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Efficacy of a preservative-free cationic emulsion vehicle eye drop in a mouse model of dry eye

Authors:

Abstract

Purpose:Artificial tears (AT) represent the first line therapy for the management of symptoms in mild to moderate dry eye disease (DED). Preservative-free cationic emulsions-based AT or drug vehicles are innovative eye drop formulations with interesting tear film stabilization properties. The aim of the present study was to evaluate the efficacy of a cationic emulsion of cetalkonium chloride (0.005%, CE-CKC) AT on clinical signs of dry eye in a mouse model of DED, and compare its efficacy to various marketed AT. Methods:Eight to 12-week-old female C57BL6 mice with tail patches of scopolamine (replaced every other days) were housed in controlled environment room to induce dry eye. At day three, following dry eye confirmation by corneal fluorescein staining (CFS, score 0-15) and phenol red thread (PRT) lacrimation test, the mice (n=10/gp) were treated in both eyes with different AT at their recommended dosing regimen: Vismed (four times a day, ie Qid), Systane Ultra (Qid), Aquarest (Qid), Optive (Qid), Refresh (Qid), Systane Balance (Qid), and CE-CKC (twice a day, ie Bid). The untreated animals group served as control. Aqueous tear production (PRT) and CFS scores were assessed at baseline and at days 3, 6 and 10. Results:The PRT lacrimation test confirmed the scopolamine-induced decrease in aqueous production by the lacrimal gland (vs baseline). Changes in lacrimation over time remained small for the different AT. Only the CE-CKC was able to significantly increase tear secretion at day 10 (2.9±0.9 mm) vs day 6 (1.7±0.6 mm). After 7 days of treatment (at day 10), Vismed and Optive were not able to reduce CFS, which increase by 12.4 and 2.3%, respectively. At day 10 the CFS score reduction (vs. dry eye baseline) ranged from -1.7 to -20.9% for the other AT, with CE-CKC ranking first (-20.9%) followed by Aquarest (-12.4%), Systane Ultra (-6.4%), Systane Balance (-5.7%), and Refresh (-1.7%). Conclusions:This study indicates that twice daily instillations of the CE-CKC is very effective at decreasing the clinical signs of dry eye. Twice daily instillations of CE performed better than all the other AT instilled four times daily. CE-CKC with its improved clinical efficacy associated to a convenient twice daily dosing regimen represents a promising new AT for the management of moderate to severe signs of DED in patients.
D0131
Abstract D0131 presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) 2016, May 1–5; Seattle, WA, USA
Efcacy of a preservative-free cationic emulsion vehicle eye drop in a mouse model of dry eye
Yann Quentric1, Philippe Daull2, Laurence Feraille1, Pierre-Paul Elena1, Jean-Sebastien Garrigue2
1Iris Pharma, La Gaude, France; 2Santen SAS, Novagali Innovation Center, Evry, France
INTRODUCTION
Articial tears (AT) represent the rst-line therapy for the
management of symptoms in mild to moderate dry eye disease
(DED).1 Preservative-free cationic emulsion-based AT or drug
vehicles are innovative eye drop formulations with interesting tear
lm stabilization properties.2,3 They contain nonpolar oil or polar
positively charged andneutral surfactants as well as a hypo- or
iso-osmolar aqueous phase.4 The appropriate combination of the
different excipients in a cationic emulsion exerts benecial effects
on both the aqueous and lipid phases of the ocular surface tear lm.5
PURPOSE
The aim of the present study was to compare the efcacy of a cationic emulsion of
cetalkonium chloride (0.005%, CE-CKC)6 to various commercially available AT on clinical
signs of dry eye in a mouse model of DED.
Table 1. Summary of the physiochemical characteristics of the ATs
Vismed®7 Systane Ultra®Aquarest®Optive®7 Refresh® Optive
Advanced
Systane
Balance®7 CE-CKC
Description
Solution Gel Solution Anionic o/w
nanoemulsion
Cationic o/w
nanoemulsion
0.18%
HA
0.4% PEG400
0.3% propylene
glycol
0.2%
carbomer
0.5% CMC
0.9% glycerin
0.5% CMC
1% glycerin, 0.05%
polysorbate 80
0.6%
propylene clycol
2% MCT
0.005% CKC
Aspect Colorless solution Opaque
gel Colorless solution White emulsion, Tyndall effect
pH 7.2 7.8 6.9 7.2 5.4 7.0 6.0
Osmolality (mOsm/kg) 154 285 249 331 275 277 270
Conductivity (mS/cm) 9.0 6.0 0.9 4.9 13.5 1.8 0.45
Particle size (nm) NA NA NA NA 16–60 220 183
Zeta potential (mV) –38.6 –5.0 NA NA NA –48.4 +27.4
Viscosity (mPa/s) 1.0 NA NA 1.0 NA 1.0 1.1
Surface tension (mN/m) 65.5 NA NA 68.4 NA 45.3 40.1
Preservative PF 0.001%
polyguatemium-1 PF 0.01% Purite®0.001%
polyquaternium-1 PF
CE-CKC, 0.005% cationic emulsion of cetalkonium chloride; CMC, carboxymethylcellulose sodium; HA, sodium hyaluronate;
MCT,medium-chain triglycerides; NA, not applicable; o/w, oil-in-water; PEG, polyethlyene glycol; PF, preservative-free.
