Effect on Gel Formation Time of Adding Topical Ophthalmic Medications to ReSure Sealant,an In Situ Hydrogel

Abstract

Purpose:

The purpose of this study was to describe the gel formation times of ReSure^® Sealant, an in situ hydrogel approved to seal cataract surgery incisions, when commercially available topical medications are mixed with the sealant.

Methods:

In this experimental laboratory study, the commercial product, ReSure Sealant, was used as per the product insert. Two drops of diluent were mixed with the polymer and time to gel formation was measured. Following this, various commercial antibiotic, nonsteroidal anti-inflammatory drug and steroid drops were used in substitution of one of the drops of the diluent. Combinations of 2 medications were also tested. Each condition was performed in triplicate and the mean gel time was calculated.

Results:

The addition of bromfenac slightly reduced mean gel time from 19 s (ReSure alone) to 13 s. All other medications, including moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, loteprednol etabonate, prednisolone acetate, dexamethasone, ketorolac, and nepafenac, increased mean gel time, ranging from 49 s to >120 s. The addition of bromfenac to moxifloxacin, ofloxacin, or gatifloxacin reduced their mean gel times from ≥105 s to 18–29 s.

Conclusions:

Certain medications, specifically bromfenac, may not substantially alter time to gel formation of ReSure Sealant when added to the hydrogel. In fact, bromfenac added to moxifloxacin, ofloxacin, or gatifloxacin reduced gel formation time to acceptable levels. All other medications and combinations of medications added to ReSure Sealant produced unacceptably long gel times to be used routinely. Clinical studies may be considered based on these results to assess the safety and efficacy of this strategy.

Introduction

The rate of endophthalmitis has increased over the past 2 decades despite shorter surgical times, smaller incisions, improved technology and techniques, and advances in medications.^1,2 One hypothesis for this increase is the introduction of the clear corneal incision by I. Howard Fine and the popularity of the technique since 1991.^3,4 Peter J. McDonnell's group has shown the potential for these incisions to allow particles the size of bacteria to traverse from epithelial to endothelial surface. In addition, they showed how these incisions actually gape more as the intraocular pressure is reduced.^5–7 Shingleton et al., in a separate publication, showed that a significant number of successful, uncomplicated, small-incision phacoemulsification cataract surgery cases result in hypotony immediately after the completion of the surgery.^8,9 Due to the fact that temporal clear corneal incisions allow better access to the eye, reduce the most common axis of astigmatism, decrease the overall time of the procedure, decrease hyperemia, injection, and hemorrhage, and reduce overall discomfort for the patient, surgeons have and probably will continue to utilize this surgical incision technique despite the increased risk of postoperative infection.^10,11

Although sutures to close cataract surgery incisions have been used and recommended for imperfect wounds,¹² infections have occurred despite sutures, and sutures may have even been the nidus of the postoperative infections, even years after an uneventful surgery.^13–15 Various groups have reported on possible sealants, with one recently completing the rigorous US Food and Drug Administration premarket approval (PMA) process to earn approval with an indication to seal post cataract surgery incisions.^16,17 ReSure^® Sealant (Ocular Therapeutix, Bedford, MA), an in situ forming hydrogel, is indicated for intraoperative management of clear corneal incisions (up to 3.5 mm) with a demonstrated wound leak, for which a temporary dry surface can be achieved, in order to prevent postoperative fluid egress from such incisions following cataract surgery with intraocular lens (IOL) placement in adults. The pivotal study showed that the sealant is superior to suture in terms of fewer adverse events and superior to preventing wound leaks (95.9% for sealant vs. 65.9% for sutures).¹⁸

Since 1964, when Henry Allen and his group showed the benefits of perioperative antibiotics, cataract surgeons have been using topical antibiotics to prophylaxis against endophthalmitis.¹⁹ Other medications such as topical steroids and topical nonsteroidal anti-inflammatory drugs (NSAIDs) have also been used to help reduce postoperative inflammation, pain, and macular edema. Inevitably, with the approval of the new polymer hydrogel sealant, surgeons will consider the off-label mixing of typical postoperative medications with the sealant. The obvious question is whether this off-label use of the sealant and medications will lead to an alteration of the sealant's pharmacokinetics. The purpose of this article was to describe the pharmacokinetics of gel formation of the sealant, when used on label and when used off label by mixing with various standard topical ophthalmic medications.

Methods

ReSure Sealant is an in situ forming hydrogel that creates a temporary, soft, and lubricious sealant to prevent fluid egress following cataract or IOL placement surgery. ReSure hydrogel persists for approximately 1–3 days (up to 7 days in some cases), or until reepithelialization occurs. The cross-linked hydrogel is approximately 89% water at application. The hydrogel is polyethylene glycol (PEG) based; PEG is commonly used in pharmaceutical, cosmetic, and ophthalmic applications. ReSure hydrogel softens over time through hydrolysis, detaches, and is sloughed off in the tears. A ReSure Sealant Kit consists of one plastic dropper bottle filled with diluent solution (an isotonic buffered saline solution), a tray with 2 mixing wells containing lyophilized deposits of reactants (one blue deposit and one white deposit in each well), and 2 applicators. ReSure Sealant is formed by mixing the diluent with the dried deposits of reactants. The blue color serves as a visualization aid to ensure proper placement of ReSure Sealant and diffuses from the hydrogel within hours of the application.

