Ophthalmic drug design based on the metabolic activity of the eye: Soft drugs and chemical delivery systems

Abstract

A BSTRACTDespite its apparent easy accessibility, the eye is, in fact, well protected against the absorption of foreign materials, including therapeutic agents, by the eyelids, by the tearfl ow, and by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other. Most existing ophthalmic drugs were adapted from other therapeutic applications and were not specifi cally developed for the treatment of eye diseases; hence, they are not well suited to provide eye-specifi c effects without causing systemic side effects. A real breakthrough in the area of ophthalmic therapeutics can be achieved only by specifi cally designing new drugs for ophthalmic applications to incorporate the possibility of eye targeting into their chemical structure. Possibilities provided along these lines by designing chemical delivery systems (CDSs) and soft drugs within the framework of retrometabolic drug design are reviewed here. Both are general concept applicable in almost any therapeutic area. This review will concentrate on ␤ -adrenergic agonists and anti-infl ammatory corticosteroids, where clinical results obtained with new chemical entities, such as betaxoxime, adaprolol, loteprednol etabonate, and etiprednol dicloacetate, exist to support the advantages of such metabolism-focused, ophthalmic-specifi c drug design approaches.K EYWORDS: beta-blockers , corticosteroids , eye-targeted delivery , glaucoma , intraocular pressure , oxime OCULAR DRUG DESIGN AND DELIVERY: CHALLENGESFor the therapeutic treatment of most ocular problems, topical administration clearly seems the preferred route, because for systemically administered drugs, only a very small fraction of their total dose will reach the eye from the general circulatory system. Even for this fraction, distribution to the inside of the eye is further hindered by the blood-retinal barrier (BRB), which is almost as effective as the blood-brain barrier (BBB) in restricting the passage of xenobiotics from the blood stream. 1 At fi rst sight, the eye seems an ideal, easily accessible target organ for topical treatment. However, the eye is, in fact, well protected against absorption of foreign materials, fi rst by the eyelids and tear-fl ow and then by the cornea, which forms the physical-biological barrier. When any foreign material or medication is introduced on the surface of the eye, the tear-fl ow immediately increases and washes it away in a relatively short time. Under normal conditions, the eye can accommodate only a very small volume without overfl owing. Commercial eyedrops have a volume of ~30 L, which is about the volume of the conjunctival sac in humans; however, after a single blink, only an estimated 10 L remains. 2 Consequently, there is a window of only ~5 to 7 minutes for any topically introduced drug to be absorbed, and in many cases, no more than 2% of the medication introduced to the eye will actually be absorbed. 2-4 The rest will be washed away and absorbed through the nasolacrimal duct and the mucosal membranes of the nasa...

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review

“…Glucocorticoid soft drugs such as Loteprednol Etabonate, and Etiprednol Dicloacetate and  -blockers such as Betaxoxime, and Adaprolol are some of the new chemical entities developed as soft drugs for ocular applications. Besides, many of these soft drugs have already reached the clinical development phase in various ophthalmic areas and one of them Loteprednol Etabonate has already been marketed [ 24]. Herein we review the important aspects of the development of new generation glucocorticoids through prodrug approach with special reference to the development of the first and second generation glucocorticoid soft drugs by the application chemical delivery systems (CDSs) and retrometabolic drug design approaches towards ophthalmic therapeutics.…”

“…Soft corticosteroids or Soft glucocorticoids can be termed as a unique class of new generation glucocorticoids that are designed specifically for ophthalmic therapeutics [24][25][26][27]. The new generation glucocorticoids developed by prodrug approach as described earlier have brought revolution in treating a plethora of disease including psoriasis, allergies, asthma, rheumatoid arthritis and lupus because of their minimized systemic side effects.…”

“…Even distribution for this fraction to the inside of the eye is further hindered by the blood-retinal barrier (BRB), which is almost as effective as blood-brain barrier (BBB) in restricting the passage of xenobiotics from the blood stream [34]. Therefore despite its apparent accessibility, the eye, in fact, is well protected against the absorption of foreign materials, including drug molecules, by the eyelids, by flow of tears, and also by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other side as mentioned above [24]. Because of this a significant portion of the applied drug is absorbed through nasolacrimal duct and the mucosal membranes of the nasal, oropharyngeal, and gastrointestinal tract to pass to the system.…”

“…All these new generation glucocorticoids are not designed for ophthalmic therapeutics. Hence a real breakthrough in the field of ophthalmic therapeutic could be achieved only by specifically designing new drug entities to incorporate the eye targeting possibility into their chemical structure [24,25]. Chemical Delivery Systems (CDSs) and Retrometabolic drug design principles have led to development of a new but unique class of glucocorticoids which are safe and effective in treating a wide variety of ocular inflammatory conditions including giant papillary conjunctivitis, seasonal allergic conjunctivitis, and uveities as well as in the treatment of ocular inflammation and pain following cataract surgery.…”

“…Chemical Delivery Systems (CDSs) and Retrometabolic drug design principles have led to development of a new but unique class of glucocorticoids which are safe and effective in treating a wide variety of ocular inflammatory conditions including giant papillary conjunctivitis, seasonal allergic conjunctivitis, and uveities as well as in the treatment of ocular inflammation and pain following cataract surgery. This new and unique class of glucocorticoids are now known as soft glucocorticoids which are associated with highly minimized ADRs to justify terming them as `soft drugs' [24,26].…”