Interactions of Benzalkonium Chloride With Soft and Hard Contact Lenses Jack M.
Chapman, OD, MD; Lisa Cheeks; Keith Green, PhD,
\s=b\ We measured the uptake and washout of benzalkonium chloride, using radioactive tracer, by representative hard and soft contact lenses. Uptake by soft contact lenses after 7 days of continuous exposure is high (30 to 56 \g=m\g/mg of lens weight), with a low percentage of washout in 24 hours (between 0.2% and 1.5% of total uptake). High-water content lenses absorb greater quantities of benzalkonium than do low-water content lenses. Hard lenses take up a much smaller quantity of benzalkonium but release between 30% and 60% of total uptake during washout for 24 hours. Fluorosilicone-acrylate polymer lenses adsorb and release the most preservative, while polymethylmethacrylate lenses (Paragon Optical Inc, Mesa, Ariz) adsorb and release the least. The released benzalkonium from either soft or hard lenses is of a sufficient concentration to be at or above the upper limits of safety.
(Arch Ophthalmol. 1990;108:244-246)
"D enzalkonium chloride is a widely used, cationic preservative present in a variety of topical ophthalmic so¬ lutions and in solutions used to disin¬ fect polymethylmethacrylate (PMMA
[Paragon Optical Ine, Mesa, Ariz])
or
gas permeable (RGP) contact lenses. In lens care solutions the con¬
rigid
centration of benzalkonium varies from 0.004% to 0.01%.' Chlorhexidine digluconate, another preservative, is Accepted for publication October 20, 1989. Departments of Ophthalmology (Drs Chapman and Green and Ms Cheeks) and Physiology and Endocrinology (Dr Green), Medical College of Georgia, Augusta. Reprint requests to Department of Ophthalmology, Medical College of Georgia, Augusta, GA 30912-3400 (Dr Chapman). From the
DSc
absorbed
(taken up within the lens material) rapidly and to a great extent by soft lenses2 but is only adsorbed (taken up only onto the lens surface) by hard lenses to a small degree.3 Ben¬ zalkonium has chemical and physical properties similar to those of chlor¬ hexidine, and its adsorption by RGP
konium concentrations, a carbon 14labeled C-14 benzalkonium chloride was used in representatives of both soft and hard (PMMA and RGP) lenses to measure uptake and release kinet¬ ics.
lenses has been measured.1'4-5 Ben¬ zalkonium is reported not to adsorb to RGP or PMMA lenses but to be ab¬ sorbed strongly by soft lenses.1-5 Con¬ siderable differences have been re¬ ported in the adsorption of benzalko¬ nium by Boston II lenses (Polymer
Unworn hard and soft lenses were ob¬ tained from manufacturers and immersed in solutions containing radioactive 14C-labeled C-14 benzalkonium chloride (New England Nuclear Corp, Boston, Mass) at a concentration of 0.005%. Hard lenses were bathed in Wet-N-Soak (Allergan, Irvine, Calif), which contains benzalkonium chlo¬ ride at 0.004%, resulting in a final 0.009% solution after the addition of radioactive material; soft lenses were bathed in Unisol 4 (CooperVision, San Juan, Puerto Rico) that does not contain nonlabeled benzalko¬ nium, and the addition of radioactive ma¬ terial gave a benzalkonium chloride con¬ centration of 0.005%. The procedure was as follows: lenses were immersed in 20-mL glass scintillation vials containing radioactive uptake solution (Wet-N-Soak or Unisol 4) for a total of 7 days at room temperature, with other glass vials containing only the same uptake solu¬ tion but no lens. All vials were capped securely to prevent evaporation. The glass vial uptake studies were made to measure benzalkonium adsorption to glass, since it might behave like chlorhexidine, which shows glass adsorption.2 At the end of the uptake period, lenses were removed from the solution, rinsed in 0.9% saline solution, and blotted lightly before being transferred to 1 mL of 0.9% saline solution for washout. The latter was conducted for 1 day at room temperature. Lenses were removed from the washout solution, rinsed, and blotted lightly prior to weighing. One hundred-microliter samples of the uptake and washout solution were taken. No determinations were made of any breakdown of benzalko¬ nium because the experiments were per-
Technology Corp, Wilmington, Mass), with at least a fourfold difference iden¬ tified in in vitro studies when lenses are bathed in solutions for up to 21
days.1-5
