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Drugs are administered to the eyes in a wide variety of dosage forms, some of which require special consideration. They are discussed in the following paragraphs.
Ophthalmic ointments are ointments for application to the eye. Special precautions must be taken in the preparation of ophthalmic ointments. They are manufactured from sterilized ingredients under rigidly aseptic conditions and meet the requirements under Sterility Tests 71. If the specific ingredients used in the formulation do not lend themselves to routine sterilization techniques, ingredients that meet the sterility requirements described under Sterility Tests 71, along with aseptic manufacture, may be employed. Ophthalmic ointments must contain a suitable substance or mixture of substances to prevent growth of, or to destroy, microorganisms accidentally introduced when the container is opened during use, unless otherwise directed in the individual monograph, or unless the formula itself is bacteriostatic (see Added Substances under Ophthalmic Ointments 771). The medicinal agent is added to the ointment base either as a solution or as a micronized powder. The finished ointment must be free from large particles and must meet the requirements for Leakage and for Metal Particles under Ophthalmic Ointments 771. The immediate containers for ophthalmic ointments shall be sterile at the time of filling and closing. It is mandatory that the immediate containers for ophthalmic ointments be sealed and tamper-proof so that sterility is assured at time of first use.
The ointment base that is selected must be nonirritating to the eye, permit diffusion of the drug throughout the secretions bathing the eye, and retain the activity of the medicament for a reasonable period under proper storage conditions.
Petrolatum is mainly used as a base for ophthalmic drugs. Some absorption bases, water-removable bases, and water-soluble bases may be desirable for water-soluble drugs. Such bases allow for better dispersion of water-soluble medicaments, but they must be nonirritating to the eye.
Ophthalmic solutions are sterile solutions, essentially free from foreign particles, suitably compounded and packaged for instillation into the eye. Preparation of an ophthalmic solution requires careful consideration of such factors as the inherent toxicity of the drug itself, isotonicity value, the need for buffering agents, the need for a preservative (and, if needed, its selection), sterilization, and proper packaging. Similar considerations are also made for nasal and otic products.
Lacrimal fluid is isotonic with blood, having an isotonicity value corresponding to that of a 0.9% sodium chloride solution. Ideally, an ophthalmic solution should have this isotonicity value; but the eye can tolerate isotonicity values as low as that of a 0.6% sodium chloride solution and as high as that of a 2.0% sodium chloride solution without marked discomfort.
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, dilution with lacrimal fluid takes place rapidly so that discomfort from the hypertonicity is only temporary. However, any adjustment toward isotonicity by dilution with tears is negligible where large volumes of hypertonic solutions are used as collyria to wash the eyes; it is, therefore, important that solutions used for this purpose be approximately isotonic.
Many drugs, notably alkaloidal salts, are most effective at pH levels that favor the undissociated free bases. At such pH levels, however, the drug may be unstable so that compromise levels must be found and held by means of buffers. One purpose of buffering some ophthalmic solutions is to prevent an increase in pH caused by the slow release of hydroxyl ions by glass. Such a rise in pH can affect both the solubility and the stability of the drug. The decision whether or not buffering agents should be added in preparing an ophthalmic solution must be based on several considerations. Normal tears have a pH of about 7.4 and possess some buffer capacity. The application of a solution to the eye stimulates the flow of tears and the rapid neutralization of any excess hydrogen or hydroxyl ions within the buffer capacity of the tears. Many ophthalmic drugs, such as alkaloidal salts, are weakly acidic and have only weak buffer capacity. Where only 1 or 2 drops of a solution containing them are added to the eye, the buffering action of the tears is usually adequate to raise the pH and prevent marked discomfort. In some cases pH may vary between 3.5 and 8.5. Some drugs, notably pilocarpine hydrochloride and epinephrine bitartrate, are more acid and overtax the buffer capacity of the lacrimal fluid. Ideally, an ophthalmic solution should have the same pH, as well as the same isotonicity value, as lacrimal fluid. This is not usually possible since, at pH 7.4, many drugs are not appreciably soluble in water. Most alkaloidal salts precipitate as the free alkaloid at this pH. Additionally, many drugs are chemically unstable at pH levels approaching 7.4. This instability is more marked at the high temperatures employed in heat sterilization. For this reason, the buffer system should be selected that is nearest to the physiological pH of 7.4 and does not cause precipitation of the drug or its rapid deterioration.
An ophthalmic preparation with a buffer system approaching the physiological pH can be obtained by mixing a sterile solution of the drug with a sterile buffer solution using aseptic technique. Even so, the possibility of a shorter shelf-life at the higher pH must be taken into consideration, and attention must be directed toward the attainment and maintenance of sterility throughout the manipulations.
Many drugs, when buffered to a therapeutically acceptable pH, would not be stable in solution for long periods of time. These products are lyophilized and are intended for reconstitution immediately before use (e.g., Acetylcholine Chloride for Ophthalmic Solution).
The sterility of solutions applied to an injured eye is of the greatest importance. Sterile preparations in special containers for individual use on one patient should be available in every hospital, office, or other installation where accidentally or surgically traumatized eyes are treated. The method of attaining sterility is determined primarily by the character of the particular product (see Sterilization and Sterility Assurance of Compendial Articles 1211).
Whenever possible, sterile membrane filtration under aseptic conditions is the preferred method. If it can be shown that product stability is not adversely affected, sterilization by autoclaving in the final container is also a preferred method.
Buffering certain drugs near the physiological pH range makes them quite unstable at high temperature.
Avoiding the use of heat by employing a bacteria-retaining filter is a valuable technique, provided caution is exercised in the selection, assembly, and use of the equipment. Single-filtration, presterilized disposable units are available and should be utilized wherever possible.
Ophthalmic solutions may be packaged in multiple-dose containers when intended for the individual use of one patient and where the ocular surfaces are intact. It is mandatory that the immediate containers for ophthalmic solutions be sealed and tamper-proof so that sterility is assured at time of first use. Each solution must contain a suitable substance or mixture of substances to prevent the growth of, or to destroy, microorganisms accidentally introduced when the container is opened during use.
Where intended for use in surgical procedures, ophthalmic solutions, although they must be sterile, should not contain antibacterial agents, since they may be irritating to the ocular tissues.
A pharmaceutical grade of methylcellulose (e.g., 1% if the viscosity is 25 centipoises, or 0.25% if 4000 centipoises) or other suitable thickening agents such as hydroxypropyl methylcellulose or polyvinyl alcohol occasionally are added to ophthalmic solutions to increase the viscosity and prolong contact of the drug with the tissue. The thickened ophthalmic solution must be free from visible particles.
Ophthalmic suspensions are sterile liquid preparations containing solid particles dispersed in a liquid vehicle intended for application to the eye (see Suspensions). It is imperative that such suspensions contain the drug in a micronized form to prevent irritation and/or scratching of the cornea. Ophthalmic suspensions should never be dispensed if there is evidence of caking or aggregation.
Fluorescein sodium solution should be dispensed in a sterile, single-use container or in the form of a sterile, impregnated paper strip. The strip releases a sufficient amount of the drug for diagnostic purposes when touched to the eye being examined for a foreign body or a corneal abrasion. Contact of the paper with the eye may be avoided by leaching the drug from the strip onto the eye with the aid of sterile water or sterile sodium chloride solution.