CENDO EYE FRESH EYE DROP

Spesifikasi Produk
Komposisi
HPMC 3,00 mg , Dextran(70) 1,00 mg.
Indikasi
Mengurangi iritasi pada mata yang kering karena kekurangan sekresi air mata,
melindungi mata terhadap iritasi lebih lanjut, mengurangi rasa tidak nyaman karena iritasi
mata ringan, terkana angin dan sinar matahari
Kelompok Obat
mata
Bentuk
drop
Cara Pakai
tetes
Peringatan Khusus
hanya untuk pemakaian luar, tidak dianjurkan untuk anak, jika mata terasa sakit dan
prubahan pengelihatan selama 72ja, hentikanpemakaian dan konsultasikan ke dokter

SEDIAAN OBAT MATA

Ophthalmic Preparations
Obat mata tersedia dalam berbagai bentuk sediaan,
beberapa diantaranya memerlukan perhatian khusus.
Larutan Larutan obat mata adalah larutan steril,
bebas partikel asing, merupakan sediaan yang dibuat
dan dikemas sedemikian rupa hingga sesuai digunakan
pada mata. Pembuatan larutan obat mata
membutuhkan perhatian khusus dalam hal toksisitas
bahan obat, nilai isotonisitas, kebutuhan akan dasar,
kebutuhan akan pengawet (dan jika perlu pemilihan
pengawet) sterilisasi dan kemasan yang tepat.
Perhatian yang sama juga dilakukan untuk sediaan
hidung dan telinga.
Nilai isotonisitas Cairan mata isotonik dengan darah
dan mempunyai nilai isotonisitas sesuai dengan larutan
natrium klorida P 0,9%. Secara ideal larutan obat mata
harus mempunyai nilai isotonis tersebut, tetapi mata
tahap terhadap nilai isotonis rendah yang setara dengan
larutan natrium klorida P 0,6% dan tertinggi setara gangguan nyata.
Beberapa larutan obat mata perlu hipertonik untuk
meningkatkan daya serap dan menyediakan kadar
bahan aktif yang cukup tinggi untuk menghasilan
efek obat yang cepat dan efektif. Apabila larutan obat
seperti ini digunakan dalam jumlah kecil, pengenceran
dengan air mata cepat terjadi sehingga rasa perih
akibat hipertonisitas hanya sementara. Tetapi
penyesuaian isotonisitas oleh pengenceran dengan air
mata tidak berarti, jika digunakan larutan hipertonik
dalam jumlah besar sebagai koliria untuk membasahi
mata. Jadi yang penting adalah larutan obat mata
untuk keperluan ini harus mendekati isotonik.
Pendaparan Banyak Obat, khususnya garam
alkaloid, paling efektif pada pH optimal bagi
pembentkan basa bebas tidak terdisosiasi. Tetapi pada
pH ini obat mungkin menjadi tidak stabil, sehingga pH
harus diatur dan dipertahankan dengan penambahan
dapar. Salah satu maksud pendaparan larutan obat
mata adalah untuk mencegah kenaikan pH yang
disebabkan pelepasan lambat ion hidroksil dari wadah
kaca. Kenaikan pH dapat mengganggu kelarutan dan
stabilitas obat. Penambahan dapar dalam pembuatan
obat mata harus didasarkan pada beberapa
pertimbangan tertentu. Air mata normal memiliki pH
lebih kurang 7,4 dan mempunyai kapasitas dapar
tertentu. Penggunaan obat mata merangsang
pengeluaran air mata dan penetralan cepat setiap
kelebihan ion hidrogen atau ion hidroksil dalam
kapasitas pendaparan air mata. Berbagai obat mata
seperti garam alkaloid bersifat asam lemah dan hanya
mempunyai kapasitas dapar yang lemah. Jika hanya
satu atau dua tetes larutan yang mengandung obat
tersebut diteteskan pada mata, pendaparan oleh air
mata biasanya cukup untuk menaikan pH sehingga
tidak terlalu merangsang mata. Dalam beberapa hal,
pH dapat berkisar antara 3,5 dan 8,5. Beberapa obat,
seperti pilokarpin hidroklorida dan epinefrin bitartrat,
lebih asam sehingga melebihi kapasitas dapar air
