DEVELOPMENT & EVALUATION OF MUCOADHESIVE

MICROSPHERES OF PIOGLITAZONE MALEATEBy

*1Sanwarmal, 1Manisha Gupta,2Ram Chand Dhakar, 2Sheo Datta Maurya

1HIMT College of Pharmacy, Gr Noida

2 Department of Pharmacy, IEC Group of Institution, Gr Noida

For Correspondence

Sanwarmal

Lecturer, HIMT College of Pharmacy, Gr Noida, INDIA-201308

E-mail: snas_kir@yahoo.co.in

AIM, SCOPE & OBJECTIVES OF THE STUDY

AIM: The present work was aim to formulate & evaluate

mucoadhesive microspheres of Pioglitazone maleate.

Microspheres were prepared by emulsification solvent

evaporation method using SCMC, CP & SA as

mucoadhesive polymers.

SCOPE: Prepared microspheres are expected to adhere in

the gastrointestinal mucosa and can be utilized for

controlled release of Pioglitazone maleate for an

extended period in the management of Diabetes type-II.

Objectives: Reduce the Dosing frequency

Fluctuations in therapeutic blood level is avoid

Increase patient compliance

Decrease in dose-related side effects

INTRODUCTION

What is microspheres?

Microspheres are solid spherical particles

consisting of protein or synthetic polymers

ranging in size from 1-1000μm.

A Microsphere has its drug dispersed throughout the particle i.e. the

internal structure is a matrix of drug and polymeric excipients.

However, the success of these microspheres is limited owing to their

short residence time at the site of absorption. This problem can be

avoid by coupling mucoadhesion characteristics to the microspheres

and developing mucoadhesive microspheres.2-6

What is mucoadhesive microspheres?

These microspheres are made by polymers that bind or Adhere

to the mucosal tissue and offer local as well as systemic

controlled release of drug for longer duration.

Selection of drug and Polymers:

Pioglitazone maleate is an antidiabetic drug belongs to

thiazolidinediones class. It requires control release due to

its short t1/2 of 3-4 hours11. To reduce the dosing

frequency of drug, it’s necessary to develop a newer

formulation which release drug in sustained release

manner. Thus mucoadhesive microspheres of

pioglitazone would become promising candidate in

management of diabetes type-II.

Literature survey revealed that SCMC, SA & CP shows

good mucoadhesive property & efficiently controlled the

drug release. Thus these are the suitable candidate for

mucoadhesive microspheres of pioglitazone maleate.

Drug dissolved in DMSOAq. Sol. of SCMC, SA & CP

D-P Solution

Preparation of microspheres12, 15

W/O Emulsification solvent evaporation method

·

liquid paraffin containing

0.5 % span 20

Stirring at 500 RPM

··

D+P droplets

Syringe containing

D-P solution

500 RPM, 800C

for 4 Hours

Evaporation of solvent

Solidification of D-P droplets

FiltrationWashingDrying

Microspheres

Table-1 Composition of drug loaded microspheres

Formulation

code

Drug SCMC CP-934 P Na-alginate

F1 100 mg 900 mg -- --

F2 100 mg -- 900 mg --

F3 100 mg -- -- 900 mg

F4 100 mg 450 mg 450 mg --

F5 100 mg 450 mg -- 450 mg

F6 100 mg -- 450 mg 450 mg

All formulation were prepared at 2% polymer conc. and 500 rpm stirring speed

Surface morphology:

visualize by SEM at BSIP, Lucknow.

Drug entrapment efficacy17:

50 mg of microsphere were taken and drug was extracted

from microspheres by digesting for 24 hours with 10 ml

of simulated gastric fluid(pH 1.2). During this period the

suspension was agitated. After 24 hours, the solution was

filtered & the filtrate was analyzed for the drug content.

The drug entrapment efficiency was calculated using the

following formula:

Entrapment efficiency = (Actual drug content/theoretical

drug content) 100

Particle Size17, 18: by optical microscopy

A small amount of dry microspheres was suspended in n-

hexane (10 mL).

A small drop of suspension thus obtained was placed on a

clean glass slide. The slide containing microspheres was

mounted on the stage of the microscope and particles

were measured using a calibrated ocular micrometer. The

average particle size was determined by using the

Edmondson's equation

D mean = ∑nd/∑n,

where n= number of microspheres

and d= mean size range.

In-vitro mucoadhesivity19:

By in-vitro wash-off test.

A 1 1 cm piece of rat stomach mucosa was

tied onto a glass slide using thread.

