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Interest and safety of a preservative-free carbomer 0.2% eye gel on canine dry eye: a case series

Sarah Muller1, Laurent Bouhanna2, Christelle Navarro3*, Bruno Jahier4,and Carole Gard5

¹45 boulevard Marcel Pagnol, 06130 Grasse, France.
²Clinique Vétérinaire OPHTAVET, 38 Quai Henri IV, 75004 Paris.
³MP Labo, 45 boulevard Marcel Pagnol, 06130 Grasse, France.
⁴MP Labo, 45 boulevard Marcel Pagnol, 06130 Grasse, France.
⁵MP Labo, 45 boulevard Marcel Pagnol, 06130 Grasse, France.

*Corresponding author

*Christelle Navarro, MP Labo, 45 boulevard Marcel Pagnol, 06130 Grasse, France.

Abstract

Dry eye is a common ophthalmic disorder in dogs that can lead to serious ocular complications. The objective of this case series was to evaluate a new preservative-free carbomer 0.2% eye gel in five dogs with dry eyes. Ophthalmic examination was performed on D0, D15, and D30, rating conjunctivitis, keratitis, ocular discharge and irritation from 0 to 3. Global ocular clinical (GOC) score was obtained by the sum of the individual scores. Tear film quantity and quality were measured using STT1 and tear film break-up time (TBUT). The dogs’ quality of life (QoL) was assessed by the owners. GOC, conjunctivitis, and ocular discharge scores decreased significantly on D15 and D30 compared to D0 (p = 0.0062, 0.0152, and 0.0152, respectively). QoL significantly improved at each time point compared to baseline (p = 0.0008). However, the decrease of keratitis and ocular irritation scores and the increase of STT1 and TBUT values were not significant. The use of the preservative-free carbomer 0.2% eye gel could be an interesting option for dry eye management in dogs by significantly improving clinical signs and tear production while avoiding potential sides effects of preservatives.

Keywords: Dry eye, Dogs, Carbomer, Preservative-free.

Introduction

The tear film is a thin fluid layer that plays an important role by providing ocular surface comfort as well as mechanical and immune protection, epithelial health, and smooth refractive surface for vision [1-4]. Consequently, lacrimal insufficiency frequently results in inflammation and consecutive infection of the conjunctiva and cornea.

Dry eye syndrome is a common ocular disorder in the canine population, with a reported incidence of 1 to 4% [5, 6]. It usually results from dysfunction in the components of the lacrimal functional unit leading to a decreased production of the aqueous portion of the tear film and/or excessive evaporation of the tear film [6]. Local immune-related destruction of the lacrimal gland is the most common cause of fry eye syndrome in dogs [7, 8]. Other etiologies include adenitis, congenital hypoplasia, drug-induced toxicity, neurologic dysfunction, and traumatic injury of the lacrimal glands [7]. The risk factors for KCS are aging, breed predisposition, overweight, hypothyroidism, medications (atropine, sulfonamides), surgical excision of the third eyelid gland, distemper, and mainly, autoimmune factors [6-8]. The main clinical signs observed are mucoid or mucopurulent secretion, conjunctival hyperemia, pigmentation, vascularization and opacity of the cornea, blepharitis, blepharospasm, and, in most severe cases, corneal ulcer that can be perforating [6, 8]. It is a significant disease in dogs with an impact on their quality of life consecutive to ocular discomfort and visual disturbance [9, 10]. The diagnosis of dry eye is based on history, recognition of clinical signs, and Schirmer tear test (STT) values below 15 mm/min, results comprised between 6 and 10 mm/min characterizing moderate stage of dry eye. When left untreated or incorrectly treated, dry eye may cause pain, ulcers, scars on the cornea, and even severe ocular complications as eyesight impairment or blindness [9, 11]. Thus, a correct medical or surgical management of dry eye syndrome is essential. The medical approach of dry eye aims to improve corneal hydration, control inflammation and superinfections, and manage ulcer formation. Treatment options include the use of topical medications acting as lacrimomimetics to stimulate increased tear production, tear supplements to provide moisture and lubrication. Besides, most topical lacrimomimetics have to be used 2 to 4 times a day or even more [5, 9]. Therefore, it has been suggested that a longer acting tear supplement requiring a lower frequency of administration may improve compliance and treatment success [12].

Carbomer gels used in dogs are water-soluble polymeric resins whose pH and osmolarity are similar to those of the normal animals’ tear film. They diffuse rapidly on the surface of the eyes and maintain a transparent, lubricating, and wetting film over a prolonged period of time, making it possible to reduce the number of applications. Many studies done in vitro, in animals, and in humans, have demonstrated the toxicity of preservatives in eye drops [13, 14] and have shown a significant decrease of deleterious effects with the use of preservative free eye products [14, 15]. To avoid preservatives in eye drop while maintaining microbial clearance, several options exist depending on duration of use and the composition: single dose, preservative free multidose container, waterless composition.