mata. Secara ideal larutan obat mata mempunyai pH
dan isotonisitas yang sama dengan air mata. Hal ini
tidak selalu dapat dilakukan karena pada pH 7,4
banyak obat yang tidak cukup larut dalam air.
Sebagian besar garam alkaloid mengendap sebagai
alkaloid bebas pada pH ini. Selain itu banyak obat
tidak stabil secara kimia pada pH mendekati 7,4.
Ketidakstabilan ini lebih nyata pada suhu tinggi yang
digunakan pada sterilitasi dengan pemanasan. Oleh
karena itu sistem dapar harus dipilih sedekat mungkin
dengan pH fisiologis yaitu 7,4 dan tidak menyebabkan
pengendapan obat atau mempercepat kerusakan obat.
Pembuatan obat mata dengan sistem dapar
mendekati pH fisiologis dapat dilakukan dengan
mencampurkan secara aseptik larutan obat steril
dengan larutan dapar steril. Walaupun demikian,
perlu diperhatikan mengenai kemungkinan
berkurangnya kestabilan obat pada pH yang lebih
tinggi, pencapaian dan pemeliharaan sterilitas selama
proses pembuatan.
Berbagai obat, bila didapar pada pH yang dapat
digunakan secara terapetik, tidak akan stabil dalam
larutan untuk jangka waktu yang lama. Sediaan ini
dibeku-keringkan dan direkonstitusikan segera
sebelum digunakan (misalnya Asetikolin Klorida untuk
Larutan Obat Mata).
Sterilisasi Pada larutan yang digunakan untuk
mata yang luka, sterilitas adalah yang paling penting.
Sediaan steril dalam wadah khusus untuk penggunaan
perorangan pada pasien harus tersedia pada setiap
rumah sakit atau instalasi lain yang melakukan
perawatan mata karena kecelakaan atau pembedahan
mata. Metode untuk mencapai sterilitas terutama
ditentukan oleh sifat sediaan tersebut (seperti yang
tertera pada Sterilisasi dan Jaminan Sterilitas Bahan
Kompendia <1371>).
Jika memungkinkan, penyaringan dengan
penyaring membran steril secara aseptik merupakan
metode yang lebih baik. Jika dapat ditunjukkan bahwa
pemanasan tidak mempengaruhi stabilitas sediaan,
sterilisasi obat dalam wadah akhir dengan otoklaf juga
merupakan metode yang baik.
Pendaparan obat tertentu disekitar pH fisiologis,
dapat menyebabkan obat tidak stabil pada suhu tinggi.
Penyaringan menggunakan penyaringan bakteri
adalah suatu cara yang baik untuk menghindari
pemanasan, namun perlu perhatian khusus dalam
pemilihan, perakitan dan penggunaan alat-alat. Sedapat
mungkin gunakan penyaring steril sekali pakai.
Pengawet Larutan obat mata dapat dikemas dalam
wadah takaran ganda bila digunakan secara perorangan
pada pasien dan bila tidak terdapat kerusakan pada
permukaan mata. Wadah larutan obat mata harus
tertutup rapat dan disegel untuk menjamin sterilitas
pada pemakaian pertama. Larutan harus mengandung
zat atau campuan zat sesuai untuk mencegah
pertumbuhan atau memusnahkan bakteri yang
mungkin masuk pada waktu wadah dibuka saat
digunakan.
Sedangkan untuk penggunaan pada pembedahan,
disamping steril, larutan obat mata tidak boleh
mengandung bahan antibakteri karena dapat
menimbulkan iritasi pada jaringan mata.
Bahan pengental Metilselulosa khusus untuk
sediaan farmasi (misal 1% bila kekentalan 25 sentipois
atau 0,25% bila kekentalan 4000 sentipois) atau bahan
pengental lain yang sesuai seperti hidroksipropil
metilselulose atau kadang-kadang polivinil alkohol
dapat ditambahkan untuk meningkatkan kekentalan
sehingga obat lebih lama kontak dengan jaringan.
Larutan obat mata yang dikentalkan harus bebas dari
partikel yang dapat terlihat.