Benzalkonium is known to
cause
physiological and morphological dis¬ turbances of the corneal epithelium,614 which is not surprising since it is physically restricted to the corneal ep¬ ithelium and conjunctiva alone after topical administration.15" These unde¬
sirable effects of benzalkonium can be minimized through the use of low con¬ centrations in topical ophthalmic so¬ lutions and by reduction in exposure to the agent. Because of the difference in findings of benzalkonium adsorption to contact lenses, the possibility of consumers using the incorrect solution at some stage in the cleaning/disinfecting pro¬ cess for lenses (ie, use of a benzalko¬ nium solution with soft lenses), and the possibility of topical eye drops that contain benzalkonium being used in conjunction with soft contact lenses, we undertook the present studies. To ensure that we measured true benzal-
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MATERIALS AND METHODS
formed entirely in vitro, with no access to tissue where metabolism could occur. Ben¬ zalkonium breakdown was deemed minimal when in contact only with inert materials such as glass and contact lenses. For hard lenses the uptake solution was sampled at the beginning of the uptake pe¬ riod and at intervals over the first 7 days. Final 7-day samples were taken of lens so¬ lutions and glass uptake solutions. Total benzalkonium uptake by hard lenses was calculated by the difference between the 7-day uptake solution value minus the glass uptake solution change, plus the washout value. For soft lenses the uptake solution was also sampled periodically, but due to the rapid absorption of benzalkonium, which reduced the count rate (and concentration) of benzalkonium by about 50%, additional labeled benzalkonium was added to restore the concentration to that of the original so¬ lution. This was performed at 72 and 96 hours after initial placement of the lens in the radioactive solution. One hundred-microliter samples were taken of each solu¬ tion, including parallel glass uptake vials. After washout in saline solution, soft lenses were digested in 3 mL of a 3:1 mixture of concentrated sulfuric acid and nitric acid at 50°C in capped scintillation vials: 100-/jL samples were diluted in 1 mL of distilled water and scintillation fluid was added. To determine the percentage recovery of 14Clabeled benzalkonium, lenses that had not been exposed to labeled benzalkonium were placed in acid mixture together with 100 pL of the uptake solution and digested imme¬ diately. This acid digest was treated in an identical manner to other lens digests. A comparison of the recovered counts with those placed in the vial provided an indica¬ tion of any loss of '"C-labeled benzalkonium due to the acid digest procedure. RESULTS
The recovery of benzalkonium under conditions of acid digestion was 100% ; thus, no correction was required for loss of benzalkonium during acid di¬ gestion. Glass uptake of benzalkonium was undetectable. To calculate total lens uptake, one must take into ac¬ count both the residual-bound benzal¬ konium plus that lost in the 24-hour washout period; by addition of these two numbers it is possible to obtain an estimate of the total amount of ben¬ zalkonium in a lens after 7 days of up¬ take. The data for soft lenses are shown in Table 1. Each type of soft lens showed a large uptake of benzalkonium, with washout ranging from 0.3% to 1% of the total lens uptake. There is more benzalkonium uptake in higher-water content lenses. Although both Acuvue (Johnson & Johnson, Jacksonville, Fla) and B&L 58% (Bausch & Lomb, Roch¬ ester, NY) lenses are made of the same material (etafilcon A), they are manu¬ factured differently, which possibly
Table 1.—Benzaikonium Chloride Kinetics in Soft Lenses Benzalkonium chloride,
Mg/mg of Lens Weight Lens Lens Use Extended wear
Extended wear
Type
(Trade Name)* High water content
Lens
Uptake
Washout
56.81 ± 1.42
0.75 ± 0.04
45.73 ± 2.84
0.42 ± 0.04
30.63 ± 2.48
0.09 ± 0.00
Total Lens
Uptake
57.56 ± 1.43
etafilcon A
(Acuvue) High water content etafilcon A
(B&L 58%) Daily wear
Low water content deltafilcon A
(Aquasight) The manufacturers of the contact lenses are as follows: Acuvue, Johnson & Johnson, Jacksonville. Fla; B&L 58%, Bausch & Lomb, Rochester, NY; and Aquasight, Chanel Laboratories Ine, Norfolk, Va.
