OPTHALMICS

FORMULATION OF OPHTHALMIC PREPARATIONS

• DEFINITION:• Ophthalmic preparations may be defined as;

“These are the sterile preparations intended for installation into the eyes for the treatment of eye diseases, for the relief of symptoms, for diagnostic purposes, for washing of eyes & as an adjuvant in the surgical procedures.”

or• “These are the sterile preparation that are

compounded & packed for installation into the eye.”

• Drugs are commonly applied to the eye for the localized effect of the medication on the surface of the eye or on its interior. Most frequently aqueous solutions are employed; however non aqueous solutions, suspensions & ophthalmic ointments are also commonly used. Recently ophthalmic inserts, impregnated with drug, have been developed to provide for the continuous release of medication. These inserts are of particular usefulness for those drugs requiring frequent day time & night time administration.

• Since the capacity of the eye to retain liquid & ointment preparations is limited, they are generally administrated in small volumes. Larger volumes of liquid preparations may be used to flush or wash the eye. The normal volume of tears in the eye is 7µl, whereas a non blinking eye can accommodate a maximum of 30 µl of fluid, blinking eyes can hold only 10µl.

• Excessive liquids both normally produced & externally added are rapidly drained from the eye. Thus the effective “dose” of medication administered by ophthalmic route can be varied by the

• strength of medication administered• the volume administered • the retention time of the medication in

contact with the surface of the eye• the frequency of administration.

DRUGS WHICH ARE USED AS OPTHALMICS

• The major types of drugs used ophthalmically are as follows:-

1.Miotics:-Miotics are used primarily in the treatment of glaucoma. Miotics reduce intraocular pressure associated with glaucoma. Among the miotics are physostigmine, pilocarpine, neostigmine, methacholine, carbachol etc.

2.Mydriatics & Cycloplegics:-Mydriatics allow examination of the fundus of the eye thought the dilatation of the pupil. The stronger mydriatics having a long duration of action are called cycloplegics. Among mydriatics & cycloplegics are Atropine, hyoscyamine, scopolamine, hematropine, Cocaine& cyclopentolate etc.

3.Local Anesthetics:-Local anesthetics allow for the relief of pain pre-operatively, post operatively, following trauma &during ophthalmic examination. Among the local anesthetics used ophthalmically are Tetracaine, benoximate, proparacaine, cocaine, dyclonine & phenacaine etc.

4.Anti-InflammatoryAgents:-These agents combat inflammation of the eye. Most prominent among these are hydrocortisone, prednisolone & dexamethsone salts.

5.Local Antiseptics:-Local antiseptics are employed topically to reduce microbial presence on the eye. Among these are certain organic mercury compounds as trimerosal & ammoniated mercury & silver nitrate.

6. Anti-Microbial Agents:-Antimicrobial agents are used specifically to combat infection of the eye. They are frequently employed both systemically & locally for their effect. Among those applied topically to the eye are chloramphenical, sulfacetamide sodium, Gentamycin, Tetracycline & Neomycin.

7. Astringents: -These agents are generally used in the treatment of conjunctivitis (inflammation of the conjunctiva characterized by redness and often accompanied by a discharge). Most preparations for this purpose utilize Zinc-compounds, particularly Zinc Sulfate, as the astringent.

8. Topical Protectants:-These agents are employed as artificial tears or as a contact lens fluid. Examples of agents used in these solutions are methylcellulose & hydroxypropyl-methylcellulose.

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.

• The lens is a transparent, biconvex structure, encased in a thin transparent covering. The function of the lens is to refract and focus incoming light onto the retina.

• The retina is the innermost layer in the eye. It converts images into electrical impulses that are sent along the optic nerve to the brain where the images are interpreted.

• The macula is located in the back of the eye, in the center of the retina. This area produces the sharpest vision

• The inside of the eyeball is divided by the lens into two

fluid-filled sections.

• The larger section at the back of the eye is filled with a

colorless gelatinous mass called the vitreous humor.

The smaller section in the front contains a clear, water-like

material called aqueous humor.

• The conjunctiva is a mucous membrane that begins at

the edge of the cornea and lines the inside surface of the

eyelids and sclera, which serves to lubricate the eye.

Absorption of drugs in the eye

Factors affecting drug availability:1- Rapid solution drainage by gravity, induced

lachrymation, blinking reflex, and normal tear turnover:

- The normal volume of tears = 7 µl, the blinking eye can accommodate a volume of up to 30 µl without spillage, the drop volume = 50 ul

lacrimal nasal drainage:

FORMULATION OF OPTHALMIC PREPARATIONS

• The primary requirement for the ophthalmic preparation is that it should be sterile. As most of the ophthalmic preparations cannot be sterilized in the final containers due to the sensitivity of the active ingredients &/or excipients or package to the elevated heat, therefore these products are sterilized individually. They are blended aseptically, filled aseptically in pre-sterilized containers using aseptic capping technique. Due to these restrictions of sterility & purity the ophthalmic products are prepared in completely sterile environment using aseptic techniques to minimize the chances of contamination during the preparation & filling.