Pada pasien dry eye syndrome terjadi penurunan jumlah air mata, sensitifitas permukaan, fungsi
ketajaman penglihatan, dapat terjadi pula reaksi infeksi dan inflamasi sehingga sangat berbahaya
karena mengakibatkan penurunan penglihatan (Catania et al., 2010; Alkhozi et al., 2013). Penurunan
volume lapisan air mata serta munculnya gejala-gejala tersebut perlu segera ditangani untuk mencegah
kondisi klinis pasien yang semakin memburuk. Tujuan dari terapi adalah pengurangan gejala,
peningkatan diameter lapisan air mata dan perbaikan kondisi klinis pada permukaan mata (Asbell et
al., 2010). Rekomendasi terapi berdasarkan dengan gejalanya yang disusun dalam International Dry
Eye Workshop pada tahun 2007 mengkategorikan tingkatan terapi menjadi empat. Tingkat 1 adalah
manajemen lingkungan, mengeliminasi pengobatan sistemik, dan penggunaan artificial tears. Apabila
terapi tersebut tidak dapat mengatasi keluhan maka naik ke tingkat 2 dan seterusnya (Pflugfelder et al.,
2007). Penanganan yang paling penting dan paling sering diberikan adalah artificial tears (Asyari
Fatma, 2007). Artificial tears atau air mata buatan bertujuan untuk mengurangi osmolaritas,
homeostasis normal dari permukaan mata, membersihkan kotoran pengiritasi dan toksik pada lapisan
air mata dan melindungi permukaan mata (Pflugfelder et al., 2007; Asyari Fatma, 2007). Adapun
tujuan dalam penelitian ini adalah untuk mengkaji penggunaan artificial tears dalam mengatasi
keluhan akibat dry eye syndrome terhadap pasien yang dirawat di Klinik Mata Surabaya. Penelitian
dilakukan secara observasional prospektif terhadap data tes schirmer dan kuesioner pasien selama
periode 1 Maret – 6 Juni 2016. Jumlah total pasien yang mendapatkan terapi artificial tears adalah
sebanyak 27 pasien. Namun hanya 10 pasien yang melakukan kontrol sehingga data outcome terapi
diambil dari 10 pasien tersebut.
Dalam penelitian ini artificial tears yang digunakan terdiri dari berbagai macam bahan yaitu sodium
hyaluronat, hidroksi propil metil selulosa (HPMC), Dextran 70, Gliserin, Polyvinyl pirolidon, vitamin
A, CMC sodium, carbomer, fexofenadin, metil selulosa (MC), natrium klorida, dan kalium klorida.
Bahan yang paling banyak digunakan sebagai terapi adalah sodium hyaluronat yaitu sebanyak 85,2%
pasien. Sodium hyaluronat mempunyai duration of action yang panjang serta dapat mencegah
kerusakan mata dengan cara menyimpan molekul H2O sehingga mencegah penguapan,
menghilangkan rasa terbakar, iritasi dan ketidaknyamanan yang disebabkan karena kekeringan pada
mata sehingga dapat mempercepat perbaikan permukaan mata yang rusak (Chris et al., 2013; Asyari
Fatma, 2007; Essa Laika, 2014). Viskositasnya yang sesuai dapat menstabilkan lapisan air mata,
mengurangi gejala berpasir dan terbakar (Essa Laika, 2014). Dari hasil penelitian yang dilakukan
diketahui bahwa artificial tears dapat mengatasi keluhan akibat dry eye syndrome yang dibuktikan
dengan hasil perhitungan statistik metode paired sample t test data volume air mata pasien sebelum
dan sesudah terapi menggunakan parameter schirmer’s test yang didapatkan sig 0,000 < 0,05. Hal ini
menunjukkan adanya perbedaan volume lapisan air mata sebelum dan setelah terapi artificial tears.
Serta dibuktikan dengan wawancara yang dilakukan kepada pasien melalui kuesioner McMonnies
yang menunjukkan adanya pengurangan gejala hingga hilangnya semua gejala. Berdasarkan penelitian
yang dilakukan tidak ditemukan adanya efek samping pemberian artificial tears pada pasien dry eye
syndrome serta tidak ditemukan pula adanya interaksi dengan pemberian obat-obatan lain yang
digunakan. Hal ini menunjukkan bahwa terapi artificial tears aman digunakan dalam penyembuhan
dry eye syndrome. Namun penelitian selanjutnya perlu dilakukan dengan waktu yang lebih lama untuk
melihat efektivitas dari terapi artificial tears terhadap pasien dry eye syndrome.

