The term demulcent is often used rather loosely—an agent with demulcent properties is one that soothes inflamed or otherwise irritated areas of the epithelium. More specifically, a demulcent usually accomplishes this symptom amelioration by targeting and protecting mucus membranes with its oily or mucilaginous consistency. Falling under the more general heading of "lenitives" (substances providing any sort of relief from pain or discomfort), demulcents should not be confused with emollients—the latter provide a similar soothing action for internal surfaces, while demulcents are agents exclusively providing alleviation of external discomfort.
Most commonly incorporated in artificial tears used to manage dry eye, ophthalmic demulcents are usually expected to lubricate, as well as soothe, the ocular surface. In fact, the term "lubricant" is used interchangeably with "demulcent" when labeling ophthalmic products. A demulcent can imbue an artificial tear or other formulation with the ability to enhance ocular surface lubricity, easing the wear and tear on the ocular surface caused by a lid during the blink process. Also, the often mucilaginous makeup of demulcents provides them with a water-binding capacity that can help keep the ocular epithelium hydrated.
The U.S. Food and Drug Administration recognizes six categories of ophthalmic demulcents, with each category containing one or more compounds: cellulose derivatives; dextran 70; gelatin; liquid polyols; polyvinyl alcohol and povidone. Cellulose derivatives and polyols are the demulcents most frequently used as active or supplementary components of new tear substitutes. Every compound in the U.S. FDA monograph of ophthalmic agents that appears in the Code of Federal Regulations is assigned a range of concentration—a demulcent contained in a tear substitute must remain within this range in order for the eye drop to be allowed by the FDA as an over-the-counter formulation.3 In some cases these concentration ranges have not been arrived at empirically—there are no dose-response curves supporting the ranges. It is acceptable for an ophthalmic preparation to contain up to three monographed demulcents of any type, and in some cases, as with dextran 70, combination with another demulcent is required. One or more (again, up to three) demulcents may additionally be combined with either a single ophthalmic vasoconstrictor or a vasoconstrictor/astringent combination to yield a formulation with multiple ingredients with different actions. This has become more common recently, as evidence continues to suggest the benefit of incorporating demulcents into products that target ocular allergy; they have traditionally been used more in artificial tears for chronic and acute dry eye, contact lens care solutions and similar formulations. The four categories of demulcents that may be included in these preparations can differ in many ways—for instance, in terms of concentration, action or implementation, though soothing ocular irritation is the ultimate goal in each case.
Here's a look at each demulcent category:
• Cellulose derivatives. These have become popular active ingredients for tear substitutes in recent years. In addition to providing a transient palliative effect on surface irritation, they can be used to enhance the viscosity of a preparation to theoretically increase residence time. The most notable and widely used demulcents of this class include carboxymethylcellulose sodium (CMC) and hydroxypropyl methylcellulose (HPMC). All monographed cellulose derivatives are allowable in over-the-counter ophthalmic formulations in concentrations between 0.2% and 2.5%. HPMC is found in, among other products, the GenTeal (Novartis) line of artificial tears. GenTeal Mild is an artificial tear intended for patients with only early-stage signs and symptoms of dry eye, and therefore it contains only the lowest possible concentration of HPMC (0.2%). GenTeal products aimed at more advanced dry-eye sufferers contain a 0.3% HPMC concentration. Drops containing HPMC can be formulated as oil-in-water emulsions, and the mucoadhesive properties of the polymer in combination with an oil can help supplement both the mucin and lipid components of the tear film.4 According to a study presented at the Southeastern Council of Optometry meeting, HPMC is also a popular component of contact lens solutions due to its water-retentive abilities and a molecular structure that prevents it from penetrating the lens itself.
These properties allow for other applications. In a recent study, an HPMC-containing gel formulation maintained corneal clarity while serving as a wetting and lubricating agent in several cases of small-gauge cataract surgery. (Pruzon J, et al. IOVS 2006;47: ARVO E-Abstract 686)
CMC is a common demulcent that can be used to increase the viscosity of an ophthalmic formulation, though at the risk of making an eye drop cause post-instillation blurring. Like HPMC, CMC has a very high molecular weight. The active agent in the Refresh (Allergan) line of artificial tears, CMC is found in 0.5% concentrations in the products designed for early-stage dry-eye sufferers. That concentration is doubled (to 1%) in Refresh Liquigel, a much more viscous tear substitute intended to offer greater relief for dry-eye signs and symptoms for patients with more advanced cases. TheraTears (Advanced Vision Research) is an artificial tear that contains a lower, 0.25% concentration of CMC, making for a more free-flowing drop. In addition to CMC and HPMC, other cellulose derivative monographed demulcents include similar polymers: hydroxyethyl cellulose and methylcellulose.
• Dextran 70. This is a high-molecular-weight polysaccharide that constitutes its own category of demulcent. A primarily safe compound that finds many applications that are medical, commercial and even veterinary in nature, dextran is only capable of enhancing the demulcent qualities of an over-the-counter formulation when used in combination with another monographed demulcent, usually HPMC. It is most notably incorporated into the Tears Naturale (Alcon) line of lubricant eye drops, in which 0.3% HPMC and 0.1% dextran 70 act simultaneously to create a viscous and soothing drop. The number 70 refers to the 70-kilodalton molecular weight of the macromolecule—in the Tears Naturale formulation, this high molecular weight of the dextran constituent helps allow for a relatively long, two-hour retention time for the drop.5 Dextran 70 may only be used in a 0.1% concentration in monographed ophthalmic preparations.
