Ocular toxicity, ophthalmic formulations

Current guidelines for toxicity evaluation of ophthalmic formulations involve both single and multiple applications, dependent on the proposed clinical use [39]. The multiple applications may extend over a 9-month period and incorporate evaluations of ocular irritation and toxicity, systemic toxicity, and determinations of systemic exposure (toxicokinetics). In many cases the systemic exposure from an ocular route is less than by parenteral administration, information that will assist in determining whether additional studies may be needed to establish systemic safety of the ophthalmic preparation. U.S. and international guidance documents are available [71,72], and regulations and tests have been summarized for ophthalmic preparations [39,73,74],... 

There are a limited number of regulatory approved antimicrobial preservatives which can be used in ophthalmic products, and some of these are becoming less favoured because of increasing awareness of ocular toxicity concerns. Therefore, it can be a challenging exercise for the formulator to find a preservative to use with the following attributes ... 

This preservative is comparatively new to ophthalmic preparations and is a polymeric quaternary ammonium germicide. Its advantage over other quaternary ammonium seems to be its inability to penetrate ocular tissues, especially the cornea. It has been used at concentrations of 0.001-0.01% in contact lens solutions as well as dry eye products. At clinically effective levels of preservative, POLYQUAD is approximately 10 times less toxic than benzalkonium chloride [87,137], Various in vitro tests and in vivo evaluations substantiate the safety of this compound [137,141,142], This preservative has been extremely useful for soft contact lens solutions because it has the least propensity to adsorb onto or absorb into these lenses, and it has a practically nonexistent potential for sensitization. Its ad-sorption/absorption with high water and high ionic lenses can be resolved by carefully balancing formulation components [143],... 

Surfactants. The use of surfactants is greatly restricted in formulating ophthalmic solutions. The order of surfactant toxicity is anionic > cationic >> nonionic. Several nonionic surfactants are used in relatively low concentrations to aid in dispersing steroids in suspensions and to achieve or to improve solution clarity. Those principally used are the sorbitan ether esters of oleic acid (Polysorbate or Tween 20 and 80), polymers of oxyethylated octyl phenol (Tyloxapol), and polyoxyl 40 stearate. The lowest concentration possible is used to perform the desired function. Their effect on preservative efficacy and their possible binding by macromolecules must be taken into account, as well as their effect on ocular irritation. The use of surfactants as cosolvents for an ophthalmic solution of chloramphenicol has been described [271]. This com-... 

Recognizing that long-term therapy with frequently applied preserved solutions can be toxic to the ocular surfece, manufecturers have formulated some ophthalmic solutions in imit-dose dispensers without preservatives (Figure 3-7). 

Miconazole Topical 1% ophthalmic suspension 1 drop qlh Subconjunctival 10 mg/0.5 ml Topical side effects of burning, itching, tearing Not commercially available both topical and subconjunctival formulations must be compounded fV brand discontinued in United States Good ocular penetration with topical and subconjunctival use Toxic conjunctival necrosis may occur with subconjunctival use Pregnancy category C lactation safety unknown... 

There is no doubt that 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 as reflected by a recent publication where the authors showed that under appropriate experimental conditions and optimal formulation, it is possible to reduce markedly the ocular surface toxicity of quaternary ammonium following its incorporation in a cationic nanoemulsion. Indeed, a free drug cationic nanoemulsion (Cationorm , Novagali Pharma, France) has been recently launched in the French market for moderate dry eye syndrome treatment. Research efforts are underway to further explore and enhance the ocular clinical performance of nanoemulsions. 

Ophthalmic diseases are most commonly treated by topical instillation of eye drops. These formulations evidence limitations like poor stability and efficacy, reduced cor-neal/scleral permeability, systemic toxicity and lack of compUance [2]. In this sense, the development of effective therapies for visual disorders is of high priority [1], which makes the field of ocular delivery one of the most interesting and challenging areas for pharmaceutical scientists [3]. There has been significant research directed towards the development of new systems for controlled drug delivery in ophthalmology such... 

---