Artificial tears adalah larutan yang terkandung dalam obat tetes mata, dan memiliki
kemiripan dengan air mata asli manusia, sehingga disebut air mata buatan. Bahan-bahan
artificial tears biasanya berupa garam yang dapat menjaga tekanan osmotik pada mata,
misalnya sodium chloride (NaCl) dan potassium choride (KCl). Artificial tears baik untuk
mengatasi mata kering.

Masoud Safarzadeh,a,⁎ Parvin Azizzadeh,b and Pedram Akbarshahic

Author information ► Article notes ► Copyright and License information ► Disclaimer
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Introduction
Dry eye syndrome (DES) is a multifactorial disease of the ocular surface. Rapid
evaporation of tear film, inadequate production of tears, and inflammation of the ocular
surface are among the causes of this syndrome. This condition can result in the ocular
symptoms of foreign body sensation, redness, and discomfort, as well as the signs of
surface damage in the cornea and conjunctiva, all leading to detrimental visual
performance.1, 2, 3, 4 DES is a common problem worldwide and can reduce the working
efficiency of an individual. Dry eye is therefore a frequent complaint that patient present
to eye care clinics. Common patient's complaints related to dry eye include reduced
vision, difficulty reading, difficulty driving at night and difficulty doing computer
work.5A key principle for the management of dry eye disease is augmentation of the tear
film through the topical administration of artificial tear substitutes. These products
enhance tear stability thus reducing loss by evaporation; this, in turn, helps to retain
moisture in the eye and relieve the chronic ocular inflammation associated with dry eyes.
Artificial tear substitutes help to reduce patient discomfort, improve quality of life and
reduce the risk of damage to the corneal epithelium.6 Artificial tears are among the first
line of therapy in management of DES.8 They may be used along with other treatments
such oral omega-3 essential fatty acid supplements, mucin secretagogues, short term
steroids and daily cyclosporine A, to combat the inflammatory nature of the disease.9
Frequent eye care visits and different treatment options impose high costs to patients and
health care systems.10 Due to their non-invasive nature and low side effect profile,
artificial tears have remained the main stay of therapy for DES.11 Almost all tear
substitutes rapidly replace the moisture layer of tears12 and quickly reduce the
symptoms. In USA, approximately 7 to 10 million Americans spend 320 million dollars
per year on artificial tear products.13 In USA, many clinical trials have been conducted to
evaluate their efficacy and to compare them with each other.14 In report of Dry Eye
WorkShop (DEWS) was concluded that although many topical lubricants with various
viscosities improve symptoms there is no evidence to suggest that any one agent is
superior to another.7 However, ocular surface inflammation can be exacerbated by the
presence of preservatives. Benzalkonium chloride (BAK) is a preservative frequently
used in ophthalmic preparations. In patients with mild dry eye, benzalkonium chloride
containing products may be well tolerated when used four to six times a day or less.
Preservative free formulations are also indicated for those with a known history of allergy
to preservatives and those who wear contact lenses.22 Preservative-free formulations are
available in a variety of delivery systems. Many are supplied as single-dose units. These
are often small tubes or plastic ampoules designed to administer one drop and to be
discarded. These can usually be used to administer a drop into both eyes before
discarding. In addition to the presence or absence of lipid, artificial tear formulations may
be available in multidose bottles containing a preservative, or alternatively provided as
preservative-free formulations in unit-dose packaging.20 Multi-dose bottle preparations
of ocular lubricants are convenient to store and transport. Those licensed as medicinal
products must have a 28 day expiry after opening but many ocular lubricants registered as
medical devices have extended shelf lives of up to six months after first opening. Single
dose units are bulky to store, particularly if several different eye drops are used. They are
less convenient for the patient to carry, especially if they are being used many times a
day. They have a greater unopened shelf-life than multidose vials but generate more
waste.7, 20 A large number of artificial tear drops are available in the market. Selecting
the proper product that suits the patient, with reduced costs remains a challenge for the
clinician and the patients. The present study aimed to compare the clinical efficacy of two
different products of hydroxypropyl methylcellulose (HPMC) based artificial tear drops
on the improvement of dry eye syndrome after four weeks.
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Patients and methods

