REVIEW TherapeuticTopics
`
`A look at the
`
`varieties of this
`
`common agent
`
`and how they can
`
`help soothe
`
`patients’ eyes.
`
`Demystifying
`Dumulcents
`
`DRY EYE AND OCULAR ALLERGY ARE
`both conditions that can and often do cause
`ocular surface irritation in those patients that
`suffer from them. Roughly 11 to 22 percent
`of the American population is estimated to
`have signs and symptoms of dry eye,1 while
`another 20 percent or more experience some
`form of ocular allergy.2 The symptoms pro-
`duced by epithelial desiccation or other sur-
`face irritation can greatly affect quality of life
`for afflicted patients. Formulations used to
`combat these symptoms generally turn to a
`group of compounds with a name dating back
`to when our field was a guild, not a profession.
`They turn to the class of soothing agents
`called demulcents. Although the term is
`ancient, the average clinician’s understanding
`of demulcents is minimal.
`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 con-
`sistency. Falling under the more general head-
`ing 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 in-
`ternal surfaces, while demulcents are agents ex-
`clusively providing alleviation of external dis-
`comfort.
`Most commonly incorporated in artificial
`tears used to manage dry eye, ophthalmic de-
`mulcents 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 prod-
`ucts. A demulcent can imbue an artificial tear
`
`Mark B. Abelson, MD, and Russell Anderson
`North Andover, Mass.
`
`or other formulation with the ability to enhance
`ocular surface lubricity, easing the wear and
`tear on the ocular surface caused by a lid dur-
`ing the blink process. Also, the often mucilagi-
`nous 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 rec-
`ognizes six categories of ophthalmic demul-
`cents, 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 sub-
`stitutes. 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 con-
`tained in a tear substitute must remain within
`this range in order for the eye drop to be al-
`lowed by the FDA as an over-the-counter for-
`mulation.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 mono-
`graphed 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 additional-
`ly be combined with either a single ophthalmic
`vasoconstrictor or a vasoconstrictor/astringent
`combination to yield a formulation with multi-
`ple ingredients with different actions. This has
`become more common recently, as evidence
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`patients with only early-stage signs
`and symptoms of dry eye, and there-
`fore it contains only the lowest possi-
`ble concentration of HPMC (0.2%).
`GenTeal products aimed at more
`advanced dry-eye sufferers contain a
`0.3% HPMC concentration. Drops
`
`Ophthalmic Demulcents
`
`Cellulose derivatives
`• Carboxymethylcellulose sodium
`• Hydroxyethyl cellulose
`• Hypromellose
`• Methylcellulose
`Dextran 70
`
`Gelatin
`Polyols (liquid)
`• Glycerin
`•
`Polyethylene glycol 300
`•
`Polyethylene glycol 400
`•
`Polysorbate 80
`•
`Propylene glycol
`Polyvinyl alcohol
`Povidone
`
`Demulcent
`
`continues to suggest the benefit of in-
`corporating demulcents into products
`that target ocular allergy; they have
`traditionally been used more in artifi-
`cial tears for chronic and acute dry
`eye, contact lens care solutions and
`similar formulations. The four cate-
`gories of de-
`mulcents that may
`be included in
`these preparations
`can differ in many
`ways—for
`in-
`stance, in terms of
`concentration,
`action or imple-
`mentation, though
`soothing ocular
`irritation is the
`ultimate goal in
`each case.
`Here’s a look at
`each demulcent
`category:
`• Cellulose
`d e r i v a t i v e s .