Table 2.—Benzalkonium Chloride Kinetics in Hard Lenses Benzalkonium chloride, ¿jg/mg ot Lens
Weight
Total Lens Lens Type Washout Lens Uptake Uptake (Trade Name)* 0.060 ± 0.006 0.020 ± 0.002 0.042 ± 0.005 Polymethylmethacrylate Silicone-acrylate 0.067 0.095 i 0.008 0.030 ± 0.003 polymer (Boston II) Fluorosilicone-acrylate 0.193 ± 0.008 0.031 0.162 ± 0.006 polymer (Fluoroperm 90) *The manufacturers of the contact lenses are as follows: polymethylmethacrylate and Fluoroperm 90, Par¬ agon Optical Inc. Mesa, Ariz, and Boston II, Polymer Technology Corp, Wilmington, Mass.
explains their different behavior
to¬
ward benzalkonium. The lower-water content lens (43% water) did not lose as much benzalkonium as the higherwater content lens (58% water). Hard lenses (Table 2) showed little lens uptake relative to soft lenses, with different degrees of washout on subse¬ quent bathing in 0.9% saline solution. Each type of hard lens adsorbed ap¬ proximately the same amount of ben¬ zalkonium chloride to a maximum of about 0.042 µg/mg of lens weight. Poly¬ methylmethacrylate lenses showed a low benzalkonium chloride washout (0.02 ug/mg of lens weight), followed by the silicone-acrylate polymer lenses, which had three times more benzalkonium loss, and fluorosilicaneacylate polymer lenses, which had the largest washout of about 0.15 Mg/mg of lens weight. COMMENT
Benzalkonium is a mixture of differ¬ alkyl chain lengths, of which C-14 is one representative. While the bio¬ logic activity of different benzalko¬ nium chain lengths may vary,18 the physical and chemical characteristics of each chain length are very similar. There is, therefore, no reason to be¬ lieve that the behavior of any lens to the mixture that constitutes benzalko¬ nium will differ from that seen to C-14 benzalkonium in the present experi¬ ments. Similarly, there is no reason to ent
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suspect that the behavior of the
ra¬
diolabeled benzalkonium toward the lenses would differ from that of unla¬ beled benzalkonium. Although the soft lenses were subjected to variations in benzalkonium concentrations with time, the values obtained represent near-maximal values since the reduc¬ tion from the second replenishment of benzalkonium at 96 hours through 7 days was small. This procedure, of
adding more benzalkonium, was neces¬ sitated by the limited supply of 14C-
labeled benzalkonium. The data indicate large differences between soft and hard lenses toward the adsorption of benzalkonium, as well as differences between lens types within each major subdivision. Soft lenses lose a maximum of 0.75 µg of benzalkonium chloride per milligram of lens weight during washout in 0.9% saline solution. This solution is basic, ie, has a pH less than 7.0, and the washout rate could be influenced by ambient pH of the tears. Assuming that all of the benzalkonium chloride is lost immediately from a 16-mg lens on placement onto an eye with a tear vol¬ ume of 8 ßL, the maximum tear con¬ centration would be 0.12%. This con¬ centration is far above the limits of benzalkonium chloride concentrations used in topical ophthalmic medica¬ tions, namely, 0.004% to 0.02%, and would be predicted to induce adverse effects on the corneal epithelium. In
addition, the cornea and conjunctiva take up benzalkonium and then release it slowly into the tear film.1517 A soft lens, therefore, could undergo constant recycling of benzalkonium from the lens to the tissue. Implicit in this calculation, however, is the fact that the kinetics of released benzalkonium would be exactly the same as that found after drop applica¬ tion. Benzalkonium could be held in the tear film under the lens, thereby prolonging exposure time and raising the possibility of increasing tissue up¬ take, thus enhancing any adverse ef¬ fects. Based on the uptake data, which are not available at short time inter¬ vals, one would predict that if a patient used an eye drop containing benzalko¬ nium while wearing soft contact lenses a proportion of the benzalkonium re¬ maining in the tear film after the first blink would be adsorbed to the lens. Given the avidity of the lens for ben¬ zalkonium, it would be surprising if the preservative would be lost imme¬ diately from the lens. While the above reasoning may be true for a lens not
previously exposed
to
benzalkonium,
the situation would become worse af¬ ter repeated lens exposure to benzal¬ konium. The behavior of benzalkonium would probably be similar to that seen with chlorhexidine,2 where a cyclic phenomenon occurs in which the pre¬ servative is taken up by the lens and a little is lost during wearing, with a continued buildup of chlorhexidine un¬ til all the absorptive sites are satu¬ rated. If accidental exposure of extendedwear lenses occurred to a benzalko-
nium-containing solution (eg, an artifical tear solution), the uptake/release