This is a randomized patient-masked clinical trial. The subjects for this study were
recruited from patients with dry eye syndrome in Tehran, Iran. At first, the subjects
completed the ocular surface disease index (OSDI) questionnaire. The examination of the
ocular surface and the eyelids was performed with a slit lamp biomicroscope to rule out
any other ocular diseases. The inclusion criteria were: having a score >20 in OSDI
questionnaire and no use of any types of artificial tears during the previous three months.
The exclusion criteria were as follows: patients with an allergy, infection, or eye surface
problems (e.g. pterygium); patients using contact lenses; patients using ophthalmic drugs,
such as steroidal or non-steroidal anti-inflammatory, antihistamines, and glaucoma
medications during the previous month, or systemically using drugs influencing tear
production, such as antihistamines, cortisones, hormones, beta-blockers, antidepressants,
and chemotherapy drugs; patients with a history of ophthalmic surgical operations;
patients undergoing radiotherapy; patients allergic to hydroxypropyl methylcellulose; and
pregnant or breastfeeding patients. For the patients who met the above criteria, the
purpose of the study was explained. If they were willing to participate, they were asked to
sign the informed consent form which was prepared based on the Declaration of Helsinki.
The patients were examined in two visits; one before the intervention and one after 30 ± 2
days of using the specified artificial tear. To assess patients’ DES-related symptoms, a
validated OSDI questionnaire was used. The OSDI, is a 12-question survey, with a five
point scale answers (0 = none of time and 4 = all of the time), with higher scores
representing greater disability. The total OSDI score is calculated based on the following
formula = 100 (sum of severity for all questions answered)/4 (Total number of questions
answered), where the severity was graded on a scale of: 0 = none of the time, 1 = some of
the time, 2 = half of the time, 3 = most of the time, 4 = all of the time. A score of 100
corresponds to complete disability while a score 0 corresponds to no disability. Following
the completion of the questionnaire, the tear break up time (TBUT) assessment was
performed using Lowther's method15 (A method for use of fluorescein strip in which the
portion of the fluorescein strip which is designed to be wetted, is approximately 5 mm
wide by 15 mm long to deliver a limited dose of from 0.5 to 1.0 μl of liquid to the surface
of the cornea) in right eye. A sterile fluorescein strip (Indicator, Tuba Teb Co., Iran) was
moistened using non preserved saline and excessive solution was shaken off. The strip
was touched gently to the superior bulbar conjunctiva or lid margin taking care not to
instill too much solution or cause excessive reflex tearing. The patients were asked to
blink two or three times naturally and then after one closure try to keep the eyes open.
The time from the opening until the appearance of first dry spot was measured in
seconds. The measurements were taken two times by stopwatch. For each subject, the
TBUT were averaged and the average values were compared before and after the
intervention. The subjects with TBUT < 10 s meeting the criteria for dry eye were
enrolled into the study. The conjunctiva and the cornea were examined after instillation of
fluorescein, with cobalt blue filter of SL-1E biomicroscope (Topcon, Japan). Punctuate
staining was recorded using a standardized grading system of 0-3 for each of the five area
on the corneal diagram.16 The Schirmer test was performed in right eye, with anesthetic,
measuring the basic tear secretion; a drop of Tetracaine 0.5% (Anestocaine, Sina Darou,
Iran) was applied to the eye. 5 min after instilling one drop of tetracaine 0.5% into the
conjunctival sac for test, the paper strips (Tuba Teb Co., Iran) were placed over the
junction of the temporal and medial one-third of the lower eyelid margin. The eyes were
closed during the test, and the length of the wet portion was measured in millimeters.17
The wetting strip counted <10 mm per 5 min were enrolled into the study. The subjects
meeting the inclusion criteria were divided into two groups based on their score in OSDI.
Artificial tears drops used into two groups were as follows: Group (A) Tear Naturale®
single dose eye drops from England, Alcon company, containing dextran 70, 1 mg/ml and
hypromellose, 3 mg/ml hydroxypropyl methylcellulose, sodium chloride, potassium
chloride, calcium chloride, magnesium chloride, zinc chloride, sodium hydrogen
carbonate, carbon dioxide (to adjust pH) and purified water as non-preservative. Group
B) Tearlose® multidose eye drops from Iran, Sina Darou company, containing
hydroxypropyl methylcellulose 0.3 g and 0.1 g of dextran 70, with 0.01% benzalkonium
chloride (BAK) as preservative which are available in 10 mL plastic bottles with nozzle
droppers and pilferproof caps. Using random blocks, the first group and the second group
received Tear Naturale® and Tearlose® eye drops, respectively. The patients were blind
to the names of the medication and were instructed to use the eye drops 2 times a day for
4 weeks. In addition, lid hygiene was recommended in the mornings; the base of lashes
had to be cleaned at the lid margins by Eyesol Ophthalmic Cleansing Shampoo, (Livar
Co, Iran). The patients were asked to return to the clinic for a follow-up visit in thirty
days. Before using a statistical procedure, the preconditions for its use were verified (e.g.
the normal distribution of the variables). If the preconditions were largely fulfilled,
parametric methods were used for the evaluation. If the preconditions were not fulfilled, a
non-parametric method was selected. Statistical analysis was performed using SPSS
version 18.0 (SPSS Inc., Chicago, IL, USA). Kolmogorov–Smirnov test was performed
to assess normality for continuous variables. The outcomes were compared between the
two groups using an independent t-test for continuous variables or the Chi-square test for
categorical variables. The comparisons of outcome measures between the baseline and 4-
week after intervention in each group were performed using a paired t-test and the
differences in the degree of change were compared between the two groups using an
independent t-test. To compare changes in Group A and B, repeated-measures analysis of
variance was used. A value of p < 0.05 was considered significant.
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Results
A total of 100 participants were recruited into the trial, 88 patients (41 patients in the
Group A and 47 patients in the Group B) completed the entire protocol. A total of 12
subjects (9 patients in the Group A and 3 patients in the Group B) failed to complete the
trial. The difference between the two groups in terms of sex distribution was not
significant (p = 0.135). The mean age of the participants in the Group A and the Group B
was 44.08 ± 6.29 years (range, 33–58 years) and 45.83 ± 8.42 years (range, 31–60 years),
respectively, and there was no significant difference between the groups (p = 0.379).
Demographic features of patients in the Group A and B are stated in Table 1. The means
and standard deviations of OSDI scores, TBUT, conjunctival and corneal staining scores,
Schirmer test scores of Groups A and B, before and after the intervention are presented in
Table 2. The OSDI scores after the intervention showed a significant decrease compared
to those before the intervention in both groups (p < 0.001). However, there was no
significant difference in the efficacy of the two artificial tear products (p = 0.440), and
repeated-measures analysis of variance did not demonstrate significant interaction
between type of product and change over time in the trend of mean OSDI in the Group A
and B (p = 0.468). The TBUT results after the intervention showed a significant increase
compared to those before the intervention, although not statistically significant (Group A;
p = 0.027 and Group B; p = 0.013). Also, in comparing the mean results of each tests
carried out, there was no significant difference in the efficacy of the two products (p =
0.497). The difference of interaction between the two groups and change over time in the
trend of mean TBUT was not statistically significant (p = 0.834). The conjunctival
staining scores 4-week after the intervention showed a significant decrease compared to
those before the intervention (p < 0.001). The two artificial tear products compared in
two groups showed similar effects (p = 0.822). Furthermore, the interaction of product
type and change over time in the trend of conjunctival staining score between the Group
A and B was not significant (p = 0.080). The corneal staining scores after the intervention
also showed a significant decrease compared to those before the intervention (p < 0.001).
However, two products of artificial tear drops did not show different effects (p = 0.793),
and the interaction the type of artificial tear and change over time in the trend of corneal
staining score was not statistically significant (p = 0.894). The Schirmer test scores, after
the intervention showed an increase compared to those before the intervention, but the
differences were not significant in either group (Group A; p = 0.129 and Group B; p =
0.115). Both products showed similar effects (p = 0.441), and the interaction between
type of artificial tear and change over time in the trend of Schirmer test was not
significant (p = 0.475).

