Ophthalmic Preparations

Dr.ismail M.Mahmoud

 Ophthalmic Preparations

Ophthalmic preparations are sterile products essentially free from foreign particles, suitably compounded and packaged for instillation into the eye. Ophthalmic pharmaceutical dosage forms serve as delivery vehicles for a wide range of drugs with pharmacological activity in the eye. The most commonly Ophthalmic preparations include: solutions, suspensions, ointments, and solid dosage forms. The solutions and suspensions are, for the most part aqueous. Ophthalmic ointments usually contain a white petrolatum mineral oil base.

 Ophthalmic preparations Also included are the newest dosage forms for ophthalmic drug delivery are: gels, gel-forming solutions, ocular inserts , intravitreal injections and implants.

Drugs used in the eye:

Miotics e.g. pilocarpine Hcl Mydriatics e.g. atropine Cycloplegics e.g. atropine Anti-inflammatories e.g. corticosteroids Anti-infectives (antibiotics, antivirals and antibacterials) Anti-glucoma drugs e.g. pilocarpine Hcl Surgical adjuncts e.g. irrigating solutions Diagnostic drugs e.g. Sodium fluorescein Anesthetics e.g. tetracaine

The single dominant factor characteristic of all ophthalmic products is the specification of sterility. Any product intended for use in the eye regardless of form, substance, or intent must be sterile. This requirement increases the similarity between ophthalmic and parenteral products; however the physiology of the human eye in many respects imposes more rigid formulation requirements.

GENERAL SAFETY CONSIDERATIONS

A-Sterility
Every ophthalmic product must be manufactured under conditions validated to render it sterile in its final container for the shelf life of the product

Every ophthalmic product must be sterile in its final container and the pH, buffer capacity, viscosity, and tonicity of the formulation

Ideally, all ophthalmic products would be terminally sterilized in the final packaging.

Only a few ophthalmic drugs formulated in simple aqueous vehicles are stable to normal autoclaving temperatures and times (121C for 20-30 min). *Such heat-resistant drugs may be packaged in glass or other heat-deformation-resistant packaging and thus can be sterilized in this manner.

Most ophthalmic products, however cannot be heat sterilized due to the active principle or polymers used to increase viscosity are not stable to heat

Most ophthalmic products are aseptically manufactured and filled into previously sterilized containers in aseptic environments using aseptic filling-and-capping techniques.

A. Sterility (cont.):

Isotonicity

Lacrimal fluid is isotonic with blood having an isotonicity value Corresponding to that of 0.9% Nacl solution

Some ophthalmic solutions are necessarily hypertonic in order to enhance absorption and provide a concentration of the active ingredient(s) strong enough to exert a prompt and effective action. Where the amount of such solutions used is small, rapidly so dilution with lacrimal fluid takes place that discomfort from the hypertonicity is only temporary.

To maintain physiological pH upon topical administration. The exposure of the eye to acidic or alkaline fluids may cause damage to the epithelial cells, resulting in ocular irritation and discomfort. To enhance drug penetration through changes in the degree of drug ionization. The penetration of drug across the cornea can be improved by selecting the pH that favors the un-ionized form of the drug. Transcorneal flux of weak organic bases such as procaine was found to increase as the solution became more alkaline. To improve the stability of the product.

pH Adjustment and Buffers: The physiologic pH tears is approximately 7.2-7.4. Thus, from a comfort and safety standpoint, this would be the optimal pH of ophthalmic solutions. This may not be possible, however, from a perspective of solubility, chemical stability or therapeutic activity. Thus, some compromise must be made and product stability must be considered paramount. When a formulation is administered to the eye, it stimulates the flow of tears. Tear fluid is capable of quickly diluting and buffering small volumes of added substances, thus the eye can tolerate a fairly wide pH range. Ophthalmic solutions may range from pH 4.5 - 11.5. But the useful range to prevent corneal damage is 6.5 to 8.5

pH & buffer

C- pH Adjustment and Buffers:

Conclusion:

If buffers are required, their capacity is controlled to be as low as possible ?? 1- to enable the tears to bring the pH of the eye back to the physiological range 2- to avoid effect of buffers on tonicity
Examples of buffer vehicles used: - Boric acid vehicle: pH of slightly below 5 - Isotonic phosphate vehicle: pH ranges from 5.9 - 8

C.Preservation and preservatives:

o Preservatives are included in multiple-dose eye solutions for

maintaining the product sterility during use. o Preservatives not included in unit-dose package. o The use of preservatives is prohibited in ophthalmic products that are used at the of eye surgery because, if sufficient concentration of the preservative is contacted with the corneal endothelium, the cells can become damaged causing clouding of the cornea and possible loss of vision. So these products should be packaged in sterile, unit-of-use containers.
The most common organism is Pseudomonas aeruginosa that

grow in the cornea and cause loss of vision.

