectin as a Natural Polymer Deb Jyotirmoy*1, Ghosh Amitava1, Sen Kumar Kalyan3, Prasenjit Paul4, Ananta Choudhury1 1Himalayan Pharmacy Institute, Majhitar, East Sikkim, Sikkim-737136, India 3Gupta College of Science and Technology, Asansole, West Bengal-713301, India 4Dr. Shri R. M. S. Institute of Science and Technology, Bhanpura, Madhya Pradesh-458775, India
ABSTRACT The present study outlines a systematic approach for design and development of pectin (a natural agent) loaded floating tablets of Metformin HCl to enhance the bioavailability and therapeutic efficacy of the drug. Floating tablet Metformin HCl have been shown sustained release there by proper duration of action at a particular site and are designed to prolong the gastric residence time after oral administration. Five batches of tablets were prepared by the wet granulation by using HPMCE15 (floating agent) and Pectin (obtained in nature) as polymers along with sodium bicarbonate as gas generating agent. The physicochemical properties of different formulations, their Buoyancy lag time and total floating time and swelling index were evaluated. It was found that the hardness of the tablets were effects the Buoyancy characteristic of the dosage form. All five formulations possessed good floating properties with total floating time between 8 – 12 hrs. The in vitro release studies indicated that the floating dosage forms containing pectin showed slower release. The cumulative % of in vitro drug release of formulation F1, F2, F3, F4, and F5 were 97.5%, 97.98%, 95.47%, 91.42% and 75.50%. Drug release to be enhanced by formulation F4 in compared with the marketed product. The results indicate that gas powered floating tablets of Metformin HCl containing 100mg Pectin provides a better option for sustained release action and improved bioavailability. Key words: Floating tablet, gastric residence; natural polymer, Buoyancy lag time
INTRODUCTION Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form. Oral route is considered most natural, uncomplicated, convenient and safe due to its ease of administration, patient acceptance, and cost-effective manufacturing process [1]. Pharmaceutical products designed for oral delivery are mainly conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption. In order to overcome the drawbacks of conventional drug delivery systems, several technical advancements have led to the development of controlled drug delivery system that could revolutionize method of medication and provide a number of therapeutic benefits [2]. Controlled drug delivery systems have been developed which are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of drug to a tissue. Controlled drug delivery or modified drug delivery systems are conveniently divided into four categories such as delayed release, sustained release, site-specific targeting, receptor targeting etc [3]. Oral controlled release drug delivery is a drug delivery system that provides the continuous oral delivery of drugs at predictable and reproducible kinetics for a predetermined period throughout the course of GI transit and also the system that target the delivery of a drug to a specific region within the GI tract for either local or systemic action [4]. All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of the mode of delivery (immediate sustained or controlled release) and the design of dosage form (solid, dispersion or liquid), must be developed within the intrinsic characteristics of GI physiology. Therefore the scientific framework required for
the successful development of oral drug delivery systems consists of basic understanding of (i) physicochemical, pharmacokinetic and pharmacodynamic characteristics of the drug; (ii) the anatomic and physiologic characteristics of the gastrointestinal tract and (iii) physicochemical characteristics and the drug delivery mode of the dosage form to be designed. Conventional oral controlled dosage forms suffer from mainly two adversities. The short gastric retention time (GRT) and unpredictable gastric emptying time (GET). A relatively brief GI transit time of most drug products impedes the formulation of single daily dosage forms. These problems can be overwhelmed by altering the gastric emptying time. Therefore it is desirable, to formulate a sustained release dosage form that gives an extended GI residence time [5-7]. It is evident from the recent scientific and patient literature that an increased interest in novel dosage forms that are retained in stomach for a prolonged and predictable period of time exists today in academic and industrial research groups. One of the most feasible approaches for achieving a prolonged and predictable drug delivery in the GI tract is to control the gastric residence time (GRT), i.e. gastro retentive dosage form (GRDF or GRDS). GRDFs extend significantly the period of time over which the drugs may be released. They not only prolong dosing intervals, but also increase patient compliance beyond the level of existing controlled release dosage form [8-9]. The stomach creates a barrier to the delivery of drugs to small intestine. A number of approaches have been used to increase the GRT of a dosage form in stomach by employing a variety of concepts. Floating Systems Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids and thus remain buoyant in the stomach for a prolonged period of time, without affecting the gastric emptying rate.
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Deb et al_______________________________________________________________________________________________________ISSN: 0976 – 5700
dessicator. A light brown coloured power was obtained after complete removal of moisture. The yield of crude pectin was 8g/kg. The phytoconstituents were identified by chemical tests, which showed the presence of various phytoconstituents mainly in the pet ether extract, chloroform extract, acetone extract, alcohol extract and aqueous extract [12-13]. Phytochemical examination Preliminary tests were performed to confirm the nature of mucilage obtained. The chemical tests that were conducted are: Ruthenium red test, Molisch test, test for reducing sugars and Ninhydrin test.
