ORAL BIOA V AILABILITY ENHANCEMENT OF POORLY SOLUBLE AND POORLY PERMEABLE DRUGS USING SELF-MICROEMULSIFYING DRUG DELIVERY SYSTEMS AND THE EFFECT OF PIPERINE
Loading...
Date
2010-01
Authors
MALLIKARJUN, CHITNENI
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
There are approximately 40% of new drug molecules discovered and some drug
molecules that are available in the market, having poor bioavailability due to poor
solubility and/or poor permeability. The present study aimed at formulating a selfmicroemulsifying
drug delivery system (SMEDDS) using two BCS class IV drugs,
namely sulpiride and norfloxacin. Sulpiride is a P-gp substrate and norfloxacin is a
substrate of MRP2, BCRP and an unknown efflux pump. From the solubility studies
of drugs in various oils, surfactants and co-surfactants, oleic acid, Tween 80 and
propylene glycol were chosen to prepare SMEDDS formulations. Two formulations
were chosen for further study based on droplet size and solubility. The first
formulation consisted of 4.76% w/w of oleic acid, 63.49% w/w of Tween 80 and
31.7 5% w/w of propylene glycol, with a mean droplet diameter of 9.27 nrn and drug
solubility of 22 mg/1000 mg for sulpiride, 9.57 nrn and 17.33 mg/1000 mg for
norfloxacin respectively. The other formulation consisted of 17.71% w/w of oleic
acid, 55.14% w/w of Tween 80 and 27.15% w/w ofpropylene glycol, with a mean
droplet diameter of 85 nrn and drug solubility of 32 mg/1 000 mg for sulpiride, 92 nrn
and 27.53 mg/1000 mg for norfloxacin. !socratic HPLC- fluorescence methods were
developed and validated for the determination of sulpiride and norfloxacin in rat
intestinal perfusates and rabbit plasma separately. The in situ permeability
experiment was performed on three intestinal segments, duodenum, jejunum and
ileum in rats using single-pass perfusion technique. The SMEDDS formulation and
micellar solution exhibited significant increase in the effective permeability
XXXIX
coefficient of the drug across all the three intestinal segments compared with drug
solution for the two drugs. There was no significant difference in the effective
permeability coefficients values between SMEDDS formulation and micellar
solution for both drugs. When the effect of droplet sizes on jejunum permeability
was studied, it was found that there was no significant difference in permeability
coefficients with droplet sizes of less than 100 nm. From the in vivo bioavailability
study performed in rabbits, it was found that there was a significant decrease in the
T max and significant increase in the Cmax and AUC of the SMEDDS formulations
when compared with Dogmatil®/Norfloxin® respectively. On the other hand, the rate
and extent of absorption of sulpiride/norfloxacin were not significantly affected,
when the droplet sizes of less than 100 nm were compared. When the effect of
dietary spice piperine on the oral bioavailability of sulpiride/norfloxacin suspension
and SMEDDS formulations was evaluated, it was found that concomitant
administration of both the drugs with piperine in suspension and SMEDDS
formulations significantly enhanced the oral bioavailability of these two drugs.
Concomitant administration of piperine with SMEDDS formulation further increased
the bioavailability of the drugs. Hence, SMEDDS can be used to increase the
bioavailability of poorly soluble and poorly permeable drugs.
Description
Keywords
ORAL BIOA V AILABILITY ENHANCEMENT OF POORLY SOLUBLE