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122_RPK6_TTopics 10/23/06 12:16 PM Page 122 REVIEW Therapeutic Topics
A look at the
DRY EYE AND OCULAR ALLERGY ARE both conditions that can and often do cause Mark B. Abelson, MD, and Russell Anderson
varieties of this
ocular surface irritation in those patients that North Andover, Mass.
suffer from them. Roughly 11 to 22 percent common agent
of the American population is estimated to or other formulation with the ability to enhance have signs and symptoms of dry eye,1 while ocular surface lubricity, easing the wear and and how they can another 20 percent or more experience some
tear on the ocular surface caused by a lid dur- form of ocular allergy.2 The symptoms pro- ing the blink process. Also, the often mucilagi- help soothe
duced by epithelial desiccation or other sur- nous makeup of demulcents provides them face irritation can greatly affect quality of life with a water-binding capacity that can help for afflicted patients. Formulations used to keep the ocular epithelium hydrated.
combat these symptoms generally turn to a The U.S. Food and Drug Administration rec- group of compounds with a name dating back ognizes six categories of ophthalmic demul- to when our field was a guild, not a profession.
cents, with each category containing one or They turn to the class of soothing agents more compounds: cellulose derivatives; dextran called demulcents. Although the term is 70; gelatin; liquid polyols; polyvinyl alcohol and ancient, the average clinician's understanding povidone. Cellulose derivatives and polyols are of demulcents is minimal.
the demulcents most frequently used as active The term demulcent is often used rather or supplementary components of new tear sub- loosely—an agent with demulcent properties is stitutes. Every compound in the U.S. FDA one that soothes inflamed or otherwise irritated monograph of ophthalmic agents that appears areas of the epithelium. More specifically, a in the Code of Federal Regulations is assigned a demulcent usually accomplishes this symptom range of concentration—a demulcent con- amelioration by targeting and protecting mucus tained in a tear substitute must remain within membranes with its oily or mucilaginous con- this range in order for the eye drop to be al- sistency. Falling under the more general head- lowed by the FDA as an over-the-counter for- ing of "lenitives" (substances providing any sort mulation.3 In some cases these concentration of relief from pain or discomfort), demulcents ranges have not been arrived at empirically— should not be confused with emollients—the there are no dose-response curves supporting latter provide a similar soothing action for in- the ranges. It is acceptable for an ophthalmic ternal surfaces, while demulcents are agents ex- preparation to contain up to three mono- clusively providing alleviation of external dis- graphed demulcents of any type, and in some cases, as with dextran 70, combination with Most commonly incorporated in artificial another demulcent is required. One or more tears used to manage dry eye, ophthalmic de- (again, up to three) demulcents may additional- mulcents are usually expected to lubricate, as ly be combined with either a single ophthalmic well as soothe, the ocular surface. In fact, the vasoconstrictor or a vasoconstrictor/astringent term "lubricant" is used interchangeably with combination to yield a formulation with multi- "demulcent" when labeling ophthalmic prod- ple ingredients with different actions. This has ucts. A demulcent can imbue an artificial tear become more common recently, as evidence 122_RPK6_TTopics 10/23/06 12:16 PM Page 123 continues to suggest the benefit of in- patients with only early-stage signs ing as a wetting and lubricating agent corporating demulcents into products and symptoms of dry eye, and there- in several cases of small-gauge cata- that target ocular allergy; they have fore it contains only the lowest possi- ract surgery. (Pruzon J, et al. IOVS traditionally been used more in artifi- ble concentration of HPMC (0.2%).
2006;47: ARVO E-Abstract 686) cial tears for chronic and acute dry GenTeal products aimed at more CMC is a common demulcent that eye, contact lens care solutions and advanced dry-eye sufferers contain a can be used to increase the viscosity of similar formulations. The four cate- 0.3% HPMC concentration. Drops an ophthalmic formulation, though at the risk of making mulcents that may an eye drop cause these preparations can differ in many a very high molec- stance, in terms of 0.2 – 2.5 %
0.2 – 2.5 %
active agent in the 0.2 – 2.5 %
Refresh (Allergan) mentation, though 0.2 – 2.5 %
line of artificial Dextran 70
0.1 % (when used with another
polymeric demulcent agent in
irritation is the concentrations in signed for early- 0.2 – 1 %
stage dry-eye suf- Polyethylene glycol 300
0.2 – 1 %
ferers. That con- Polyethylene glycol 400
0.2 – 1 %
centration is dou- 0.2 – 1 %
d e r i v a t i v e s .
