Abstract

The present study outlines a systematic approach for designing and development of Glipizide floating tablets to enhance the bioavailability and therapeutic efficacy of the drug. Floating tablets of Glipizide have shown controlled release thereby proper duration of action at a particular site and are designed to prolong the gastric residence time after oral administration. Different formulations were formulated by wet granulation technique using HPMC K100M (floating agent) and Xanthan gum as polymers along with sodium bicarbonate as gas generating agent. The formulations were evaluated for their physicochemical properties, buoyancy lag time, total floating time, swelling index and in­vitro drug release. It was found that the hardness of the tablets affects the Buoyancy characteristic of the dosage form. All nine formulations possessed good floating properties with total floating time between 8 – 12 hrs.

Introduction

I. INTRODUCTION

Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. Several difficulties are faced in designing controlled release systems for better absorption and enhanced bioavailability. One of such difficulties is the inability to confine the dosage form in the desired area of the gastrointestinal tract. Drug absorption from the gastrointestinal tract is a complex procedure and is subject to many variables. It is widely acknowledged that the extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal mucosa.Thus, small intestinal transit time is an important parameter for drugs that are incompletely absorbed. Basic human physiology with the details of gastric emptying, motility patterns, and physiological and formulation variables affecting the cosmic emptying are summarized.

Gastroretentive systems 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 for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patient.

Glipizide is an anti-diabetic drug4 which cures the type II diabetes and with narrow therapeutic index. The recommended adult dose is 5 mg twice daily (or) 10mg once daily, due to the low bioavailability and short biological half-life (4 hours) of Glipizide following oral administration favors development of a controlled release formulation. It also leads to reduction in frequency of dosing & drug toxicity which in turn improve patient compliance. The gastro retentive drug delivery systems 5 can be retained in the stomach and assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract. These systems help in continuously releasing the drug before it reaches the absorption window, thus ensuring optimal bioavailability. Glipizide is taken because the absorption of drug is in the stomach. In the present investigation floating tablets of Glipizide were prepared by effervescent approach using two different grades of hydroxyl propyl methyl cellulose polymers . The aim of the work was to evaluate the effect of polymers on floating properties and release characteristics of Glipizide tablets.

II. MATERIALS AND EQUIPMENTS

A. List of Materials and Supplier

Glipizide (Supra Chemicals,Thane ). HPMC K100M (Yarrow Chem Products, Mumba). Xanthan gum( Loba chemicals, Mumbai, India). Sodium bicarbonate (Research Lab Fine Chem Industries, Mumbai). PVP k3 ( Research Lab Fine Chem Industries, Mumbai). Microcrystalline cellulose ( Research Lab Fine Chem Industries, Mumbai). Talc (Research Lab Fine Chem Industries, Mumbai). Magnesium stearate (Research Lab Fine Chem Industries, Mumbai).

B. List of Equipment and Manufacturer

Electronic Weighing Balance (Shimadzu, Mumbai )(Model: AU220) Rotary tablet compression machine( Karnavati Engineers Pvt. Ltd, Mumbai) (Model: MINI PRESS- II MT). UV Spectrophotometer ( Jasco, Japan) (Model: V-530 &V-630). FTIR Spectrophotometer (Shimadzu, Japan) (Model: FTIR- 8400$). Differential Scanning calorimeter ( Mettler Tolendo, Mumbai) (Model: Stare SW 920). USP Tablet Dissolution Apparatus (Electro lab, Mumbai) (Model: TDT-06P). Tap density tester( Labinda, Mumbai) (Model: TD1025). Roche friability tester( Labinda, Mumbai) (Model: FT1020). Hardness tester ( Labinda, Mumbai) (Model: TH 1050 M). pH Meter( Labinda, Mumbai) (Model: GMPH).

C. Diabetes Mellitus

Diabetes mellitus is an endocrinological and/or metabolic disorder with an increasing global prevalence and incidence. High blood glucose levels are symptomatic of diabetes mellitus as a consequence of inadequate pancreatic insulin secretion or poor insulin- directed mobilization of glucose by target cells. Diabetes mellitus is aggravated by and associated with metabolic complications that can subsequently lead to premature death.