`These have be-
`come popular ac-
`tive ingredients
`for tear substi-
`tutes in recent years. In addition to
`providing a transient palliative effect
`on surface irritation, they can be used
`to enhance the viscosity of a prepara-
`tion to theoretically increase residence
`time. The most notable and widely
`used demulcents of this class include
`carboxymethylcellulose
`sodium
`(CMC) and hydroxypropyl methylcel-
`lulose (HPMC). All monographed cel-
`lulose derivatives are allowable in
`over-the-counter ophthalmic formula-
`tions in concentrations between 0.2%
`and 2.5%. HPMC is found in, among
`other products, the GenTeal (No-
`vartis) line of artificial tears. GenTeal
`Mild is an artificial tear intended for
`
`Allowable concentration
`
`0.2 – 2.5 %
`0.2 – 2.5 %
`0.2 – 2.5 %
`0.2 – 2.5 %
`0.1 % (when used with another
`polymeric demulcent agent in
`this section)
`0.01 %
`
`0.2 – 1 %
`0.2 – 1 %
`0.2 – 1 %
`0.2 – 1 %
`0.2 – 1 %
`0.1 – 4 %
`0.1 – 2 %
`
`ing as a wetting and lubricating agent
`in several cases of small-gauge cata-
`ract 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 molec-
`ular weight. The
`active agent in the
`Refresh (Allergan)
`line of artificial
`tears, CMC
`is
`found in 0.5%
`concentrations in
`the products de-
`signed for early-
`stage dry-eye suf-
`ferers. That con-
`centration is dou-
`bled (to 1%) in
`Refresh Liquigel,
`a much more vis-
`cous tear substi-
`tute intended to
`offer greater relief for dry-eye signs
`and symptoms for patients with more
`advanced cases. TheraTears (Ad-
`vanced Vision Research) is an artificial
`tear that contains a lower, 0.25% con-
`centration 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-mole-
`cular-weight polysaccharide that con-
`stitutes its own category of demulcent.
`A primarily safe compound that finds
`many applications that are medical,
`commercial and even veterinary in
`
`containing HPMC can be formulated
`as oil-in-water emulsions, and the mu-
`coadhesive properties of the polymer
`in combination with an oil can help
`supplement both the mucin and lipid
`components of the tear film.4 Ac-
`cording 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 ap-
`plications. In a recent study, an
`HPMC-containing gel formulation
`maintained corneal clarity while serv-
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`REVIEW TherapeuticTopics
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`nature, dextran is only capable of en-
`hancing the demulcent qualities of an
`over-the-counter formulation when
`used in combination with another
`monographed demulcent, usually
`HPMC. It is most notably incorporat-
`ed 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 molec-
`ular 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 oph-
`thalmic formulations for this purpose.
`A more common ophthalmic applica-
`tion of gelatin is in the form of intra-
`canalicular 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 concentra-
`tion of another demulcent or a car-
`bopol-type gel. Gelatin is nevertheless
`a reliable viscosity agent for oph-
`thalmic formulary purposes, and is
`allowable in a 0.01% concentration in
`over-the-counter products.
`• Liquid polyols. The fourth cate-
`gory of monographed ophthalmic
`demulcents includes five different liq-
`uid 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 cellu-
`lose derivatives, they may be used in
`
`Both glycerin and
`polysorbate 80 are
`included as inactive
`ingredients in Allergan’s
`Restasis, the dry-eye
`prescription product
`using the active agent
`cyclosporine A.
