Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation
and pain (Escribano et al., 2003:203). Diclofenac, a classical NSAID, is considerably more
effective as an analgesic, antipyretic and anti-inflammatory drug than other traditional NSAIDs,
like indomethacin and naproxen (Grosser et al., 2011:986). However, the use of diclofenac is
known for its many side effects, such as gastric disorders, while fluid and sodium retention are
also commonly observed (Rossiter, 2012:391).
Since topical diclofenac offers a more favourable safety profile, it is a valuable substitute for oral
NSAID therapy in the treatment of osteoarthritis (Roth & Fuller, 2011:166). The benefits of
topically applied NSAIDs, compared to oral administration and systemic delivery, include the
easy cessation of treatment, should effects become troublesome (Brown et al., 2006:177), the
avoidance of extensive, first-pass metabolism (Cleary, 1993:19; Kornick, 2003:953; Prausnitz &
Langer, 2008:1261; Lionberger & Brennan, 2010:225), reduced systemic side effects (Colin
Long, 2002:41), convenience of application and improved patient compliance (Cleary, 1993:19;
Prausnitz & Langer, 2008:1261).
An approach that is often applied in optimising the solubility and dissolution rate of poorly water
soluble, weak electrolytes is to prepare a salt of the active pharmaceutical ingredient (API)
(Minghetti et al., 2007:815; O’Connor & Corrigan, 2001:281-282). Diclofenac is frequently
administered as a salt, due to the high partition coefficient and very low water solubility of this
molecule (Fini et al., 1999:164).
Formulating for efficacy (FFETM) is a software programme designed by JW Solutions to facilitate
the formulation of cosmetic ingredients or solvents into a product that would optimally deliver
active ingredients into the skin. The notion is built upon solubility, i.e. solubility of the active
ingredient in the formulation and solubility of the formulation in the skin. This programme could
also be employed to optimise amounts of predetermined ingredients, to propose formulations
that would ensure optimal drug delivery, to calculate the skin delivery gap (SDG) and to
demonstrate transdermal permeation of active ingredients and excipients (JW Solutions
Software, 2013a). When the SDG is known, it mathematically indicates the optimal active
ingredient and topical delivery vehicle to use (JW Solutions, 2013b).
In this study, diclofenac sodium (DNa), diclofenac diethylamine (DDEA) and diclofenac N-(2-
hydroxyethyl) pyrrolidine (DHEP) were each formulated in the following emulgels:
* An emulgel optimised towards the stratum corneum (SC) (enhancing drug delivery into
this layer and deeper tissues) (oily phase ~30%), * A more hydrophilic emulgel (oily phase ~15%), and * A more lipophilic emulgel (oily phase ~45%).
Components of the oily phase and its respective amounts, as well as the SDG of formulations
were determined by utilising the FFETM software of JW Solutions (2013a).
The aqueous solubilities of DNa, DDEA and DHEP were determined and their respective values
were 11.4 mg/ml, 8.0 mg/ml and 11.9 mg/ml, all indicative of effortless percutaneous delivery
(Naik et al., 2000:319). Log D (octanol-buffer distribution coefficient) (pH 7.4) determinations for
DNa, DDEA and DHEP were performed and their values established at 1.270 (DNa), 1.291
(DDEA) and 1.285 (DHEP). According to these values, diclofenac, when topically applied as a
salt in a suitable vehicle, should permeate transdermally without the aid of radical intervention
(Naik et al., 2000:319; Walters, 2007:1312).
Membrane release studies were also carried out in order to determine the rate of API release
from these new formulations. Results confirmed that diclofenac was indeed released from all
nine of the formulated emulgels. The more hydrophilic DNa formulation released the highest
average percentage of diclofenac (8.38%) after 6 hours. Subsequent transdermal diffusion
studies were performed to determine the diclofenac concentration that permeated the skin. The
more hydrophilic DNa emulgel showed the highest average percentage skin diffusion (0.09%)
after 12 hours, as well as the highest average flux (1.42 ± 0.20 μg/cm2.h).
The concentrations of diclofenac in the SC-epidermis (SCE) and epidermis-dermis (ED) were
determined through tape stripping experiments. The more lipophilic DNa emulgel demonstrated
the highest average concentration (0.27 μg/ml) in the ED, while the DNa emulgel that had been
optimised towards the SC, had the highest concentration in the SCE (0.77 μg/ml). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/12003 |
| Date | January 2013 |
| Creators | Smith, Hanri |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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