Application on Metformin Hydrochloride

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Current Drug Delivery, 2013, 10, 336-342

Development of Novel Floating Delivery System based on Psyllium: Application on Metformin Hydrochloride Mahalaxmi Rathnanand, Rajkiran Narkhede, N. Udupa and Atin Kalra* Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India Abstract: psyllium, a medicinally active gel forming natural polysaccharide and a dietary fiber has been used as a medicine in myriad of conditions such as constipation and inflammatory bowel syndrome. One of its more recent uses that have received attention has been its ability to reduce blood sugar levels in diabetics. Therefore present work is an attempt to formulate anti diabetic drug Metformin as a controlled release floating delivery making use of pysllium as release retardant and to assist the drug in stabilizing blood sugar level in type II diabetics. Drug and excipients compatibility studies were monitored by thermal analysis using differential scanning calorimeter (DSC) and Fourier transform infra red (FTIR). The DSC thermogram and FTIR of drug and drug-polymer mixture did not reveal any incompatibility. psyllium was tried in different concentrations along with other polymers like HPMC K15M and carbopol 940 to achieve the desired release profile. The total drug: polymer ratio was kept between 1:0.4 to 1:0.5, and different polymer combinations were tried to achieve desired drug release for 12 hours. The prepared tablets were evaluated for in vitro release studies and floating behavior. Our conclusion from the present study indicated that pysllium could potentially be used in conjunction with other polymers to formulate controlled release formulations of anti-diabetic drugs to provide better control over blood glucose levels.

Keywords: psyllium, Metformin hydrochloride, Floating drug delivery. INTRODUCTION Diabetes is a metabolic disorder characterized by high blood glucose either due to less production of insulin or because cells do not respond to the insulin that is produced. Over the years there has been considerable success in diabetic research, whether it’s the development of novel molecules like incretin mimetics or non-invasive delivery of insulin, last decade has seen it all and there has been plethora of strategies like these to better the management of diabetes. One of them has been the use of dietary fibers that have emerged in the past as a factor in the nutrition that appears to have complex physiological and clinical implications [1]. Dietary fiber pysllium has been reported as a medicinally active gel forming natural polysaccharide. It has been used in traditional medicine for the treatment of constipation, diarrhea, inflammatory bowel diseases and colon cancer. Their ability to reduce blood sugar levels and low density lipoproteins (LDL) have found use to compliment drug therapy in the management of diabetes and thus have the potential to reduce the chances of disease advancing to other complications like Coronary Heart Disease (CHD) in diabetics [2-4]. psyllium is the common name used for several members of the plant genus Plantago and its seeds are commercially used for the production of mucilage, a white fibrous material of hydrophilic nature which forms a clear colorless mucilaginous gel by absorbing water. The gel forming nature and *Address correspondence to this author at the Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India; E-mails: [email protected]; [email protected]

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composition of the polysaccharides extracted from the seeds of the Plantago ovata has been well reported [5] and this very property has been used to develop controlled release drug delivery systems [6]. One study involved development of ofloxacin gastroretentive tablets containing blend of pysllium and other release retarding polymers and evaluated for in vitro and in vivo studies [7]. Studies involving understanding the release mechanism and diffusion coefficient of the model drugs salicylic acid and tetracycline hydrochloride from the polymeric matrix of psyllium based hydrogels revealed non-fickian release from the hydrogels [1]. In the present study metformin hydrochloride (MF) that acts by lowering the amount of glucose absorbed from intestine was formulated as bilayered gastroretentive tablet comprising immediate release and controlled release layer. The need for the same has been supported by numerous studies, including the one involving the effect of metformin on intestinal glucose absorption in the perfused rat intestine [9]; and pre-clinical evaluation of pharmacokinetic and pharmacodynamics rationale for oral control released (CR) metformin [10]. Thus, over the years there has been many studies to better the delivery of metformin hydrochloride in order to achieve an optimal therapy. These efforts include development of sophisticated gastroretentive systems like microcapsules prepared by solvent evaporation technique [11] and floating beads of metformin using gelucire [12]. Another study reported formulation of single unit floating tablet of MF by using various grades of low density polymers having various grades of low density polymers has also been reported [13]. Recently o-carboxymethyl chitosan nanoparticles of MF were formulated for preferential deliv© 2013 Bentham Science Publishers

Development of Novel Floating Delivery System based on Psyllium

Current Drug Delivery, 2013, Vol. 10, No. 3

ery to pancreatic cancer cells for treating pancreatic cancer [14]. In addition to other excipients, tablets in present study were formulated with Pysllium as a release controlling polymer and as an agent that could mitigate some of the side effects related to metformin therapy like bloating, diarrhea and also to delay the absorption of carbohydrate that could help the diabetics to better the management of disease [8].