Therefore, this French multicentric field study evaluated the interest of a new preservative-free carbomer eye gel in dogs with dry eyes.

Materials and Methods

Animals

Client-owned dogs presented with dry eye syndrome were enrolled in the study. Inclusion criteria were based on the presence of keratitis (cornea with oedema, vessels and/or pigmentation), conjunctivitis (conjunctival hyperemia and/or chemosis), and/or serous or mucoid ocular discharge, and Schirmer tear test 1 (STT1) values comprised between 5 and 10 mm/min. Mucopurulent or purulent eye discharge and other ocular disorders than dry eye including corneal ulceration, systemic diseases with ocular manifestations or requiring a treatment that could have an impact on tear secretion, were reasons for non-inclusion in the trial. Furthermore, dogs that had been administered lubricative eye drops within 2 days prior to enrollment or that had received topical NSAIDs, SAIDs, or immunomodulatory drugs within 2 weeks before the start of the study were not eligible for the trial.

Treatments

Two drops of a preservative-free carbomer 0.2% eye gel (Lacri-protect®, MP Labo, France) were instilled in the conjunctival sac of each dog, twice per day for a duration of 30 days, after cleansing of the eye contour with a compress impregnated with physiological serum. In case of unilateral dry eye, only the affected eye was treated. In case of bilateral dry eye, both eyes were treated. On the days of scheduled visits at clinical sites, treatment had to be performed by the animals’ owners at home, at least 2 hours and at most 12 hours prior to the appointment. Systemic medications with a possible risk of interference with tear secretion and any other eye product were forbidden during the study.

Clinical follow-up

A clinical examination was performed by the investigators on Day (D) 0, D15, and D30. The animals’ general health condition was assessed.

Eye examination

A comprehensive eye examination including direct and slit-lamp examination, direct and indirect ophthalmoscopy, and tonometry, was carried out by the investigators on D0, D15, and D30. At each examination, the size, position, direction, movements, and facial symmetry of the eyeballs, as well as the presence of eye disorders, were inspected. Eye conditions and symptoms including conjunctivitis, ocular discharge, eye irritation, and corneal opacity, pigmentation, and vessels, were rated on a scale of 0-3 using direct observation as well as direct and indirect ophthalmoscopy (Table 1). A global ocular clinical (GOC) score, rated from 0 to 12, was calculated by adding the four individual scores. A subjective evaluation of dry eye symptom improvement was evaluated on D2 by the owners as “Absent”, “Partial”, “Good”, or “Very Good”, and on D15 and D30 by the investigators as “Poor”, “Good”, “Very Good” or “Excellent”.

Table 1: Scoring system for the severity of eye conditions and symptoms adaptated from Amalfitano et al. 2019 [16].

At each time point, eye tests including STT1, fluorescein eye stain test (FT), and tear film break-up time (TBUT) were performed. STT1 used to determine whether the eyes produced enough tears to keep them moist, was carried out without anaesthesia in all clinical investigation centres using standardized sterile 5x35 mm strips introduced into the conjunctival sac for 1 minute. The distance of tear migration by capillarity was measured on the strip. Values lower than 10 mm/min were considered to demonstrate dry eye syndrome. FTs used 1% fluorescein eye drops and a cobalt-blue filter on a slit lamp to detect corneal ulcers in the eye. In testing for TBUT, a drop of 1% fluorescein was applied to the lower fornix in a standardized manner by all clinicians and the cornea was scanned under low magnification of a slit-lamp using a cobalt blue filtered light. Time of appearance of first black spot from last blink measured the tear film BUT. Values less than 10 seconds were considered abnormal.

Quality of Life (QoL) assessment

QoL was assessed by both investigators and owners at D0, D15, and D30 by completing a multiple-choice questionnaire inspired by the Dry Eye Questionnaire (DEQ) used to characterize the symptoms of dry eye in humans [17, 18]. There were four choices for each of the eleven questions: Not at all (scored 0), A little (scored 1), Quite a bit (scored 2), and Very much (scored 3) (Table 2).

Table 2: Questions asked in the multiple-choice questionnaire

Tolerance evaluation

Adverse events were recorded throughout the study period.

Statistical analysis

The experimental unit was the eye. In case of bilateral dry eye only the right eye was arbitrarily assessed for the purpose of the study. A generalized linear mixed-effects model was used for the analysis of eye scores, eye test results, and QoL score over time. In case of significance, post hoc pairwise comparisons were performed using the Fisher's least significant difference (LSD) procedure. The significance level was set at p < 0.05. Analyses were performed by using the Statgraphics® Centurion software, version XVI.II.