0.2 – 1 %
Refresh Liquigel, 0.1 – 4 %
0.1 – 2 %
cous tear substi- tutes in recent years. In addition to containing HPMC can be formulated offer greater relief for dry-eye signs providing a transient palliative effect as oil-in-water emulsions, and the mu- and symptoms for patients with more on surface irritation, they can be used coadhesive properties of the polymer advanced cases. TheraTears (Ad- to enhance the viscosity of a prepara- in combination with an oil can help vanced Vision Research) is an artificial tion to theoretically increase residence supplement both the mucin and lipid tear that contains a lower, 0.25% con- time. The most notable and widely components of the tear film.4 Ac- centration of CMC, making for a used demulcents of this class include cording to a study presented at the more free-flowing drop. In addition to Southeastern Council of Optometry CMC and HPMC, other cellulose (CMC) and hydroxypropyl methylcel- meeting, HPMC is also a popular derivative monographed demulcents lulose (HPMC). All monographed cel- component of contact lens solutions include similar polymers: hydroxyethyl lulose derivatives are allowable in due to its water-retentive abilities and cellulose and methylcellulose.
over-the-counter ophthalmic formula- a molecular structure that prevents it • Dextran 70. This is a high-mole-
tions in concentrations between 0.2% from penetrating the lens itself.
cular-weight polysaccharide that con- and 2.5%. HPMC is found in, among These properties allow for other ap- stitutes its own category of demulcent.
other products, the GenTeal (No- plications. In a recent study, an A primarily safe compound that finds vartis) line of artificial tears. GenTeal HPMC-containing gel formulation many applications that are medical, Mild is an artificial tear intended for maintained corneal clarity while serv- commercial and even veterinary in 122_RPK6_TTopics 10/23/06 12:16 PM Page 124 REVIEW Therapeutic Topics
nature, dextran is only capable of en- most notable application of these in polysorbate 80, which is usually incor- hancing the demulcent qualities of an current ophthalmic products is the porated into oil emulsion drops such over-the-counter formulation when inclusion of propylene glycol 0.3% as Soothe (Alimera Sciences) and used in combination with another (PG) and polyethylene glycol 400 Refresh Endura (Allergan). Oil emul- monographed demulcent, usually 0.4% (PEG 400) in the aqueous tear sions generally target the lipid layer of HPMC. It is most notably incorporat- Systane (Alcon) and the gel Systane the tear film, which can become de- ed into the Tears Naturale (Alcon) Free. Because polyols are not as pleted, particularly in those dry-eye line of lubricant eye drops, in which prone to increasing viscosity as cellu- patients suffering from meibomian 0.3% HPMC and 0.1% dextran 70 act lose derivatives, they may be used in gland dysfunction. Both glycerin and simultaneously to create a viscous and polysorbate 80 are also included as soothing drop. The number 70 refers inactive ingredients in Restasis (Aller- Both glycerin and
to the 70-kilodalton molecular weight gan), the dry-eye prescription product of the macromolecule—in the Tears polysorbate 80 are
utilizing the active agent cyclosporine Naturale formulation, this high molec- A. Polyethylene glycol 300 (PEG 300) included as inactive
ular weight of the dextran constituent is the fifth and final monographed helps allow for a relatively long, two- ingredients in Allergan's
demulcent in the polyols category.
hour retention time for the drop.5 • Polyvinyl alcohol. PVA was one
Restasis, the dry-eye
Dextran 70 may only be used in a of the original non-saline lubricants 0.1% concentration in monographed included in artificial tears dating back ophthalmic preparations. using the active agent
to the 1980s. Effective as a solo or • Gelatin. Though monographed
combinative agent, and allowable in for use as an ophthalmic demulcent, concentrations ranging from 0.1% to gelatin is seldom included in oph- 4%, polyvinyl alcohol was a reliable thalmic formulations for this purpose.
combination with a gelling agent. In all-purpose lubricant for many years.