The compositions of the tablet formulations (F1-F7) are given in (Tables 1, 2). Table 1.

MATERIALS AND METHODS Materials Metformin hydrochloride and Polyvinyl pyrrolidine K-30 (PVP K 30) were kindly gifted by Panacea Biotech Pvt. Ltd., Lalaru, India. psyllium husk was purchased from local pharmacy shop. HPMC K15M was obtained as gift sample from Zydus research centre, Ahmadabad, India. Lactose and purified talc were purchased from E. Merck., India Ltd. All other ingredients were of analytical grade. Methods

337

Composition of Immediate Release layer for F1-F7

Ingredients

Quantity (mg)

Metformin HCl

264

Starch Soluble (5.0 %)

13.2

Polyvinyl pyrrolidone K 30

q.s.

Magnesiun. Stearate

1%

Talc

1%

Flow Properties The flow properties of prepared granules were characterized in terms of angle of repose, Carrs index and Hausner ratio.

Tablet Formulation

Drug-Excipient Compatibility Studies

psyllium husk was purchased from local pharmacy. It was dried in oven at 50 oC for 2 hours. Then it was transferred into mixer-grinder and grinded for 15 min. The powdered husk was passed through sieve no 80. The husk retained onto the sieve was discarded and passed quantity was used to formulate the dosage form.

Drug excipient studies were carried out using Differential Scanning Calorimetry (Operating software TA 60, Shimadzu corporation, Japan).

Metformin bilayered tablets were prepared by wet granulation method, using PVP K30 in isopropyl alcohol (10% solution) as granulating agent. Drug and excipients were blended together in a mortar, and sufficient quantity of PVP solution was added to form a dough mass. This mass was then passed through sieve no. 12 to obtain raw granules, which were then dried in a oven at 50oC for 30 min. After drying, the granules were passed through sieve No. 22 superimposed on sieve No. 44. Then 22/44 fraction was then blended with magnesium stearate and talc (1% w/w each). For the preparation of the two-layered tablets, the die of the tableting machine was filled with granules of sustained release layer and a precompression was done followed by filling of the immediate release granules, and then compressed to the final tablet.

Table 2.

Evaluation of Floating Tablets The prepared tablets were evaluated for uniformity of weight using 20 tablets and percentage deviation calculated. Hardness (Monsanto type) and friability was calculated using 10 tablets (roche type friabilator). Optimised formulation was subjected to swelling index study. The in vitro dissolution study was carried out using USP II (Paddle) dissolution apparatus. The study was carried out in 900 ml of 0.1N HCl for the total duration of 12 hours. The dissolution medium was maintained at 37±0.5 o C. The preweighed tablet was then introduced into the dissolution jar and the paddle was rotated at 75 rpm. At pre-determined time intervals, 5 ml sample was withdrawn, filtered and analyzed spectrophotometrically at 233 nm for the drug release. To maintain sink conditions 5 ml of corresponding medium was replaced into the dissolution flask. In vitro buoyancy was determined by floating lag time. Floating behavior of the tablets studies were performed in a

Composition of Sustained Release Tablet Formulations.

Ingredients (mg)

F1

F2

F3

F4

F5

F6

F7

Metformin HCl

570

570

570

570

570

570

570

psyllium husk

230

180

-

180

194

210

215

HPMC K15M

-

50

230

20

20

20

20

Carbopol 940

-

-

-

30

30

30

30

Sodium Bicarbonate

60

60

60

60

60

60

60

PVP K 30

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

338 Current Drug Delivery, 2013, Vol. 10, No. 3

Rathnanand et al.

Fig. (1). Theoretical release profile.

