Oral administration is the most versatile, convenient and commonly employed route of drug delivery for systemic action [1]. Oral controlled release drug delivery have recently been of increasing interest in pharmaceutical field to achieve improved therapeutic advantages, such as ease of dosing administration, patient compliance and flexibility in formulation [2]. A controlled drug delivery system with prolonged residence time in the stomach is of particular interest for drugs that [1] are locally active in the stomach, [2] have narrow absorption window in gastrointestinal tract, [3] are primarily absorbed from stomach and upper part of GIT, [4] are unstable in the intestinal or colonic environment, [5] disturb normal colonic bacteria and [6] exhibit low solubility at high pH values [2,3]. The controlled gastric retention of solid dosage forms may be achieved by mucoadhesive systems that causes bioadhesion to stomach mucosa [2], floating systems, swelling and expanding systems, modified-shape systems, high density systems and other delayed gastric emptying devices [4]. Gastro retentive dosage form can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility of drugs that are less soluble in a high pH environment. Gastro retention helps to provide better availability of new products with suitable therapeutic activity and substantial benefits for patients [5]. Glipizide is selective second generation sulfonylureas used in the treatment of hyperglycemia. It is poorly soluble in acidic environment [6] and water, it is a weak acid (pKa = 5.9), and highly permeable (Class II drugs in accordance to Biopharmaceutics Classification System, BCS). The oral absorption is uniform, rapid, and complete; its bioavailability is nearly 100% and its elimination half-life is 2–4 hrs [7], thereby requiring two to three times daily dosing in large number of patients, which often leads to non-compliance.

The present study was aimed towards the development of controlled release gastro retentive floating tablets of glipizide based on effervescent technology. In this study, an attempt has been made to enhance the solubility of glipizide by the incorporation of accelerating agents such as dispersants, alkalising agents (hydrophilic electrolyte) in conjunction with hydrophilic swell able polymer such as hydroxypropylmethylcellulose and present it in the form of gastro retentive floating tablets to increase the efficacy and stability of the drug in the stomach, which will help to retain the dosage form in the stomach and to increase gastric residence time, resulting in prolonged drug delivery in stomach. The developed formulations were evaluated for various physico-chemical parameters. A formulation that combined excellent buoyancy and controlled release characteristics both were chosen for further evaluation of Gastric Retention Using X-Ray Imaging in rabbit for 5 hrs.

Materials

Glipizide was received as a gift sample from USV Ltd, Mumbai. Hydroxypropylmethylcellulose (HPMC K15M, HPMC K100M) were obtained as a gift samples from Colorcon Asia Pvt Ltd, Goa. Carbopol 940 procured from Corel Pharma Chem Ltd. Ahmedabad. sodium bicarbonate, PVP K30, anhydrous citric acid and all other ingredients used were of analytical grade.

Method

Preparation of glipizide floating tablets: Floating tablets containing glipizide were prepared by direct compression technique using varying concentrations of different grades of polymers with sodium bicarbonate and citric acid.

All the powders were accurately weighed and passed though an 80 mesh sieve (180 micrometer size). Then, except magnesium stearate all other ingredients were blended uniformly in glass mortar. After sufficient mixing of drug as well as other components, magnesium stearate was added, as post lubricant, and further mixed for additional 2-3 minutes. The blend was compressed into tablets having average weight of 330 mg using a single punch tableting machine ( Cadmach, India) fitted with a 10 mm round flat punches. The Glipizide Floating Tablets were compressed at 3 N compression forces. The compositions of all formulations are given in (Table 1) [8-10].

Table 1: Composition of Gastroretentive Floating Tablets of Glipizide (F1 to F7).

Precompression parameters

Prior to the compression, the formulation powder blends were evaluated for their bulk and tapped density and from these values compressibility index and Hausner ratio were calculated. While the flow properties of the powder bled were accessed from the angle of repose.

Evaluation of Floating Tablets

Post compression parameters: The prepared tablets were evaluated for quality control tests like weight variation, hardness, thickness, friability and content uniformity.

Weight variation: Ten tablets were selected randomly from each batch and weighed individually, calculating the average weight and comparing the individual tablet weight to the average. From this; percentage weight difference was calculated and then checked for USP specifications.

Hardness and friability: Hardness of tablet was determined by Monsanto hardness Tester. Ten tablets were randomly picked from each batch and analyzed for hardness. The mean and standard deviation were also calculated. Friability test was done by Roche friabilator. Ten tablets were weighed and were subjected to the combined effect of attrition and shock by utilizing a plastic chamber that revolve at 25 rpm dropping the tablets at distance of 6 in. with each revolution. Operated for 100 revolutions, the tablets were de-dusted and reweighed. The percentage friability was calculated.

Tablet Dimensions: Thickness and diameter of tablets were measured using a calibrated dial calliper. Three tablets of each formulation were picked randomly and dimensions determined. It is expressed in mm and standard deviation was also calculated [11].