Microspheres were spread on the wet, rinsed,

tissue specimen & prepared slide was hung onto one of the

groves of a USP tablet disintegrating test apparatus.

The apparatus was operated such that the tissue specimen was

given regular up and down movements in a beaker

containing the simulated gastric fluid (pH 1.2).

At hourly intervals up to 10 hours, the number of

microspheres still adhering onto the tissue was counted.

% mucoadhesion = (no. of microspheres remains / no. of

applied microspheres) 100

In-vitro drug release13

USP XXI paddle type dissolution test apparatus

Dissolution medium: simulated gastric fluid (pH 1.2), 900

ml

100 mg Microspheres are spread on wet double layer muslin

cloth and hanged with the paddle of disso apparatus.

Temperature of bath=37 1 C.

Paddle speed = 50 rpm.

Sample volume= 10 ml,

Sampling interval= 1 hour

Sample analyzed for drug content by UV-Visible

spectrophotometer at 268.9 nm.

RESULTS AND DISCUSSION

Surface morphology: Examined by SEM.

The SEM showed that the mixture of SCMC and CP

produced spherical with smooth surface microspheres due

to their high solubility in water6.

While SA microspheres were of irregular shape with a rough

morphology due to less water solubility & non uniform

evaporation of water from the surface of microspheres.

Figure : SEM of formulation F1 showing population of microspheres

Particle size analysis:

Average p. size was found to be in the range of 31.20 to 47.54 μm.

Drug entrapment efficiency:

It was found in the range of 54.00 to 80.00 % .

Formulation F2 containing CP showed max drug loading about 80 %

Formulation F6 containing CP/SA shows min drug loading about 53%

Microspheres of SA are irregular in shape therefore more drug loss

from surface during washing leads to less drug entrapment efficiency.

Rank order of % drug loading of various formulations:

F2 > F4 > F1 > F5 > F3 > F6

Increase in polymer conc

high viscosity of polymer sol

Particle size increases

Increase in stirring speed

produce high energy for breaking

of droplets

Particle size decreased

Table –2 Comparative % yield, Particle size, % drug

entrapment and % mucoadhesion of microspheres

Formulation

code

% yield Particle size

(µm)

% Mucoadhesion

after 1 hr

% Drug

entrapment

F1 73.45 3.20 34.54 2.43 94.33 2.33 69 2.45

F2 71.56 2.80 31.20 1.88 89.22 2.43 80 3.23

F3 79.10 2.95 47.54 3.24 87.23 2.83 57 2.86

F4 75.52 2.84 38.62 2.78 72.20 1.90 78 2.75

F5 72.12 3.10 43.12 2.84 95.33 2.95 63 2.84

F6 74.44 2.60 41.85 3.15 76.44 2.32 54 3.68

Values are represented as mean standard deviation (n=3).

All formulation were prepared at 2% polymer conc. and 500 rpm stirring speed

In-vitro mucoadhesivity test:

Formulation F1 containing SCMC showed the highest mucoadhesivity

due to anionic nature of the polymer.

Formulation F6 containing SA/CP-934 showed the lowest

mucoadhesivity due to the irregular surface of microspheres.

Rank order of % mucoadhesivity, after 8 hours was found to be as

follows: F1 > F2 > F3 > F5> F4 > F6

DRUG RELEASE STUDY:

Dissolution medium: SGF(pH 1.2), Temp: 370C 1.

Drug release form these microspheres were found to be

slow, extended and dependent on the type and conc. of

polymer used.

Formulation F1 containing SCMC showed the max. release

91.45 % after 10 hrs, due to rapid swelling property and high

dissolution of SCMC in SGF.

High swelling of SCMC Faster drug release

Dissolution medium permeation is facilitated

While SA microspheres showed the slow drug release due to

less swelling action as compared to SCMC.

Figure : Comparative % drug release of microspheres formulations

CONCLUSION

The SEM reveals smooth surface microspheres.

The particle size of microspheres ranged from 31-47 μ.

The entrapment efficiency ranged between 54-80%.

All the formulation show significant mucoadhesion

property and it depends on the type of polymer used.

The in-vitro release & the mucoadhesion studies shows

SCMC formulation was the best which released 98.60%

drug at the end of 12th hour.

ACKNOWLEDGEMENT:

Authors is highly thankful to HIMT College of Pharmacy,

& Dept of Pharmacy, IEC Group of Institution, Greater

Noida for providing us best lab facilities and Indswift Labs

Pvt ltd, for providing drug sample.

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Thank You