Table 1
Demographic features of patients.

Group A (N = 41) Group B (N = 47) p Value

Mean age ± 44.08 ± 6.29 45.83 ± 8.42 0.379
SD (range: 33–58 (range: 31–60
years) years)
Male/Femal 19/22 21/26 0.135
e
Group A: patients assigned to use of the product of Tear Natural® single dose eye drops.
Group B: patients assigned to use of product of Tearlose® multidose eye drops.
p value: p values were derived from an independent t-test for continuous data and the
Chi-square test for categorical data.
N: number of patients.

Table 2
Comparison of the clinical characteristics of the two groups.

Group A Group B

Type of Baselin 4-Week pValue Baselin 4-Week pValue pValue pValue

test e visit (1) e visit (1) (2) (3)
OSDI 43.58 ± 31.92 ± <0.001 39.51 ± 29.97 ± <0.001 0.339 0.440
score 16.96 15.21 15.77 16.18
TBUT 7 ± 2.2 7.64 ± 0.027 7.15 ± 8.09 ± 0.013 0.640 0.497
(sec) 2.60 2.25 2.74
Conjuncti 6.67 ± 5.53 ± <0.001 7.34 ± 5.09 ± <0.001 0.334 0.822
val score 2.88 2.27 2.20 1.67
Corneal 1.23 ± 0.49 ± <0.001 1.15 ± 0.44 ± <0.001 0.807 0.793
score 1.33 0.78 1.07 0.57
Schirmer 6.04 ± 6.56 ± 0.129 6.64 ± 7.10 ± 0.115 0.676 0.441
test (mm) 5.25 5.46 6.12 6.40
OSDI: Ocular Surface Disease Index questionnaire; TBUT: tear break up time; Group A:
patients assigned to use of the product of Tear Natural® single dose eye drops; Group B:
patients assigned to use of product of Tearlose® multidose eye drops.
p Value (1): indicates the significant level of paired t-test within A or B groups between
baseline and four weeks after intervention.
p Value (2): indicates the significant level of independent t-test for comparing between A
and B groups before intervention.
p Value (3): indicates the significant level of independent t test for comparing between A
and B groups after four weeks.
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Discussion
In this study, hydroxypropyl methylcellulose (HPMC) as the active principle in Tear
Naturale® and Tearlose® eye drops reduced the symptoms DES equally. The mean score
of the OSDI questionnaire decreased significantly after the intervention in both groups.
When Toda et al.18 studied the effect of 0.5% HPMC without any preservative on
Sjögren and non-Sjögren dry eye patients, they observed that the symptoms were reduced
in both groups. Nguyen et al.19 examined the effect of inserts containing HPMC on
patients with DES and found that inserts were significantly effective in DES treatment.
Lanz20 also compared preserved HPMC (GenTeal, 0.3% HPMC, with sodium perborate
as preservative) vs nonpreserved HPMC (Tears Naturale, 0.3% HPMC, 0.1% dextran 70)
and found no significant difference between the symptoms of two groups after the
intervention. These findings agree with the result of this study. Lanz20 also found better
improvement in the Schirmer test with the preserved Genteal. In this study, a slightly
better improvement was observed with the preserved drop but the difference was not
significant. This difference could be due different preservatives used (sodium perborate
vs BAK) in two studies. In both groups, the conjunctival and corneal staining scores, after
the intervention, were reduced significantly (p < 0.001). In study performed by
Climent,23 GenTeal Tears® with preservative, and preservative-free Tears Naturale®
(Alcon Laboratories, Inc.) were compared. After 4 weeks of treatment, patients were
evaluated with TBUT, Schirmer's test, and corneal staining as well as via a symptom
questionnaire. A total of 37 patients completed the study. Both TBUT and Schirmer
testing improved in the GenTeal group but not in the Tears Naturale® group (p = 0.27).
These differences in two studies could be due to the preservative used in the group
GenTeal Tears and the amount of HPMC used in formulation of artificial tear drops.
Subjective symptoms were not different between the two treatments. In this study, the
results of Schirmer test (with anesthetic) before the intervention did not differ
significantly from those after the intervention. According to previous studies
performed,30, 31, 32 an increase in the volume of baseline tear was expected after the use
of artificial tears, but no change was observed. The increase in volume might have
happened shortly after the application of the eye drops and at the time of testing, a long
time might have passed since the instillation of the drop. In this study, a slightly better
improvement was observed with the preserved drop but the difference was not
significant. In both groups, the conjunctival and corneal staining scores, after the
intervention, were reduced significantly (p < 0.001). The improvement of epithelial cells
in the cornea and conjunctiva were in line with reduction of patients’ complaints. The
absence of preservative does not appear to be advantageous in terms of reducing the
corneal and conjuntival stains. Agents such as hydroxypropyl methylcellulose (HPMC),
which decrease rose bengal staining in dry eye subjects,33 may either coat and protect the
surface epithelium or help restore the protective effect of mucins. However, these results
might be due to the short-term use of these eye drops. McCann et al.21 compared the
efficacies of HPMC (Dacrisol unidose; Alcon, Italy), sodium hyaluronate (Lubristil
0.15% unidose, SIFI, Catania, Italy) and a new oil-in-water emulsion (Emustil unidose:
SIFI) in the management of patients with DES caused by impaired lipid bilayer. They
found that the symptoms and tear evaporation were reduced in the three groups, but the
differences for sodium hyaluronate or the HPMC group statistically were not significant.
This difference could be due to different preservatives used (sodium perborate vs BAK)
in two studies. Peter et al.24 demonstrated that both unit-dose and multi-dose artificial
tear drops are similar in terms of efficacy. Peter study observed statistically significant
improvements in OSDI scores from baseline at 30 days. There were no clinically
significant differences in performance in TBUT, corneal staining, conjunctival staining,
and Schirmer's test among the artificial tear formulations. In Peter et al. study, subjects
used artificial tears a median of three times a day, thus there may have been a difference
between the adverse effects observed with preservative vs non-preservative formulations
in subjects who used the eye drops more frequently for treatment of more severe dry eye.
Some studies have emphasized the side effects of preservatives on eye surface and tears,
including corneal and conjunctival tissue damage, loss of goblet cells, preventing the
growth of new cells, and accelerating cell death.25, 26, 27, 28 Benzalkonium chloride
(BAK) is the most frequently used preservative in topical ophthalmic preparations, as
well as in topical lubricants. Its epithelial toxic effects have been well established.11,
29The toxicity of BAK is related to its concentration, the frequency of dosing, the level
or amount of tear secretion, and the severity of the ocular surface disease. In the patient
with mild dry eye, BAK-preserved drops are usually well tolerated when used 4–6 times
a day or less. In patients with moderate-to-severe dry eye, the potential for BAK toxicity
is high, due to decreased tear secretion and decreased turnover.25, 26, 28, 29 The
incidence of most of the side effects depends on concentration of preservatives and long
duration of their use. Although other preservatives have shown better safety profile than
BAK,11but we did not observe any side effects for short time about the drop containing
BAK. Preservative-free formulations are absolutely necessary for patients with severe dry
eye with ocular surface disease and impairment of lacrimal gland secretion, or for
patients on multiple, preserved topical medications for chronic eye disease. Therefore,
artificial tears without preservatives are still recommended for patients with persistent
symptoms or those who require higher doses of the drops. Nonpreserved, single unit-dose
tear substitutes are more costly for the manufacturer to produce, more costly for the
patients to purchase, and less convenient to use than bottled artificial tear drops.22, 23
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Conclusion
The two artificial tears compared in this study, equally reduced the signs and symptoms
of dry eye syndrome in four weeks.
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Funding
This project is funded by department of ophthalmology, Bahman Hospital, Tehran, Iran.
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Conflict of interest
The authors have no financial interest in the products discussed in this article.
Go to:ﾧ

