Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery
Introduction
In the past decade nonionic surfactants have found increasing applications in pharmaceutical preparations due to the implementation of high throughput techniques for screening new compounds for pharmacological activity. The high throughput has produced a large number of new therapeutic candidates with poor aqueous solubility [1]. These poorly water soluble candidates, categorized as class II or IV compounds according to the biopharmaceutical classification scheme (BCS) [2], impose a significant challenge for scientists in drug development to provide effective delivery systems. Several approaches utilizing nonionic surfactants to increase the bioavailability of the BCS II/IV compounds and thereby the efficacy of the drugs have increasingly been taken such as lipid based delivery systems, drug-polymer amorphous dispersions, and particle size reduction [3].
Poor aqueous solubility of compounds affects pharmaceutical product development in nearly all therapeutic areas including ophthalmology. Despite the accessibility of the front of the eye, efficient delivery of drug to treat various ocular disorders is a challenge to the formulation scientist in addition to the often low drug solubility. The majority of ophthalmic medications are formulated as eye drops delivered topically to the eye. Due to anatomical constraints, the volume that can be administered is limited to approximately 30 μL. This, together with the efficient clearance system that exists in the front of the eye, makes it difficult to maintain an effective pre-ocular drug concentration for a desired length of time [4]. The bioavailability of eye drops is typically less than 5% in spite of frequent instillations.
Various formulation strategies have been used to increase aqueous solubility of active pharmaceutical ingredients and pre-ocular retention of eye drops. The most successful of these has been the inclusion of polymeric surface active agents, particularly those able to undergo a transition from a solution to a gel under the conditions of the pre-ocular area and those that can interact with the mucous layer on the eye surface. Different dosage forms including micellar systems, emulsions, liposomes, and nanosized suspensions which generally require the presence of surface active agents have also been reported to be useful to overcome insufficient drug solubility and increase efficiency of drug delivery, especially when the target site is intro-ocular.
Nonionic surfactants are the major type of surface active agents used in ophthalmic delivery systems since their advantages with respect to compatibility, stability, and toxicity are quite significant compared to the cationic, anionic, or amphoteric counterparts [5], [6]. They are generally less toxic, less hemolytic, and less irritating to the ocular surface, and tend to maintain near physiological pH values when in solution. The nonionic molecules are comprised of both polar and non-polar segments, possessing a broad range of interfacial activity and versatile functions as wetting agents, emulsifiers, solubilizers, ocular permeability enhancers, and in some cases P-glycoprotein inhibitors.
Polyoxyethylated nonionic surfactants are of great importance and find widespread applications in ophthalmics among the nonionics. Well known examples are Polysorbates, Tyloxapol, and Poloxamers. Applications of other polyoxyethylated surfactants such as Cremophor EL, Brij, and alpha-Tocopherol TPGS have also been reported in the literature. These surfactants are often referred as polymeric ethers since they all contain a common hydrophilic moiety of the molecules, polyethylene oxide or polyethylene glycol, which has a repeated (CH2CH2O)n ether structure with n generally in a range of 10 to 100 units (Table 1).
The purpose of this review is to summarize the surface and thermodynamic properties of polyoxyethylated nonionic surfactants, evaluate the recent advancement of these surface active agents in ophthalmic topical drug delivery, and analyze advantages and potential pitfalls of using them as ocular formulation ingredients to address solubility, compatibility, and bioavailability issues. The effects of these surfactants on biopharmaceutics of the ocular drugs are assessed and information on their safety to the eye tissues over chronic exposure is provided. Understanding of usefulness and appropriate functions of these surfactants in topical ocular dosage forms will aid in effective and efficient ophthalmic drug product development.
Section snippets
Surface and thermodynamic properties
Polyoxyethylated nonionic surfactants are amphiphiles, that is, they have a dual nature with part of the molecule exhibiting hydrophilicity and the other lipophilicity. Unlike the ionics, the exact region of the nonionic molecule comprising the hydrophilic polar head or the lipophilic alkyl tail may not be readily elucidated from the molecular structure. A generally accepted view is that the polyoxyethylene chain serves as the hydrophilic region while the remainder of the molecule or a portion
Applications
Polyoxyethylated nonionic surfactants have been widely used in the topical delivery of ophthalmic drugs for the treatment of various ocular disorders such as dry eye, inflammation, allergy, ocular hypertension, glaucoma, etc. The dosage forms in which these surfactants are applicable to are micellar solution, emulsion [24], microemulsion [25], suspension [26], noisome [27], and liposome [28], [29]. The functional roles these surfactants play in the ophthalmic preparations range from wetting,
Ocular absorption
Drugs are commonly applied to the eye for a localized action on the surface or in the interior of the eye [4]. A major problem in ocular therapeutics is the attainment of an optimal drug concentration at the site of action. Poor bioavailability of drugs from ocular dosage form is mainly due to the pre-corneal loss caused by tear dynamics, systemic absorption, transient residence time in ocular surface, binding by the lacrimal proteins, limited corneal area, and the relative impermeability of
Safety
Topical ophthalmic drug delivery bears a resemblance to the other routes of drug delivery with techniques aimed at facilitating drug penetration through the skin and different epithelia (buccal, nasal, intestinal, rectal, and pulmonary, etc). However, the unique characteristics and high sensitivity of the corneal and conjunctival tissues impose distinctive safety requirements and great restrictions on the selection of the components that can be used in the topical ocular preparations. A special
Conclusions
Polyoxyethylated nonionic surfactants used in topical ocular drug delivery systems play a critical role in relation to their success in overcoming the constraints imposed by the eye and by the physicochemical properties of drugs. It has been demonstrated that these surfactants have a profound impact on the in-vitro and in-vivo performance/characteristics of topically applied ophthalmic drugs/products. Existing ocular drug delivery systems are fairly primitive and inefficient, but the stage is
Acknowledgements
The author is grateful to the opportunity of working with many Pfizer colleagues on the formulation aspects of ophthalmic products. Special thanks to Debra Pereira and Karl Gelotte for their review of the manuscript and helpful suggestions.
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