Emulsion ocular applications

The rationale for introducing emulsions as a DDS for topical ocular application is their ability to incorporate within their oil inner phase lipophilic active molecules, which exhibit low water solubility and cannot be normally administered in an aqueous eyedrop formulation. Thus, the preferred emulsion for topical ocular application should be of the oil-in-water type formulation. 

In conclusion, the approval of Restasis by the FDA is an important milestone in lipid emulsion research for ophthalmic application. This approval reflects the achievements of the last decade in terms of the availability of better ingredients, improved manufacturing processes, feasibility of sterilization, and better understanding of the optimization process. In all of the comparative studies done so far, positively charged SME achieved better ocular bioavailability regardless of the studied drug. Research efforts are underway to further explore the mechanism of interaction of positively charged SMEs with ocular tissues and to translate the results of this research into enhanced clinical performance. 

Emulsions have been used for centuries for the oral administration of medical oils and vitamins and as dermatological vehicles. Recently, their application has been extended as drug carriers in the delivery and targeting of ophthalmic drags. An indomethacin emulsion has been reported to increase ocular bioavailability and efficacy compared to commercially available formulation in rabbits. 0.4% indomethacin emulsion showed 2.2 fold increase in the area under the anterior aqueous drag concentration/time curve compared to a 1% indomethacin suspension. The emulsion formulation also reduced ocular surface irritation caused by indomethacin Similar advantages have been shown for a pilocarpine emulsion which produced a prolonged therapeutic effect in comparison with pilocarpine hydrochloride eyedrops in man. It can be administered only twice a day, rather than four times daily for conventional formulation. 

It has been reported in an ocular pharmacokinetic study of cyclosporin A incorporated in deoxycholic acid-based anionic and stearylamine-based cationic emulsions in rabbit that, when compared to anionic emulsion, the cationic emulsion showed a significant drug reservoir effect of more than 8 h in corneal and conjunctival tissues of the rabbit eye following topical application [106], Since cornea and conjunctiva are of anionic nature at physiological pH [107], the cationic emulsion would interact with these tissues electrostatically to implicate the observed cyclosporin A reservoir effect. This hypothesis is supported, in principle, by an ex vivo study which showed that cationic emulsion carrier exhibited better wettability properties on rabbit cornea than either saline or anionic emulsion carrier [108],... 

It has been shown in a number of studies that the incorporation of drug in o/w nanosized emulsions significantly increased the absorption of the drug when compared with the equivalent aqueous solution administered orally [132-135], However, the use of emulsions for oral application is limited since other attractive alternatives, such as self-emulsifying oil delivery systems, which are much less sensitive and easy to manufacture, are available [136,137], Thus the potential of nanosized emulsions after administration with parenteral and traditional nonparenteral topical routes such as ocular, percutaneous, and nasal is covered in this section. 

It has to be clear that, once diluted and injected (or administered in ocular and other routes), the emulsion stability and fate are determined by three measurable parameters. The first is the partition coefficient of each emulsion component (including added drugs and agents) between the emulsion assembly and the medium. To some extent this partition coefficient is related to oil-water and/or octanol-water partition coefficients. For example, it was well demonstrated that per component of which logP is lower than 8, the stability upon intravenous (IV) injection is questionable [42,138], The other two parameters are kQff, a kinetic parameter which describes the desorption rate of an emulsion component from the assembly, and kc, the rate of clearance of the emulsion from the site of administration. This approach is useful to decide if and what application a drug delivery system will have a chance to perform well [89],... 

In two large, randomized controlled trials in 977 patients, the adverse effects associated with ciclosporin ophthalmic emulsion for the treatment of dry eye disease were minimal and consisted mostly of mild ocular burning and stinging (46). However, topical application of ciclosporin eye-drops was the suspected cause of severe visual loss with bilateral white comeal deposits in a 45-year-old patient with dry eye sjmdrome caused by graft-versus-host disease (47). Infrared spectroscopy and X-ray analysis suggested that the deposits contained ciclosporin. A reduction in tear clearance and compromised epithelial barrier function caused by the concomitant use of oxybu-procaine may have precipitated this adverse effect. 

The phenomenon of microemulsification is mainly governed by factors such as (1) nature and concentration of the oil, surfactant, co-surfactant and aqueous phase, (2) oil/surfactant and surfactant/co-surfactant ratio, (3) temperature, (4) pH of the environment and (5) physicochemical properties of the API such as hydrophilicity/lipophilicity, plformulating microemulsions. From a pharmaceutical perspective, one of the most important factors to be considered is acceptability of the oil, surfactant and co-surfactant for the desired route of administration. This factor is very important while developing micro emulsions for parenteral and ocular delivery as there is only limited number of excipients which are approved for the parenteral and ocular route. In Chapter 3 of this book a more general overview of formulating microemulsions is given and formulation considerations with respect to the components of microemulsions used in pharmaceutical applications are discussed below. 

The following conclusions can be offered at the end of this brief review. Emulsion systems, particularly, mtcroemulsions, seem to be developing rapidly toward commercial applications and possibly will become the vehicles of choice for lipid-soluble ophthalmic drugs. Traditional suspensions, used for ocular administration of drugs both water- and lipid-insoluble, after some initial uncertainties have apparently reached a stale of technical perfection. However, both emulsions and suspensions are not exempt of drawbacks and problems such as stability, sterilization, bioavailability. etc., which may limit their practical usefulness. 

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