CHAPTER # 2 (c

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FORMULATION OF OPHTHALMIC PREPARATIONS
Introduction: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, and the retention time of the medication in contact with the surface of the eye & the frequency of administration. Types of Drugs Used Ophthalmically: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. 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, scopalamine, hematropine, Cocaine & cyclopentolate etc.

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Local Anesthetics:Local anesthetics allow for the relief of pain pre-operatively, post operatively, following trauma & during ophthalmic examination. Among the local anesthetics used opthalmically 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.

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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. 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, Gentramycin, Tetracyclline & Neomycine. 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. 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. Formulation of Ophthalmic 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)

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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 & non living) 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. Manufacturing Techniques: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. 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. 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. Additives Used In Ophthalmic Preparations:In addition to the active drug, the ophthalmic preparations contain the following excepients (additives). 1. 2. 3. 4. Vehicle Tonicity Modifiers Buffers Stabilizers (Antioxidants)

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Preservatives Viscosity imparting agents.

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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.

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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 isoosmotic/ 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. 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).

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Stabalizers (Antioxidants):“Stabalizers are the agents which stabalize the product by preventing reducing-oxidation process”. Some commonly used antioxidants are metabisulfite, Ascorbic acid, isoascorbic acid, acetyl cystine & 8 hydroxy quinoline. Preservatives:“Preservatives are the agents which preserve the product by inhibiting the growth of micro organism”. 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. Ophthalmic solutions intended to be used during surgery or in traumatized eye generally do not contain preservatives, since they are irritating to the tissues within the eye. These solutions are usually packed in single dose containers & any unused solution is discarded. The recommended preservatives are Benzalkonium chloride, methyl parabin, propyl parabin, chlorhexidine, polyamino propyl biguanide, boric acid, borax etc. Viscosity imparting agents / Thickening agent: 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.

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Types of ophthalmic preparations:-

Ophthalmic preparations are available in different forms. Some commonly used ophthalmic preparation includes: 1. Ophthalmic solutions 2. Ophthalmic suspensions 3. Ophthalmic ointments 4. Ophthalmic inserts 1. Ophthalmic 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. Ophthalmic 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 a more 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. Ophthalmic Ointments: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. Ophthalmic Inserts: 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

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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. Packaging of Ophthalmics:Ophthalmic solutions & suspensions:Ophthalmic solutions & suspensions should be packed so that they are easily administered & their sterility maintained. Most ophthalmic solutions, being administered by drop, are packaged in a glass or plastic containers with a dropper service. Some plastic packages contain a fixed, built in dropper that release the medication when held in inverted position. The tip of the dropper must not come intact with the tissue during use, in order to avoid contamination. In selecting the packaging material for an ophthalmic solution, it must be determined that the container does not interfere with the stability or efficacy of the preparation. Plastic materials have been shown to interact with preservatives rendering them unavailable for this function. Thus particular precautions should be exercised when using plastic containers. Ophthalmic ointments:Ophthalmic ointments are filled into the sterile tin or plastic tubes. These tubes are typically small, holding approximately 3.5 gm of ointment & fitted with narrow gauge tips which permit the expulsion of narrow bands of ointment. This is convenient for placement of the ointment onto the margin of the eyelid, the usual site of application.

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