characteristics of the lens would be conducive to a situation of enhancing the possibility of adverse effects. Re¬ peated exposure to benzalkonium would allow uptake and subsequent release that could provide sufficiently high bathing concentrations of ben¬ zalkonium chloride to cause some of the adverse effects noted in the litera¬ ture even at 0.02%.19 The amount of benzalkonium lost from PMMA or RGP lenses is small (about 0.4% of that lost from soft lenses) and would give rise to low tear film concentrations, even assuming that all of the benzalkonium was re¬ leased instantly. The data indicate that the majority of adsorbed ben¬ zalkonium is lost within 24 hours of washout. The lens uptake values for silicone-acrylate polymer lenses con¬ form to those found in other studies45 and support the notion that benzalko¬ nium uptake does not continue un¬ abated, as has been suggested.1 The amount of benzalkonium chlo¬ ride washout from hard lenses is at a maximum from the fluorosiliconeacrylate polymer type that, using the same calculations for tear film volume, etc, as for soft lenses, would result in a tear film concentration of about 0.02%. This is at the maximum limit of the concentration used in topical eye drops where adverse effects on the conjunc¬ tiva, tear film, and corneal epithelium have been noted.20 If adverse effects are noted with those lenses, for which benzalkonium is used in the preserva¬ tive solutions, then any contact of
benzalkonium with extended-wear lenses, where the benzalkonium loss is greater, would be detrimental. The present data indicate that ben¬ zalkonium is taken up avidly by soft
lenses, as suggested previ¬ ously,21 but that only a small fraction is contact
lost to the environment on washout. The adsorption or absorption of ben¬ zalkonium to the different lens types is a function of the number of binding sites available for the detergent on the particular lens material. All the ben¬ zalkonium in the water volume of the highest-water content lens only amounts to about 3% of the benzalko¬ nium washout, indicating that most of the washout benzalkonium is from binding sites on the lens material. This total amount of washout benzalkoni¬ um, however, exceeds acceptable limits of safety tolerance. Hard contact lenses, in contrast, take up a very small amount of benzalkonium, with a cor¬ responding loss on washout that ap¬ proaches the upper limit of safety. Calculations, based on the uptake and washout data, indicate that tear film concentrations of benzalkonium, such as after eye drop use in the presence of soft contact lenses or after inadvertent use of a benzalkonium-containing so¬ lution to soak or rinse the lens, could result in adverse effects to the sur¬ rounding tissues. The study was supported in part by research grant EY04558 (KG) from the National Eye Institute, Bethesda, Md, and in part by an unre-
stricted departmental award from Research to Prevent Blindness Inc, New York, NY. We thank X-CEL Contacts Inc, Atlanta, Ga, for their generous donation of the contact lenses and bathing solutions.
References 1. Rosenthal P, Chou MH, Salamore JC, Israel SC. Quantitative analysis of chlorhexidine gluconate and benzalkonium chloride adsorption on silicone/acrylate polymers. CLAO J. 1986;12:43\x=req-\ 50. 2. MacKeen DL, Green K. Chlorhexidine kinetics of hydrophilic contact lenses. J Pharm Pharmacol. 1978;30:678-682. 3. MacKeen DL, Green K. Chlorhexidine kinetics in hard contact lenses. J Pharm Pharmacol.
1979;31:714-716. 4. Wong MP, Dziabo AJ, Kiral RM. Adsorption of benzalkonium chloride by RGP lenses. Contact
Lens Forum. November 1986:25-32. 5. Wong MP, Dziabo AJ, Kiral RM. Dynamics of BAK adsorption by silicone acrylate lenses. Contact Lens Spectrum. November 1986:49-53. 6. Green K, Tonjum AM. The effect of benzalkonium chloride on the electropotential of the rabbit cornea. Acta Ophthalmol. 1975;53:348-357. 7. Green K, Downs SJ. Ocular penetration of pilocarpine in rabbits. Arch Ophthalmol. 1975; 93:1165-1168. 8. Green K, Hull DS, Vaughn ED, Malizia A, Bowman K. Rabbit endothelial response to ophthalmic preservatives. Arch Ophthalmol. 1977; 95:2218-2221. 9. Green K, Johnson RE, Chapman JM, Nelson
E, Cheeks L. Surfactant effects on the rate of rab-
bit corneal epithelial healing. J Toxicol Cutaneous Ocular Toxicol. 1989;8:251-267. 10. Burstein NL, Klyce SD. Electrophysiologic and morphologic effects of ophthalmic preparations on rabbit cornea epithelium. Invest Ophthalmol. 1977;16:899-911. 11. Burstein NL. Preservative cytotoxic threshold for benzalkonium chloride and chlorhexidine digluconate in cat and rabbit corneas. Invest Ophthalmol Vis Sci. 1980;19:308-313. 12. Tonjum AM. Permeability of rabbit corneal epithelium to horseradish peroxidase after the influence of benzalkonium chloride. Acta Ophthalmol. 1975;53:335-347. 13. Green K, Tonjum AM. Influence of various agents on corneal permeability. Am J Ophthalmol.