• Gelatin. Though monographed for use as an ophthalmic demulcent, gelatin is seldom included in ophthalmic formulations for this purpose. A more common ophthalmic application of gelatin is in the form of intracanalicular implants for inhibiting tear drainage in dry-eye patients. It is also an ingredient in some oral-delivery capsules intended to improve ocular-surface or tear-film health through delivery of components such as omega 3 fatty acids.
Even in the case of gelatinous tear substitutes, the gel structure is not attained through inclusion of gelatin itself, but rather through a gelling agent like HP-Guar, a high concentration of another demulcent or a carbopol-type gel. Gelatin is nevertheless a reliable viscosity agent for ophthalmic formulary purposes, and is allowable in a 0.01% concentration in over-the-counter products.
• Liquid polyols. The fourth category of monographed ophthalmic demulcents includes five different liquid polyols. Polyols are sugar-like hydrogenated carbohydrates that are also called polyhydric alcohols. The most notable application of these in current ophthalmic products is the inclusion of propylene glycol 0.3% (PG) and polyethylene glycol 400 0.4% (PEG 400) in the aqueous tear Systane (Alcon) and the gel Systane Free. Because polyols are not as prone to increasing viscosity as cellulose derivatives, they may be used in combination with a gelling agent. In the Systane line, this is accomplished with the inclusion of HP-Guar, which combines with the two liquid demulcents to form a cross-linked mucomimetic layer that can help protect the corneal surface and allow for epithelial self-repair.5 A comparative study demonstrated that a tear substitute containing PG and PEG 400 provided better lubricity than a tear containing HPMC, which in turn was more effective at creating lubricity between two moving surfaces than a product containing CMC.6
All of the polyhydric alcohol demulcents are allowable in concentrations ranging from 0.2% to 1% in over-the-counter formulations. Glycerin is usually used in 0.2% or 0.3% concentrations combined with other lubricants, although in some instances it may be used as the only demulcent in a product when thickly concentrated (1% concentration). Another monographed demulcent often used in combination with other agents is polysorbate 80, which is usually incorporated into oil emulsion drops such as Soothe (Alimera Sciences) and Refresh Endura (Allergan). Oil emulsions generally target the lipid layer of the tear film, which can become depleted, particularly in those dry-eye patients suffering from meibomian gland dysfunction. Both glycerin and polysorbate 80 are also included as inactive ingredients in Restasis (Allergan), the dry-eye prescription product utilizing the active agent cyclosporine A. Polyethylene glycol 300 (PEG 300) is the fifth and final monographed demulcent in the polyols category.
• Polyvinyl alcohol. PVA was one of the original non-saline lubricants included in artificial tears dating back to the 1980s. Effective as a solo or combinative agent, and allowable in concentrations ranging from 0.1% to 4%, polyvinyl alcohol was a reliable all-purpose lubricant for many years.
Although most new dry-eye formulations opt for more viscous or lubricating demulcents, polyvinyl alcohol is still a primary component in some hypotonic tear solutions such as AKWA Tears (Akorn) and HypoTears (Novartis). In the former formulation it acts alone, and in the latter it's combined with PEG 400. Polyvinyl alcohol is also used in some soft contact lens care products, and PVA hydrogels have even been tested as contact lens materials.7 In Murine Tears (Prestige Brands), which targets dry eye, a 0.5% concentration of PVA acts in conjunction with another standard ophthalmic lubricant, povidone (in a 0.6% concentration).
• Povidone. This demulcent, also known as polyvinylpyrrolidone, has numerous applications and, like dextran 70, is sometimes used medically to expand blood plasma. More commonly, povidone is combined with iodine to form povidone-iodine complex, a potent epithelial antiseptic that is capable of being used for topical ophthalmic antiseptic purposes. Povidone is a traditional monographed demulcent, allowable in concentrations ranging from 0.1% to 2%, and has recently seen positive results in a new capacity—as a lubricating and soothing component in ocular anti-allergy drops.
A novel anti-allergy formulation, olopatadine 0.2% (Alcon), contains the demulcent povidone. As compared to Patanol (olopatadine 0.1%, Alcon), the increased concentration in the reformulated drop gives it an impressive 24-hour duration of action—allowing for once-a-day dosing—yet it retains safety and comfort levels comparable to Patanol.8 The inclusion of povidone has facilitated this success both by acting as a lubricating agent for those patients with allergy and concomitant ocular surface damage, and by enhancing the solubility of olopatadine. This novel formulation of olopatadine, along with the anti-allergy drop azelastine (Optivar, MedPointe), which contains the lubricant HPMC, should help to pave the way for the incorporation of demulcents into ocular anti-allergy products.
Ophthalmic demulcents are vital components of both over-the-counter and prescription formulations used for managing dry eye, allergy and for caring for contact lenses. They may be used to thicken a drop or to lubricate the epithelium, but they always contribute to soothing the symptoms of surface irritation. Being familiar with the classes of demulcents and their useful and allowable concentrations can help any clinician better treat or manage a patient's condition. Knowledge is power, and with the mystery surrounding demulcents now cleared up, you can handle your patients' ocular discomfort more effectively.
Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Mr. Anderson is a medical writer at Ophthalmic Research Associates in North Andover.
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3. Code of Federal Regulations. Title 21, Vol. 5, Sec. 349.12,349.3,349.6.
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