When reviewing the progress of a patient who shows little sign of improvement, too often we hear the words, “Well, I may have forgotten to take a few doses ... ” Poor patient compliance with drug dosing regimens can be a major impediment to effective treatments. And while the topical application of ophthalmic drugs is straightforward in principle, as clinicians we know that poor compliance is widespread.

So what’s so hard about taking eye drops? Start with a drop that stings on application, combine with patients forgetting to take every dose, add in the difficulty of applying drops accurately (especially for older patients), mix with hit-or-miss renewal of costly prescriptions and then finish with an asymptomatic disorder. If we combine all this with low drug absorption and fast washout, it’s a wonder that topicals work at all. But they do. In terms of both efficacy and safety, topical delivery of drugs, especially for front-of-the-eye indications, is superior to all other options of administration.1 Of course, superior doesn’t mean perfect, so there is plenty of room for improvement, from reinforcing medication instructions to engineering better medications.

Both physicians and patients underestimate the impact of non-compliance. For glaucoma patients, estimates of non-compliance range from 23 percent to 60 percent.2-6 In this case, the cost of non-compliance is high, with progressive vision loss and eventual blindness as the result. In conditions such as dry eye or allergy, non-compliance can diminish patients’ quality of life and productivity, and increase their frustration with continuing symptoms. When patients unknowingly fail to comply with dosing guidelines, their frustration with their condition as well as their “ineffective” treatments establishes a vicious cycle reducing the likelihood of successful treatment.

This month, we’ll discuss several specific strategies to address the general issues of patient compliance and drug delivery optimization. First we’ll provide a checklist for overcoming the patient-related issues of compliance, with the goal of optimizing the routine of reliable adherence to prescribing instructions. Then we’ll consider advantages, limitations and regulatory hurdles associated with combination therapies. Finally, we’ll describe approaches available now and in the near future that enhance efficacy by improving delivery formulations, making every drop count. Each of these strategies can contribute to an overall recipe for compliance success.

Personalize Treatments

Most medications require some degree of physician oversight, so any discussion of patient compliance issues starts with the doctor-patient relationship. Keep in mind that patients’ compliance does not occur in a vacuum, and they are often juggling multiple medications, each with its own treatment regimen. While they may not volunteer such information, when asked, patients may admit to forgetting doses or having difficulty with proper administration of their eye drops.7 It may be that a patient is not complying with her dosing regimen because of negative side effects. Encourage patients to discuss any possible side effects of their medications, since undesirable side effects can often underlie poor patient compliance. Sometimes, specific side effects that a patient is experiencing are known to be associated with a particular drug or formula excipient, so the solution may be as simple as a change in medication.8,9 Additional communication efforts can include patient education, such as training in proper eye-drop application, and sending reminders to patients to take their medication on-schedule and keep follow-up appointments. Other options include smartphone medication monitors, as well as enlisting family members to help patients remember to take all doses and correctly apply their eye drops.5,10,11 Finally, remember that although ophthalmologists are nearly infallible, pharmacists are only human, so if there’s a problem with any medication it’s worth re-checking the prescription to insure accurate dispensing.

Complex drug dosing regimens have been cited as a significant barrier to patient compliance.12,13 Simplifying dosing can be achieved either by prescribing treatments that require once- or twice-daily dosing rather than multiple daily doses, or by considering fixed-combination medications. Prescribing fewer daily doses (q.d. or b.i.d.) rather than more frequent, multiple daily doses can often improve patient compliance.10,14 Once-daily medications are available for most indications, including glaucoma or allergic conjunctivitis, but when thinking about compliance it’s the switch from t.i.d. to b.i.d. that is critical: This improvement converts a drop from something that must be carried throughout the day to one that can function effectively at the nightstand or the medicine cabinet.

Sometimes the treatment effects from one medication, including q.d. medications, can wane. In such cases it’s best to first try switching from one monotherapy to another, before adding more, separate treatments.15 If a patient requires multiple medications, he should be instructed to apply the two drugs at least five minutes apart,16 since the second eye drop can wash out the first and reduce drug effectiveness.

Combination Therapies

Not all patients respond to monotherapy, and some may require more than one medication. Fixed-dosage ophthalmic drug combinations of different pharmacological classes can be efficacious, reduce the side effects of each component and improve patient compliance. This isn’t as simple as “mix and apply” however, and the Food and Drug Administration has established extensive guidelines for the approval of therapeutic drug combinations. Along with considerations of both pharmacodynamics and pharmacokinetics, development of combination products presents a unique mixture of opportunity and challenge.

The building block of hyaluronic acid, used in many tear-substitute formulas, is a modified disaccharide composed of glucuronic acid and n-acetyl glucosamine. The chemistries possible from this starting point are virtually limitless.
Any fixed-dose combination of drugs should be composed of individual compounds with different mechanisms of action and, most often, similar pharmacokinetics. Having distinct MOAs allows for the best prospects for therapeutic synergy while minimizing possible shared adverse effects of the two agents. Combinations designed to lower intraocular pressure, for example, often include one agent that increases outflow with one that decreases aqueous humor production. Regulatory guidelines dictate that the combination must be superior to either of the individual components alone, however, so any combination product must reach this therapeutic hurdle.