Content uniformity test: The Glipizide floating tablets were tested for their drug content. Five tablets were finely powdered; quantities of the powder equivalent to 15 mg of Glipizide were accurately weighed and transferred to a 100 ml of volumetric flask. The flask was filled with 0.1N HCL (pH 1.2 buffer) solution and mixed thoroughly. The solution was made up to volume and filtered. Dilute 10 ml of the resulting solution to 100 ml with 0.1N HCL and measure the absorbance of the resulting solution at 276 nm using a Shimadzu UV-visible spectrophotometer. The linearity equation obtained from calibration curve was used for estimation of Glipizide in the tablet formulations [6,11].

In vitro buoyancy studies: The in vitro buoyancy was determined by floating lag time, as per the method described by Rosa et al. The tablets were placed in a 250 ml beaker, containing 200 ml of 0.1 N HCl. The time required for the tablet to rise to the surface and float was determined as Floating Lag Time (FLT) and the time period up to which the tablet remained buoyant is determined as Total Floating Time (TFT) [12,13].

Swelling study: The floating tablets were weighed individually (designated as W0) and placed separately in glass beaker containing 200 ml of 0.1 N HCl and incubated at 37°C ± 1°C. At regular 1-hr time intervals until 24 hrs, the floating tablets were removed from beaker, and the excess surface liquid was removed carefully using the tissue paper. The swollen floating tablets were then re-weighed (Wt), and % swelling index (SI) (Figure 2) was calculated using the following formula [13,14].

Figure 1: In vitro Buoyancy studies of IGF Tablet (F7).

Figure 2: Swelling Index of Gastroretentive Floating Tablets of Glipizide (F1 to F7).

SI (%) = (Wt – W0/ W0). 100

In vitro Dissolution Studies: The In vitro dissolution study was performed by using a United States Pharmacopeia (USP) type II (paddle) apparatus at a rotational speed of 100 rpm. Exactly 900 ml of 0.1 N HCl was used as the dissolution medium and the temperature was maintained at 37oC ± 0.5oC. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus at specified time interval for 24 hrs and the same volume was replaced with pre -warmed fresh dissolution media. The samples were filtered through a whatman filter paper and diluted to a suitable concentration with 0.1 N HCl. Absorbance of these solutions was measured at 276 nm using a UV spectrophotometer [15].

Curve fitting analysis: The mechanism of Glipizide release from the floating tablets was studied by fitting the dissolution data of optimized formulation (F7) in following models

1. Zero order

2. First order

3. Higuchi model

4. Korsemeyer and Peppas equation

Based on the slope and the R2 values obtained from the above models the mechanism of drug release was decided [16].

Evaluation of gastric retention using X-Ray imaging: Before starting the study, permission was taken from the institutional ethical board. (Institutional ethics committee, JN Medical College, Belgaum) For X-Ray Imaging test, tablet prepared by incorporation of the X-ray opaque material BaSO₄ was necessary to ensure visibility by X-ray. The X-ray imaging was performed in one healthy female Albino rabbit weighing 2.5 kg. In each experiment, an unanaesthetized animal was fasted for 24 hrs and the first X-ray was made to ensure the absence of radipaque material in the stomach (Figure 3). The tablet was administered by natural swallowing to rabbit followed by 50 ml of water. During the experiment the rabbit was not allowed to eat, but water was available. After the determined time intervals X-ray of the abdomen were taken using an X-ray machine from rabbit in a standing position. The distance between the source of X-rays and the object was the same for all imaging. This allowed us to see the tablet in the body of stomach, antrum and or pyloric part of the stomach so that observations of the tablet movements could be made. Gastric X-ray imaging was done at 30-min time intervals for a period of 5 hrs using an X-ray machine [13,17,18].

Figure 3: In vitro Drug release profile of formulations F1 to F7.

Figure 4: Evaluation of Gastric retention of IGF tablet (F7) using X-ray imaging.

Figure 5: In vitro drug release profile of optimized formulation F7 during stability studies at 40oC and 75% RH for one month.

Stability studies: The optimized formulation of Glipizide were packed in strips of 0.04 mm thick aluminium foil laminated with poly vinyl chloride by strip packing and these packed formulations were stored in ICH certified stability chambers (Thermo labs, Mumbai) maintained at 40οC and 75% RH for 1 month (zone III conditions as per ICH Q1 guidelines). The samples were withdrawn periodically and evaluated for their hardness, content uniformity and for in vitro drug release (Figure 3) [19].