C.Preservation and preservatives:

Examples of preservatives: 1- Cationic wetting agents:

Benzalkonium chloride (0.01%) It is generally used in combination with 0.01-0.1% disodium edetate (EDTA). The chelating, EDTA has the ability to render the resistant strains of PS aeruginosa more sensitive to benzalkonium chloride.
2- Organic mercurials: Phenylmercuric nitrate 0.002-0.004% phenylmercuric acetate 0.005-0.02%.

C.Preservation and preservatives:

3-Esters of p-hydroxybenzoic acid: Mixture of 0.1% of both methyl and propyl hydroxybenzoate (2 :1)
4- Alcohol Substitutes: Chlorobutanol(0.5%). Effective only at pH 5-6. Phenylethanol (0.5%)

Anatomy and Physiology of the Eye:

The sclera: The protective outer layer of the eye, referred to as the white of the eye and it maintains the shape of the eye. The cornea: The front portion of the sclera, is transparent and allows light to enter the eye. The cornea is a powerful refracting surface, providing much of the eye's focusing power.

The choroid is the second layer of the eye and lies between the sclera and the retina. It contains the blood vessels that provide nourishment to the outer layers of the retina.
The iris is the part of the eye that gives it color. It consists of muscular tissue that responds to surrounding light, making the pupil, or circular opening in the center of the iris, larger or smaller depending on the brightness of the light.

ANATOMICAL FEATURES OF THE EYE

The eye can be divided into an anterior segment and a posterior segment by the lens, where the anterior segment includes the cornea, iris, the ciliary body, the anterior chamber, and the posterior chamber and the posterior segment includes the retina and the vitreous body. A. ANTERIOR SEGMENT OF THE EYE The anterior segment of the eye is composed of the :

cornea, the conjunctiva, the iris, the ciliary body, the anterior and posterior chambers, and the lens.
B. POSTERIOR SEGMENT OF THE EYE The posterior segment of the eye is composed of the :

retina, vitreous, the choroid, the sclera, and the optic nerve

 he human eye is a challenging subject for topical T administration of drugs. The basis of this can be found in the anatomical arrangement of the surface tissues and in the permeability of the cornea. The protective operation of the eyelids and lachrymal system in such that there is rapid removal of material instilled into the eye, unless the material is suitably small in volume and chemically and physiologically compatible with surface tissues. .

ROUTES OF OCULAR DRUG DELIVERY

Topical Administration
The topical route of administration is used to treat diseases that affect the anterior segment of the eye such as keratitis, conjunctivitis, and glaucoma. However, topical delivery may not provide the desired therapeutic concentration of the drug in the posterior segment of the eye to treat diseases there. Drug delivery vehicles used for topical administration include: solutions, colloids, emulsions, suspensions, ointments, solid hydrophilic inserts, therapeutic contact lenses, rate-controlled release systems, and new delivery systems such as liposomes and particulates.

The advantages of topical administration are:

Convenient mode of administration Noninvasive Easy enough for self-administration Fewer systemic drug effects The disadvantages of topical administration are: Low ocular bioavailability Ineffectiveness in the treatment of posterior segment diseases

Ocular Bioavailability
Ocular bioavailability is an important factor in the effectiveness of an applied medication. Physiologic factors that can affect a drug's ocular bioavailability include: Protein binding, Drug metabolism, Lacrimal drainage.

Factors Affecting the Bioavailability of Topically Administered Drugs

In developing an effective topical drug delivery system, a thorough understanding of the physiological factors affecting the bioavailability is required. The major factors determining the bioavailability of topically applied drugs are : precorneal, corneal, and postcorneal factors.