1971;72:897-905.
14. Tonjum AM. Effects of benzalkonium chloride upon the corneal epithelium studied with scanning electron microscopy. Acta Ophthalmol.
1975;53:358-366. 15. Green K, Chapman JM, Cheeks L, Clayton RM, Wilson M, Zehir A. Detergent penetration
into young and adult rabbit eyes: comparative pharmacokinetics. J Toxicol Cutaneous Ocular Toxicol. 1987;6:89-107. 16. Green K, Cheeks L, Chapman JM. Surfac-
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 07/01/2015
pharmacokinetics in the eye. In: Saettone MF, Bucci M, Speiser PP, eds. Ophthalmic Drug Delivery: Biopharmaceutical, Technological and Clinical Aspects, 1988. Padua, Italy: Lithania Press; 1987:171-177. 17. Champeau EJ, Edelhauser HE. Effect of ophthalmic preservatives on the ocular surface: conjunctival and corneal uptake and distribution tant
of benzalkonium chloride and chlorhexidine digluconate. In: Holly F, ed. The Preocular Tear Film in Health, Disease, and Contact Lens Wear. Lubbock, Tex: Dry Eye Institute Inc; 1987:292-302. 18. Erhart M, Zilliox P, De Burlet GL, Andermann G. Differences in ocular toxicity and antimicrobial activity of benzalkonium chloride. In: Hockwin O, ed. Drug-Induced Ocular Side Effects and Ocular Toxicology. New York, NY: S Karger AG; 1987:145-151. 19. Gasset A. Benzalkonium chloride toxicity to the human cornea. Am J Ophthalmol. 1977; 84:169-171. 20. Bier N, Lowther GE. Contact Lens Correction. Stoneham, Mass: Butterworths; 1977. 21. Richardson NE, Davies DJG, Meakin BJ, Norton DA. The interaction of preservatives with
polyhydroxyethylmethacrylate (poly HEMA).
J Pharm Pharmacol. 1978;30:469-475.
Chapman, OD, MD; Lisa Cheeks; Keith Green, PhD,
\s=b\ We measured the uptake and washout of benzalkonium chloride, using radioactive tracer, by representative hard and soft contact lenses. Uptake by soft contact lenses after 7 days of continuous exposure is high (30 to 56 \g=m\g/mg of lens weight), with a low percentage of washout in 24 hours (between 0.2% and 1.5% of total uptake). High-water content lenses absorb greater quantities of benzalkonium than do low-water content lenses. Hard lenses take up a much smaller quantity of benzalkonium but release between 30% and 60% of total uptake during washout for 24 hours. Fluorosilicone-acrylate polymer lenses adsorb and release the most preservative, while polymethylmethacrylate lenses (Paragon Optical Inc, Mesa, Ariz) adsorb and release the least. The released benzalkonium from either soft or hard lenses is of a sufficient concentration to be at or above the upper limits of safety.
(Arch Ophthalmol. 1990;108:244-246)
"D enzalkonium chloride is a widely used, cationic preservative present in a variety of topical ophthalmic so¬ lutions and in solutions used to disin¬ fect polymethylmethacrylate (PMMA
[Paragon Optical Ine, Mesa, Ariz])
or
gas permeable (RGP) contact lenses. In lens care solutions the con¬
rigid
centration of benzalkonium varies from 0.004% to 0.01%.' Chlorhexidine digluconate, another preservative, is Accepted for publication October 20, 1989. Departments of Ophthalmology (Drs Chapman and Green and Ms Cheeks) and Physiology and Endocrinology (Dr Green), Medical College of Georgia, Augusta. Reprint requests to Department of Ophthalmology, Medical College of Georgia, Augusta, GA 30912-3400 (Dr Chapman). From the
DSc
absorbed
(taken up within the lens material) rapidly and to a great extent by soft lenses2 but is only adsorbed (taken up only onto the lens surface) by hard lenses to a small degree.3 Ben¬ zalkonium has chemical and physical properties similar to those of chlor¬ hexidine, and its adsorption by RGP
konium concentrations, a carbon 14labeled C-14 benzalkonium chloride was used in representatives of both soft and hard (PMMA and RGP) lenses to measure uptake and release kinet¬ ics.