Instructions for standard preparation and application of the ReSure sealant

Using sterile technique, transfer the contents of the Tyvek pouch onto the sterile field. Tear open the foil pouches and remove the mixing tray. Remove end cap from the diluent dropper. Select one channeled well for mixing and add 2 drops of the diluent to the blue deposit. Do not add any drops to the white deposit in the same channeled well. Mixing the 2 reactant deposits and applying ReSure Sealant must be complete in less than 30 s as the sealant forms a pliable solid hydrogel. Use the applicator to thoroughly and rapidly mix the solution using a back and forth motion to dissolve the deposits (about 5 s). Holding the applicator handle with the side edge of the foam tip facing down, dip the foam tip into the solution, picking up the material. Generously apply ReSure Sealant over the entire length, width, and edges of the incision, ensuring full coverage of the margins.

Commercially available topical medications tested

In this laboratory study, the antibiotics evaluated as a substitute for the diluent were moxifloxacin 0.5% (MOX) (Alcon, Inc., Fort Worth, TX), gatifloxacin 0.5% (GAT) (Allergan, Inc., Irvine, CA), ciprofloxacin 0.3% (CIP) (Alcon, Inc.), and ofloxacin 0.3% (OFX) (Allergan, Inc.). NSAIDs used were bromfenac 0.09% (BROM) (Valeant/Bausch & Lomb, Tampa, FL), ketorolac 0.5% (KET) (Falcon, Fort Worth, TX), and nepafenac 0.1% (NEP) (Alcon, Inc.). Steroids tested were loteprednol etabonate 0.5% (LOT) (Valeant/Bausch & Lomb), dexamethasone 0.1% (DEX) (Alcon, Inc.), and prednisolone acetate 1.0% (PRED) (Pacific Pharma, Irvine, CA).

Investigational preparation of the ReSure Sealant

First, ReSure Sealant was mixed as per the product insert, as described above. Two drops of diluent were mixed with the reactant deposits and time to formation of a solid hydrogel (gel time) was measured using a stop watch. This was performed in a triplicate manner. This process was then repeated using each of the 10 commercial antibiotics, NSAID, and steroid drops as substitution for one of the drops of the diluent. Each time, this was performed in triplicate and the mean gel time was measured and recorded. Combination medications were also tested in triplicate. For the combinations, a total of 3 drops were added to the reactant deposits—one drop diluent and one drop each of topical medication.

Results

The mean gel time for ReSure Sealant was 19 s (Table 1). Except for BROM, all evaluated drugs, when substituted for a drop of ReSure Sealant diluent, including MOX, GAT, CIP, OFX, LOT, PRED, DEX, KET, and NEP, increased mean gel time (range, 49 s to >120 s). BROM slightly reduced mean gel time from 19 s for the commercial product without medications to 13 s. KET had a mean gel time of 49 s; all other topical medications, when substituted for a drop of diluent, had mean gel times >60 s.

Table 1.

Time to Gel Formation With and Without Adding/Mixing Commercially Available Topical Medications

ReSure Sealant ± medication	Mean time to gel formation (sec)
Hydrogel alone
2 gtt hydrogel diluent	19
With 1 topical medication
1 gtt hydrogel diluent +1 gtt BROM	13
1 gtt hydrogel diluent +1 gtt KET	49
1 gtt hydrogel diluent +1 gtt LOT	83
1 gtt hydrogel diluent +1 gtt PRED	90
1 gtt hydrogel diluent +1 gtt MOX	105
1 gtt hydrogel diluent +1 gtt OFX	105
1 gtt hydrogel diluent +1 gtt GAT	>120
1 gtt hydrogel diluent +1 gtt CIP	>120
1 gtt hydrogel diluent +1 gtt DEX	>120
1 gtt hydrogel diluent +1 gtt NEP	>120
With 2 topical medications
1 gtt hydrogel diluent +1 gtt BROM +1 gtt GAT	18
1 gtt hydrogel diluent +1 gtt BROM +1 gtt OFX	18
1 gtt hydrogel diluent +1 gtt BROM +1 gtt MOX	29
1 gtt hydrogel diluent +1 gtt BROM +1 gtt CIP	>120
1 gtt hydrogel diluent +1 gtt NEP +1 gtt MOX	>120

BROM, bromfenac 0.09%; CIP, ciprofloxacin 0.3%; DEX, dexamethasone 0.1%; GAT, gatifloxacin 0.5%; KET, ketorolac 0.5%; LOT, loteprednol etabonate 0.5%; MOX, moxifloxacin 0.5%; NEP, nepafenac 0.1%; OFX, ofloxacin 0.3%; PRED, prednisolone acetate 1.0%.