USP II (Paddle) apparatus at a speed of 75 rpm in 900 ml simulated gastric fluid (SGF, pH 1.2, no enzyme) at 37±0.5 oC for 24 hrs to mimic in vivo conditions. Parameters like floating lag time and relative matrix integrity were determined. The latter parameter was determined on the basis visual inspection. For determination of drug content, tablets were individually crushed and powder was dissolved in 50 ml of 0.1 N hydrochloric acid (HCl). After sonication the solution was filtered through 0.45 microns membrane filter, analyzed spectrophotometrically at 233 nm after sufficient dilution with 0.1 N HCl. Swelling index study was carried out for optimized formulation (Fig. 5) by taking initial weight of tablet (W1) and placing the table in glass beaker containing 200 mL of 0.1 N HCl at 37°C±1°C. After every one hour (till twelfth), tablet was removed from beaker and the excess surface liquid was removed carefully using the paper. The swollen tablet was then re-weighed (W2), and swelling index (SI) was calculated using the following formula: SI = (W2-W1)/ W1 RESULTS AND DISCUSSION Drug Excipient Compatibility DSC thermogram revealed sharp melting endothermic for metformin at 230.70°C, corresponding to its melting point/ transition temperature. There was no appreciable change observed in the melting endotherms of the physical mixture (metformin and excipients) compared to pure drug, indicating absence of any interaction between drug and excipients used in the formulation. FTIR spectrum of drug-excipients combination did not produce major shift in principal peaks, indicating no interaction (Figs. 2, 3). Flow Properties Pure drug showed higher values for flow properties indicating poor flow. After granulation all the formulations showed superior flow properties (Table 3).

Evaluation of Prepared Tablets Weight of the tablet varied between 825-840 mg/ tablet with low deviation indicating uniformity of weight. Tablets from different formulations showed hardness in the range of 9.4-9.8 kg/cm indicating good mechanical strength. The friability of prepared tablets was below 1% complying to pharmacopeia requirements. All formulations passed the USP requirement in terms of weight variation and drug content (Table 4). During formulation development, the ingredients were selected on the basis of sequential approach for achieving sustained drug release for twelve hours. In addition to pysllium other polymers used were methocel K15M and carbopol 940, both having high viscosity and ability to swell. Floating drug delivery is based on the swelling property and density of polymers. Other factors that play pivotal role is the concentration of a gas generating agent in the delivery system [15]. In the present study sodium bicarbonate was used as gas generating agent and its concentration of 60 mg was kept constant for all the formulations after finding this concentration to be optimal during initial trials. Sodium bicarbonate reacts with gastric fluids and produces carbon dioxide which is entrapped into the matrix providing buoyancy to the formulation. Drug release from the controlled release floating unit was designed considering two main requirements namely amount of drug released at the end of 30 minutes and ability of the formulation to provide sustained drug release for twelve hours [16]. Formulation F1, which contained pysllium alone as a release retarding polymer failed to control drug release and most of the drug was released within half an hour exhibiting significant burst release. Matrix integrity was not maintained beyond eight hours, and system failed to achieve desired drug release profile. Theoretically, immediate release dose should be released within half an hour, which is 31 % of total drug present in the formulation (Fig. 1). Possible explanation that could be attributed to this



Fig. (2). DSC curves (A)- Metformin HCl, (F)- Formulation F 1, (G)- Formulation F6 and (H)- Formulation F7.

Fig. (3). Infra-red spectrum of pure drug (A), formulation F 1 (B) and formulation F 6 (C). Table 3.

Flow Properties of Pure Drug and Prepared Granules.

Sample

Angle of Repose (°)

Carr’s Index (%)

Hausner’s Ratio

Pure Drug

41.980±2.13

31.699±1.88

1.465±0.48

F1

25.906±1.79

12.704±1.64

1.146±0.65

F2

27.14±1.88

12.550±2.10

1.140±0.43

F3

28.270±0.29

13.336±1.67

1.154±0.22

F4

25.345±0.55

10.566±1.78

1.118±0.53

F5

26.940±1.33

13.394±1.10

1.155±0.45

F6

28.033±1.45

13.479±1.22

1.156±0.76

F7

28.193±2.46

14.648±2.20

1.172±0.25

339


Rathnanand et al.

Fig. (4). Comparative evaluation of formulation F1-F7.

Fig. (5). Swelling index study for formulation F6.

burst release (Fig. 4) is the lag time before the pysllium could swell and control the high solubility of metformin in dissolution media. Therefore, in addition to pysllium which takes time to swell, other polymers like methocel (K 15 M) which swells faster was used in subsequent formulations. Therefore, F2 was developed containing equal proportion of pysllium and methocel (K 15 M). This formulation exhibited lesser burst release and maintained matrix integrity for a period of 12 hours (Fig. 4), however the release profile was more than the theoretical release profile. Formulation F3 contained only methocel (K 15 M) to ascertain whether slow gelling property of pysllium was contributing towards the burst release. As expected drug release profile for F3 was comparable to earlier formulations (Fig. 4), thus requiring inclusion of another polymer that could swell faster than both psyllium and methocel (K 15 M).