lenses has been measured.1'4-5 Ben¬ zalkonium is reported not to adsorb to RGP or PMMA lenses but to be ab¬ sorbed strongly by soft lenses.1-5 Con¬ siderable differences have been re¬ ported in the adsorption of benzalko¬ nium by Boston II lenses (Polymer
Unworn hard and soft lenses were ob¬ tained from manufacturers and immersed in solutions containing radioactive 14C-labeled C-14 benzalkonium chloride (New England Nuclear Corp, Boston, Mass) at a concentration of 0.005%. Hard lenses were bathed in Wet-N-Soak (Allergan, Irvine, Calif), which contains benzalkonium chlo¬ ride at 0.004%, resulting in a final 0.009% solution after the addition of radioactive material; soft lenses were bathed in Unisol 4 (CooperVision, San Juan, Puerto Rico) that does not contain nonlabeled benzalko¬ nium, and the addition of radioactive ma¬ terial gave a benzalkonium chloride con¬ centration of 0.005%. The procedure was as follows: lenses were immersed in 20-mL glass scintillation vials containing radioactive uptake solution (Wet-N-Soak or Unisol 4) for a total of 7 days at room temperature, with other glass vials containing only the same uptake solu¬ tion but no lens. All vials were capped securely to prevent evaporation. The glass vial uptake studies were made to measure benzalkonium adsorption to glass, since it might behave like chlorhexidine, which shows glass adsorption.2 At the end of the uptake period, lenses were removed from the solution, rinsed in 0.9% saline solution, and blotted lightly before being transferred to 1 mL of 0.9% saline solution for washout. The latter was conducted for 1 day at room temperature. Lenses were removed from the washout solution, rinsed, and blotted lightly prior to weighing. One hundred-microliter samples of the uptake and washout solution were taken. No determinations were made of any breakdown of benzalko¬ nium because the experiments were per-
Technology Corp, Wilmington, Mass), with at least a fourfold difference iden¬ tified in in vitro studies when lenses are bathed in solutions for up to 21
days.1-5
Benzalkonium is known to
cause
physiological and morphological dis¬ turbances of the corneal epithelium,614 which is not surprising since it is physically restricted to the corneal ep¬ ithelium and conjunctiva alone after topical administration.15" These unde¬
sirable effects of benzalkonium can be minimized through the use of low con¬ centrations in topical ophthalmic so¬ lutions and by reduction in exposure to the agent. Because of the difference in findings of benzalkonium adsorption to contact lenses, the possibility of consumers using the incorrect solution at some stage in the cleaning/disinfecting pro¬ cess for lenses (ie, use of a benzalko¬ nium solution with soft lenses), and the possibility of topical eye drops that contain benzalkonium being used in conjunction with soft contact lenses, we undertook the present studies. To ensure that we measured true benzal-
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MATERIALS AND METHODS
formed entirely in vitro, with no access to tissue where metabolism could occur. Ben¬ zalkonium breakdown was deemed minimal when in contact only with inert materials such as glass and contact lenses. For hard lenses the uptake solution was sampled at the beginning of the uptake pe¬ riod and at intervals over the first 7 days. Final 7-day samples were taken of lens so¬ lutions and glass uptake solutions. Total benzalkonium uptake by hard lenses was calculated by the difference between the 7-day uptake solution value minus the glass uptake solution change, plus the washout value. For soft lenses the uptake solution was also sampled periodically, but due to the rapid absorption of benzalkonium, which reduced the count rate (and concentration) of benzalkonium by about 50%, additional labeled benzalkonium was added to restore the concentration to that of the original so¬ lution. This was performed at 72 and 96 hours after initial placement of the lens in the radioactive solution. One hundred-microliter samples were taken of each solu¬ tion, including parallel glass uptake vials. After washout in saline solution, soft lenses were digested in 3 mL of a 3:1 mixture of concentrated sulfuric acid and nitric acid at 50°C in capped scintillation vials: 100-/jL samples were diluted in 1 mL of distilled water and scintillation fluid was added. To determine the percentage recovery of 14Clabeled benzalkonium, lenses that had not been exposed to labeled benzalkonium were placed in acid mixture together with 100 pL of the uptake solution and digested imme¬ diately. This acid digest was treated in an identical manner to other lens digests. A comparison of the recovered counts with those placed in the vial provided an indica¬ tion of any loss of '"C-labeled benzalkonium due to the acid digest procedure. RESULTS