Fig.1: Anatomy of Stomach
While the system is floating on the gastric contents, the drug is released slowly at a desired rate from the system. After the release of the drug, the residual system is emptied from the stomach. This results in an increase in the GRT and a better control of fluctuations in the plasma drug concentrations. Floating systems can be classified into two distinct categories, non-effervescent and effervescent systems [10].
Excipient properties of pectin
EXPERIMENTAL
Formulation of floating tablet
Materials
Several suspending agents are available in the market. However, newer and better agents always come into the market and are evaluated routinely. Pectin has been previously proved to be effective as suspending agent for drugs like aluminium hydroxide. This study is an extension with Paracetomol, Ibuprofen and Nimesulide drugs [14].
Table 1 Composition of floating tablet of Metformin HCl
Natural polymer pectin was extracted from orange peel collected from Sikkim Himalayan Region. The pure drug Metformin HCl was obtained by Karanatak Antibiotices, Bangalore (Karnataka, India). HPMC-E15 floating agent obtained by Loba Chemie (Kerala, India). Magnesium Stearate was used as a lubricant obtained by Loba Chemie (Kerala, India). All other chemicals used were of reagent grade.
Ingredients
F1
F2
F3
F4
F5
Metformin HCl
500
500
500
500
500
HPMC- E15
50
100
-
-
50
Pectin
-
-
50
100
50
Citri acid
15
15
15
15
15
Sodium Bicarbonate
50
50
50
50
50
Talc
10
10
10
10
10
Magnesium Stearate
10
10
10
10
10
PVPK
75
75
75
75
75
Extraction and purification of pectin from orange peel Two distinctive water-soluble high-molecular-weight pectic polysaccharide materials that occur in orange peel have been extracted by using suitable solvent and studied in their chemical and rheological properties in our laboratory, namely, the well-known mucilage and a calcium-sensitive gelling fraction. Mucilage is present in the characteristic slimy fluid secreted by cladodes and fruits and it does not gel in the presence of calcium. Pectin of low degree of methoxyl occurs in the cell wall and can be extracted using a mild alkali process aided with a chelating agent. It shows remarkably good gelling properties in the presence of CaCl2 by a cooperative Ca2+ “eggbox” binding mechanism [11]. The orange peel were sliced, homogenised with ten times its weight of water and then heated at 800C for 10 minutes to inactivate any enzymes present and also to completely extract the active constituents into solvent. The heated solution was then filtered using a muslin cloth and the filtrate was centrifuged at 4000g for 15 mins and to obtain clear, viscous solution was added 3 volumes of ethanol to precipitate out the mucilage. It was then washed with diethyl ether to remove any impurities and the obtained cream coloured product was dried under vacuum in a
Buoyancy / Floating Test The time between introduction of dosage form and its buoyancy on the simulated gastric fluid and the time during which the dosage form remain buoyant were measured. The time taken for dosage form to emerge on surface of medium called Floating Lag Time (FLT) or Buoyancy Lag Time (BLT) and total duration of time by which dosage form remain buoyant is called Total Floating Time (TFT). Effect of hardness on Buoyancy Lag Time (BLT) or Floating Lag Time (FLT) Formulation F4 was selected to study the effect of hardness on buoyancy lag time. The tablets of batch F4 were compressed at
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Deb et al_______________________________________________________________________________________________________ISSN: 0976 – 5700 Table 2: Tablet density, Buoyancy lag time, total floating time
three different compression pressures to get the hardness of 5kg/cm2, 7kg/cm2 ,8kg/cm2and 9kg/cm2. The tablets were evaluated for Buoyancy Lag Time. The method followed is same as that of Buoyancy test [15].
Batch
Tablet density (gm/cc)
Buoyancy Lag Time (Sec)
Total Floating Time (hrs)
F1
0.93
32 sec
>8 hrs
F2
0.82
68 sec
>8 hrs
F3
0.89
24 sec
>12hrs
F4
0.99
40 sec
> 12hrs
F5
0.97
62 sec
>12hrs
In-vitro Dissolution Study USP Dissolution Apparatus: All the five formulation of prepared floating tablets of Metformin HCl were subjected to in vitro release studies these studies were carried out using dissolution apparatus, phosphate buffer (pH 6.8). In-vitro release studies were carried out using USP XXIII, paddle dissolution test apparatus. 900ml of phosphate buffer (pH 6.8) was taken in dissolution vessel and the temperature of the medium were maintained at 370C0.20C. The speed was 75 rpm. 1ml of sample was withdrawn at predetermined time intervals for 12 hours and same volume of fresh medium was replaced. The samples were analyzed for drug content against phosphate buffer (pH 6.8) as a blank at max 233 nm using U.V. spectrophotometer [16].