GAT alone, when substituted for a drop of the diluent, produced a mean gel time of >120 s; BROM added to GAT produced a mean gel time of 18 s. Similarly, OFX alone produced a mean gel time of 105 s; BROM added to OFX produced a mean gel time of 18 s. MOX alone produced a mean gel time of 105 s; and BROM added to MOX produced a mean gel time of 29 s. No other combination of drugs and diluent produced gel times that were <60 s.

Discussion

Despite strong medical evidence in the peer reviewed literature that clear corneal incisions may increase the rate of postoperative endophthalmitis, this technique is entrenched as the most common and popular method of incision for cataract surgery.^20–26 A novel way to possibly reduce the risk of microbes traversing incisions postoperatively, and potentially reduce the rate of postoperative infections in cataract surgery, is sealing the entire wound with a hydrogel. ReSure Sealant is a new FDA approved commercial polymer hydrogel, which has been found to be superior to 10-0 nylon sutures in terms of sealing a cataract surgery incision. The pivotal study showed that it produces fewer adverse events and prevents more wound leaks.¹⁸

Another method, which virtually all US cataract surgeons utilize to reduce the potential for postoperative infections, is topical antibiotics.²⁷ Inevitably, with the approval of the new polymer hydrogel sealant, surgeons are bound to consider the off-label mixing of typical postoperative medications like antibiotics with the sealant. This study was performed to address whether this off-label use would lead to an alteration of the sealant's pharmacokinetics.

The data show that when the sealant was mixed with the fluoroquinolones MOX, OFX, GAT, or CIP, it resulted in unacceptably long mean gel times of 105 s or longer. Significantly, prolonged gel times may result in a reduction in the cross-link density of the hydrogel and may shorten its persistence on the ocular surface. The steroids LOT, DEX, and PRED also produced prolonged mean gel times from 83 s to >120 s. The NSAID KET caused an increase in the gel time to 49 s, but the NSAID BROM caused no increase, possibly even reducing the gel time (from 19 s to 13 s). What was more remarkable was that when BROM was added to the fluoroquinolones MOX, GAT, or OFX, the time to gel formation was substantially reduced compared with fluoroquinolones alone.

We hypothesize that elements of the BROM's formulation, such as elevated pH and the presence of the amine group, caused the significant reduction of gel time even when added to medications that alone increased the time to gel formation.

We chose to test fluoroquinolones since the vast majority of US surgeons use these medications surrounding ocular surgery, despite the fact that it is an off-label use of the topical medication.²⁷ In further studies, it might also be interesting to test the ReSure Sealant gel times with other classes of antibiotics, especially those with a pH and/or chemical structure, such as the amine group, which might not prolong the gel time of the sealant.

We tested BROM, KET, and NEP since these are the NSAIDs that are the most prescribed in the United States. BROM improved not only the gel time when used alone but also more surprisingly, decreased the time to gel formation when added to fluoroquinolone antibiotics MOX, GAT, and OFX, producing gel times that would not substantially delay surgery.

The sealant, when mixed with a steroid, had a significantly increased gel time such that it would not be practical to be considered in clinical practice. We did not mix the BROM with the steroids DEX, PRED, and LOT in this study. This may be the focus of future studies.

We also did not evaluate all generics since each generic formulation may be different, thereby increasing the number of possible combinations to be considered.

ReSure Sealant is indicated for intraoperative management of clear corneal incisions (up to 3.5 mm) with a demonstrated wound leak, for which a temporary dry surface can be achieved, in order to prevent postoperative fluid egress from such incisions following cataract surgery with IOL placement in adults. Incorporating medications into the hydrogel is an off-label use of the FDA-approved ReSure Sealant and this article does not recommend or discourage that use. We are simply reporting our in vitro findings since we felt it was a natural question that might be asked in clinical practice. Any modification of the diluent of ReSure Sealant that significantly prolongs the gelling time of the product may decrease the tensile strength properties of the polymerized gel, and this consideration needs to be taken into account when contemplating the strategies examined in this article. Incorporation of a topical drug during the hydrogel formation enables uniform distribution of the drug within the hydrogel matrix and optimal localization of the drug at the site of the wound, providing a direct path into the anterior chamber. The incorporation of the drug into the hydrogel may also potentially provide an extended release, although this would need to be tested in additional studies. We would warn that prolonged contact of a topical NSAID on the ocular surface may not be recommended in this manner, as high-risk patients have had adverse events following routine uncomplicated cataract surgery. Steroids on a bare stromal surface may predispose to melting due to stimulation of collagenases. Clinical studies should be done to complement and fill the evidence-based literature.

Footnotes

Author Disclosure Statement

The author received an unrestricted research grant from Ocular Therapeutix for this study. The author is a consultant to Ocular Therapeutix, Inc., as well as to the following companies: Alcon, Allergan, AMO, Bausch & Lomb, CoDa, ForeSight, NovaBay, PolyActiva, Shire, and TearLab.

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