The recovery of benzalkonium under conditions of acid digestion was 100% ; thus, no correction was required for loss of benzalkonium during acid di¬ gestion. Glass uptake of benzalkonium was undetectable. To calculate total lens uptake, one must take into ac¬ count both the residual-bound benzal¬ konium plus that lost in the 24-hour washout period; by addition of these two numbers it is possible to obtain an estimate of the total amount of ben¬ zalkonium in a lens after 7 days of up¬ take. The data for soft lenses are shown in Table 1. Each type of soft lens showed a large uptake of benzalkonium, with washout ranging from 0.3% to 1% of the total lens uptake. There is more benzalkonium uptake in higher-water content lenses. Although both Acuvue (Johnson & Johnson, Jacksonville, Fla) and B&L 58% (Bausch & Lomb, Roch¬ ester, NY) lenses are made of the same material (etafilcon A), they are manu¬ factured differently, which possibly
Table 1.—Benzaikonium Chloride Kinetics in Soft Lenses Benzalkonium chloride,
Mg/mg of Lens Weight Lens Lens Use Extended wear
Extended wear
Type
(Trade Name)* High water content
Lens
Uptake
Washout
56.81 ± 1.42
0.75 ± 0.04
45.73 ± 2.84
0.42 ± 0.04
30.63 ± 2.48
0.09 ± 0.00
Total Lens
Uptake
57.56 ± 1.43
etafilcon A
(Acuvue) High water content etafilcon A
(B&L 58%) Daily wear
Low water content deltafilcon A
(Aquasight) The manufacturers of the contact lenses are as follows: Acuvue, Johnson & Johnson, Jacksonville. Fla; B&L 58%, Bausch & Lomb, Rochester, NY; and Aquasight, Chanel Laboratories Ine, Norfolk, Va.
Table 2.—Benzalkonium Chloride Kinetics in Hard Lenses Benzalkonium chloride, ¿jg/mg ot Lens
Weight
Total Lens Lens Type Washout Lens Uptake Uptake (Trade Name)* 0.060 ± 0.006 0.020 ± 0.002 0.042 ± 0.005 Polymethylmethacrylate Silicone-acrylate 0.067 0.095 i 0.008 0.030 ± 0.003 polymer (Boston II) Fluorosilicone-acrylate 0.193 ± 0.008 0.031 0.162 ± 0.006 polymer (Fluoroperm 90) *The manufacturers of the contact lenses are as follows: polymethylmethacrylate and Fluoroperm 90, Par¬ agon Optical Inc. Mesa, Ariz, and Boston II, Polymer Technology Corp, Wilmington, Mass.
explains their different behavior
to¬
ward benzalkonium. The lower-water content lens (43% water) did not lose as much benzalkonium as the higherwater content lens (58% water). Hard lenses (Table 2) showed little lens uptake relative to soft lenses, with different degrees of washout on subse¬ quent bathing in 0.9% saline solution. Each type of hard lens adsorbed ap¬ proximately the same amount of ben¬ zalkonium chloride to a maximum of about 0.042 µg/mg of lens weight. Poly¬ methylmethacrylate lenses showed a low benzalkonium chloride washout (0.02 ug/mg of lens weight), followed by the silicone-acrylate polymer lenses, which had three times more benzalkonium loss, and fluorosilicaneacylate polymer lenses, which had the largest washout of about 0.15 Mg/mg of lens weight. COMMENT
Benzalkonium is a mixture of differ¬ alkyl chain lengths, of which C-14 is one representative. While the bio¬ logic activity of different benzalko¬ nium chain lengths may vary,18 the physical and chemical characteristics of each chain length are very similar. There is, therefore, no reason to be¬ lieve that the behavior of any lens to the mixture that constitutes benzalko¬ nium will differ from that seen to C-14 benzalkonium in the present experi¬ ments. Similarly, there is no reason to ent
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 07/01/2015
suspect that the behavior of the
ra¬
diolabeled benzalkonium toward the lenses would differ from that of unla¬ beled benzalkonium. Although the soft lenses were subjected to variations in benzalkonium concentrations with time, the values obtained represent near-maximal values since the reduc¬ tion from the second replenishment of benzalkonium at 96 hours through 7 days was small. This procedure, of
adding more benzalkonium, was neces¬ sitated by the limited supply of 14C-
labeled benzalkonium. The data indicate large differences between soft and hard lenses toward the adsorption of benzalkonium, as well as differences between lens types within each major subdivision. Soft lenses lose a maximum of 0.75 µg of benzalkonium chloride per milligram of lens weight during washout in 0.9% saline solution. This solution is basic, ie, has a pH less than 7.0, and the washout rate could be influenced by ambient pH of the tears. Assuming that all of the benzalkonium chloride is lost immediately from a 16-mg lens on placement onto an eye with a tear vol¬ ume of 8 ßL, the maximum tear con¬ centration would be 0.12%. This con¬ centration is far above the limits of benzalkonium chloride concentrations used in topical ophthalmic medica¬ tions, namely, 0.004% to 0.02%, and would be predicted to induce adverse effects on the corneal epithelium. In