METHODS
To induce dry eye, female C57BL/6 mice (8–12 weeks old) were housed in a controlled
environment room (CER) and tail patches of scopolamine were replaced every 2 days.8
Dry eye was conrmed at Day 3 by corneal uorescein staining (CFS; score 0–15) and the
phenol red thread (PRT) lacrimation test. Mice (10 per cohort) were treated in both eyes
with one of the following AT formulas at the recommended dosing regimen: Vismed®,
Systane Ultra®, Aquarest®, Optive®, Refresh® Optive Advanced or Systane Balance®
(fourtimes a day; qid) or CE-CKC (twice a day; bid). Untreated animals served as control.
Aqueous tear production and CFS scores were assessed at baseline and at Days 3, 6and 10.
RESULTS
Figure 1. Tear secretion over time in mice with induced dry eye treated with different eye drops
Untreated Vismed®
qid
Systane Ultra®
qid
Aquarest®
qid
Optive®
qid
Refresh®
qid
Systane Balance®
qid
CE-CKC
bid
0
2
4
6
8
PRT (mm)
Baseline Day 3 – before treatment Day 6 Day 10
**** ***
**
*
****
****
**** ***
2020 20 20 20 20 1919 20 20 2020 20 20 2020 20 20 2020 20 20 2020 20 20 20 2019 20 20 18
*p=0.05, **p=0.001, ***p=0.0001, ****p<0.0001. Numbers within columns indicate the number of eyes evaluated per group. Data are mean + standard deviation.
bid, two times daily; CE-CKC, 0.005% cetalkonium chloride cationic emulsion; PRT, phenol red thread; qid, four times daily.
Figure 2. Lacrimation improvement (A) and mean reduction in CFS score (B) in mice at Day 10 following induction of dry eye (vs Day 3)
–150
–50
–100
0
100
50
A
Lacrimation improvement (%)
n=20 n=19 n=20 n=20 n=20 n=20 n=20 n=18
Untreated Vismed®
qid
Systane
Ultra®
qid
Aquarest®
qid
Optive®
qid
Refresh®
qid
Systane®
Balance
qid
CE-CKC
bid
–50
0
100
50
B
Reduction in CFS score (%)
** *** *
*
** ****
n=20 n=18 n=20 n=20 n=20 n=20 n=20 n=17
Untreated Vismed®
qid
Systane
Ultra®
qid
Aquarest®
qid
Optive®
qid
Refresh®
qid
Systane
Balance®
qid
CE-CKC
bid
*p=0.05, **p=0.001, ***p=0.0001, ****p<0.0001. n numbers indicate the number of eyes evaluated per group. Data are mean + standard deviation.
bid, two times daily; CE-CKC, 0.005% cetalkonium chloride cationic emulsion; CFS, corneal uorescein staining; qid, four times daily.
Figure 3. Mean CFS score over time in mice with induced dry eye treated with different eye drops
Untreated Vismed®
qid
Systane Ultra®
qid
Aquarest®
qid
Optive®
qid
Refresh®
qid
Systane Balance®
qid
CE-CKC
bid
0
5
10
15
CFS score
Baseline Day 3 – before treatment Day 6 Day 10
**
*
**
***
*
***
* * *** * *** *
2020 20 20 2020 18 18 2020 20 20 2020 20 20 2020 20 20 2020 20 20 2020 20 20 2020 19 17
*p=0.05, **p=0.001, ***p=0.0001. Numbers within columns indicate the number of eyes evaluated per group. Data are mean + standard deviation.
bid, two times daily; CE-CKC, 0.005% cetalkonium chloride cationic emulsion; qid, four times daily.