D. Glipizide

An oral hypoglycemic agent, is one the most commonly prescribed drugs for the treatment of patients with type II Diabetes mellitus . It is practically insoluble in water. Glipizide has relatively short elimination half-life (2-4 hrs), there by requiring twice daily dosing in large number of patients, which often leads to non compliance. Thus there is strong clinical need and market potential for a dosage form that will deliver glipizide in a sustained manner to a patient needing this therapy, thereby resulting in a better patient compliance.

Glipizide belongs to a class II of Biopharmaceutical Classification System (BCS) having low water solubility which is rate limiting step in absorption of drug in GI tract. Very few researchers have tried to resolve the poor solubility of drug, which could hamper its release from compressed hydrophilic matrices. Hence there is strong need to explore new technique to enhance its solubility. To avoid the problem of solubility previous researchers use trimethylamine as a solubility modifier.

???????E. Method Of Preparation

1. Wet granulation
2. Direct compression
3. Dry granulation

???????III. PREFORMULATION STUDY OF GLIPIZIDE

1. Organoleptic Properties: The obtained sample was examined for its appearance, color and odor and observations are reported.
2. Solubility: The solubility of compound was determined methanol, water.
3. Melting Point: Melting point of the glipizide was determined by open capillary tube method using Thiele’s tube. One sided closed capillary filled with drug attached to graduated thermometer and put into the Thiele’s tube contains paraffin oil and constant heat was supplied to the assembly. Temperature was noted at which solid drug changed into liquid. The melting point is reported.
4. UV-Visible Spectroscopy: The Glipizide was dissolved in methanol, was scanned between 200-400 nm to determine its absorption maxima. The UV spectrum of glipizide.
5. Fourier Transform Infrared (FTIR) spectral Analysis: The compatibility of drugs and excipients used under experimental condition were studied. The study was performed by preparing KBr pellets with the help of KBr press taking 1 mg sample in 100 mg KBr. The scanning range was 400 to 4000 cm-1 and there solution was 1cm-1.
6. Calibration curve: Preparation of Acid buffer pH 1.2

a. Preparation of 0.2 M Potassium Chloride: 0.2 M potassium chloride was prepared according to IP 1996. A quantity of 14.9 grams of potassium chloride was dissolved in water and make up the volume to 1000 ml using water.

b. Preparation of 0.2 M HCL: 0.2 M HCL prepared by diluting 17 ml of conc. Hcl in to water and make up the volume to 1000 ml using water.

c. Preparation of Acid buffer pH 1.2: The acid buffer pH 1.2 prepared according to IP 1996 by mixing 50 ml of 0.2 M potassium chloride and 85 ml of 0.2 M HCL and make up the volume to 200 ml using water.

7. Preparation of phosphate buffer pH 7.4

a. Preparation of 0.2 M Potassium Dihydrogen Phosphate: 0.2 M potassium dihydrogen phosphate was prepared according to IP 1996. A quantity of 27.2 grams of potassium dihydrogen phosphate was dissolved in water and make up the volume to 1000ml using water.

b. Preparation of 0.2 M NaOH: 0.2 M NaOH prepared by dissolving 8 grams of NaOH in to water and make up the volume to 1000 ml using water.

8. Preparation of Stock Solution: Weighed accurately 10 mg of glipizide , transfer it to 100 ml volumetric flask, add Acid buffer pH 1.2 or Phosphate buffer pH 7.4 sonicated to dissolve Glipizide. Filtered this solution through 0.45 micron membrane filter (Whatmann filter paper) to get clear solution. Concentration of stock solution is 100 microgram per ml.

9. Preparation of Working Solution: From prepared stock solution pipette out 1, 2, 3, 4, 5 and 6 ml transfer to 10 ml volumetric flask and make the volume up to 10 ml with acid buffer pH 1.2 or Phosphate buffer pH 7.4 to get 10, 20, 30, 40 50 and 60 microgram per ml concentration of Glipizide. Measured the absorbance at 274 nm by using UV spectrophotometer. Plotted curve of concentration vs absorbance.