The density decreased due to this expansion and upward force of CO2 gas generation. This plays an important role in ensuring the floating capability of the dosage form. To provide good floating behavior in the stomach, the density of the tablets should be less than that of the gastric contents the density below (1.004g/cm3) than of gastric fluid. The density for the formulation were carried out and the results shown in Table 2 [17] . Buoyancy Study
Modified Dissolution Method 150ml capacity plastic bottle was modified by cutting the base of the bottle and securing tightly its mouth by means of cork: so that the bottle can hold 70ml of dissolution medium. A plastic tube was inserted into the mouth of the bottle such that the medium comes out from the end of the tube at a rate of 2ml/min. the reservoir containing dissolution medium was mounted at a level higher than the dissolution assembly, so as to deliver the medium at the same flow rate. The modified assembly was placed into the dissolution Metformin HCl floating tablet was introduced in the modified bottle containing 70ml of SGF. When the tablets floated, the contents were stirred at a speed of 75 rpm using USP apparatus without the wire mesh. Temperature of the dissolution medium was maintained at 37±0.5oC. In order to maintain sink condition for study, SGF was added at rate of 2ml/min to 70ml of dissolution medium, simultaneously withdrawing 2ml/min from the bottom outlet. The modified dissolution assembly is shown in plate 2. aliquots were filtered, diluted with SGF to obtain concentration of 20 µg/ml and its absorbance measured spectrophotometrically at 233nm to determine drug release [16].
On immersion in phosphate buffer (pH 6.8) at 370C, the tablets floated, and remained buoyant without disintegration. The results of Buoyancy study shown in (Table 2) and Fig.6 to Fig.7 shows Buoyancy character of prepared tablet. From the results it can be concluded that the batch containing only HPMC polymers showed good Buoyancy lag time (BLT) and Total floating time (TFT). Table 3: Physicochemical properties of Tablets of Batch F1 to F5
Batches
Diameter (mm)
Thickness (mm)
Hardness (Kg/cm2)
Friability (%)
Weight Variation (mg)
Drug content uniformity (mg)
F1
9.09 0.040
5.16 0.010
4.50.47
0.96
800.65 1.29
97.01
F2
9.08 0.006
5.14 0.012
5.40.32
0.72
801.50 1.74
99.5
F3
9.09 0.067
5.12 0.06
7.10.54
0.91
799.55 1.18
98.01
F4
9.08 0.070
5.16 0.011
8.30.42
0.86
800.05 1.37
97.4
F5
9.08 0.056
5.18 0.012
9.10.35
0.79
801.65 1.49
98.4
Comparison with conventional marketed product The promising formulation was compared with marketed product (Glyciphage) formulation by checking various physicochemical parameters. Determination of floating behavior Tablet density When tablet contacts the test medium, tablet expanded (because of swellable polymers) and there was liberation of CO2 gas (because of effervescent agent, NaHCO3).
Formulation F4 containing HPMC-E15 showed good BLT of 40 sec, while the formulation containing pectin alone showed highest BLT, and TFT of more than12 hrs. This may be due to the amount of polymer and gas generating agent, which were kept constant in the present study. The gas generated cannot be entrapped inside the gelatinous layer, and it escapes leading to variation in BLT and TFT [17-18].
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Deb et al_______________________________________________________________________________________________________ISSN: 0976 – 5700 Table 4: Swelling index of tablets of batch F1 to F5 Swelling index (%) Time
The experimental design supported product development and optimization procedure yielded the desired floating tablet of Metformin HCl with drug release equivalent to those of the marketed single unit Metformin hydrochloride, and may be used for effective management of NIDDM.
F1
F2
F3
F4
F5
1 hr
41
36
35
32
30
ACKNOWLEDGEMENT
2 hrs
51
46
42
39
41
3 hrs
62
56
49
41
46
4 hrs
73
64
57
49
54
We thank Karnata antibiotic laboratory for the generous gift of Metformin hydrochloride. We also thank Chairman and Principal, Dr. Shree R. M. S. Institute of Science and Technology (College of Pharmacy), Madhya Pradesh, India, for providing infrastructure facilities for the research work.
5 hrs
90
77
68
56
60
Stability studies Stability studies of the prepared formulations were performed at ambient humidity conditions, at room temperature, at 40oc and 4oc a period up to 30 days. The samples were withdrawn after periods of 7 days, 15 days and 30 days and were analyzed for its appearance, hardness, friability, floating test, drug cont and in vitro release [19].
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RESULTS AND DISCUSSION Apparent tablet density of all samples showed below (1.004g/cm3) than of gastric fluid. The density decreased due to this expansion and upward force of CO2 gas generation. This plays an important role in ensuring the floating capability of the dosage form. To provide good floating behavior in the stomach, the density of the tablets should be less than that of the gastric contents.
Fig: 6
Fig: 7
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Fig: 7- showing TFT
Fig: 8- showing floating behavior
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CONCLUSION
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i
*Corresponding author Deb Jyotirmoy Himalayan Pharmacy Institute, Majhitar, East Sikkim, Sikkim-737136, India Email:
[email protected]
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