A more common ophthalmic applica- the Systane line, this is accomplished Although most new dry-eye formu- tion of gelatin is in the form of intra- with the inclusion of HP-Guar, which lations opt for more viscous or lubri- canalicular implants for inhibiting tear combines with the two liquid demul- cating demulcents, polyvinyl alcohol is drainage in dry-eye patients. It is also cents to form a cross-linked muco- still a primary component in some hy- an ingredient in some oral-delivery mimetic layer that can help protect potonic tear solutions such as AKWA capsules intended to improve ocular- the corneal surface and allow for Tears (Akorn) and HypoTears (No- surface or tear-film health through epithelial self-repair.5 A comparative vartis). In the former formulation it delivery of components such as omega study demonstrated that a tear substi- acts alone, and in the latter it's com- 3 fatty acids.
tute containing PG and PEG 400 pro- bined with PEG 400. Polyvinyl alco- Even in the case of gelatinous tear vided better lubricity than a tear con- hol is also used in some soft contact substitutes, the gel structure is not taining HPMC, which in turn was lens care products, and PVA hydrogels attained through inclusion of gelatin more effective at creating lubricity be- have even been tested as contact lens itself, but rather through a gelling tween two moving surfaces than a materials.7 In Murine Tears (Prestige agent like HP-Guar, a high concentra- product containing CMC.6 Brands), which targets dry eye, a 0.5% tion of another demulcent or a car- All of the polyhydric alcohol demul- concentration of PVA acts in conjunc- bopol-type gel. Gelatin is nevertheless cents are allowable in concentrations tion with another standard ophthalmic a reliable viscosity agent for oph- ranging from 0.2% to 1% in over-the- lubricant, povidone (in a 0.6% con- thalmic formulary purposes, and is counter formulations. Glycerin is usu- allowable in a 0.01% concentration in ally used in 0.2% or 0.3% concentra- • Povidone. This demulcent, also
over-the-counter products. tions combined with other lubricants, known as polyvinylpyrrolidone, has • Liquid polyols. The fourth cate-
although in some instances it may be numerous applications and, like dex- gory of monographed ophthalmic used as the only demulcent in a prod- tran 70, is sometimes used medically demulcents includes five different liq- uct when thickly concentrated (1% to expand blood plasma. More com- uid polyols. Polyols are sugar-like concentration). Another mono- monly, povidone is combined with hydrogenated carbohydrates that are graphed demulcent often used in iodine to form povidone-iodine com- also called polyhydric alcohols. The combination with other agents is plex, a potent epithelial antiseptic that 122_RPK6_TTopics 10/23/06 1:01 PM Page 126 is capable of being used for topical ophthalmic antisepticpurposes. Povidone is a traditional monographed demul-cent, allowable in concentrations ranging from 0.1% to2%, and has recently seen positive results in a new capaci-ty—as a lubricating and soothing component in ocularanti-allergy drops.
A novel anti-allergy formulation, olopatadine 0.2% (Alcon), contains the demulcent povidone. As comparedto Patanol (olopatadine 0.1%, Alcon), the increased con-centration in the reformulated drop gives it an impressive24-hour duration of action—allowing for once-a-day dos-ing—yet it retains safety and comfort levels comparable toPatanol.8 The inclusion of povidone has facilitated this suc-cess both by acting as a lubricating agent for those patientswith allergy and concomitant ocular surface damage, andby enhancing the solubility of olopatadine. This novel for-mulation of olopatadine, along with the anti-allergy dropazelastine (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
handle your patients' ocular discomfort more effectively.RO
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 writerat Ophthalmic Research Associates in North Andover. 1. Brewitt H, Sistani F. Dry eye disease: The scale of the problem. SurvOphthalmol 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 ofthe efficacy of an artificial tear solution containing hydroxypropyl-guar as agelling 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 hydrochlorideophthalmic solution 0.2% compared with placebo in patients with allergic con-junctivitis or rhinoconjunctivitis: A randomized, double-masked environmentalstudy. Clin Ther 2004;26:8:1237-1248.



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