Acknowledgements
This article is the result of a clinical research prepared by the research committee at
department of ophthalmology, Bahman Hospital, Tehran, Iran.
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References
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3. Historical Treatment of Dry Eye Related to Lacrimal Gland Dysfunction

Regrettably, the treatment of dry eye related to tear film insufficiency has made little
progress in recent years. Most current therapies aim to reduce drainage of tears from the
eye, that is, punctual occlusion with cautery or plugs, or to replace insufficient aqueous
production from the lacrimal gland with artificial tears. Each of these therapies reduces
dry eye symptoms but each has significant drawbacks. For example, punctal plugs have
poor retention rates; can migrate into the lacrimal system; predispose the eye to infection;
and cause epiphora [86]. Punctal cautery can cause similar issues but is much more
difficult to reverse with patient intolerance. Artificial tears are a more benign therapeutic
option but the preservatives within them can be toxic to the cornea with frequent dosing
[87]. This issue has been circumvented by the production of preservative-free
preparations. While the ingredients have significantly changed, artificial tears were first
described nearly 3,500 years ago and are unfortunately rapidly removed from the ocular
surface [88]. It was not until the 1980s that natural or synthetic polymers were added to
preparations increasing viscosity and retention time. Such compounds as 1% glycerin
have shown prolonged benefit compared to propylene and polyethylene glycol are one
such example [89]. Even with these advancements, artificial tears are only a temporary
measure and do not provide important proteins produced by the lacrimal gland for ocular
health as previously discussed and are short-lived. As such, artificial tears and punctal
occlusion remain viable options for dry eye treatment but do not address the underlying
lacrimal gland dysfunction.
Further advancements have been made with the introduction of cyclosporine. The
compound was initially isolated from the fungus Tolypocladium inflatum, a potent
inhibitor of T cell activity [90, 91]. Therapy with this medication has shown great effect
by increasing goblet cell density and TGF-β. It has also been shown in mice to better
reduce epithelial staining compared to prednisone in an inflammatory dry eye model [92].
However, this therapy is presumably most effective in an inflammatory dry eye
minimizing its therapeutic use to these specific conditions. Additionally, poor patient
compliance further reduces its widespread application due to ocular irritation and
prolonged use necessary to see any appreciable benefit frustrating even the most
compliant patients.
Multiple surgical attempts have been made to bypass the lacrimal gland altogether by
transposing the parotid gland duct onto the lower conjunctiva, a technique developed in
the 1950s [93]. This has shown great promise in dogs with keratoconjunctivitis sicca with
a success rate as high as 92% [94], but the results are difficult to interpret in animals
unable to voice complaints of dry eye or excessive tearing. We, as well as others, have all
but abandoned the technique due to lack of any appreciable benefit, excessive tear
secretion, and high rates atrophy of the gland following surgery [95]. Consequently, this
technique is rarely used today except in animals due to inconsistent results and significant
side effects.
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4. Emerging Therapies for Dry Eye

