When we make a choice about a therapeutic, most of our attention is focused on the active pharmaceutical ingredient. However, any given ophthalmic product is more excipient than drug substance. These ‘inert’ substances that act as diluent or vehicle to the active drug play an essential role in therapeutic effectiveness. The number of components in topical agents seems to be ever-increasing, yet we rarely stop to consider: “Why did they add that ingredient?” This month, we’ll examine a variety of constituents found in ocular medications. Understanding the roles played by excipients is critical to tailoring therapy to the needs of your patients.

The Basics
If we were to postulate a primordial eye drop, we could imagine that it would contain a single active ingredient in plain water. But it doesn’t take long to realize the limitations of such a formulation. Today, constituents of even the simplest preparations of aqueous drops must allow for sufficient ocular residence time and corneal penetration of the active drug; they must be free from microorganisms, and have a suitable pH and tonicity to minimize irritation of the ocular surface and adverse effects. Often, the characteristics of excipients are multi-faceted, allowing them to perform more than one of these key functions.

Preservatives have been an essential component of multi-dose formulations, and can be classified according to their chemical characteristics, such as detergent (Polyquad), oxidizing (Purite) and chelating (edetate disodium) agents. Compounds such as EDTA have multiple functions, acting as a buffer for free divalents and preventing their buildup in the cornea, while also enhancing the antimicrobial action of other preservatives. Perhaps the most widely used preservative is benzalkonium chloride, a highly effective antimicrobial that’s stable at a wide range of pH and temperature. While generally well-tolerated, there may be a concern in some patients that chronic use of one or multiple BAK-preserved topical medications may lead to ocular surface damage. Conversely, there
have been many studies demonstrating the benefits and safety of this agent.1 Overall, concerns about preservative effects have fueled the growing trend toward the use of preservative-free, single-dose formulations.

Control of pH through the addition of buffers is necessary not only for comfort, but also for drug stability and solubility. Since tear fluid has a very low buffering capacity, ophthalmic formulations contain excipients that maintain a pH range of 4.75 to 7.40. Topical products also require adjustment of tonicity close to that of natural tears. Generally, a range of 0.5% to 2% saline tonicity is well-tolerated. Irritating hypertonic solutions can induce tearing, which increases tear outflow and reduces the concentration and efficacy of the drug in the tears, while hypotonic solutions are often used effectively in tear substitutes to compensate for the high tonicity in the tears of dry-eye subjects.

Some excipients increase drug permeability and residence time in ocular tissues by enhancing corneal permeability, either by modifying the continuity of the epithelium, changing cell-to-cell junctions or altering the lipid/protein components of cell membranes. Often these effects are mediated by the same compounds that act as preservatives or buffers: chelating agents (EDTA); preservatives (BAK); surfactants (polyoxol 40); tonicity agents (NaCl, propylene glycol); and bile acid salts exhibit these properties, again lending credence to the multi-tasking nature of many excipients.2,3

Vehicular Variation
Topical instillation is the primary mode of administration for the treatment of anterior segment diseases.4 Conventional products such as aqueous drops and solutions are relatively simple to formulate, have minimal storage limitations and are relatively easy to administer. Conversely, delivery and bioavailability are hampered by the rapid clearance and fluid turnover intended to maintain a stable tear film. The therapeutic dose delivered by a drop is quickly reduced by the action of blinking and nasolacrimal drainage. Only about 20 percent of the dose is retained in the pre-corneal pocket,5 and less than 5 percent of that dose reaches deeper ocular tissues.6 A key role of inactive constituents is to combat this physiological drive to clear added agents, and to prolong the effective residence time of the active drugs.

Ointments contain a non-irritating solid or semisolid hydrocarbon base with a melting point close to human body temperature, so that the combination of temperature and lid action yields an even distribution across the ocular surface. As we would expect, compared to ophthalmic solutions, ointments typically provide a longer contact time.7 Ointments are usually applied at night before bed to minimize the blurred vision that occurs when the formulation spreads over the cornea, distorting optical quality. Use of an ointment lubricant right before bedtime is especially effective for individuals with dry eye, as the eye can recover during the night from the irritation and keratitis suffered all day because of an unstable and insufficient tear film. The ointment’s micro-emulsion residence time is longer than daytime solutions, and the effects on vision aren’t problematic during sleep.

