Pharmaceutical nanotechnologyA potential carrier based on liquid crystal nanoparticles for ophthalmic delivery of pilocarpine nitrate
Graphical abstract
Introduction
Glaucoma is the most common cause of irreversible blindness, which will affect 79.6 million people in 2020 worldwide (Quigley and Broman, 2006). The causes of glaucoma include increased intraocular pressure (IOP), oxidative stress and impaired ocular blood flow. As a miotic agent, pilocarpine nitrate (PN) has been used for the treatment of chronic open-angle glaucoma and acute angle-closure glaucoma for over 100 years (Nair et al., 2012). However, the high hydrophilicity of PN usually possesses several limitations such as poor corneal penetration, precorneal tear clearance and short preocular retention which sharply reduce the ocular bioavailability of PN (less than 5% or even below 1%) (Nagarwal et al., 2009). Therefore, it is required for frequent administration of a large quantity of PN, which will induce several undesirable side effects, such as myopia and miosis (Ticho et al., 1979). To overcome these shortcomings of the conventional remedy, ointments, gel, or ocusert have been developed as new topical formulations with prolonged ocular residence time (Anumolu et al., 2009, Miller and Donovan, 1982, Shell, 1984, Sieg and Robinson, 1979). However, gel and ointments with high viscosity might adversely accelerate the blinking frequency, leading to a discomfort feeling. Non-erodible inserts of ocusert are considered to be a technical breakthrough even though they also limit patient compliance, due to the requirement of weekly insertion and difficulty of their removal. To enhance the ocular residence time on the cornea and prolong the drug's pharmacological activity, colloidal dosage formulations of drug delivery systems (DDSs) such as liposomes (Li et al., 2009), nanoparticles (Ibrahim et al., 2010), nanocapsules (Desai and Blanchard, 2000), microspheres (Gavini et al., 2004), and microemulsions (Vandamme, 2002) could be used for glaucoma therapy. Liquid crystalline phases of both the bulk and dispersed forms with multidimensional structures (Mulet et al., 2013), based on the underlying crystal lattices, are increasingly recognized as offering more desirable properties than other nano-carriers. Despite the intense interest in these systems, liquid crystalline phases are still over-shadowed by the other colloidal formulations particularly for the investigation of their application in ophthalmic drug delivery.
GMO, a nontoxic, biodegradable, and biocompatible amphiphilic lipid, swells in the water, and then spontaneously form well-ordered liquid crystalline phases. The most common liquid crystalline phases are lamellar phase (Lα), inverted hexagonal phase (H2), and cubic phase (V2) (Bansal et al., 2012, de Campo et al., 2004, Yaghmur and Glatter, 2009a). These phases can be readily dispersed into nanoparticles through high energy input methods, which is influenced by temperature and water content (Thadanki et al., 2011). It has been reported that LCNPs associated with their bulk phase could retain their internal structure, morphology and stability, and show some unique properties such as small particle size, low viscosity and good biocompatibility (Guo et al., 2010). The structure of LCNPs in terms of their high internal interfacial area is separated into hydrophilic and hydrophobic domains, which gives a possibility of encapsulating hydrophilic, lipophilic as well as amphiphilic drugs (Vandoolaeghe et al., 2006). Therefore, PN may be well trapped into LCNPs. Taking into account of nontoxicity, bioadhesive nature and sustained-release behavior (Drummond and Fong, 1999), LCNPs may be a good candidate for PN ocular delivery. Furthermore, because of the similarity to biological membrane, LCNPs may enhance the drug delivery topically (Gan et al., 2010, Lopes et al., 2006) as well as orally and intravenously (Chung et al., 2002, Johnsson et al., 2006).
In this study, the PN-loaded LCNPs were constructed by top-down approach (Guo et al., 2010) and characterized by TEM and SAXS. The in vitro release profiles of PN were studied using a dynamic dialysis method. An ex vivo penetration study was performed using freshly excised rabbit cornea. The irritation and safety of the PN-loaded LCNPs were evaluated by Draize (Draize et al., 1944a) method, corneal hydration levels and historical examination. Finally, the in vivo efficacy of IOP reduction was evaluated.
Section snippets
Materials
Glyceryl monoolein (GMO) with glyceryl monoolein purification of ≥80% was purchased from Aladdin Reagent Co. Ltd (Shanghai, China). Poloxamer 407 (F127) was obtained by BASF (Ludwigshafen, Germany). Pilocarpine nitrate (PN) was purchased from Leawell International Ltd (Brazil). Double distilled water was purified using Milli-Q (Gradient). All other chemicals and reagents used in the study were of analytical grade.
Animals
Adult New Zealand white rabbits (3.0–3.5 kg) were supplied by Animal Experimental
Morphology of PN-LCNPs
The PN-LCNPs were milky white with a low viscosity. A typical electron micrograph was shown in Fig. 1, which indicated that PN-LCNPs were indeed formed. However, it should be emphasized that it is not possible to determine the exact nature of formed nanostructures by TEM method. These internal structures were further confirmed by SAXS method discussed in the following section.
Particle size, pH and osmotic pressure
The particle size is a key factor affecting dispersions of ophthalmic formulations. The mean diameter of the PN-LCNPs
Conclusion
In summary, the present study has demonstrated the potentials that LCNPs-mediated PN delivery would reduce its limitation and improve bioavailability superior to commercial eye drops. The formulation of PN-LCNPs was found to be nano-sized, uniformly dispersed, and exhibited low ocular irritating properties as evaluated by the Draize method, corneal hydration levels and histological examination. The in vitro results showed that the PN-LCNPs might allow a sustained release compared to eye
Acknowledgments
We are grateful for the financial supports from the National Natural Science Foundation of China (81273457); Natural Science Foundation of Jiangsu Province (BK2012445, BK2012843) and Science and Technology Development Foundation of Nanjing Medical University (2011NJMU271).
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