SUMMARY
nThe PRT lacrimation test conrmed the scopolamine-induced
decrease in aqueous production by the lacrimal gland (Figure 1)
nChanges in lacrimation over time for the different AT
formulations tested were small
nOnly CE-CKC was able to signicantly increase tear secretion at
Day 10 (2.9±1.0 mm) vs Day 6 (1.7±0.6 mm)
nAfter 7 days of treatment, Vismed® and Optive® increased mean
CFS scores by 12.4% and 2.3%, respectively (Figure 2)
nFor all other AT formulations tested, reduction in mean
CFS scores after 7 days of treatment ranged from –1.7%
to –20.9%, with CE-CKC demonstrating the greatest
improvement (–20.9%) followed by Aquarest® (–12.4%),
Systane Ultra® (–6.4%), Systane Balance® (–5.7%) and Refresh®
(–1.7%)
CONCLUSIONS
nThis study indicates that twice-daily
instillation of CE-CKC is more effective
in improving clinical signs of dry eye in a
mouse model of DED, compared with other
AT types instilled four times daily
nThe study provides supporting preclinical
evidence for the efcacy of this cationic
emulsion (CE-CKC) AT with a convenient
twice-daily dosing regimen as a promising
newAT for the treatment of moderate to
severe DED
nThese data conrm the benecial effects
of the cationic emulsions observed in the
rat corneal scraping assay7 and the mouse
DED model9 and support clinical evidence
ofefcacy in improving signs and symptoms
of DED10,11
REFERENCES 1. DEWS. Ocul Surf 2007:5;163–179. 2. Amrane M et al. J Fr Ophtalmol
2014;37:589–598. 3. Georgiev GA , Yokoi N , Ivanova S, Tonchev V , Daull P. ARVO 2016, Poster
#6188. 4. Vandamme TF. Prog Retin Eye Res 2002;21:15–34. 5. Lallemand F, Daull P, Benita S,
Buggage R, Garrigue JS. J Drug Deliv 2012;2012:604204. 6. Bague S, Philips B, Rabinovich L, Lambert
G, Garrigue JS. US Patent 2007-0248645. Santen, 2007. 7. Daull P, Feraille L, Elena PP, Garrigue JS.
JOcul Pharmacol Ther 2016;32:109–118. 8. Barabino S et al. Invest Ophthalmol Vis Sci
2005;46:2766–2771. 9. Daull P, Feraille L, Barabino S, Garrigue JS. ARVO 2015, Poster #4468.
10.Daull P, Lallemand F, Garrigue JS. J Pharm Pharmacol 2014;66:531–541. 11. Leonardi A et al.
Eur J Ophthalmol 2016; doi: 10.5301/ejo.5000779. 2016 Apr 7 [Epub ahead of print].
ACKNOWLEDGEMENTS/DISCLOSURES
Y. Quentric, L. Feraille and P.-P. Elena are employees of Iris Pharma (E). P. Daull and J.-S. Garrigue are
employees of Santen SAS (E).
... At 6 months, 48.1% of the patients treated with the CE AT experienced a 2-grade reduction in CFS score, and among them 14.4% saw their CFS score decrease by 3 grades (CFS score decreased from 4 to 1). In a mouse model of DED, a similar improvement in CFS scores was observed on treatment with the CE AT. 52,53 Interestingly, in this mouse model of DED, the CE AT was as effective at reducing CFS scores as 1% methylprednisolone, a potent glucocorticoid used for its anti-inflammatory properties. ...
Article
Dry eye disease (DED) is a complex multifactorial disease that affects an increasing number of patients worldwide. Close to 30% of the population has experienced dry eye (DE) symptoms and presented with some signs of the disease during their lifetime. The significant heterogeneity in the medical background of patients with DEs and in their sensitivity to symptoms renders a clear understanding of DED complicated. It has become evident over the past few years that DED results from an impairment of the ocular surface homeostasis. Hence, a holistic treatment approach that concomitantly addresses the different mechanisms that result in the destabilization of the tear film (TF) and the ocular surface would be appropriate. The goal of the present review is to compile the different types of scientific evidence (from in silico modeling to clinical trials) that help explain the mechanism of action of cationic emulsion (CE)-based eye drop technology for the treatment of both the signs and the symptoms of DED. These CE-based artificial tear (AT) eye drops designed to mimic, from a functional point of view, a healthy TF contribute to the restoration of a healthy ocular surface environment and TF that leads to a better management of DE patients. The CE-based AT eye drops help restore the ocular surface homeostasis in patients who have unstable TF or no tears.
... scores(Quentric et al., 2016). The present performance of the Ikervis vehicle (ie. ...
