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l PURPOSE: To investigate the effect of ophthalmic solution components on the surface of acrylic intraocular lenses (IOLs). SETTING: Department of Opthalmology, Showa University School of Medicine. METHODS: Measurement of the contact angles of ophthalmic solutions on 3 acrylic IOLs was performed. The solutions were diclofenac sodium (Diclod), bromfenac sodium (Bronuck), betamethasone phosphate (Rinderon), dibekacin sulfate (Panimycin), polysorbate 80 (Tween 20), benzalkonium chloride, chlorobutanol, methylparahydroxybenzoate, and propylparahydroxybenzoate. The IOLs were incubated at 35 degrees C for 2 weeks in undiluted ophthalmic solutions and in 1:10 dilutions of ophthalmic solution components. The IOLs were sectioned and observed by scanning electron microscopy. RESULTS: The contact angle of Diclod and Bronuck solutions was the smallest. The contact angle of Rinderon and Panimycin was similar to that of distilled water. Scanning electron microscopy examination of IOLs incubated in ophthalmic solution components showed intralenticular changes. The IOLs immersed in ophthalmic solutions did not show any change, even after extended incubation. CONCLUSION: The chemical components of ophthalmic solutions, such as surfactants and solvents, permeate acrylic IOLs, suggesting the potential for long-term adverse effects of eyedrops in pseudophakic eyes.
l Drugs are administered to the eye for local effects such as miosis, mydriasis, and anesthesia, or to reduce intraocular pressure in treating glaucoma. The ophthalmic formulation delivers the drug on the eye, into the eye, or onto the conjunctiva. Transcorneal transport (i.e., drug penetration into the eye) is not an effective process. It is estimated that only one-tenth of a dose penetrates into the eye.
l Formulations used include aqueous solutions, aqueous suspensions, ointments, and inserts. Every ophthalmic product must be sterile in its final container to prevent microbial contamination of the eye. Preservatives are added to the formulation to maintain sterility once the container has been opened. Ophthalmic formulations also require that the pH, buffer capacity, viscosity, and tonicity of the formulation is carefully controlled.
l entitled, "Pharmacy-Prepared Ophthalmic Products." The bulletin gives a sketch of the many considerations that are inherent in compounding ophthalmic formulations. The bulletin then stresses the need for established policies and procedures. It states that all compounding must be performed in a laminar air flow hood, and gives some general information about how to filtration sterilize solutions. Ophthalmic suspensions and ointments cannot be filtration sterilized and must either be sterilized as a finished product, or have each component separately sterilized and then combined using aseptic techniques.
l Solutions and Suspensions
l Ophthalmic solutions are sterile, free from foreign particles, and specially prepared for instillation in the eye. Most ophthalmic solutions are dispensed in eye dropper bottles. Patients should be shown how to properly instill the drops in their eyes, and every effort should be made to emphasize the need for instilling only one drop per administration, not two or three. When more than one drop is to be administered, wait at least five minutes between administrations. Immediately after instilling a drop on the eye, place pressure on the lacrimal sac for one or two minutes. This will reduce the rate of drug loss through this pathway.
l Ophthalmic suspensions are aqueous formulations that contain solid particles. The particle size must be kept to a minimum to prevent irritation of the eye. It has been recommended that particles be less than 10 microns in size to minimize irritation to the eye. The micronized form of the drug can be used to meet this requirement. There is a tendency of the solid undissolved particles to adhere to the conjunctiva. As drug is absorbed, these solid particles will dissolve to replenish the absorbed drug. This reservoir effect increases the contact time and duration of action of a suspension compared to a solution.
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l Ointments and Inserts |
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l In an effort to maintain longer contact between the drug and ocular tissue, ointments and inserts have been used.
l Ophthalmic ointments tend to keep the drug in contact with the eye longer than suspensions. Most ophthalmic ointment bases are a mixture of mineral oil and white petrolatum and have a melting point close to body temperature. Sometimes anhydrous lanolin is used to take up an ingredient that was dissolved in a small amount of water to affect dissolution. The aqueous solution is incorporated into the lanolin and then the lanolin is mixed with the remaining ointment base ingredients.
l Ointments must be nonirritating and free from grittiness so the micronized form of the ingredients is required. Sterile ointments are prepared by first sterilizing all of the individual ingredients and then combining them under aseptic conditions. The prepared ointment is then packaged in a sterile container such as an ointment tube.
l Most ointments tend to blur patient vision as they remain viscous and are not removed easily by the tear fluid. Thus ointments are generally used at night as adjunctive therapy to eye drops used during the day. Ophthalmic ointment tubes are typically small holding approximately 3.5 g of ointment and fitted with narrow gauge tips which permit the extrusion of narrow bands of ointment.
l Ocular inserts are not compounded but must be manufactured. Ocusert?is a nonerodible device designed to deliver pilocarpine for several days in the treatment of glaucoma. Some inserts are designed to dissolve in tear fluid. These inserts are made of dried polymeric solutions that have been fashioned into a film or rod. An example of this type of insert is Lacrisert?used to treat moderate to severe dry eye syndrome. Inserts are placed in the cul-de-sac between the eyeball and the eyelid. The biggest disadvantage of inserts is their tendency to float on the eyeball, particularly in the morning upon arising.
l FORMULATION FACTORS TO CONSIDER
l Solution pH
l The physiologic pH of blood and tears is approximately 7.4. Thus, from a comfort and safety standpoint, this would be the optimal pH of ophthalmic and parenteral 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.
l 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.
l Once we have determined the optimal pH of a product, we need a mechanism for adjusting and maintaining the pH of the solution.
l Buffers and Buffer Capacity
l Buffers are compounds that resist changes in pH upon the addition of limited amounts of acids or bases. Buffer systems are usually composed of a weak acid or base and its conjugate salt. The components act in such a way that addition of an acid or base results in the formulation of a salt causing only a small change in pH.
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