• Thus for the preparation of safe, sterile & therapeutically active product, the following factors must be controlled: - 1.Environment

2.Manufacturing Techniques 3.Raw Material 4.Machinery (equipment)

1) ENVIRONMENT• The environment required for the preparation of

ophthalmic product is same as that for parenterals. Ophthalmic preparations are manufactured & processed in aseptic area which needs the requirements of class-100 space. Class-100 space is an area having not more than 100 particles (living & nonliving) larger than 25µm. Now this aseptic area is constructed of hard, impervious material. The ceiling, walls & floor are such that they can be washed easily with disinfectant after each cycle.

• The air supplied to that area must be sterile i.e. air is passed through the HEPA Filters. A positive pressure is maintained in the rooms (i.e. inside pressure is more than outside) so that when the door is opened the air flows outside rather than coming inside. The personnel working in that area must wear the sterile gowns, gloves & foot covers. The inward & outward traffic should be minimum.

2) MANUFACTURING TCHNIQUES

• In case of eye drops water soluble ingredients are dissolved in water & then they are sterilized either by heat or filtration process. In case of suspension, which cannot be sterilized by filtration process, dry powder is either heat sterilized or ethylene oxide or by radiation. If dry powder is sensitive to heat & radiation then it is dissolved in suitable solvent, sterilized by filtration & then crystallized aseptically .In case of ophthalmic ointments, the base is first melted, heat sterilized & then filtered to remove large particles.

• Then pre sterilized active ingredients & excipients are mixed aseptically with molten base. Then this molten mass is passed through sterilized colloidal mill & then it is filled in previously sterilized container.

3) RAW MATERIALS: The raw materials used for the ophthalmic

preparation (i.e. Active ingredients & excepients) must be of highest purity & quality. Specifications for the raw material of every product should be established & each lot of material purchased should be checked for the established specifications

4) MACHINERY/EQUIPMENTS

• Equipments used for the ophthalmic preparation have same requirements as those used for parenterals. All parts of the equipments coming in contact with the product are made up of corrosion free material, which can easily be disassembled, cleaned & sterilized. Preferably they are made up of high grade stainless steel. Moreover machinery used should be cleaned regularly in order to avoid the risk of contamination.

General safety considerations

A. Sterility- Ideally, all ophthalmic products should 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 (121°C 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.

B. Ocular toxicity and irritation

- Albino rabbits are used to test the ocular toxicity and irritation of ophthalmic formulations.

- The procedure based on the examination of the conjunctiva, the cornea or the iris.

- E.g. USP procedure for plastic containers:

1- Containers are cleaned and sterilized as in the final packaged product.

2- Extracted by submersion in saline and cottonseed oil.

3- Topical ocular instillation of the extracts and blanks in rabbits is maintained and ocular changes examined.

C) PRESERVATIVES• “Preservatives are the agents which preserve

the product by inhibiting the growth of microorganism”. All ophthalmic solutions should be sterile when dispensed. Preservatives / Antimicrobials are used in multi dose containers in order to inhibit the growth of micro-organisms which may contaminate the product during withdrawl of the dose.

Preservation and preservatives

• Preservatives are included in multiple-dose eye solutions for maintaining the product sterility during use.

• The use of preservatives is prohibited in ophthalmic products that are used at end the of eye surgery otherwise they will cause irritation to the eye

So these products should be packaged in sterile, unit dose containers and any unused solution is discarded.

• The most common organism is Pseudomonas aeruginosa that grow in the cornea and cause loss of vision.

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 Pseudomonas aureginosa more sensitive to benzalkonium chloride.

2- Organic mercurials:• Phenylmercuric nitrate 0.002-0.004%

phenylmercuric acetate 0.005-0.02%.

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%)

Ideal ophthalmic delivery system

Following characteristics are required to optimize ocular drug delivery system:

• Good corneal penetration. • Prolong contact time with corneal tissue. • Simplicity of instillation for the patient. • Non irritative and comfortable form • Appropriate rheological properties

ADDITIVES USED IN OPTHALMIC PREPARATIONS

Inactive Ingredients in Topical Drops

1) VEHICLES• “Vehicle is a medium in which the drug is dissolved,

suspended or emulsified & which functions to carry the drug to the target site”.

