EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.
Issue link: https://digital.eyeworld.org/i/387844
by Keith A. Walter, MD Maximizing penetration of anti-inflammatory agents to prevent edema and relieve pain Keith A. Walter, MD The importance of the vehicle used to deliver ophthalmic drugs cannot be overlooked and may play a role in both patient compliance and drug effica y N umerous ophthalmic med- ications are now being marketed in once daily formulations or in preser- vative-free formulations. How the medication is delivered to the target tissue (the vehicle) is possibly the second most important variable after the active ingredient. Today's newer vehicles decrease toxicity, increase solubility, increase ocular concentrations, and decrease dosing. Yet even with these advanc- es, the majority of eye drops have less than 5 minutes of ocular surface contact time. 1 Studies have shown that a 50 µL drop will result in only 5% of the original dose reaching the target tissue. 1,2 During that 5 minutes, tear- ing and blinking, tear film turnove , conjunctival and scleral absorption, and corneal absorption can disrupt the delivery of that drug. 1–4 A sub- stantial obstacle in drug delivery is ensuring the maximal drug concen- tration is achieved at the desired site of action. 5 (See Figure 1.) The role of the vehicle Achieving sufficient corneal pe - etration and prolonged contact time with the corneal tissue can be accomplished by increasing the effective dose, increasing the active drug concentration, improving the molecular design (increasing lipophilicity and solubility), or increasing the frequency of instilla- tion. 1,5–7 Opting to increase the number of drops a patient must instill daily is not optimal and has been shown to decrease patient compliance. 8 Increased lipophilicity will re- sult in a soluble compound that can more easily penetrate the cornea. 9 Reducing the impact of cataract surgical stress by mitigating inflammation and reducing ultrasound energy Both bromfenac and nepafenac (two well-known nonsteroidal anti- inflammato y drugs, or NSAIDs) have unique chemical structures that facilitate penetration through cell membranes. Bromfenac is a highly lipophilic molecule that rap- idly penetrates to produce early and sustained drug levels in all ocular tissues. It manifests in a rapid reduc- tion of postsurgical inflammation and pain. 9 Nepafenac is not very lipophilic, but as a prodrug it can cross the cornea more rapidly. Nepafenac 0.3% utilizes a new product formulation with a higher viscosity realized by the introduc- tion of guar gum. It also features a reduced particle size and a more physiological pH (7.4). 10 The topical corticosteroid loteprednol gel 0.5% uses mucoadhesive technology; it has been engineered to adhere to the ocular surface. This adaptive technology allows the agent to start as a gel and as the patient blinks, the force of the blink alters the com- position to its liquid form. 11 Lipid emulsion increases bioavailability and provides uniform medication in the most recent difluprednate fo - mulation. 12 A benefit of this techno - ogy is that it remains in suspension, eliminating the need for patients to shake the bottle before instillation. Polycarbophil USP is a polymer that provides the gel structure to the formulation to prevent sedimenta- tion. It also functions as a mucoad- hesive and viscoelastic suspending agent. From a clinical perspective, the new non-settling formulation delivers consistent, full doses to the ocular surface for reliable drug delivery and subsequent clinical effect. It is currently being used in loteprednol gel and DuraSite drug delivery vehicles. In a rabbit study, the administration of azithromycin ophthalmic solution 1% in DuraSite resulted in 18-fold higher maximum concentrations (Cmax) in rabbit superior bulbar conjunctiva than 1% azithromycin aqueous formulation (without DuraSite drug delivery vehicle). 13 Not all vehicles are the same. New products must undergo animal studies, clinical studies, and bio- availability analyses, costs spiral into the hundreds of millions, and it may take up to 12 years to bring a single new entity to market. 14 In both Canada and the U.S., generic for- mulations must demonstrate similar bioequivalence to the original drug and show comparable absorption. 15 However, generic manufacturers can vary the nonactive ingredients, bottle design, and drop volume. Drop size is directly related to the outer orifice diameters and can va y widely from name brand to generic, resulting in highly variable drop volume. 15 Figure 1. Key vehicle parameters that affect penetration. Numerous factors can adversely impact the amount of active ingredient that penetrates the ocular surface to reach the target tissue area. Image adapted from Bausch + Lomb