Pharmacokinetics of combinations should also be similar, to avoid the potential for mismatches in steady-state levels of each component. An exception to this is when the individual agents act to treat distinct symptoms. For example, a combination product for ocular allergy may include a vasoconstrictor to relieve redness and an antihistamine for ocular itching. In this case, one agent provides immediate treatment (for redness) while the other acts both to reduce itch and to prevent subsequent itching, so a longer duration for the antihistamine component is actually beneficial.

The best examples of fixed-dose combination formulations are those used as IOP-lowering drugs in primary open-angle glaucoma or ocular hypertension. An example of a fixed-combination drug to lower IOP in glaucoma patients is a combination of timolol maleate (a beta blocker) and dorzolamide hydrochloride (a carbonic anhydrase inhibitor) taken twice daily. Another example is a fixed-combination of brinzolamide (a carbonic anhydrase inhibitor) and brimonidine tartrate (an alpha-2 adrenergic receptor agonist) taken three times daily. While some fixed-combination drugs require more than once- or twice-daily dosing, they may still simplify dosing regimens and thus can contribute to better patient compliance.

A survey of Swiss ophthalmologists was conducted for 98 of their patients who switched from taking timolol and dorzolamide separately to a fixed combination of these medications. A 4.6-percent reduction in average IOP occurred after the treatment switch; this enhanced efficacy was attributed to improved patient compliance. About 85 percent of patients chose to continue the fixed-combination treatment.17

Similarly, in a Japanese study, 162 patients with glaucoma or ocular hypertension who had been taking latanoprost and timolol maleate concomitantly switched to a fixed combination of these two drugs once daily. The IOP-lowering effect of the two drugs was maintained by the combined formulation. About 82 percent of patients reported that they preferred the fixed-combination therapy. Also, patients who reported that they “never” forgot to take their eye drops increased from 59 percent before the switch to 71 percent a month after the switch, and those who forgot to take their drops “over five times” decreased from about 9 percent before to about 2 percent after the switch.18

Avoiding the Corneal Barrier

The relatively impermeable cornea serves as a barrier, protecting the eye from deleterious foreign substances, but also limiting drug absorption. Conventional topical administration of eye-drop solutions encounters the challenge of limited corneal penetration, and many enhanced drug delivery systems seek to address this issue. Improving drug delivery may help reduce the effects of patient non-compliance. Drug delivery that increases ocular residence time has significant potential advantages, including increased drug effectiveness and reduced local and systemic side effects. Some of these methods may decrease dosing frequency, a key factor in patient compliance.

Typically, less than 5 percent of an eye drop penetrates the cornea and is bioavailable, and less than 1 percent reaches the aqueous humor; the rest of the drug is lost through spillage, tear-fluid turnover, drainage and systemic absorption through the conjunctiva and nasolacrimal duct.19

Lipophilic drugs can permeate the outer corneal epithelium, which has an affinity for lipids, better than hydrophilic drugs, while the inner layer of the cornea, the stroma, is hydrophilic. Optimal ocular drug delivery involves a balance of lipophilic and hydrophilic properties to achieve good solubility and permeability through the cornea. In addition, some drug delivery methods (e.g., gels) provide more sustained topical drug delivery, which can reduce the amount of drug needed.

Methods used or being explored to improve topical drug delivery for the anterior of the eye include pro-drugs, excipients, gels, cyclodextrins, liposomes and nanoparticles. By enhancing the net delivery of active agent to the target tissue, each of these approaches has the potential to improve efficacy and thus alleviate the impact of poor patient compliance.

One strategy to improve the delivery of drugs involves compounds administered in an inactive or less active form that are converted to a more active form through metabolic processes in vivo. These compounds are called pro-drugs. Targeting pro-drugs to specific transporter or receptor tissues in the eye can increase drug absorption, with the pro-drug acting as a substrate for endogenous enzymes.1,20 The increased drug absorption improves drug efficacy and can reduce side effects and dosing frequency by concentrating active drug at target sites. The prostaglandin latanoprost, commonly used for reducing IOP in glaucoma treatment, is an example of a lipophilic pro-drug that is topically administered in eye-drop form and then hydrolyzed in the body to a more biologically active form, latanoprost acid. Lipophilic ocular pro-drugs can increase the permeability, absorption and bioavailability of hydrophilic drugs. Conversely, hydrophilic pro-drugs used as substrates can improve the solubility of poorly soluble lipophilic drugs (e.g., cyclosporine A).19, 21