• Some vehicles used in ophthalmic preparation are:-i. For the ophthalmic drops purified water or normal saline

is used as vehicle. In some cases the viscosity increasing polymers are also added to increase the drug retention time in the eye.

ii. If a drug is sensitive to water or moisture then oils are used as vehicles. Different oils used for this purpose. The oil used should be of highest purity, free from rancidity. The oil should be free from antioxidant because antioxidants may be irritating to the eye.

iii. In the ophthalmic ointment, ointment base is used. White petroleum is mixed with liquid petroleum to produce the base of desired consistency. Some oil is also used to decrease the melting point. This petroleum base is widely used due to its anhydrous nature & its inertness.

2) TONICITY MODIFIERS• Tonicity modifiers are used to make the

ophthalmic solutions isotonic with the lacrimal fluid. Body fluids, including blood & lacrimal fluid, have an osmotic pressure corresponding to that of a 0.9% solution of NaCl. Thus a NaCl solution of this concentration is said to be iso osmotic/ isotonic, or having an equal osmotic pressure with physiologic fluids. The term isotonic means “of equal tone or osmotic pressure”.

• The solutions with a lower osmotic pressure than body fluids or a 0.9% NaCl solution are called “Hypotonic” whereas solutions having a greater osmotic pressure than body fluids are called “Hypertonic”. Theoretically, a hypertonic solution added to the body’s system will have a tendency to draw water from the body tissues toward the solution in effort to dilute & establish concentration equilibrium. In eye, this solution could cause the drawing of water toward the site of the topical application. Conversely, a hypotonic solution might induce the passage of water from the site of an ophthalmic application through the tissue of the eye.

• Both of these conditions are undesirable. Thus tonicity modifiers are used to adjust the tonicity of the eye solutions. The agents used for this purpose are NaCl, KCl, sucrose, dextrose, PEG etc. In practice, the Isotonicity limits of an ophthalmic solution in terms of NaCl or its osmotic equivalent may range from 0.6 – 2% without marked discomfort to the eye

3) BUFFERS• “Buffers are the agents which resist change in

PH of the solution. "Buffers may be used in an ophthalmic solution for one or all of the following reasons:-1.To reduce discomfort to the patient.2.To ensure drug stability & solubility.3.To control the therapeutic activity of the drug substance.

• Normal tears, having a PH of about 7.4, possess some buffer capacity. The introduction of a medicated solution into the eye stimulates the flow of tears, which attempts to neutralize any excess H+ or OH- ions introduced with the solution. Normally, the buffering action of the tears is capable of neutralizing the ophthalmic solution & is thereby able to prevent marked discomfort. However a few drugs e.g. pilocarpine HCl are quite acidic & overtax the buffer capacity of the lacrimal fluid.

• For maximum comfort, an ophthalmic solution should have the same PH as the lacrimal fluid i.e. 7.4.The tolerable PH range is 6-8.Mostly the drugs are most active therapeutically at PH levels which favor the undissociated molecule, because at this PH these are more lipid soluble & hence are easily absorbed. However the PH that permits greatest activity may also be the PH at which the drug is least stable.

• For this reason, a compromise PH is generally selected for solution & maintained by buffers to permit the greatest activity while maintaining stability.PH also plays an important role in the drug solubility. In general, for acidic drug an increase in PH will increase the solubility while for basic drug an increase in PH will decrease the solubility.(Because unionized form is less soluble).

• pH adjustment is very important as pH can:1- render the formulation more stable2- improve the comfort, safety and activity of

the product.3- enhance aqueous solubility of the drug.4- enhance the drug bioavailability5- maximize preservative efficacy

4- Stabilizers & Antioxidants

5- Surfactants

6-VISCOSITY IMPARTING AGENTS/THICKENING AGENTS

• Viscosity is a property of a liquid that is closely related to the resistance to flow. The reciprocal of viscosity is fluidity. In the preparation of ophthalmic solutions, a suitable thickening agent is frequently added to increase the viscosity & thereby aid (help) in holding the drug in contact with the tissues so as to enhance the therapeutic

effectiveness. Generally methylcellulose, hydroxypropyl methylcellulose & polyvinyl alcohol are used as thickeners in ophthalmic solutions. Viscosity for ophthalmic solutions is considered optimal in the range of 15-25 Cps.

TYPES OF OPTHALMIC PREPARATIONS

Ophthalmic preparations

Definition: They are specialized dosage forms designed to be instilled onto the external surface of the eye (topical), administered inside (intraocular) or adjacent (periocular) to the eye or used in conjunction with an ophthalmic device.

The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments.

These preparations when in stilled into the eye are rapidly drained away from the ocular cavity due to tear flow and lacrimal nasal drainage.

The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming solutions, ocular inserts , intravitreal injections and implants.

