Development of Metoprolol Tartrate Microspehere for Mucoadhesive Drug Delivery System

About Author: Binit V. Patel1*, D. S. Patel2
1. Sri Satya Sai College of Pharmacy - Sehore
2. Shree Leuva Patel Trust Pharmacy Mahila College – Amreli

Metoprolol tartrate is a selective β1 adrenergic antagonist. It lacks interensic sympathomimetic activity and to have little or no membrane stabilizing activity and is widely used to treat essential hypertension. It completely absorbed from gastrointestinal tract but is subjected to considerable first pass metabolism and half life is 3 to 4 hr.

The objective for the designing mucoadhesive microspehere is to release the drug over extended period of time in order to avoid first pass metabolism for improving in bioavailability and improve patient compliance.

Reference ID: PHARMATUTOR-ART-1130

Materials and Methods:
Metoprolol tartrate& Hydroxyl propyl methyl cellulose K15M was received as gift samples from Sagun Pharmaceuticals, Indore. Sodium alginate, Sodium cmc were received from Care pharma chem pvt.ltd. The chemicals used were of reagent grade from Loba Chemical, Bombey.

Calibration curve for Metropolol Tartrate :
10 mg of Metoprolol tartrate was dissolved in 100ml of the solvent to obtain the working standard of 100µg /ml. Aliquots of 1 ml to 3.5 ml from the stock solution representing 10 to 35 µg/ml of drug were prepared by using phosphate buffer (pH7.2) and measured at 274nm.

In vitromucoadhesive strength determination of polymer.
Rotating Cylinder Method:
100 mg  of  HPMC K15M & sodium cmc were taken & compressed individually in tablet punching machine to form disc.The prepared disc of HPMC K15M was adhered to the freshly excised gastric mucosa of rat (male or female ) by hydrating the disc with little amount of water & then this mucosa along with the disc was pasted on USP- II paddle having(FIG.ii)  900ml phosphate buffer(ph 7.2)maintained at 37±1 & rotated at 125 rpm & the time required  for the polymer disc to detach from the stomach or to disintegrate was noted.

Formulation of Mucoadhesive Microspeheres.
Ionic  Gelation Technique
A dispersion of each sodium alginate (5% v/v in Calcium chloride) was used in the preparationof the microspeheres. A different concentration of metoprolol tartrate powder,HPMC K15M and Na CMC was dispersed in 25 ml ofdispersion &stirred along with heating at 40ºC toform homogeneous mixture.The dispersion was further extruded drop wise, with the aid of syringe into pure calcium chloride solution with magnetic stirrer. The mixture was stirred at 500 rpm for 20 min.So prepared microspeheres were retained in the mixture for 20 minutes filtered off and dried in hot air oven at 40c for 12 hours.

CARE:It should be taken into consideration that while injecting the tip of needle should not touch t the surface of Cacl2 solution.

Blockage of syringe is avoided by using warm solution in the syringe by heating it upto 40-45 ^?C

Characterization of microspeheres:

Yields of Production:Yields of production of microspeheres were calculated by dividing practical weight of microspeheres with total weight of drug & polymer used initially to form microspeheres. It is calculated using the formula mentioned below, & were reported in Table iv.

Production yield   =   Practical weight   (of microspeheres) x 100

                                     Theoretical weight (of Polymer + Drug )

Encapsulation Efficiency(Or entrapment efficiency) :-
A quantity(100 mg) of the microspehere was placed in a beaker containing 100 ml of the phosphate buffer(pH 7.2).The dispersion was vortexed repetedly to break up the microspehere and cause them to discharge their drug content completely. The solution was then filtered and analysed spectrophotometrically at a wavelength in UV-Vis spectrophotometer (SHIMADZU UV 1500). The drug concentration in each batch of microspehere was calculated from calibration curve of Metoprolol Tartrate.

Shape & Size of Microspehere :-
The shape & size of microspehere prepared were determined through optical microscopy. The size of around 200 microspehere were measured add average particle size determined

Bioadhesive test of microspehere OR In vitro mucoadhesive strength determinationby Wash off technique (Number Method)
The glass slide was fitted on a semicylindrical Plastic tube. This pipe was placed on a beaker in such a way so as to fit to a burette stand as shown in figure iv & the assembly was set up.Gastric and intestinal mucosal region of male Albino rat (200g-250g) was taken and small piece of it was pasted on it. Initially 15 numbers of microspeheres were allowed to be adhered on jejunum & they

were washed with phosphate buffer (pH 7.2) for 20min at the rate of 22 ml/min and the no of microspeheres getting detached from the mucosal region was counted.

The % adhesive strength was calculated using formula given below:

           % Adhesive Strength = No- Ns   x 100

                                                     NS

Where N0=Initial numbers of microspeheres

Ns=number of microspeheres left after performing wash off technique

In vitro release study
The USP II paddle method was adopted in this study. The release medium consist of freshly prepared phosphate buffer (pH7.2) maintained at 37 ± 0.5 ^?C. A known quantity of (50 mg) of each batch of microspehere was placed into release apparatus & agitated at 100 rpm. At predetermined time interval of 60 minute, 5ml of sample was withdrawn, appropritly diluted & assayed spectrophotometricaly(U.V.SHIMADZU 1500) at  274 nm. At every time 5ml of phosphate buffer (pH7.2) was added to replace the sample that was withdrawn. The concentration of samples were calculated from calibration graph.

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Result & Discussion
In vitro mucoadhesive strength determination of various polymers by Rotating cylinder method.
Time for detachment is greater for HPMC K15M than sodium CMC. The former has greater mucoadhesive strength than sodium CMC, so only the formulations containing HPMC as a mucoadhesive polymer were selected for further studies.

In vitro drug release studies
The release profile of metoprolol tartrate microspehere in phosphate buffer pH7.2 shown in FIG vi. It also show constant increase in drug release over 240 min. The drug release was highest in microspehere prepared by formulation (F1) means decrease in release rate as the concentration of HPMC 15M increase.

Physical characterisation of microspehere
The yield of HPMC K15M microspehere was obtained in range of (52-65%) & all batches were almost spherical in shape & the size range found as per table-iv.

Percentage mucoadhesive strength was found in range from 66.67% to 93.33%. Thus microspehere

prepared were found to be having good mucoadhesion property. Polymer ratio increases i.e. greater the amount of mucoadhesieve polymers in the formulation, greater will be the mucoadhesieve strength of the formulation.

The entrapment efficiency was also obtained in the range from 34.56% to 46.87%.

Acknowledgements:
The author is grateful to Sagun Pharmaceuticals for providing gift sample of drug. The author are also thankful to supporting staff for providing help to fulfil the work.

References:

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Tables:
Table-i: Formulation of mucoadhesive microspeheres prepared by ionic gelation technique.