A- Precorneal Factors

i-Precorneal fluid drainage: After instillation of the liquid dosage form, a significant part (80 to 90%) of it is drained into the nasolacrimal duct. This loss occurs primarily due to tendency of the eye to maintain the precorneal fluid volume at 7 to 10 l at all times as a protective physiological mechanism. Therefore excess fluid present in the cul-de-sac is drained into the nasolacrimal duct.

Lacrimal drainage. in man, the rate of tear production is approximately 2 microliters per minute; thus, the entire tear volume in the eye turns over every 2 to 3 minutes. This rapid washing and turnover also accounts for loss of an ophthalmic dose in a relatively short period of time The estimated maximum volume of the cul-de-sac is about 30 l, with drainage capacity far exceeding lacrimation rate. The outflow capacity accommodates the sudden large volume resulting from the instillation of an eye drop. Most commercial eye drops range from 50 to 75 l. in volume - The normal volume of tears = 7 ul, the blinking eye can accommodate a volume of up to 30 ul without spillage, the drop volume = 50 ul

 Rapid solution drainage by gravity, induced lachrymation, blinking reflex, and normal tear turnover:
Are factors that affect avialability of drugs applied topically into the eye

Various factors that influence the drainage rate are :

The instilled volume, viscosity, pH, tonicity, and drug type.

The rate of solution drainage from the conjunctival sac is directly

proportional to the instilled volume Increasing viscosity can prolong the residence time of an instilled dose in the conjunctival sac. The physiological pH of tear fluid is ~7.4. Since tears have poor buffer capacity, instillation of an acidic or alkaline solution causes excessive tear secretion and loss of drug. To prolong drug retention at the eye surface, ophthalmic preparations must have a pH between 7.0 and 7.7. Drugs that act on the lacrimal gland can affect precorneal fluid dynamics. Agents such as epinephrine induce tear production, and local anesthetics such as tetracaine suppress tear turnover.

The concept of dosage-volume drainage and cul-de-sac capacity directly affects the prescribing and administering of separate ophthalmic preparations. The first drug administered may be diluted significantly by the administration of the second. On this basis combination drug products for use in ophthalmology have considerable merit.

ii. Drug binding to tear proteins:

The protein content of tears in humans is about 0.7% of the total body protein. Normally, tears contain 0.6 to 2.0% of protein, including abumin and globulins, but disease states (e.g., uveitis) can raise these protein level Therefore the drug binding to the tear proteins may result in a reduction in free drug concentrations available for pharmacological action at the target site. Protein-bound drugs are incapable of penetrating the corneal epithelium because of the size of the protein-drug complex

Because of the brief time an ophthalmic solution may remain in the eye, the protein binding of a drug substance can quickly negate its therapeutic value by rendering it unavailable for absorption. Although ocular protein binding is reversible, tear turnover results in the loss of both bound and unbound drug As in the case with other biologic fluids, tears contain enzymes (e.g., lysozyme) capable of metabolic degradation of drug substances

iii.Conjunctival drug absorption: The conjunctiva is a highly vascularized mucous membrane lining the inside of the eyelids and the anterior sclera. Drugs are better absorbed across conjunctiva than cornea because of its greater surface area and high permeability. However, such nonproductive conjunctival absorption is a major precorneal loss factor and may lead to side effects, since it serves as a major route of entry into systemic circulation. Superficial absorption of drug into the conjunctiva and sclera and rapid removal by the peripheral blood flow: .

iv.Systemic drug absorption: A fraction of the topically applied dose that reaches the nasal mucosa through the nasalacrimal duct drainage may be absorbed systemically, leading to potential systemic side effects

B.Corneal Factors
The cornea consists of a hydrophilic stromal layer placed between a lipoidal epithelial layer and a single cell layer of endothelial cells. Drugs administered by instillation must penetrate the eye and do so primarily through the cornea. Corneal absorption is much more effective than scleral or conjunctival absorption, in which removal by blood vessels into the general circulation occurs.

Low corneal permeability (act as lipid barrier)

- As a general rule corneal epithelium acts as a major barrier to the

transport of hydrophilic drugs, whereas the hydrophilic stromal layer offers resistance to the passage of relatively lipophilic compounds.

Various strategies such as prodrug derivatization,penetration

enhancers, liposomes, and nanoparticles have been employed to deliver drugs across the cornea.