Some excipients used in topical ocular formulations offer another way to improve drug delivery. These added ingredients include preservatives (e.g., BAK, ascorbic acid), surfactants and drug stabilizers (e.g., chelating agents such as EDTA). Beyond their action as preservatives or chemical stabilizers, some excipients may increase the viscosity, pre-corneal retention or permeability of ocular medications.19

Liposomes consisting of hydrophilic segments (A) and hydrophobic segments (B) can increase a drug’s residence time, absorption and transport.
An interesting example of this often reported in the literature is the ability of BAK to increase corneal permeability, although we think this case is more urban legend than scientific fact. A recent study of the effects of BAK in glaucoma patients showed that efficacy of the prostaglandin latanoprost was not dependent on the presence of BAK.22 Other head-to-head comparisons have showed the same non-inferiority of preservative-free formulations. Most concerns regarding additives have involved side effects, such as ocular discomfort, tearing, dry-eye sensation, burning or itching.17 Some patients, particularly those with ocular surface disease, may have trouble tolerating formulations with preservatives. In some cases these compounds induce a detergent effect in the eye (resulting in a loss of tear-film stability), damage the corneal and conjunctival epithelium and cause an immuno-allergic reaction.16,17 It’s clear that using excipients to improve drug absorption is a valid strategy, but not a quick fix for addressing problems of patient compliance.

Another group of drug excipients acts not simply by altering permeability, but also by increasing a drug’s residence time on the ocular surface. Ophthalmic gel formulations increase the viscosity, muco-adhesion and pre-corneal residence time of eye-drop solutions. The gels provide sustained release, improve bioavailability and may reduce the number of daily doses required. For example, timolol solution is prescribed for twice-daily use, while timolol gel is a once-daily dose for IOP reduction.

Ophthalmic gels include hydrogels and in situ activated gels. Both types are composed of polymers that may also decrease systemic side effects associated with topical ophthalmic drugs.23

Often used in tear substitute formulations, hydrogels can increase ocular penetration of a drug, particularly water-soluble drugs, via longer corneal residence time. Hyaluronic acid is a biological hydrogel polymer that is naturally present in the aqueous humor and vitreous of the eye, and is commonly used in cataract surgery. Most hydrogels currently in use are synthetic bioadhesives.23 A significant limitation of hydrogels is that they often result in blurred vision.21

This adverse effect is not seen with in situ activated gels, viscous liquids that change from a solution to a gel state after topical ocular administration based on temperature or other physiological conditions (e.g., pH). Gellum gum, a common gelling agent, is often used in ophthalmic formulations as an in situ activated gel. Combinations of a polymer and methylcellulose (or another non-toxic substance) are also used. The gel is considered non-toxic and is well tolerated by patients.

Commonly used in the food, pharmaceutical and chemical industries, cyclodextrins are modified polysaccharides that have a lipophilic center and a hydrophilic outer surface, making them great candidates for improving topical drug delivery. Cyclodextrin-drug complexes can increase the corneal solubility and bioavailability of poorly soluble lipophilic ocular drugs (e.g., steroids, carbonic anhydrase inhibitors), improve drug stability and reduce side effects.19,23,24

Cyclodextrins can also be cross-linked to form polymers for drug delivery. Some cyclodextrin-drug complexes have reduced corneal drug toxicity and irritation and this appears to be the primary benefit for hydrophilic drugs.23 A study of a dexamethasone-cyclodextrin complex indicated a 2.6 higher area under the receiver operator curve result in the aqueous humor compared to a dexamethasone suspension.19,25 Several cyclodextrin eye-drop products are currently available in Europe, and non-ophthalmic pharmaceutical uses are approved in the United States. The toxicity of cyclodextrin, however, has been raised as a possible issue.

Other potential delivery modalities include liposomes and nanoparticles. Liposomes are microscopic vesicles that typically contain an aqueous area surrounded by a lipid bilayer, and thus can accommodate both lipophilic and hydrophilic drugs. Encapsulating a topical ocular drug in liposomes and delivering it as an eye-drop solution may increase the drug’s corneal residence time, absorption and transport, thus increasing drug effectiveness and reducing dosing frequency.21,23 Liposomes are biocompatible and biodegradable.

Nanoparticles composed of bioadhesive polymers can potentially increase pre-corneal residence time, improve the uptake and transport of drugs with either poor permeability or poor solubility and prolong a drug’s duration of action.19,23,24 A drug is dissolved, entrapped, encapsulated, adsorbed or attached to the nanoparticle.

Personalizing treatment regimens and improving drug delivery represent two sides of the compliance issue. Encouraging our patients to be conscientious about their medication regimens is a simple, if sometimes daunting, route to optimizing treatment outcomes. By enhancing delivery strategies we can go a long way toward simplifying these regimes, significantly improving the odds of therapeutic success.

When it comes to solving the conundrum of patient compliance, this simple formula of equal parts patient participation and pharmaceutical fine-tuning should be a recipe for success.  REVIEW

Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Ms. Stein is a medical writer at Ora Inc.

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