Design and ocular tolerance of flurbiprofen loaded ultrasound-engineered NLC
Introduction
One of the most common disorders in ophthalmic therapy is the ocular inflammatory disease affecting any part of the eye or the surrounding tissues [1], [2]. Inflammation involving the eye can range from the familiar allergic conjunctivitis of hay fever to rare [3], potentially blinding, conditions such as keratitis, scleritis or episcleritis, uveitis, optic neuritis, orbital pseudo-tumour and chronic conjunctivitis [1]. Others, e.g. the postoperative inflammation [4], are characterized by a severe inflammation usually affecting the uvea. Since uvea presents many blood vessels nourishing various parts of the eye, this structure plays an important role in the human vision mechanism. Thus, the presence of a damaging inflammatory disorder may lead to vision impairment [5].
Topically applied non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in the management and prevention of ocular inflammation and cystoid macular edema (CME) related to cataract surgery and the maintenance of mydriasis during cataract surgery [6], [7]. Although steroidal agents have been the standard treatment for ocular inflammation [8], [9], the use of NSAIDs has increased over the past two decades [8], [10], [11], [12]. The main advantage of using topical NSAIDs is the avoidance of undesirable effects of steroidal agents, namely, the decreased immunological response to infection, cataract formation, steroid-induced raised intraocular pressure (IOP) and inhibition of re-epithelisation following epithelial denudation [13]. However, several NSAIDs have been associated with some side effects, mainly affecting the gastrointestinal tract [14].
Flurbiprofen (FB), a water insoluble and acidic anti-inflammatory drug, is currently used as a first line ophthalmic medication for the inhibition of miosis induced during the course of cataract surgery [15]. In order to minimize occurrence of miosis and to improve therapeutic efficiency of NSAIDs, the development of novel delivery systems for ocular instillation is a demand. Within these approaches, nanostructured lipid carriers (NLC) have been gathering attention from researchers worldwide [16], [17]. NLC are systems composed of a solid lipid matrix with a certain content of liquid lipid useful to increase the solubility of lipophilic drugs. These carriers show great promise as drug delivery devices for the eye, due to their biocompatibility, modified release kinetics [18], avoidance of organic solvents during the production process, easy large scale production and reduction of drug leakage during storage. Different techniques can be employed to prepare lipid carriers, being the hot homogenization technique the most commonly applied [19]. Nevertheless, it requires the use of appropriate devices which are not commonly available in research labs. On the other hand, ultrasounds are frequently used to disperse two immiscible phases, such as lipid and water, and can be easily applied to produce nanosuspensions of lipid materials [20], [21]. This technology is based on the extreme conditions generated within the collapsing cavitational bubbles of the inner phase leading to size reduction [22]. Ultrasonic processing is fast and highly reproducible if the operating parameters (e.g., ultrasonication time and power, operating temperature), are critically controlled. Ultrasound probes are practically self-cleaning, they account for negligible sample losses, and can be used for high scale production. The factorial design is frequently used for the planning of a research because it provides the maximum amount of information and requires the least amount of experiments [23]. Although the common method of experimental design to optimize operating conditions is by changing 1 variable at a time, this is time-consuming and gives no guarantee for optimal parameter determination.
This paper reports a factorial design approach as a guideline for the development and characterization of a new ocular delivery system, namely FB-loaded NLC, composed of stearic acid (SA) and castor oil (CO). FB-loaded NLC were produced by an ultrasound method and the tolerance of the optimized formulation was evaluated by the Eytex® in vitro test and by the Draize in vivo test. In order to detect destabilization phenomena stability studies were also undertaken.