Solubility enhancement is an important strategy when developing ophthalmic medications. Many drugs are poorly soluble in water, and substances must be added to increase solubility, raise the therapeutic concentration and improve bioavailability. Emulsions are oil and water mixtures that are homogenized to maintain uniformity. Emulsifying and suspending agents are added to a commercial ophthalmic emulsion such as Durezol (difluprednate) to enhance dispersion of the hydrophobic active ingredient from the oil phase into the aqueous mixture, creating a uniform product when shaken.7 Additives that improve solubility include certain surfactants, caffeine, nicotinamide derivatives and cyclodextrins.8-11
Micro-emulsions improve drug permeation across the cornea and provide extended drug release that reduces the frequency of administration. These formulations are dispersions of oil and water that require surfactants and co-surfactants to enhance stability and penetration into deeper layers of ocular structures. Additionally, micro-emulsions possess low surface tension that aids in corneal spreading and mixing with the pre-corneal tear film. Despite the advantage of extended release and residence time, potential toxicity associated with high concentrations of surfactants may restrict their use.

For other hydrophobic drugs, an alternative to ointments or emulsions is the ophthalmic suspension, such as those used in Lotemax (loteprednol etabonate 0.5%) or Azopt (brinzolamide 1%). These include solid preparations that, when reconstituted, result in a suspension. The insoluble drug is made in a micronized form, and is dispersed in a suitable vehicle that contains excipients such as suspending agents, buffers and preservatives to improve solubility and prevent irritation of the cornea.11 The limitation of suspensions, like emulsions, is that they must be shaken well before instillation.

Improved Formulations
Synthetic and natural polymers can be added to create a gel-like formulation; these improve the viscous and muco-adhesive properties of the drop, increase its residence time on the ocular surface, and slow its rapid dilution and drainage caused by tear-film turnover. Like ointments, these formulation enhancers melt at room temperature to release their constituents, but problems with blurred vision are less frequent. Many excipients possess multiple and overlapping properties, therefore combining various polymers holds promise for improved efficacy and greater compliance. Such additions can also lead to an advantageous reduction in dosing frequency.12,13 Pilocarpine and some artificial tears are examples available in gel form.

Polymeric gels are classified into two groups: preformed and in situ forming, both of which are aimed to improve bioavailability. Preformed gels behave as simple viscous solutions that don’t undergo modification after administration. In situ gelling systems contain polymers that undergo a solution-to-gel phase transition, forming a viscoelastic gel in response to external factors such as temperature, pH and the ionic strength in the tear film. These gels provide sustained drug release, prolong corneal contact time and require less frequent applications.14

Primarily developed as injectables, hydrogels are also being investigated as topical drops to reduce dosing frequency of IOP-lowering medications.15

Colloidal systems are a liquid-retention drug delivery paradigm that employs a drug-loaded polymer carrier. Colloids consist of particles suspended in an aqueous solution that range in size from 10 to 400 nm. Corneal epithelial cells take up the particles by endocytosis. Colloidal forms include liposomes, nanoparticles and niosomes. These carriers are biodegradable and can be an alternative to implants that have to be removed surgically.

On the Horizon
In general, the next push of innovation involves chemical modifications of established carriers to revise or improve their formulation enhancing properties. For example, Novaliq (Heidelberg, Germany) is developing an innovative pharmaceutical formulation platform based on semifluorinated alkanes.16 These SFAs can be used in various routes of administration to enhance drug efficacy. One such application, CyclASol, is a novel, non-aqueous and preservative-free formulation designed to enhance cyclosporine efficacy in dry eye. SFA in an aqueous formulation allows for delivery of the hydrophobic cyclosporine as a clear liquid, and is designed to improve tolerability and potentially reduce any blurring associated with emulsion-based formulations.