`
`combination with a gelling agent. In
`the Systane line, this is accomplished
`with the inclusion of HP-Guar, which
`combines with the two liquid demul-
`cents to form a cross-linked muco-
`mimetic layer that can help protect
`the corneal surface and allow for
`epithelial self-repair.5 A comparative
`study demonstrated that a tear substi-
`tute containing PG and PEG 400 pro-
`vided better lubricity than a tear con-
`taining HPMC, which in turn was
`more effective at creating lubricity be-
`tween two moving surfaces than a
`product containing CMC.6
`All of the polyhydric alcohol demul-
`cents are allowable in concentrations
`ranging from 0.2% to 1% in over-the-
`counter formulations. Glycerin is usu-
`ally used in 0.2% or 0.3% concentra-
`tions combined with other lubricants,
`although in some instances it may be
`used as the only demulcent in a prod-
`uct when thickly concentrated (1%
`concentration). Another mono-
`graphed demulcent often used in
`combination with other agents is
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`polysorbate 80, which is usually incor-
`porated into oil emulsion drops such
`as Soothe (Alimera Sciences) and
`Refresh Endura (Allergan). Oil emul-
`sions generally target the lipid layer of
`the tear film, which can become de-
`pleted, particularly in those dry-eye
`patients suffering from meibomian
`gland dysfunction. Both glycerin and
`polysorbate 80 are also included as
`inactive ingredients in Restasis (Aller-
`gan), 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 formu-
`lations opt for more viscous or lubri-
`cating demulcents, polyvinyl alcohol is
`still a primary component in some hy-
`potonic tear solutions such as AKWA
`Tears (Akorn) and HypoTears (No-
`vartis). In the former formulation it
`acts alone, and in the latter it’s com-
`bined with PEG 400. Polyvinyl alco-
`hol 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 conjunc-
`tion with another standard ophthalmic
`lubricant, povidone (in a 0.6% con-
`centration).
`• Povidone. This demulcent, also
`known as polyvinylpyrrolidone, has
`numerous applications and, like dex-
`tran 70, is sometimes used medically
`to expand blood plasma. More com-
`monly, povidone is combined with
`iodine to form povidone-iodine com-
`plex, a potent epithelial antiseptic that
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`is capable of being used for topical ophthalmic antiseptic
`purposes. Povidone is a traditional monographed demul-
`cent, allowable in concentrations ranging from 0.1% to
`2%, and has recently seen positive results in a new capaci-
`ty—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 con-
`centration in the reformulated drop gives it an impressive
`24-hour duration of action—allowing for once-a-day dos-
`ing—yet it retains safety and comfort levels comparable to
`Patanol.8 The inclusion of povidone has facilitated this suc-
`cess 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 for-
`mulation of olopatadine, along with the anti-allergy drop
`azelastine (Optivar, MedPointe), which contains the lubri-
`cant HPMC, should help to pave the way for the incorpo-
`ration 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 con-
`centrations 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
`RO
`handle your patients’ ocular discomfort more effectively.
`
`Dr. Abelson, an associate clinical professor of ophthal-
`mology at Harvard Medical School and senior clinical sci-
`entist at Schepens Eye Research Institute, consults in oph-
`thalmic pharmaceuticals. Mr. Anderson is a medical writer
`at Ophthalmic Research Associates in North Andover.
`
`1. Brewitt H, Sistani F. Dry eye disease: The scale of the problem. Surv
`Ophthalmol 2001;45:199-201.
`2. Abelson MB, Smith L, Chapin M. Ocular allergic disease: Mechanisms, dis-
`ease sub-types, treatment. Ocular Surface 2003;1:3:38-60.
`3. Code of Federal Regulations. Title 21, Vol. 5, Sec. 349.12,349.3,349.6.
`4. Rieger G. Lipid-containing eye drops: A step closer to natural tears.
`Ophthalmologica 1990;201:4:206-212.
`5. Palfalvi M, Kahan IL. Efficacy and retention time of a new tear substitute.
`Acta Ophthalmol (Copenh) 1993;71:6:836-8.
`6. Ubels JL, Clousing DP, Van Haitsma TA, et al. Pre-clinical investigation of
`the efficacy of an artificial tear solution containing hydroxypropyl-guar as a
`gelling agent. Curr Eye Res 2004;28:6:437-44.
`7. Hyon SH, Cha WI, Ikada Y, Kita M, Ogura Y, Honda Y. Poly(vinyl alcohol)
`hydrogels as soft contact lens material. J Biomater Sci Polym Ed. 1994;5:5:397-
`406.
`8. Abelson MB, Gomes PJ, et al. Clinical efficacy of olopatadine hydrochloride
`ophthalmic solution 0.2% compared with placebo in patients with allergic con-
`junctivitis or rhinoconjunctivitis: A randomized, double-masked environmental
`study. Clin Ther 2004;26:8:1237-1248.
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