Section snippets
Materials
Flurbiprofen and Tween® 80 (polyoxyethylene sorbitan monooleate) were purchased from Sigma Aldrich (Madrid, Spain). Lipids investigated included stearic acid (a saturated fatty acid (of C18) provided by Croda Industrial Specialities (Nettetal, Germany), Precifac® ATO (cetyl palmitate), Compritol® ATO 888 (glyceryl behenate), Precirol® ATO 5 (glycerol mono, di and tripalmitostearate) and Precirol® ATO WL2155 (glyceryl ditristearate) gifted by Gattefossé (Gennevilliers, France), Dynasan® 116
Results and discussion
The first step in formulating NLC dispersions is always the assessment of drug solubility in the lipid phase. This was performed by dissolving increasing concentrations of FB in various solid and liquid lipids, previously selected on the basis of their suitability for ocular administration [36]. To check the drug solubility in the solid lipids, mixtures were melted at a temperature approximately 10 °C above the melting point of the solid lipid, and the maximum FB concentration that could be
Conclusions
This study reports a first approach on the use of a 2-level 4-factors factorial design in the optimization NLC formulations produced by an ultrasound method for the encapsulation of flurbiprofen (a lipophilic NSAID drug). The derived polynomial equations and Pareto Charts proved to be satisfactory in predicting the dependent variable values for the preparation of optimum NLC with desired mean particle size, polydispersity index and surface electrical charge for ocular instillation. Optimal
Acknowledgements
This work was supported by the Ministry of Science and Innovation of the Spanish Government (R&D and Innovation Project CTQ2005-09063-C03-03) and by the Spanish-Portuguese Integrated Actions research program (HP2008-0015).
References (60)
- et al.
Allergic conjunctivitis
Immunol. Allergy Clin. North Am.
(2008) - et al.
Effect of prophylactic non-steroidal antiinflammatory drugs on cystoid macular edema assessed using optical coherence tomography quantification of total macular volume after cataract surgery
J. Cataract Refr. Surg.
(2008) - et al.
Steroidal and non-steroidal antiinflammatory medications can improve photoreceptor survival after laser retinal photocoagulation
Ophthalmology
(2007) - et al.
Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain
J. Cataract Refr. Surg.
(2009) - et al.
Flurbiprofen loaded biodegradable nanoparticles for ophtalmic administration
J. Pharm. Sci.
(2006) - et al.
Nonsteroidal anti-inflammatory drugs in ophthalmology
Surv. Ophthalmol.
(2010) - et al.
Prednisolone and flurbiprofen drops to maintain mydriasis during phacoemulsification cataract surgery
J. Cataract Refr. Surg.
(2003) - et al.
Mucoadhesive effect of thiolated PEG stearate and its modified NLC for ocular drug delivery
J. Control. Release
(2009) - et al.
Ultrasonically controlled particle size distribution of explosives: a safe method
Ultrason. Sonochem
(2008) - et al.
Cavitation—a novel technique for making stable nano-suspensions
Ultrason. Sonochem.
(2007)
Incorporation of peptides in phospholipid aggregates using ultrasound
Ultrason. Sonochem.
Effect of polymer viscosity on physico-chemical properties and ocular tolerance of FB-loaded PLGA nanospheres
Colloids Surf. B: Biointerfaces
Emulsification by ultrasound: drop size distribution and stability
Ultrason. Sonochem.
Physico-chemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential
J. Control. Release
Polymeric nanoparticulate system: a potential approach for ocular drug delivery
J. Control. Release
An in vitro method for estimating ocular irritation
Toxicol. Vitro
Acceptance of in vitro studies by regulatory authorities
Toxicol. Vitro
Nanomedicines for ocular NSAIDs: safety on drug delivery
Nanomedicine
Characterisation of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids
Int. J. Pharm.
Solid lipid nanoparticles: production, characterization and applications
Adv. Drug Deliv. Rev.
Microspheres and nanoparticles used in ocular delivery systems
Adv. Drug Deliv. Rev.
Preparation and characterization of stearic acid nanostructured lipid carriers by solvent diffusion method in an aqueous system
Colloids Surf. B: Biointerfaces
Evaluation of the physical stability of SLN and NLC before and after incorporation into hydrogel formulations
Eur. J. Pharm. Biopharm.
A controlled-release ocular delivery system for ibuprofen based on nanostructured lipid carriers
Int. J. Pharm.
Crystallization tendency and polymorphic transitions in triglyceride nanoparticles
Int. J. Pharm.
Formulating fluticasone propionate in novel PEG containing nanostructured lipid carriers (PEGNLC)
Colloids Surf. B: Biointerfaces
Physico-chemical stability of colloidal lipid particles
Biomaterials
Lipid nanoparticles for parenteral delivery of actives
Eur. J. Pharm. Biopharm.
Polyoxyethylated non-ionic surfactants and their applications in topical ocular drug delivery
Adv. Drug Deliv. Rev.
Effect of particle size on ophthalmic bioavailability of dexamethasone suspensions in rabbits
J. Pharm. Sci.
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