C. Postcorneal Factors Melanin binding: The presence of melanin pigment in the iris and ciliary body can affect the ocular bioavailabilty of the topically applied drug. Melanin imparts color to the eye. Drugs such as ephedrine and timolol can bind to the melanin with a high binding capacity, and only a small fraction of the bound drug is slowly released.

Drug metabolism: Various enzymes in the eye can metabolize the active drug, resulting in decreased ocular bioavailabilty. Drugs that are biotransformed by oxidation or reduction are less prone to metabolism than those transformed by hydrolysis because of the abundance of ocular hydrolases. The corneal epithelium and the iris ciliary body are the most metabolically active.

In addition to physiologic factors affecting ocular bioavailability, other factors, such as : The physicochemical characteristics of the drug substance and product formulation, are important. Because the cornea is a membrane barrier containing both lipophilic and hydrophilic layers, it is permeated most effectively by drug substances having both lipophilic and hydrophilic characteristics. s

2-Periocular Administration
Thismode of administration is usually employed for the treatment of anterior segment diseases when topical administration has failed. Injection is made underneath the conjunctiva Drugs administered by this route enter the eye by diffusing through the sclera, which has high permeability to different molecules compared with the cornea.

The periocular route is used for the administration of antibiotics or antivirals for the treatment of anterior segment pathologies

3-Intraocular Administration The treatment of many ocular diseases is hampered by poor penetration into the eye following systemic or topical administration. To circumvent the barrier, different routes of intraocular drug delivery have been investigated. Intraocular administration may be intravitreal (injections into the aqueous humor) or intracameral (injections into the vitreous). Intravitreal administration is employed for severe posterior segment diseases including endophthalmitis and retinitis. Repeated intravitreal injections may cause trauma to the eye and break down the blood retinal barrier. Intraocular sustained release ganciclovir implants have recently been developed for effective treatment of cytomegalovirus retinitis. These implants release a predetermined amount of drug at a constant rate, thereby avoiding repeated injections

4-Transscleral Administration Repeated long-term intravitreous delivery, which is required for treatment of chorioretinal disorders, leads to risk of local complications such as retinal detachment, endopthalmitis, and vitreous hemorrhage. Transscleral delivery may be a viable alternative to deliver drugs to the posterior segment because of the scleras large surface area and high permeability characteristics. Protein therapeutics can be administered by this route.

Types of Ophthalmic Products


CLASSIFICATION OF OCULAR DRUG DELIVERY SYSTEMS:
Topical eye drops: Solutions - Suspensions

Ointments Gels -

- Ocular inserts

- Powders for reconstitution - Sol to gel systems

A. Topical Eye drops:

1- Solutions: - Ophthalmic solutions are sterile solutions, essentially free from foreign particles, suitably compounded and packaged for instillation into the eye. This is by far the most common means of administering a drug to the eye.

1- Solutions:

Disadvantages of eye solutions:

1-The very short time the solution stays at the eye surface. The retention of a solution in the eye is influenced by viscosity, hydrogen ion concentration and the instilled volume. 2- its poor bioavailability (a major portion i.e. 75% is lost via nasolacrimal drainage) 3- the instability of the dissolved drug 4- the necessity of using preservatives.

The principal disadvantage of solutions is the relatively brief contact time between the medication and absorbing surfaces.

Contact time may be increased to some extent by the inclusion of a viscosity increasing agent )Viscosity imparting agents or viscosity enhancers(

Viscosity-Imparting Agents:

(to retard the rate of setting of particles)

Disadvantages: 1- produce blurring vision as when dry form a dry film on the eye lids 2- make filteration more difficult

2- suspensions:

to prevent irritation or scratching of the Cornea.

2- Suspensions:

3- Gel-Forming Solutions

3- Gel-Forming Solutions) Cont.)

3- Gel-Forming Solutions) Cont.)

Semisolid Dosage Forms: Ophthalmic Ointments and Gels:

Formulation:

Ointments are used as vehicles for antibiotics, sulfonamides, antifungals and anti-inflammatories. Petrolatum vehicle used as an ocular lubricant to treat dry eye syndromes. **It is suitable for moisture sensitive drugs and has longer contact time than drops.

Semisolid Dosage Forms: Ophthalmic Ointments and Gels:

*Gels have increased residence time and enhanced bioavailability than eye drops. N.B. Emulsion bases should not be used in the eye owing to ocular irritation produced by the soaps and surfactants used to form the Emulsion.