Results

Study population

Five purebred client-owned dogs participated in the survey (Table 3). The mean age was 11.2 (± 3.6) years with a minimum of 5 years and a maximum of 14 years. The mean body weight was 8.5 (± 3.1) kg (range 5.8 to 13.5 kg).

Table 3: Characteristics of the study population.

Clinical and ophthalmological observations

The animals’ health condition was assessed as « Good » in 4 out of the 5 enrolled dogs throughout the study period. The health status of the case # 2 was reported as « Average » at inclusion because of concomitant cardiomegaly and osteoarthritis and did not deteriorate until D30. The evolution over time of the ophthalmological observations for each dog is detailed in Table 4. Considering the whole study population of 5 dogs, two out of the 4 eye conditions and clinical signs rated during the present study showed a significant improvement at D15 and D30 versus baseline. The mean conjunctivitis score decreased from 1.4 (± 0.5) at D0 to 0.8 (± 0.4) and then 0.4 (± 0.5), on D15 and D30, respectively (p = 0.0152). The mean ocular discharge score dropped from 2.0 (± 0.7) at D0 to 1.2 (0.4) at D15 and 0.6 (± 0.5) at D30 (p = 0.0152). The decrease of the mean eye irritation (0.6 (± 0.9), 0.4 (± 0.5), 0.0 (± 0.0)) and corneal opacity (0.6 (± 0.5), 0.6 (± 0.5), 0.4 (± 0.5)) scores over time was not significant. Overall, the mean GOC score was significantly reduced from 4.6 (± 1.7) at D0 to 3.0 (± 1.0) at D15 and 1.4 (± 0.5) at D30 (p = 0.0062).

Table 4: Evolution over time of the individual ophthalmological scores in each dog.

Photographs 1 and 2 show the right eye of Case 5 on D0 and D15.

Figure 1: Right eye of Case 5 on D0 .

Figure 2: Right eye of Case 5 on D30 .

STT1 and TBUT values of each individual dog at each time point are presented in Table 5. The mean STT1 and TBUT values in the whole study population increased from D0 to D30 but without significant differences (7.4 (± 1.8), 10.2 (± 1.9), 11.2 (± 4.2) and 9.8 (± 5.9), 12.5 (± 6.8), 14.0 (± 8.0), respectively).

Table 5: Evolution over time of the eye test results in each dog.

*NA : Not available.

At D2, 4/5 (80%) of the owners considered that clinical improvement was « Good » and 1/5 (20%) estimated the efficacy as « Partial » (case 5). At D15, 4/5 (80%) of the investigators assessed the efficacy of the carbomer eye gel as « Good » (1/5) or « Very Good » (3/5), and 1/5 (20%) as « Poor » (case 5). At D30, 4/4 (100%) of the clinicians evaluated the efficacy as « Good » (1/4), « Very Good » (1/4) or « Excellent » (2/4).

QoL

QoL improved in each individual dog on D15 and D30 compared to baseline (Table 6). The decrease of the mean QoL, in the 4 dogs for which data were available, was highly significant from 13.8 (± 3.3) on D0 to 7.3 (± 2.5) on D15 and 3.8 (± 0.5) on D30 (p = 0.0008).

Table 6: Evolution over time of the QoL in each dog

Tolerance

One owner (case #3) reported that his dog had been scratching its eyes for a total duration of 5 days over the 30-day follow-up period. It happened several hours after some treatment administrations. Each time, the animal recovered spontaneously. No other adverse events were observed throughout the study period.

Discussion

This case series of 5 dogs with moderate dry eye syndrome is limited by its small size and the lack of control group, and should, therefore, be interpreted with considerable caution. Furthermore, since no questionnaire for the QoL assessment in dogs with dry eye was identified in the literature, we adapted a questionnaire used in humans to measure symptom frequency and intensity that is recognized to be a sensitive tool useful in clinical treatment trials for dry eye [17, 18]. The adequacy of this derived questionnaire for the evaluation of QoL in dogs with dry eye has yet to be confirmed. In addition, we chose to use the STT1 even though it was shown to cause the major discomfort, compared to other tests such as the phenol red thread test and the endodontic absorbent paper, point tear test [3]. Therefore, it cannot be ruled out that the use of STT1 in the present case series may have had a negative impact on the assessment of the QoL performed by the owners in the presence of the investigators at each control visit. Moreover, we did not consider that the STT may be influenced by several factors such as age, breed, and neuter status [11] since it remains the gold standard for demonstrating KCS. Lastly, diagnostic cut-off values of the STT1 vary in the literature from <15 mm/min [10] to ≤ 9 mm/min [7]. Moreover, some authors classified KCS as moderate for STT values between 6 mm/min and 14 mm/min [7] while others defined values comprised between 6 and 10 mm/min for mild cases of KCS. In our case series, we chose to retain values comprised between 5 and 10 mm/min for enrolment of moderate cases and values > 10 mm/min as normal values. Despite these limitations, we believe that our case series raises some interesting points.