Classification of ocular drug delivery systems

- Solutions

- Suspensions

- Powders for reconstitution

- Sol to gel systems

- Ointments

- Gels

Ocular inserts

A. Topical Eye drops:

1) SOLUTIONS• “Ophthalmic solutions are sterile solutions

that are compounded & packed for installation into the eyes. Ophthalmic solutions may be aqueous solutions or oily solutions. In addition to their sterility, their preparation requires the careful consideration of such other pharmaceutical factors as the need for Antimicrobial agents, isotonicity, buffering, viscosity & proper packaging

• Ophthalmic solutions provide more uniform dosage forms, having better bioavailability & greater ease for handling during production. Ophthalmic solutions are packed in containers with a dropper service.

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.

2) OPTHALMIC SUSPENSIONS

• Ophthalmic suspensions are employed to a lesser extent than are ophthalmic solutions; however suspensions may be used to increase the corneal contact time of a drug substance & thus provide amore sustained action. Ophthalmic suspension may be required when the drug is insoluble in the desired vehicle or unstable in solution form. Ophthalmic suspensions must also be sterile, with proper consideration given also to preservation, isotonicity, buffering, viscosity & packaging.

• Additionally ophthalmic suspensions must contain particles of such chemical characteristics & small dimensions that they are non-irritating to the eye. Moreover the suspended particles should not agglomerate into larger ones upon storage. The suspension must be shaken prior to use. Ophthalmic suspensions are packed in the same types of dropper container as are the ophthalmic solutions.

3- Powders for Reconstitution

4- Gel-Forming Solutions

Packaging

• 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 vapour 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 121°c.

• The glass bottle is made sterile by dry-heat or steam autoclave sterilization.

• Amber glass is used for light-sensitive products

B. Semisolid Dosage Forms

• Ophthalmic Ointments and Gels:• FORMULATION• Ophthalmic ointments also increase the

ocular contact time of the drug. Ophthalmic ointments, in contrast to the dermatological (skin) ointments, must be sterile. They are either manufactured from sterilized ingredients & under rigid aseptic conditions or they are sterilized following manufacture.

• The ointment base selected for an ophthalmic ointment must be non-irritating to the eye & must permit the diffusion of the drug throughout the secretions bathing the eye. Ointment bases utilized for ophthalmic have a melting or softening point close to body temperature. Ophthalmic ointments are packed in the previously sterilized tin or plastic ophthalmic tubes, fitted with a narrow gauge tips which permit the expulsion of narrow bands of ointment.

- Ointments are used as vehicles for antibiotics, sulfonamides, antifungals and anti- inflammatories.

- Petrolatum vehicle used as an ocular lubricant to treat dry eye syndromes.

• Gels have increased residence time and enhanced bioavailability than eye drops.

• Emulsion bases should not be used in the eye owing to ocular irritation produced by the soaps and surfactants used to form the Emulsion.

• It is suitable for moisture sensitive drugs and has longer contact time than drops.

• Chlorobutanol and methyl- and propylparaben are the most commonly used preservatives in ophthalmic ointments.

Packaging

• By autoclaving or by ethylene oxide

C. Solid Dosage Forms: Ocular Inserts

OPTHALMIC INSERTS

• Ophthalmic inserts are defined as sterile solid or semisolid preparations, with a thin, flexible and multilayered structure, for insertion in the conjunctival sac.

• Recently ophthalmic inserts impregnated with drug, have been developed to provide for the continuous release of the drug. The insert unit is designed to provide for the release of medication at predetermined & predictable rates permitting the elimination of frequent dosing by the patient, ensuring night-time medication & providing a better means of patient compliance.

• The insert is flexible & 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 diffusion is controlled by the polymer composition, the membrane thickness & the solubility of the drug. The devices (inserts) are sterile & do not contain preservatives.

• 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.

C. Ocular InsertsInsoluble inserts

• 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.

• Advantages of pilocarpine ocuserts over drops :

• The ocusert exposes the patient to a lower amount of the drug leading to reduced side effects .The ocusert provide a continuous control of the intra-ocular pressure The ocusert is administered only once per week & this will imporve patient compliance .The ocusert contain no preservative so they will be suitable for patients sensitive to preservatives in opthalmic solutions

Disadvantages of pilocarpine ocuserts

• They are more expensive than drops It may be inconvenient for the patient to retain the ocusert in the eye for the full 7 days.

• The ocusert must be checked periodically by the patient to see that the unit is still in place

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-free2- strict control of particulate matter3- compatible with sensitive internal tissues4-packaged as preservative-free single dosage

1- Irrigating Solutions

• It is a balanced salt solution was developed for hydration and clarity of the cornea during surgery.

2- Intraocular Injections

3- Intravitral Implant