 The main disadvantage of ointments is that they

cause blurring of vision and an increased incidence of contact dermatitis

Ointments will interfere with vision unless use is

limited to bedtime instillation.

Ophthalmic ointments generally produce greater bioavailability than the equivalent aqueous solution. Because of the greater contact time, drug levels are prolonged and total drug absorption is increased.

How to Use Eye Ointments and Gels Properly?

PRODUCTION AND PACKAGING

Factors to be considered for production of ophthalmic products are similar to those for parenterals. Ophthalmic formulations, though not introduced into internal body cavities, are in contact with tissues that are very sensitive to contamination. Therefore, similar standards to sterile products should be followed for the preparation of ophthalmic medications. Quality control tests should be conducted on incoming stock and manufacturing and finished products. Finished products should be subjected to a leaker test, a clarity test, and a sterility test. One characteristic not as important for ophthalmic medications is that the product be free from pyrogens, since pyrogens are not absorbed systemically from the eye.

Eyedrops have been packaged almost entirely in plastic dropper bottles (the Drop-Tainer plastic dispenser). The main advantage of the Drop-Tainer are: convenience of use by the patient decreased contamination potential lower weight lower cost The plastic bottle and dispensing tip is made of low-density polyethylene (LDPE) resin, which provides the necessary flexibility and inertness. The cap is made of harder resin than the bottle.

** Advantage of LDPE resin: - Compatible with a very wide range of drugs and formulation components ** Disadvantage of LDPE resin: Sorption and permeability characteristics e.g. volatile preservatives such as chlorobutanol Weight loss by water vapor transmission LDPE resin is translucent, if the drug is light sensitive, additional package protection is required (using opacifying agent such as titanium dioxide) -- LDPE resin sterilized by gamma irradiation or ethylene oxide

A special plastic ophthalmic package made of polypropylene is introduced. The bottle is filled then sterilized by steam under pressure at 121C.

The glass bottle is made sterile by dry-heat or steam autoclave sterilization. Amber glass is used for light-resistance.

Packaging:

(By autoclaving or by ethylene oxide)

Advantages: Increasing contact time and improving bioavailability. Providing a prolong drug release and thus a better efficacy. Reduction of adverse effects. Reduction of the number administrations and thus better patient compliance.

Insoluble insert is a multilayered structure consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate. The rate of drug diffusion is controlled by: The polymer composition The membrane thickness The solubility of the drug

e.g. The Ocusert Pilo-20 and Pilo-40 Ocular system - Designed to be placed in the inferior cul-de-sac between the sclera and the eyelid and to release pilocarpine continuously at a steady rate for 7 days for treatment of glucoma. - consists of (a) a drug reservoir, pilocarpine (free base), and a carrier material, alginic acid: (b) a rate controller ethylene vinyl acetate (EVA) copolymer membrane.

Soluble inserts consists of all monolytic polymeric devices that at the end of their release, the device dissolve or erode.
Based on natural polymers e.g. collagen. Based on synthetic or semi synthetic polymers e.g. Cellulose derivatives Hydroxypropyl cellulose, methylcellulose or Polyvinyl alcohol, ethylene vinyl acetate copolymer.

Types

The system soften in 10-15 sec after introduction into the upper conjuctivall sac, gradually dissolves within 1 h, while releasing the drug.

- Advantage: being entirely soluble so that they do not need to be removed from their site of application.

Other Modes of Administration PACKS These sometimes are used to give prolonged contact of the solution with the eye. cotton pledget is saturated with an ophthalmic solution, and this pledget is inserted into the superior or inferior fornix. Packs may be used to produce maximal mydriasis. In this case the cotton pledgets can be, for example, saturated with phenylephrine solution.

D. Intraocular Dosage Forms

They are Ophthalmic products that introduced into the interior

structures of the eye primarily during ocular surgery.

Requirements for formulation:

1- sterile and pyrogen-free 2- strict control of particulate matter 3- compatible with sensitive internal tissues 4- packaged as preservative-free single dosage


D. Intraocular Dosage Forms: 1- Irrigating Solutions
It is a balanced salt solution was developed for

hydration and clarity of the cornea during surgery.

