Pegylated Phospholipid Nanomicelles Containing Budesonide Or Beclimethasone Dipropionate For Pulmonary Delivery
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Date
2012
Authors
Sahib, Mohanad Naji
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Abstract
The aims of the present study were to formulate and evaluate nanomicelles
containing poorly water soluble corticosteroids, budesonide (BUD) or
beclomethasone dipropionate (BDP) for pulmonary delivery using PEGylated
polymers (PEG5000-DSPE and PEG2000-DSPE).
All the sterically stabilized phospholipid nanomicelles (SSMs) were successfully
prepared using a co-precipitation and reconstitution method. The SSMs were
characterised by different physicochemical methods. There were significant
differences between the maximum solubilisation tendencies of PEG5000-DSPE and
PEG2000-DSPE for BUD, which were approximately 605.71±6.38 and 646.27±4.93
μg/ml, respectively. The maximum solubilisation tendencies of PEG5000-DSPE and
PEG2000-DSPE for BDP were approximately 209.65±7.74 and 210.01±5.28,
respectively. These results showed that PEGylated polymers had greater tendencies
to solubilise BUD than BDP. The mean particle sizes at maximum solubilisation of
BUD:PEG2000-DSPE (15.97±1.91 nm) and BDP:PEG2000-DSPE (15.44±1.66 nm)
were smaller than BUD:PEG5000-DSPE (20.45±1.65 nm) and BDP:PEG5000-DSPE
(19.99±0.98 nm). Blank SSMs of PEG5000-DSPE were successfully lyophilised at a
concentration of about 5 mM, while 10 mM of PEG2000-DSPE was needed for
lyophilisation. There were insignificant differences in the particle size, zeta potential
and polydispersity index between drug-loaded SSMs and blank SSMs of the same PEGylated polymer before and after lyophilisation. The yield and drug loading
percentages of all the drug-loaded SSMs were more than 95% and 0.72%,
respectively. Both BUD and BDP were found to be amorphous by differential
scanning calorimeter (DSC) and did not interact chemically with the PEGylated
polymers as shown by Fourier transform infrared spectroscopy (FTIR). The
transmission electron microscope (TEM) examination showed spherical
nanoparticles, while the scanning electron microscope (SEM) investigation indicated
that the shapes of the BUD and BDP particles were very different from the
lyophilised blank and drug-loaded SSMs. Short- and long-term stability studies
showed that the lyophilised drug-loaded SSMs were stable for 1 year when stored at
both 4ºC and -20ºC.
Two simple yet sensitive HPLC methods were developed in order to analyse the
concentrations of BUD and BDP in different formulations. Aerodynamic
characterisation of drug-loaded SSMs found that the SSMs were more superior than
the marketed Pulmicort Respules® and Clenil® microsuspensions. In addition, the in
vitro dissolution studies showed more prolonged drug release from the SSMs than
their corresponding reference products. The pharmacodynamic study of drug-loaded
SSMs showed the superiority of these formulations in reducing the total and
differential cell counts and in enhancing the inhibition of inflammatory cells when
compared with the reference products. The results of the present study indicated the
great potential of the developed nanocarrier systems for the delivery of
corticosteroids to the target sites for the treatment of asthma and other airway
inflammatory diseases.
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Keywords
Adrenocortical hormones