addition, the cornea and conjunctiva take up benzalkonium and then release it slowly into the tear film.1517 A soft lens, therefore, could undergo constant recycling of benzalkonium from the lens to the tissue. Implicit in this calculation, however, is the fact that the kinetics of released benzalkonium would be exactly the same as that found after drop applica¬ tion. Benzalkonium could be held in the tear film under the lens, thereby prolonging exposure time and raising the possibility of increasing tissue up¬ take, thus enhancing any adverse ef¬ fects. Based on the uptake data, which are not available at short time inter¬ vals, one would predict that if a patient used an eye drop containing benzalko¬ nium while wearing soft contact lenses a proportion of the benzalkonium re¬ maining in the tear film after the first blink would be adsorbed to the lens. Given the avidity of the lens for ben¬ zalkonium, it would be surprising if the preservative would be lost imme¬ diately from the lens. While the above reasoning may be true for a lens not
previously exposed
to
benzalkonium,
the situation would become worse af¬ ter repeated lens exposure to benzal¬ konium. The behavior of benzalkonium would probably be similar to that seen with chlorhexidine,2 where a cyclic phenomenon occurs in which the pre¬ servative is taken up by the lens and a little is lost during wearing, with a continued buildup of chlorhexidine un¬ til all the absorptive sites are satu¬ rated. If accidental exposure of extendedwear lenses occurred to a benzalko-
nium-containing solution (eg, an artifical tear solution), the uptake/release
characteristics of the lens would be conducive to a situation of enhancing the possibility of adverse effects. Re¬ peated exposure to benzalkonium would allow uptake and subsequent release that could provide sufficiently high bathing concentrations of ben¬ zalkonium chloride to cause some of the adverse effects noted in the litera¬ ture even at 0.02%.19 The amount of benzalkonium lost from PMMA or RGP lenses is small (about 0.4% of that lost from soft lenses) and would give rise to low tear film concentrations, even assuming that all of the benzalkonium was re¬ leased instantly. The data indicate that the majority of adsorbed ben¬ zalkonium is lost within 24 hours of washout. The lens uptake values for silicone-acrylate polymer lenses con¬ form to those found in other studies45 and support the notion that benzalko¬ nium uptake does not continue un¬ abated, as has been suggested.1 The amount of benzalkonium chlo¬ ride washout from hard lenses is at a maximum from the fluorosiliconeacrylate polymer type that, using the same calculations for tear film volume, etc, as for soft lenses, would result in a tear film concentration of about 0.02%. This is at the maximum limit of the concentration used in topical eye drops where adverse effects on the conjunc¬ tiva, tear film, and corneal epithelium have been noted.20 If adverse effects are noted with those lenses, for which benzalkonium is used in the preserva¬ tive solutions, then any contact of
benzalkonium with extended-wear lenses, where the benzalkonium loss is greater, would be detrimental. The present data indicate that ben¬ zalkonium is taken up avidly by soft
lenses, as suggested previ¬ ously,21 but that only a small fraction is contact
lost to the environment on washout. The adsorption or absorption of ben¬ zalkonium to the different lens types is a function of the number of binding sites available for the detergent on the particular lens material. All the ben¬ zalkonium in the water volume of the highest-water content lens only amounts to about 3% of the benzalko¬ nium washout, indicating that most of the washout benzalkonium is from binding sites on the lens material. This total amount of washout benzalkoni¬ um, however, exceeds acceptable limits of safety tolerance. Hard contact lenses, in contrast, take up a very small amount of benzalkonium, with a cor¬ responding loss on washout that ap¬ proaches the upper limit of safety. Calculations, based on the uptake and washout data, indicate that tear film concentrations of benzalkonium, such as after eye drop use in the presence of soft contact lenses or after inadvertent use of a benzalkonium-containing so¬ lution to soak or rinse the lens, could result in adverse effects to the sur¬ rounding tissues. The study was supported in part by research grant EY04558 (KG) from the National Eye Institute, Bethesda, Md, and in part by an unre-
stricted departmental award from Research to Prevent Blindness Inc, New York, NY. We thank X-CEL Contacts Inc, Atlanta, Ga, for their generous donation of the contact lenses and bathing solutions.
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