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Application of a non-sink dissolution as a tool for development of
orodispersible ritonavir films for Paediatric HIV
S. Mirza, V.F. Patel
Department of Pharmacy, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, UK.
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Film 7
Non-sink dissolution test was used as a tool to drive the
development of ritonavir films keeping mind the physical
properties of the drug. A total of nine different films were
prepared and all of them generated thin, flexible and
uniformly consistent films. Without a solubiliser, the films
failed to disintegrate even after 10 minutes. In addition,
negligible amount (< 15%) of ritonavir was released in nonsink condition of simulated saliva after 30 minutes. On
addition of solubiliser, films demonstrated increased
dissolution of ritonavir in simulated saliva and being more
pronounced when Soluplus used as a solubiliser. It was also
noted that this effect was concentration dependant where no
significant difference in dissolution was observed when
Soluplus was used at 10%w/w of PVA and the films failed
to disintegrate even after 5 minutes. On increasing the
Soluplus concentration to 15%w/w and 30%w/w of PVA, a
significant improvement of ritonavir dissolution in
simulated saliva was observed (~38% and ~71%,
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Fig 2: Dissolution profile of ritonavir films in non-sink condition
(a) Simulated saliva pH 5.7 (b) 0.1 N HCl pH 1.2 (n=3).
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(a)
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(b)
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% Drug release
RESULTS AND DISCUSSION
Film 8
Fig 1: Disintegration profile of films in simulated saliva
MATERIALS AND METHODS
Films were prepared using the solvent casting technique
with polyvinyl alcohol (PVA) as the film forming polymer.
Solubilisers such as Soluplus, β-cyclodextrin (β-CD) and
Tween 80 were studied for their effect on disintegration and
dissolution of the films. PEG 400 and glycerine as
plasticizers were used at 20% w/w of polymer weight. Nonsink dissolution studies were performed in simulated saliva
pH 5.7 (0.84 g NaCl, 1.2 g KCl, 0.19 g CaCl2 , 0.11 g
MgCl2.6H2O and 0.34 g KH2PO4 in 1 L of purified water)
and 0.1 N HCl as dissolution medium (10 mL) and drug
release was analysed using a validated HPLC method. A
modified in vitro disintegration test was developed using
petri dish simulating surface of buccal cavity (Na CMC in
simulated saliva) and employed to evaluate the performance
of films. Other physical tests including weight variation and
thickness were also performed to ensure film uniformity.
After disintegration
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10%
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% Drug release
Poor solubility, bitter metallic taste and short term instability
due to presence of significant proportion of alcohol (~43.2%
v/v) and propylene glycol (~26.0% v/v) in the marketed
liquid formulation of ritonavir, a first-line treatment for
paediatric HIV, limits its treatment compliance and often
results in increased drug resistance and treatment failure [1].
Orodispersible films are emerging as a novel formulation of
choice not only to replace the need of liquid formulation in
children, but also as a promising alternative for improving
the stability of drugs [2]. Poor dissolution in a small volume
of saliva and incorporating a high proportion of drug are
some of the key challenges in development of novel film
formulations and as such, this study explored the non-sink
dissolution as a development tool for ritonavir films.
Disintegration Time (s)
INTRODUCTION
respectively) and the films disintegrated in < 4 minutes. The
most promising results were obtained when Soluplus was
used at 30%w/w of PVA (P<0.05). Non-sink dissolution in
0.1N HCl demonstrated almost complete ritonavir release in
15 minutes. In contrast solubilisers such as β-CD and Tween
80 failed to produce films which provide rapid
disintegration and dissolution in simulated saliva.
Before disintegration
Abstract–Current work explores the application of non-sink
dissolution test as a development tool to check effect of the
solubiliser on performance of orodispersible ritonavir films.
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Time (min)
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Fig 3: Dissolution profile of ritonavir as a function of Soluplus
concentration (n=3) in (a) simulated saliva pH 5.7 and (b) 0.1 N
HCl pH 1.2.
CONCLUSION
The study demonstrated the use of the non-sink dissolution
test to evaluate the performance of solubiliser in achieving
orodispersible films of poorly soluble drug ritonavir.
REFERENCES
[1] R.G. Strickley, Q. Iwata, S. Wu, T.C. Dahl, “Pediatric drugs--a review
of commercially available oral formulations” J Pharm Sci., 97 (2008)
1731-74.
[2] M. Preis, K. Knop, J. Breikreutz, “Mechanical strength test for
orodispersible and buccal films”, Int J. Pharm., 461 (2014) 22-29.