There are several emerging modalities that have shown at least some promise in the basic
science realm. These emerging therapies can be divided into two categories: exogenous
compounds and gland regeneration/bypass. Unfortunately, many of these treatments are
still in their infancy and have not made significant progress beyond the basic science
realm.
Exogenous compounds are delivered to host tissue through either topical or oral routes.
Many of these new agents directly inhibit proinflammatory cascades. The list of targets
includes vascular cell adhesion inhibitors, immune modulators, and immune suppressants
[96–98]. These inhibitors have shown efficacy in mouse models of inflammatory dry eye
but have not been used in humans. One of these agents is delivered in an adenoviral
vector, which would theoretically reduce the need for reapplication but raises concerns
for inducing an innate immune response that could worsen inflammation [35, 98].
Moreover, immune suppression of the ocular surface could result in frequent infectious
complications. The recently described nonimmune compound, pituitary adenylate
cyclase-activating polypeptide-derived peptide, has been shown to promote corneal
wound healing and lacrimal gland secretion in mice [99]. With the adenoviral vector as
the exception, these compounds would likely be an improvement from artificial tears but
would reduce ocular immunity. Patient compliance as seen with other topical eye
medications would also be an issue. Consequently, the untested role of these topical
therapies may be of some benefit in few select populations.
With increasing success in stem cell-based tissue regeneration, tissues and organs such as
functioning photoreceptors and the liver can now be grown in vitro [100, 101]. Attempts
of a bioengineered lacrimal gland have seen recent success in mouse models as well
[102]. Stem cells are isolated using specific lacrimal cell markers, tissue grown ex vivo,
and transplanted into the host resulting in increased tear production [102–104]. While
promising, it remains to be seen whether these results can be reproduced in humans and
provide a feasible, long lasting therapeutic option. There has also been some suggestion
of using lacrimal gland xenografts as healthy tissue, but this theoretical idea remains
untested [105]. Furthermore, these transplant models have not evaluated the effect of
transplantation with ongoing diseases such as SS that may reduce graft transplantation
rates and efficacy such as seen with a significantly higher rejection rate of herpes-infected
corneas compared to noninflammatory corneal transplants [106]. While clinical
promising and would address gland dysfunction and restore normal tear production,
lacrimal gland regeneration or xenograph transplantation remains to be years from
clinical use.
More recently, sublingual, labial, and submandibular glands have been transplanted into
the subconjunctival space as an additional means to treat severe dry eyes due to
underlying basal secretion of these glands that does not require innervation [107, 108].
The transplanted glands have shown a reduction in dry eye symptoms for at least five
years and reduce the need for tear supplementation [109]. In addition, saliva contains
many of the same contents as the lacrimal gland including secretory IgA but the two have
not been specifically compared [110]. Unfortunately, the long-term efficacy beyond 5
years is currently unknown. Furthermore, the transplantation rate is at best 72% and
requires a difficult microsurgery including vascular anastomosis of the gland to the
temporal artery and vein [111]. As such, the surgery has not gained widespread use at this
point in time. The transplants can also cause chronic inflammation exacerbating dry eye
symptoms, microcystic epithelial edema, and epiphora in approximately 40% of patients
within 3–6 months of surgery [112, 113]. While transplantation of these glands has shown
great effect on dry eye and produce more natural tears than artificial instilled ones, the
complicated surgery and risk of graft failure are staggering complications to overcome
making them less than ideal.
Lastly, there is ongoing work on an implantable device to that stimulates the lacrimal
nerve to increase tear production within the lacrimal gland and this small animal study
has shown promising results [114]. However, it remains to be seen whether this method
of hyperstimulating the lacrimal gland can and/or will overcome gland dysfunction and
whether it becomes a feasible clinical treatment option. Furthermore, will this device be
able to stimulate a diseased gland enough such as in SS to overcome the symptoms of dry
eye?
In summary, there are several new modalities emerging for severe dry eye; however,
many of these options remain unproven or require extensive, technically difficult
microsurgery.
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5. Conclusion
There are multiple disease entities that can affect the lacrimal gland and cause its
dysfunction. Untreated pathologies and downstream effects of reduced production from
the lacrimal gland can result in decompensation of the ocular surface and gross
deterioration of visual acuity. The role of this gland cannot be overstated in ocular surface
health and proper light refraction from the air-tear interface. Emerging therapies will
hopefully alleviate the large dry eye burden worldwide by addressing the issue at its core,
by attempting to regenerate a dysfunctional gland and/or controlling the proinflammatory
state that ensues with severe dry eye. As such, new modalities and therapies need to be
developed through collaborative/translational research to treat aqueous deficiency-related
dry eye. It will be interesting to see if the untested, but promising, therapies discussed
become viable treatment modalities in dry eye therapy beyond the temporary measures of
ocular lubricants.
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Acknowledgments
The authors would like to thank Dr. Nick Mamalis for images of the lacrimal gland and
Lane Bennion for the medical drawings. The authors would also like to thank Research to
Prevent Blindness for their unrestricted grant to the Moran Eye Center.