10. Differential Scanning Calorimetry: The DSC thermo gram of glipizide was carried out to confirm its purity. The DSC thermo gram was recorded on Differential Scanning Calorimetry. Glipizide was heated in crimped aluminum pan with a pierced lid at a scanning rate of 100C/min in an atmosphere of nitrogen flow (40mL/min) in the range of 30 to 250oC. DSC thermo gram of Glipizide are depicted.

11. Drug-Excipient Compatibility Study: The drug and excipient compatibility study of selected tablet of formulations performed by FTIR and DSC

???????IV. FORMULATION OF GLIPIZIDE FLOATING TABLETS

A. Design of Factorial Batches

A 32 factorial design was implemented for optimization of gastro retentive floatingtablet formulation of Glipizide. According to the model it contained 2 independent variables at 3 levels- +1, 0 and -1. According to model, total nine formulations are possible, the composition of different formulation are shown in Table 3. The different independent variables were- concentration of HPMC K100M(X1) and concentration of Xanthan gum (X2). Dependent factors included floating lag time (Y1), swelling index (Y2) and in-vitro drug release(Y3).

Table 1: Factorial design for preparation of batches F1-F9.

Table 2: Translation of coded value in actual unit.

B. Preparation of Factorial Batches

Floating tablets are formulated as per Table 3. Floating tablets containing Glipizide are prepared by Wet granulation technique using varying concentrations of different grades of polymers. All the ingredients are accurately weighed and passed through different mesh sieves accordingly. Then, exceptmagnesium stearate and talc all other ingredients are blended uniformly in glass mortar. After sufficient mixing of drug as well as other components, magnesium stearate and talc is added, as post lubricant, and further mixed for additional 2-3 minutes. The prepared powder blend was evaluate for pre- compression properties. 200 mg of powder blend is weighed and compression into 12mm size punches by using a rotary punch tablet compression machine (Kamavati MINI PRESS- IIMT). The weight of tablets is kept constant for all formulation. After compression, the tablets were evaluated for post compression parameters.

???????V. EVALUATION OF FACTORIAL DESIGN FORMULATIONS

A. Evaluation of Pre-compression Parameters of Powder Blend-

1. Bulk Density
2. Tapped Density
3. Hausner’s Ratio
4. Compressibility Index
5. Angle of Repose

B. Evaluation of Post-compression Parameters of Formulated Batches-

1. Floating Duration
2. Weight Variation Test
3. Hardness Test
4. Tablet Thickness
5. Friability Test
6. Drug Content Determination
7. In-vitro Dissolution Study

??????????????

Conclusion

One of the most feasible approaches for achieving a prolonged and predictable drug delivery profiles in the gastrointestinal tract is to control the gastric residence time using gastrorententive dosage forms that will provide us with new and important therapeutic options. Glipizide gastroretentive effervescent floating tablets were prepared with an aim to provide the drug for prolonged period of time in the stomach. Glipizide was targeted to stomach because it has the absorption window in upper part of GIT so it has been provided for prolonged period oftime in stomach for better therapeutic activity by increasing its bioavailability. The floatation was accomplished by incorporating gas generating agent, sodium bicarbonate into a swelling polymer. All the formulations had floating lag time of less than 4 minutes and total floating time of 8 hours. Among all the formulations, F7 formulation gives best results based on floating time (1 min 50 sec) and drug release profile (97.94% in 8 hours). From the study, it has been concluded that HPMC K100M and Xanthan gum can be a promising polymers for gastroretentive drug delivery system. Drug authentication was done at the start of the project. According to the authentication research, the Glipizide sample that was obtained was pure and in accordance with IP limits.

References

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Copyright

Copyright © 2023 Pavan P. Kondewad, Nilesh R. Bhosale, Rajashri S. Chavan, Prashant S. Bhosale, Shweta S. Kate, Shital A. Kasture, Pooja S. Garud, Padmaja K. Mhaske. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.