D. Intraocular Dosage Forms 2- Intraocular Injections

D. Intraocular Dosage Forms 3- Viscoelastics

D-Intraocular Dosage Forms 4- Intravitral Implant

E. Miscellaneous
1- Ocular iontophoresis: Iontophoresis is the process in which direct current drives ions into cells or tissues. If the drug molecules carry a positive charge, they are driven into the tissues at the anode; if negatively charged, at the cathode.
Ocular iontophoresis offers a drug delivery system that is fast,

painless, safe, and results in the delivery of a high concentration of the drug to a specific site.
Iontophoresis is useful for the treatment of bacterial keratitis,

Iontophoretic application of antibiotics may enhance their bactericidal activity and reduce the severity of disease

Iontophoresis

E. Miscellaneous 2- The vesicular delivery system

Liposomes

Niosomes

Advantages of Niosomes and liposomes

Contact lenses
The popularity of contact lens results from their cosmetic appeal, optical advantages and their usefulness in sporting activities

The risk associated with contact lenses wearing include recurrent corneal abrasions, microbial ulcerative

Contact Lenses & Care Solutions:

Types of contact lenses:

1- Hard contact lenses - Made of rigid plastic resin polymethylmethacrylate - Impermeable to oxygen and moisture - The lenses are 7 to 10 mm in diameter and are designed to cover only part of the cornea. - Hard lenses require an adaption period sometimes as long as a week for comfort

2- Soft contact lenses - Made of hydrophilic transparent plastic, hydroxyethylmethacrylate - Contain 30 80% water so are permeable to oxygen - Have two types: daily wear and extended wear
-

They range from about 13 to 15 mm in diameter and cover the entire cornea

Contact Lenses & Care Solutions:

Advantages of hard contact lenses and RGP lenses: 1- strength durability 2- resistant to absorption of medications and environmental contaminants 3- visual acurity Disadvantages: 1- require adjustment period of the wearer 2- more easily dislodged from the eye

Contact Lenses & Care Solutions:

Advantages of soft contact lenses:

1- worn for longer periods 2- do not dislodge easily Disadvantages: 1- have a shorter life span and the wearer must ensure that the lenses do not dry out

"soft" lens | "hard" lens

Care of Contact Lenses It is important that contact lenses receive appropriate care to retain their shape and optical characteristics and for safe use

Products for Soft Contact Lenses Cleaners Because of their porous composition, soft lenses tend to accumulate proteinaceous material that forms a film on the lens, decreasing clarity and serving as a potential medium for microbial growth. The two main categories of cleaners are: 1-Surfactants, which emulsify accumulated oils, lipids, and inorganic compounds, 2-Enzymatic cleaners, which break down and remove protein deposits. Surfactant agents are used in a mechanical washing

CARE OF CONTACT LENSES:

Products for soft contact lenses: Cleaners - To remove lipid and protein debris - formulation: 1- viscolizing surface-active agent: to enable gentle friction with fingertips 2- antibacterial-fast acting: benzalkonium chloride

PRODUCTS FOR SOFT CONTACT LENSES:

-

Rinsing and storage solutions Remove the cleaning solution, facilitate lens hydration, inactivation of microbial contamination and prevent the lens from drying out Formulation: 0.9% Nacl (isotonic) Antibacterial- 3% hydrogen peroxide for 30 min followed by inactivation with sodium pyruvate

 - For occasional cleaning followed by washing before

wearing Formulation: - Proteolytic enzyme: papain solution tablet to produce a solution when dissolved in water Enzymatic cleaning is accomplished by soaking the lenses in a solution prepared from enzyme tablets. This procedure is recommended at least once a week or twice a month in conjunction with regular surfactant cleansing. The enzyme tablets contain either papain, pancreatin, or subtilisin, which causes hydrolysis of protein to peptides and amino acids.

PRODUCTS FOR SOFT CONTACT LENSES : digest Enzyme protein

PRODUCTS FOR HARD CONTACT LENSES: Rinsing and storage solutions

For cleaning, microbial inactivation and hydration Formulation: surface-active agent - Antimicrobial: (0.01% benzalkonium chloride + 0.1% sodium edetate ) Wetting solutions - To achieve rapid wetting by the lachrymal fluid and promot comfort - Facilitate insertion of the lens - Provide lubrication Consist of: viscosity-increasing agent (hydroxy ethyl cellulose + wetting agent (polyvinyl alcohol) + preservatives (benzalknonium chloride or sodium edetate + buffers and salts to adjust pH and tonicity.
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