In the present work, Glipizide an oral hypoglycemic agent used in the treatment of non insulin dependent diabetes mellitus (NIDDM: also called type 2), has been utilized as an active drug and considered to be good candidate for reducing dose frequency, for solid oral controlled release formulation as well as more compliance in diabetics. Glipizide is poorly soluble in water so an attempt has been made to improve the solubility of the drug by the incorporation of accelerating agents, such as dispersants, alkalising agents (hydrophilic electrolyte) in conjunction with hydrophilic swellable polymer such as hydroxypropylmethylcellulose and present it in the form of gastroretentive floating tablets to provide the desired controlled and complete release for prolonged period of time (Table 5).

Floating tablets of glipizide were prepared by dry blending of solubility modifier to modulate solubility of the active drug and varying concentrations of different grades of polymers with sodium bicarbonate and citric acid by direct compression technique.

Precompression Parameters

The results of precompression evaluation parameters are shown in (Table 2). All the precomression evaluation parameters were within the USP Pharmacopoeia limits.

Table 2: Pre-compression Parameters of Designed Formulations (F1 to F7).

Postcompression Parameters

The intragastric floating (IGF) glipizide tablets were off-white, smooth, and flat shaped in appearance. The results of physicochemical characterizations are shown in (Table 3). The thickness of IGF tablets was measured by calibrated dial calliper. Tablet mean diameter and thickness (n=3) were almost uniform in all the formulations and values for tablets ranged from 10.0 ± 0.002 to 10.0 ± 0.007 and 3.0 ± 0.156 to 3.1 ± 0.130 mm respectively. The standard deviation values indicated that all the formulations were within the range and show uniform thickness.

Table 3: Physical Characterization of Gastroretentive Floating Tablets of Glipizide.

The average weight of each formulation was recorded. The values were almost uniform and lie within the USP specifications. The values of tablets ranged from 329.5 ± 0.147 to 332.9 ± 0.178 mg. All the tablets passed weight variation test as the % weight variation was within the pharmacopoeia limits of ±5% of the weight.

The hardness of all formulations was in the range of 4.5±0.165 to 5.5 ± 0.196 kg/cm². The values of standard deviation indicate that the hardness of all the formulations were almost uniform and possess good mechanical strength with sufficient hardness.

The friability values of prepared tablets are given in (Table 3). The values ranged from 0.72 to 0.97%. All the values are below 1% indicating that the tablets of all formulations are having good compactness and showing enough resistance to the mechanical shock and abrasion.

The content uniformity was performed for all seven formulations. The percent drug content of tablets was found to be in between 97.17 to 100.71% of glipizide.

In vitro buoyancy studies: All the intragastric floating (IGF) tablet formulations were prepared by effervescent approach. On immersion in 0.1 N HCl, pH 1.2 solution at 37+0.5 °C all floating effervescent tablets float immediately and remain buoyant up to 24 hrs without disintegration. The in vitro buoyancy of IGF tablets was induced by sodium bicarbonate and anhydrous citric acid in optimized ratio (9:2) without compromising the matrix integrity with the possible shortest bouncy lag time and buoyancy duration of up to 24 hrs. It was observed that the gas generated was trapped in the tablet and protected within the gel formed by hydration of polymers, thus decreasing the density of the tablet below 1, and tablet becomes buoyant. The tablet swelled radially and axially during in vitro buoyancy studies. The IGF tablets F1 and F2 containing HPMC K15 and HPMC K100M respectively, without Carbopol 940, exhibited short buoyancy lag time of 114 sec and 120 sec but the total buoyancy time was less than 24 hrs. These might be due to rapid hydration of HPMC polymers which floated in short time as compared to IGF tablets containing Carbopol 940 polymer. The IGF tablets F3 and F4 containing Carbopol 940, HPMC K15 and HPMC K100M showed FLT of 131 sec and 137 sec respectively with TFT of 16 hrs. The Carbopol produces firm gel that entrapped the gas for longer time as compared to HPMC which has high rate of hydration. As the concentration of Carbopol 940 increases the FLT also increases. The formulation F5 and F6 showed the FLT of 144 sec and 150 sec respectively with TFT of 20 hrs. Among IGF tablets F1 to F7 (Table 6), the formulation F7 showed shortest buoyancy lag time (140 sec) with more total buoyancy time (24 hrs). (Table 4) shows the results of buoyancy study and (Figure 1) shows buoyancy character of prepared tablets.

Table 4: Floating Lag Lime and Total Floating Time of Designed Formulations.

Table 5: Swelling index of Gastroretentive Floating Tablets of Glipizide (F1 to F7).

Table 6: Cumulative Percent Drug Releases of Formulations F1 to F7.

Table 7: Kinetics of In vitro Release from Optimized Formulation F7.

Swelling study

Swelling is also a vital factor to ensure buoyancy and drug dissolution of the matrix tablet. The IGF tablets composed of polymeric matrices build a gel layer around the tablet core when they come in contact with water. This gel layer governs the drug release from the matrix tablet. Swelling ratio describes the amount of water that is contained within the hydrogel at equilibrium and is a function of the network structure, hydrophilicity and ionization of the functional groups.