Formulation and Evaluation of Floating Microspheres of an Antidiabetic drug

Abstract

The primary objective of this work was to create Metformin floating microspheres to achieve longer retention in the upper GIT, which improves absorption and bioavailability. The microspheres were created using a solvent evaporation process with various ratios of rate controlling polymers ethyl cellulose and Carbopol 940, with Metformin employed at a fixed ratio in each formulation. A (1:1) mixture of dichloromethane and ethanol, with tween 80 as a surfactant. The produced microspheres were tested for percentage yield, particle size, entrapment efficiency, buoyancy, and drug release in vitro. The influence of polymer concentration on various parameters was studied. According to the findings, increasing the concentration of ethyl cellulose improved drug release from floating microspheres. The formulation F6 was selected as best formulation, and it has drug release of 94.22% at 12 hrs. entrapment efficiency 98.8%, buoyancy 94.2%.

Introduction

I. INTRODUCTION

Diabetes is one of the leading causes of death and disability worldwide. The most recent WHO estimate for the number of diabetics globally in 2000 is 171 million, with a probable increase to at least 366 million by 2030.  The medical community's focus is on disease prevention and treatment, as seen by the increasing number of research papers published on the issue each year. (1)

Oral administration has been the most popular and convenient method of drug administration. Floating microspheres are a non-effervescent gastro retentive drug delivery technique.

They are low density systems with enough buoyancy to float over gastric contents and remain in the stomach for an extended period of time. As the device floats over the gastric contents, the drug is gently released at the correct rate, resulting in enhanced gastric retention and fewer variations in plasma drug concentration. When microspheres come into contact with stomach fluid, the gel formers, polysaccharides, and polymers hydrate to produce a colloidal gel barrier that limits the rate of fluid entry into the device. and resultant drug release. As the dosage form's external surface dissolves, the gel layer is maintained by the hydration of the next hydro colloidal layer. The air captured by the expanded polymer reduces density and gives the microspheres buoyancy. (2) Metformin is an anti-diabetic, insulin-sensitizing medication from the Biguanide class of oral anti-hyperglycaemic agents.  Metformin HCl is a safe medication with a half-life of 1.5-3 hours. It is not entirely absorbed, resulting in a low bioavailability concern. Approximately 80-100% of the medication is excreted intact. Metformin HCl has a total daily need of 1.5-3g, resulting in a significant prevalence of GI side effects and toxicity. Slow but complete drug release in the stomach increases drug bioavailability and utilisation, resulting in fewer doses and GI side effects. Keeping the above facts in consideration the present study is performed with a view to formulate and evaluate floating microsphere of metformin hydrochloride in order to maintain a sustained drug concentration for longer period of time.

II. MATERIAL AND METHODS

A. Sample Collection

Metformin hydrochloride was a received from aarti Parma, Mumbai. Ethyl cellulose (14 cps), Carbopol 940, dichloromethane, ethanol, tween 80, distilled water was collected from Pharmaceutics research lab. All other chemicals were of analytical grade.

B. Preparation of Microspheres

Floating microspheres containing Metformin HCL were prepared by solvent evaporation method using Ethyl cellulose and Carbopol 940. Briefly drug and polymer were mixed in the mixture of dichloromethane and ethanol in 1:1 ratio. The slurry was slowly introduced into the 100ml water containing 0.02% tween 80 while being stirring at 500rpm by a magnetic stirrer for 2 hr. at 400C to allow solvent to evaporate completely. Microspheres were washed with petroleum ether. The collected microspheres were dried at room temperature for 24 hr.

III. CHARACTERIZATION OF MICROSPHERES

A. Particle size Analysis

All of the microspheres were sized using optical microspheres equipped with an ocular micrometer and a stage micrometer. The optical microscope was used to measure the size of more than 50 microspheres at random. The total size of the microspheres was divided by the number of microspheres to determine the average particle size.  (3) Least count of the ocular micrometer was calculated by the following formula

B. Scanning Electron Microscopy Analysis

The shape and surface morphology of microsphere samples were examined using a scanning electron microscope. Microspheres were clustered on double-sided carbon dust, which was placed on a sample carrier (9 aluminum stubs with double adhesive tape) in the shape of a cylinder with a weight of 5 mm and a diameter of 10 mm, and were coated with AU-pd (Gold Platinum) mixture under vacuum (9100 m torr) and sputter coated to a thickness of 50 nm. An electron beam with a voltage range of 5-15 KV was used to image the samples. Surface topography microphotographs with appropriate magnification were taken. (4)

C. Determination of Drug Content

An accurately weighed quantity of the floating microspheres equivalent to 20mg of drug was taken for evaluation. The amount of drug entrapped was estimated by crushing the microspheres and extracting with aliquots of phosphate buffer (pH 6.8) repeatedly. The extract was transferred to a 100ml volumetric flask and the volume was made up using phosphate buffer (pH 6.8). The solution was filtered and the absorbance was measured after suitable dilution at 233 nm by using UV-visible spectrophotometer. The drug content was estimated in triplicate using a calibration curve constructed in the same solvent.

