DECLARATION 3 ANIMAL ETHICS
2.4 Strategies to Address Limitations of ARV Drugs
Many ARVs have been delivered via alternate routes, with zidovudine having received the most interest and being investigated for delivery via all the alternative routes.
For the buccal route, studies are limited compared to the transdermal route, and have focused mostly on permeability studies with ARV drug solutions rather than formulation studies. To date, studies reporting on the delivery of ARVs via the buccal route remain limited. The majority of work thus far has focussed on in vitro drug permeability studies using only drug solutions of zalcitabine (Shojaei et al., 1999, Xiang et al., 2002), didanosine (Ojewole et al., 2012, Rambharose et al., 2013) and tenofovir (Rambharose et al., 2013). The only available published paper on buccal polymeric dosage forms containing ARVs is of zidovudine polymeric patches recently produced by Reddy et al.
(2012). Characterization studies were limited and did not include critical parameters such as in vitro permeation or mechanical properties. ARV buccal drug delivery systems have not been comprehensively investigated or characterised, and a clear need exists for formulation optimization in this field. This study focused on the development of a NDDS for delivery of an ARV via the buccal route. The following sections therefore provide an overview on buccal drug delivery and buccal films.
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Table 2.2: Summary of formulation studies exploring novel drug delivery systems (NDDS) for delivery of ARVs.
NDDS Antiretroviral Rationale for Development Reference Enteric coated
bioadhesive matrix tablets
Didanosine
Enteric-coating prevents acid-induced degradation of didanosine, whilst sustained- release and bioadhesive properties may further
improve the drug’s low oral bioavailability.
Deshmukh et al.
(2003)
Extended release matrix
tablets
Stavudine
Once daily, sustained release formulations reduce the frequency of administration and
improve patient compliance.
Saravanakumar et al. (2010)
Suspensions Indinavir
Subcutaneously administered lipid–drug complexes in suspension form can accumulate
in lymph nodes at much higher levels than the soluble form of the drug where HIV localizes.
Kinman et al.
(2003)
Gastroretentive
tablet Zidovudine
Improve the drugs low oral bioavaibility and provide sustained action through continuously
releasing the drug.
Dalavi and Patil (2009)
Ceramic
implants Zidovudine
The sustained delivery of AZT from ceramic implantable capsules could be achieved and oral as well as intravenous side effects of AZT would
be minimised.
Benghuzzi (2000)
Ethanolic
liposomes Indinavir
Penetration-enhancing quality of ethanol is well known. Ethanolic liposomes can transport drugs
more effectively through the stratum corneum into the deeper layers of the skin than
conventional liposomes.
Dubey et al.
(2010)
Micelles /
Microemulsions Saquinavir
Saquinavir is lipophilic, poorly water-soluble and undergoes extensive first-pass metabolism. By formulating it as a lipid formulation that targets intestinal lymphatic transport, oral bioavailability
may be improved.
Griffin and O'Driscoll (2006)
Niosomes Tenofovir
Niosomes offers greater stability than liposomes and are more cost-effective. Colloidal drug
carrier system would be cleared by the mononuclear phagocytes system where HIV
localizes. No pediatric liquid formulation of tenofovir is available.
Zidan et al.
(2011)
Polymeric
micelles Efavirenz
Liquid pediatric formulation of EFV not available.
Polymeric micelles would improve the aqueous solubility and the oral bioavailability of the drug.
Chiappetta et al.
(2009)
Dendrimers Efavirenz
Due to their highly branched, synthetic, monodispersed nature they can be useful for
targeted drug delivery of ARVs.
Dutta et al.
(2007)
Nanopowders Saquinavir
The dissolution rates of poorly soluble drugs can be enhanced by milling thereby increasing GIT
absorption and/or membrane permeation.
Branham et al.
(2012)
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Table 2.3: Summary of formulation studies exploring alternate routes for delivery of ARVs.
Route of
Administration Formulation Antiretroviral Reference Rationale of Route Selected
Transdermal
Suspension Zidovudine Jin et al. (2000)
Drugs exhibit dose dependent toxic side effects. Controlled drug
delivery systems are preferred for long-term treatment of HIV/AIDS.
Noninvasive zero-order delivery via the transdermal route would
be desirable.
Liposomes Lamivudine Pai and Devi (2009) Pheroid™ Stavudine Holmes et al.
(2010) Alcoholic solutions Zalcitabine Kim and Chien
(1995) Gel Zidovudine Pokharkar et al.
(2010) Niosomal gel Lopinavir Patel et al.
(2012)
Rectal
Sustained-release
suppository Zidovudine Kawaguchi et al. (1991)
Avoidance of hepatic first pass metabolism and extensive GIT degradation thereby
increasing drug bioavailability.
Solution Didanosine* Wintergerst et al. (1999) Solution Zidovudine Wintergerst et
al. (1997)
Vaginal
Polyurethane intravaginal ring
Dapivirine &
Tenofovir
Johnson et al.
(2010)
Anti-HIV microbicide can block transmission
of HIV at the vaginal mucosal epithelium.
This route is not used to achieve systemic drug
concentrations.
Intravaginal bioadhesive polymeric device
Zidovudine Ndesendo et al.
(2011) Gel Tenofovir Abdool Karim et
al. (2010)
Nasal
Suspension Zidovudine Seki et al.
(1994)
Allows for painless, minimally invasive, self-
administration of drugs and can also bypass the
blood–brain barrier when used together
with nanoparticles.
Avoiding first-pass metabolism and oral
administration side effects. Rapid absorption can be achieved due to the
highly vascularized nature.
Micelles Efavirenz Chiappetta et al.
(2013) Liquid crystal
precursor Zidovudine Carvalho et al.
(2013) Polymeric
Nanoparticles Efavirenz Seremeta et al.
(2013) Polymeric
Nanoparticles Didanosine Al-Ghananeem et al. (2010)
Buccal
Solution Didanosine Ojewole et al.
(2012)
Bypasses hepatic first pass metabolism and
GIT degradation, resulting in increased drug bioavailability. It has higher permeability the skin, has a relatively
large surface area and good accessibility.
Solution Zalcitabine Xiang et al.
(2002) Solutions Tenofovir or
Didanosine
Rambharose et al. (2013) Patches Zidovudine Reddy et al.
(2012)
* This study demonstrated suitable rectal absorption of didanosine cannot be achieved.
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