The first point is the significant improvement of the GOC, conjunctivitis, and ocular discharge scores and of the dogs’ QoL in spite of the very small number of animals. These results are similar to those find by Wang et al. in a previous study 4 weeks after administration of a carbomer-based formulation in humans four times daily [19]. But contrary to what we observed in our case series, Wang et al. also reported significantly increased STT values after treatment. The most plausible explanation for this difference is certainly the number of patients enrolled in each study (28 patients vs 5 dogs in our case series). Similarly, the absence of significant evolution of the keratitis and ocular irritation scores as well as of the TBUT values, should probably be put into perspective with the low number of dogs treated, but may also reflect the chronology of appearance of the clinical signs of the dry eye syndrome. Indeed, dry eye at first induces eye irritation and then, eye redness, swelling, or discharge. Furthermore, corneal opacity is expected to take longer to improve than the other symptoms or signs of the dry eye syndrome. Lastly, it seems reasonable to think that improvement of the tear film quality (TBUT) is a longer process than the increase of the quantity of tears (STT1). This leads us to think that if the duration of the follow-up in our study had been longer, significant improvement of those parameters may have been observed as well.

A second point that arises from this case series is the confirmation of the good efficacy of the tested eye product administered twice a day for 30 days. Many eyedrops display a short ocular time mainly due to the rapid elimination process by tear turnover. But carbomers are widely used for the treatment of dry eye because of their prolonged tear retention time on the eye surface, resulting in an extended duration of efficacy [19, 20]. The corneal residence time is in fact linked to the rheological properties of the carbomer including yield stress, relaxation times, viscosity, and compliance. Concretely, the high viscosity of the gel formulation used in our survey could explain the prolonged persistent time in the eye and therefore fewer required daily applications. That explains why successfully relieved symptoms and signs of dry eye were observed after a twice-daily administration of the tested product.

A third point highlighted by the present case series is the good tolerance of the preservative-free carbomer gel used in our case series. Preservatives used in ophthalmic preparations include mercury derivatives, alcohols, parabens, EDTA, and mainly quaternary ammonium compounds such as benzalkonium chloride (BAK) [21]. Several in vitro and in vivo investigations in humans and animals have reported dose- and time-dependent weakly allergenic but highly cytotoxic effects of preservatives on several components of the eye [22-24]. Wilson et al. demonstrated that BAK accelerates the drying of the precorneal tear film in rabbits [24]. In vitro studies showed that preservatives induce a significant concentration-dependent decrease in conjunctival epithelial cell viability and contribute to corneal epithelial cell injury [21]. Conversely, several studies reported that the switch from preservative-containing to preservative-free eye products significantly decreased ocular symptoms, signs of irritation, epithelial damage, and discomfort [2, 13, 14, 15, 23]. These improvements resulted in a better quality of life assessed by patient questionnaires [15].

Conclusion

The new preservative-free eye lubricant tested in our case series was shown to significantly improve clinical signs of dry eyes and dogs’ quality of life and was well tolerated.

The stable, long-lasting film formed after application as well as the reduction of adverse events due to the absence of preservatives, may improve compliance and adherence in the management dry eye requiring repeated use of topical eyedrops. A sterile resealable single dose is of interest for a daily use. Therefore, the use of this new preservative-free carbomer 0.2% eye gel could be an interesting option for dry eyes in dogs.

Author Contributions: Conceptualization, C.G., B.J. and C.N..; methodology, C.G., B.J., and S.M..; validation, L.B..; formal analysis, C.G..; investigation, L.B..; writing—original draft preparation, C.G., B.J., and S.M.; writing—review and editing, L.B, and C.N. All authors have read and agreed to the published version of the manuscript.

Funding: The research and the publication were funded by MP Labo, the manufacturer of Lacri-protect®.

Data Availability: the data can be available upon reasonable request to carole.guard@destaing.com.

Acknowledgments: the authors would like to thank veterinarians who participated to the study.

Conflicts of Interest:  L.B. received fees, payment, or honorarium from MP Labo. C.G., S.M., C.N., B.J. were employees of MP Labo at the time of the study.

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