Formulation F4 was developed keeping total drug: polymer ratio constant and replacing part of total methocel (K 15 M) with carbopol 940 which swells faster. Inclusion of this carbomer which readily absorbs water and swell showed significant control over burst release as compared to earlier formulations better control. Carbomers like carbopol 940 readily absorb water, get hydrated, and swell. Release pattern of formulation F4 (Fig. 4) suggested, thus the proportion of methocel K 15 M and carbopol was kept constant and proportion of pysllium husk was increased in the subsequent formulations. In addition to its hydrophilic nature, its crosslinked structure, and its insolubility in water makes carbopol a potential candidate for use in controlled drug delivery systems [17].


Table 4.


Results of Post Compression Tests for Formulated Tablets.

Formulations

Thickness (mm)

Hardness (Kp)

% Friability

Weight Variation (%)

% Drug Content

F1

0.65

9.4±1.1

0.46±0.23

0.423

99.31±2.67

F2

0.6

9.6±0.8

0.42±0.12

0.685

99.92±2.30

F3

0.62

9.7±1.5

0.54±0.21

0.370

100.05±2.22

F4

0.68

9.7±1.3

0.36±0.14

0.146

99.61±1.80

F5

0.7

9.8±0.7

0.31±0.18

0.273

99.43±2.65

F6

0.65

9.9±0.9

0.39±0.12

0.194

99.04±1.45

F7

0.66

9.6±1.1

0.46±0.14

0.088

98.10±2.10

Table 5.

341

Release Kinetics for F6. First Order

Zero Order

Higuchi

Korsmeyer and Peppas

R2

R2

R2

R2

n

0.9742±0.0009

0.8404±0.0089

0.9894±0.0068

0.997±0.067

0.331±0.059

Formulation

F6

Table 6.

Floating Behaviour Study of Formulations.

Parameter Floating lag time (min) Matrix integrity (hr)

F1

F2

F3

F4

F5

F6

F7

8

7

7.5

6.5

7

6.5

5

< 10

> 24

> 24

> 24

> 24

> 24

> 24

Formulation F5 contained drug: pysllium in ratio of 1:0.225, and total drug:polymer ratio of 1:0.425 while formulation F6 was having the respective ratios of 1:0.25 and 1:0.50. Release data of both F5 and F6 showed control over burst release (Fig. 4), but F6 complied more with theoretical release profile. The effect of concentration of pysllium on drug release is quite evident and F7 contained the maximum psyllium when compared to formulations (F2-F7), however data obtained (Fig. 4) indicated reduced drug release which could be attributed to increased diffusional pathway and it was concluded that the amount of psyllium added in F6 is the highest that could be added in present circumstances. From the preceding discussion it could be inferred that psyllium took more time to swell when compared to polymers like methocel and carbomer 940, thereby not able to control initial drug release and thus requires addition of other polymers to control the drug release. However with the passage of time it swells and forms a diffusional barrier thereby controlling the amount of drug released as the dissolution study progressed thereby implying the role of methocel and carbopol 940 in controlling the initial burst release and psyllium sustaining the drug release for the required time period. After studying the release kinetics, formulation F6 showed good correlation coefficient for korsmayer-peppas and Higuchi models, with higher values for korsmayer-peppas model indicating that erosion and diffusion both contributes to drug

release. Diffusion exponent from Korsmeyer and peppas indicates quassi fickian diffusion (Table 5). All formulations (except F1) floated for more than 10 hrs (Table 6) on the simulated gastric fluid USP, thus achieving the important parameter for absorption of metformin hydrochloride. CONCLUSION The present work involved development of floating unit of metformin hydrochloride making use of release retarding property of psyllium. In vitro evaluation of formulation containing blend of psyllium and other release retarding polymers (methocel & carbopol 940) controlled drug release for 12 hrs. All the formulations complied with compendial requirements for friability, weight variation and drug content. Except for formulation F1, all the formulations floated for more than 12 hrs. Among all the formulations prepared, F6 complied with theoretical release profile the most. Present study was an attempt to explore the feasibility of developing dosage forms formulated with excipients having multiple functions that could better the management of chronic diseases like diabetes which require more than pharmacological intervention to achieve optimum clinical outcomes while simultaneously addressing the pharmacokinetic shortcomings of drugs like metformin hydrochloride.


Rathnanand et al.

CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.

[7]

ACKNOWLEDGEMENTS

[8]

The authors are grateful to Novo Nordisk India for financial assistance and IR & DSC facility provided by Department of Science and Technology, New Delhi and Manipal University is duly acknowledged.

[9]

[10]

PATIENT CONSENT Declared none.

[11]

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Received: October 20, 2012

Revised: November 02, 2012

Accepted: February 01, 2013

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