Assessment of in vitro release profile of Corticosteroids- Cyclodextrin complexes containing two different polymers Dhilraj Channa, Ana Costa, Nélio Drumond, André Sá Couto and Helena Cabral-Marques* Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal *
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Introduction Corticosteroids (Cort), such budenoside, fluticasone propionate, mometasone fuorate are used as treatment for respiratory diseases due to high anti-inflammatory effect, but they present some limitation in terms of formulation, namely high lipophilicity. Usually, these drugs are administered through pulmonary route, requiring high doses to have a desirable effect, being consequently responsible by side effects. Cort complexation with cyclodextrins (CyDs) have been used to improve the water solubility and reduce the dose required to have a local effect at lungs, thus reducing their side effects. Moreover, the addition of water-soluble polymers can improve the solubilising effect of CyDs, as well the stability of CyD:drug complex and drug bioavailability.
Objectives Assess the in vitro release profile of CyD:Cort containing two different water-soluble polymers, namely polyvinyl alcohol (PVA) and polyethylene glycol (PEG), through Franz cells. Two different variables - polymer addition time (0 or 48 hours), and polymer concentration (0.1, 0.5 and 1%) were evaluated during this study.
Methodology Preparation of inhaled complexes CyD aqueous solution was prepared and then the Cort was added to the solution, in molar ratio 1:1. Separately, the solution of PEG and PVA were prepared in order to achieve concentration of 0.1, 0.5 and 1% and added in different time points (t=0; t=48h) to the Cort / CyD suspension; For t=0 hours, the polymer was added immediately to the suspension. For t=48 hours, the suspension was firstly agitated in a A
thermostatized shaking bath, and the polymer solution was added afterwards; Suspensions obtained at t=0 and t=48h were submitted to a Spray-Drying process for complex formation;
In vitro release studies of inhaled complexes Cellulose membranes were previously soaked in receptor phase (hydroalcoholic solution ethanol: distilled water 70:30) and inserted between the donor and the receptor compartments of a vertical diffusion Franz cell (Figure 1);
B
Each Franz cell was filled with the receptor phase and placed in a thermostatized water bath (37 ± 0.5°C), under magnetic stirring. A sample
Figure 1: Franz Cell - donor phase, Franz cell lid, receptor phase (A) and clamped together in a water bath (B).
of each powder complex was placed on the top of the membrane; Samples were collected from the receptor solution at 10, 20, 30, 60, 120, 180, 1080 minutes, and replaced with fresh receptor phase. The amount of Cort was quantified through HPLC, using a validated method. All samples were analysed in triplicate;
Results The t values (time to reach a certain percentage of Cort released) showed that for CyD:Cort+PEG 0.1% and 1.0%, at both time points, the release rate reduces over time. When PEG is added at different time points, the time taken for formulations to reach 50%
Table 1. T- values at 30, 50 and 70% of Cort released from PEG complexes CyD:Cort + PEG
Time for 30% release Time for 50% release Time for 70% release (min) (min) (min)
0.1%-0h
release from 30% is faster than the 50% release to 70%, except in the case of CyD:Cort+PEG
78.1
164.6
632.6
0.5%-0h
59.3
129.2
169.6
0.5% (Table1);
1.0%-0h
48.5
81.2
118.6
Usually formulations whose PEG was added at 48 hours were able to release the drug within
0.1%-48h
121.3
153.0
229.7
slightly shorter time periods than at 0 hours;
0.5%-48h
47.9
105.2
156.6
Increasing the concentration of PEG leads to an increased rate of drug release;
1.0%-48h
45.9
84.3
130.4
The fastest release happened for 1.0% polymer in both time points; When PVA is used (Table 2) the drug rate of release was reduced over the time analysis Table 2. T- values at 30, 50 and 70% of Cort released from PVA complexes
CyD:Cort + PVA
Time-30% release (min)
Time-50% release (min)
Time-70% release (min)
0.1% - 0h
112.7
156.5
317.4
0.5% - 0h
121.5
371.6
938.2
1.0% - 0h
73.1
111.8
249.6
and the formulations whose polymer was added at 48 hours were able to release the drug within slightly shorter time periods than at 0 hour, similarly to PEG; The PVA formulation which showed to be the most effective in terms of rapid release was the CyD:Cort+PVA 1.0% - 48 h and the better one for sustained release was the CyD:Cort+PVA 0.5% - 0 h; The fastest rate release came from the formulations with the highest PVA concentration
0.1% - 48h
55.3
97.3
226.0
0.5% - 48h
78.3
153.4
548.7
(1.0%), followed by lowest (0.1%), whereas CyD:Cort+PVA 0.5% formulation presented the
1.0% - 48h
47.9
117.8
174.1
slowest rate of release.
Overall comparing both polymers, the trend in most cases showed that PEG formulations reached the time value faster than those of PVA at the same concentrations
Conclusions PEG formulations are able to be designed as fast release formulations while PVA can be used as an excipient for delaying the release of drug (sustained release formulations).
Acknowledgments & References The financial support provided by the FCT, Fundação para a Ciência e Tecnologia (PTDC/SAU-FCF/098733/2008) is gratefully acknowledged. Crim, C.; Pierre, L.N. and Daley-Yates, P.T. A review of the pharmacology and pharmacokinetics of inhaled fluticasone propionate and mometasone furoate. Clin Ther, 23, 13391354, (2001); Derendorf, H.; Hochhaus, G.; Meibohm, B.; Möllmann, H. and Barth, J Pharmacokinetics and Pharmacodynamics of Inhaled Corticosteroids. J Allergy Clin Immunol, 101, 440446 (1998); Loftsson, T. and Másson, M. The effects of water-soluble polymers on cyclodextrins and cyclodextrin solubilization of drugs. J Drug Del Sci Tech, 14, 35-43 (2004); Hirlekar, R.; Sonawane, S. and Kadam, V. Studies on the Effect of Water-Soluble Polymers on Drug–Cyclodextrin Complex Solubility. AAPS PharmSciTech, 10, 858-63 (2009).