Another example of a new type of inactive ingredient comes from Kala Pharmaceuticals (Waltham, Mass.), which is developing a colloidal mucus-penetrating particle designed to enhance retention time by reducing mucus clearance of topically applied therapeutics. When applied to the surface of the eye, the particles spread out on the ocular surface and embed into the mucin layer, creating a depot of drug to diffuse into ocular tissues. Kala has conducted trials using a number of agents as treatments for conditions including postop cataract surgery inflammation, dry eye and meibomian gland disease, so this formulation technology should be in the pharmacy soon.
Drug development will always be a process of iterative refinement. It’s important to keep in mind that progress doesn’t always mean new therapeutics; just as often, improvements focus on solubility, enhanced retention or other means to maximize the net effect of an agent. There are many paths to success, and all have value.  REVIEW

Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Mr. Rimmer is a medical writer at Ora Inc. Dr. Hollander is chief medical officer at Ora, and assistant clinical professor of ophthalmology at the Jules Stein Eye Institute at the University of California, Los Angeles.

1. Berdy GJ, Abelson MB, Smith LM, George MA. Preservative-free artificial tear preparations. Assessment of corneal epithelial toxic effects. Arch Ophthalmol 1992;110:4:528-32.
2. Chung S-H, Lee SK, Cristol SM, et al. Impact of short-term exposure of commercial eyedrops preserved with benzalkonium chloride on precorneal mucin. Molecular vision 2006;12:415-421.
3. Morrison PW, Khutoryanskiy VV. Enhancement in corneal permeability of riboflavin using calcium sequestering compounds. International journal of pharmaceutics 2014;472:1:56-64.
4. Nisha S, Deepak K. An insight to ophthalmic drug delivery system. Int J Pharm Stud Res  2012;3:2:9-13.
5. Schoenwald RD. Ocular drug delivery. Clinical pharmacokinetics 1990;18:4:255-269.
6. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. The AAPS journal 2010;12:3:348-360.
7. Morrison PW, Khutoryanskiy VV. Advances in ophthalmic drug delivery. Ther Deliv 2014;5:12:1297-315.
8. Liang H, Brignole F, Rabinovich-Guilatt L, et al. Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions. Inv Ophthalmol Vis Sci 2008;49:13:2357-2357.
9. Evstigneev M, Evstigneev V, Santiago AH, Davies DB. Effect of a mixture of caffeine and nicotinamide on the solubility of vitamin (B 2) in aqueous solution. Eur J Pharm Sci 2006;28:1:59-66.
10. Morrison PW, Connon CJ, Khutoryanskiy VV. Cyclodextrin-mediated enhancement of riboflavin solubility and corneal permeability. Molecular pharmaceutics 2013;10:2:756-762.
11. Coffman RE, Kildsig DO. Hydrotropic solubilization—mechanistic studies. Pharmaceutical research 1996;13:10:1460.
12. Ali Y, Lehmussaari K. Industrial perspective in ocular drug delivery. Advanced drug delivery reviews 2006;58:11:1258-1268.
13. Rajasekaran A, Kumaran K, Preetha JP, Karthika K. A comparative review on conventional and advanced ocular drug delivery formulations. International Journal of PharmTech Research 2010;2:1:668-674.
14. Bonacucina G, Cespi M, Mencarelli G, Giorgioni G, Palmieri GF. Thermosensitive self-assembling block copolymers as drug delivery systems. Polymers 2011;3:2:779-811.15.
15. Yang H, Leffler CT. Hybrid dendrimer hydrogel/poly(lactic-co-glycolic acid) nanoparticle platform: an advanced vehicle for topical delivery of antiglaucoma drugs and a likely solution to improving compliance and adherence in glaucoma management. J Ocul Pharmacol Ther 2013;29:2:166-72.
16. Gehlsen U, Braun T, Notara M, et al. A semifluorinated alkane (F4H5) as novel carrier for cyclosporine A: Graefes Arch Clin Exp Ophthalmol 2017 Jan 14. [Epub ahead of print]