D. Determination of Percentage Yield

The prepared microspheres were collected and weighed. The measured weight was divided by the total amount of all non- volatile components which were used for the preparation of the microspheres. The yield percentage was determined with the following formula of Patel et al. (2009):

F. Buoyancy Determination

The microspheres about 300mg  was weighed and  were spread  over the  surface of USP dissolution type II apparatus which was filled with 900 ml of 0.1 N HCl containing 0.02% of Tween 80. The medium was agitated with a  paddle  rotating  at  100  rpm.  The floating and the settled portions of microspheres  were  recovered separately. The microspheres were dried and weighed. Buoyancy percentage was calculated as the ratio of the mass of the microspheres that remained floating and total mass of the microspheres (Debjit et al., 2009).       

Floating ability of different formulations was found to be differed according to drug polymer ratio. The percentage buoyancy for different formulation was found in range from 86.0% to 94.31%studies:

 The drug release studies were conducted using a six basket dissolution device USP type II. The microspheres were inserted in a nonreacting mesh with a mesh size smaller than the microspheres.

To keep microspheres from escaping, the mesh was knotted with nylon thread. At 37°C, 900 cc of 0.1 N hydrochloric acid was utilized as a dissolving media. At regular intervals of up to 12 hours.  After adequate dilution, 5 mL aliquots were taken and analyzed by UV spectrophotometer at 232 nm. The removed volume was replaced with an equivalent volume of fresh 0.1 N hydrochloric acid. (5)

IV. MICROMERITIC PROPERTIES

 Microspheres were characterized for their micromeritic properties such as bulk density, tapped density, compressibility index, Hausner`s ratio, and angle of repose

Conclusion

The incorporation of the highly water-soluble antidiabetic drug metformin hydrochloride was done using ethyl cellulose and Carbopol 940 as the polymer. The formulations exhibited sufficient floating properties. Percentage drug release study was affected by the polymer concentration. From this study it is concluded that the formulation F6 was a good formulation. Where the formulation was having 94.22% buoyancy with 8 hour control release or longer and would be capable of reducing the frequency of administration depending upon the formulation variable. SEM studies the formulation was found in spherical nature. So, the formulation F6 is more effective and it is concluded that the prepared floating microspheres of metformin HCl may prove to be potential candidate for safe and effective sustained drug delivery over an extended period of time which can reduce dosing frequency.

References

[1] D M Brahmankar and Sunil B Jaiswal, Biopharmaceutics and Pharmacokinetics a Trea-tise. [2] Patel AK, Ray S and Thakur RS. In vitro evaluation and optimization of controlled release floating drug delivery system of Metformin hydrochloride. Daru. 2006;14:57-64. [3] Rednick AB, Tucker SJ (1970) Sustained release bolus for animal husbandry. US Patent 3 507 952. [4] Davis SS, Stockwell AF, Taylor MJ (1986) The effect of density on the gastric emptying of single and multiple unit dosage forms. Pharm Res [5] Fix JA, Cargill R, Engle K (1993) Controlled gastric emptying. III. Gastric residence time of a non-disintegrating geometric shape in human volunteers. Pharm Res [6] S.M. Sarode, M. Mittal1, R. M. Magar, A. D. Shelke, B. Shrivastava1 and G.Vidyasagar.J. Chem. Pharm, 2011; 3(3): 775-783. [7] Lachman, L., Lieberman, H. A., Kanig, J. L. The Theory and Practice of Industrial Pharmacy.3rd ed., Varghese Publishing house, Bombay, 1991; 293-303.

Copyright

Copyright © 2023 Pooja Suresh Garud, Jitendra Vijay Shinde , Rajashree Chavan, Shital Arun Kasture , Kunal Dattatray Jadhav, Supriya Prakash Bankar, Ankita Vitthalrao Bhosale . 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.