Article
Full-text available
Dry eye disease (DED) is a complex, multifactorial pathology characterized by corneal epithelium lesions and inflammation. The aim of the present study was to evaluate the efficacy of a cationic emulsion of cyclosporine A (CsA) in a mouse model that mimics severe dry eye. Eight to 12-week-old female C57BL/6N mice with tail patches of scopolamine were housed in controlled environment chambers to induce dry eye. At day three, following dry eye confirmation by corneal fluorescein staining (CFS, score 0–15) and phenol red thread (PRT) lacrimation test, the mice (n = 10/gp) were either treated 3 times a day in both eyes with drug-free cationic emulsion, a 0.1% CsA cationic emulsion, or 1% methylprednisolone (positive control), or non-treated. Aqueous tear production and CFS scores were evaluated at baseline and throughout the treatment period. The lacrimation test confirmed the scopolamine-induced decrease in aqueous production by the lacrimal gland. A reduction of 59% in induced-CFS was observed following topical treatment with 0.1% CsA. The beneficial effect of the cationic emulsion vehicle itself on keratitis was also clearly evidenced by its better performance over 1% methylprednisolone, -36%, vs. -28% on the CFS scores, respectively. This study indicates that the cationic emulsion of CsA (0.1%) was a very effective formulation for the management of corneal epithelium lesions in a severe DED mouse model. In addition, it performed better than a potent glucocorticosteroid (1% methylprednisolone). This cationic emulsion of CsA (0.1%), combining CsA and a tear film oriented therapy (TFOT), i.e. with vehicle properties that mechanically stabilize the tear film, represents a promising new treatment strategy for the management of the signs of dry eye.
Article
Full-text available
Purpose: The SANSIKA study was conducted to assess the treatment effect of 0.1% cyclosporine A cationic emulsion (CsA CE) eye drops on signs and symptoms of patients with severe dry eye disease (DED). Methods: This was a multicenter, randomized, double-masked, 2-parallel-arm, 6-month phase III study with a 6-month open-label treatment safety follow-up. Patients with severe DED with corneal fluorescein staining (CFS) grade 4 on the modified Oxford scale were randomized to receive once-daily CsA CE (Ikervis®) or its vehicle. Results: A total of 246 patients were randomized. The proportion of patients achieving ≥2 grades improvement in CFS and a 30% improvement in symptoms (Ocular Surface Disease Index [OSDI]) by month 6 was 28.6% with CsA CE vs 23.1% with vehicle (p = 0.326) (primary endpoint). Assessment of corneal damage showed greater improvement with CsA CE over vehicle in mean adjusted CFS change from baseline to month 6 (-1.764 vs -1.418, p = 0.037). There was a reduction in ocular surface inflammation assessed by human leukocyte antigen DR expression in favor of CsA CE at month 6 (p = 0.021). The mean OSDI change from baseline was -13.6 with CsA CE and -14.1 with vehicle at month 6 (p = 0.858). The main adverse event was instillation site pain (29.2% vs 8.9% in the CsA CE and vehicle groups, respectively), and it was mostly mild. Conclusions: CsA CE was well-tolerated and effective in improving corneal damage and ocular surface inflammation and confirmed the positive benefit-risk ratio of this new formulation of CsA for the treatment of severe keratitis in DED.
  • S Barabino
J Ocul Pharmacol Ther 2016;32:109–118. 8. Barabino S et al. Invest Ophthalmol Vis Sci 2005;46:2766–2771. 9. Daull P, Feraille L, Barabino S, Garrigue JS. ARVO 2015, Poster #4468.
  • P Daull
  • F Lallemand
  • Js Garrigue
Daull P, Lallemand F, Garrigue JS. J Pharm Pharmacol 2014;66:531–541. 11. Leonardi A et al.
Elena are employees of Iris Pharma (E). P. Daull and J.-S. Garrigue are employees of Santen SAS (E)
  • Y Quentric
  • L Feraille
Y. Quentric, L. Feraille and P.-P. Elena are employees of Iris Pharma (E). P. Daull and J.-S. Garrigue are employees of Santen SAS (E).
  • M Amrane
REFERENCES 1. DEWS. Ocul Surf 2007:5;163-179. 2. Amrane M et al. J Fr Ophtalmol 2014;37:589-598. 3. Georgiev GA, Yokoi N, Ivanova S, Tonchev V, Daull P. ARVO 2016, Poster #6188. 4. Vandamme TF. Prog Retin Eye Res 2002;21:15-34. 5. Lallemand F, Daull P, Benita S, Buggage R, Garrigue JS. J Drug Deliv 2012;2012:604204. 6. Bague S, Philips B, Rabinovich L, Lambert G, Garrigue JS. US Patent 2007-0248645. Santen, 2007. 7. Daull P, Feraille L, Elena PP, Garrigue JS.
  • S Barabino
J Ocul Pharmacol Ther 2016;32:109-118. 8. Barabino S et al. Invest Ophthalmol Vis Sci 2005;46:2766-2771. 9. Daull P, Feraille L, Barabino S, Garrigue JS. ARVO 2015, Poster #4468.
  • P Daull
  • F Lallemand
  • J S Garrigue
  • A Leonardi
Daull P, Lallemand F, Garrigue JS. J Pharm Pharmacol 2014;66:531-541. 11. Leonardi A et al.