Ophthalmic products, which are introduced into the interior structures of the eye either during ocular surgery or via an intravitreal injection, are a special class that requires the application of technology from parenteral dosage forms in their design, packaging, and manufacture. The development of cytomegalovirus (CMV) retinitis as a common opportunistic infection in patients with AIDS has resulted in the initial expansion of this class of ocular product to include solid inserts and injections of antiviral agents administered directly to the vitreous cavity. As discussed previously, topical and systemic administration often fail to achieve therapeutic concentrations in the vitreous cavity.
Ophthalmic surgery has rapidly advanced in the last three decades particularly with the ability of the surgeon to operate in back of the eye. The ophthalmologist can perform vitreoretinal surgery and restore significant visual function in patients with diabetic complications, endophthalmitis, and retinal tears and detachments. Also, significant advances have been made in anterior segment surgery, especially for cataract surgery where replacement of a cloudy or opaque natural crystalline lens with a plastic or silicone intraocular lens can restore visual acuity and allow the patient to achieve a significant improvement in his or her quality of life. These technological advances have placed greater emphasis on the development of products specifically formulated and packaged for intraocular use. This has led to the development of improved irrigating solutions, intraocular injections, viscoelastics, vitreous inserts, and intravitreal injections.
An essential component of ocular surgery is the use of physiological solution to moisten and irrigate ocular tissue on the external surface as well as intraocular anterior and posterior segments of the eye. Externally, the solution maintains a moist surface, preventing cellular desiccation, which can inhibit the surgeon's ability to see inside the eye. The solution also acts as a substitute for the natural aqueous intraocular fluid and aids in the removal of blood and cellular debris. Normal saline and lactated Ringer's solution were used initially since they were available in parenteral dosage form; but they lacked key components of ocular fluids. In the 1960s, a balanced salt solution was developed specifically for ocular surgical use and became widely used. It contains the five essential ions: sodium, potassium, calcium, magnesium, and chloride. It also contains citrate and acetate ions, which provide some buffer capacity and a potential source of bicarbonate. It is formulated to be iso-osmotic with aqueous humor (about 305 mOsm) and has a neutral to slightly alkaline physiological pH (49,111,367).
Balanced salt solution (BSS®) provided an improved ocular irrigating solution; however, as the surgical techniques for cataract surgery evolved and new vitreoretinal surgical procedures were introduced, larger volumes of irrigating solutions have been used, and surgical operating times for the very delicate vitreoretinal procedures can exceed several hours. This put additional physiological demands on the irrigating solution, and an enriched BSS (BSS® Plus) was developed. The enriched product contains the essential electrolyte components of BSS with the addition of glutathione (oxidized) and dextrose as energy sources, bicarbonate as a physiological buffer, and a phosphate buffer system to maintain the products storage pH in the physiological range (112,368).
The enriched BSS formulation presented chemical and physical stability issues not present in the original BSS product. It was necessary to use a two-part formulation to develop a commercially viable product with several years of storage stability; the two parts are aseptically combined just prior to surgery. The two-part formulation consists of a large volume part containing sodium, potassium, chloride, phosphate, and bicarbonate components at physiological pH and osmolality. The second part contains the calcium and magnesium divalent ions and the oxidized glutathione and dextrose in an acidic environment for long-term storage stability. The smaller-volume second part has a minimal buffer capacity and when added to the larger-volume first part does not significantly change the final product's physiological pH. Once aseptically combined, it is stable for at least 24 hours, although it is labeled to be used within 6 hours as a sterility precaution.
Providing the product as a two-part system was necessary to overcome the physical and chemical incompatibilities inherent in the final composition. Bicarbonate is stable only in an alkaline environment while glutathione and dextrose are stable in a pH range of about 3 to 5. Consideration was also given to which of the two parts should be of the larger volume in the irrigation bottle since there could be inadvertent failure to mix the two parts prior to use. The large volume component contains a bicarbonate saline solution at physiological pH and osmolality and thus would be more tissue compatible than irrigating with a hypo-osmotic acidic pH solution.
The large volume part is packaged in type 1 glass IV bottle and as such can be autoclave sterilized. The quality of the glass is important to prevent leaching of silicates, which can increase pH during autoclaving and storage. IV parenteral grade rubber stoppers must be used to minimize coring and extraction. Type 1 glass is also used for the additive part vial with a parenteral grade rubber stoppers. With a small volume in the larger volume package, the additive part can be easily added through the stopper via a transfer needle.
Intraocular irrigating solutions are required to be preservative-free to prevent toxicity to the internal tissues of the eye, particularly the corneal endothelium, lens, and the retina (369,370). These products are intended for single use only to prevent intraocular infections, which can be difficult to treat and seriously threaten sight. In addition to being sterile, they must be nonpyrogenic, therefore requiring sterile WFI as the vehicle.
These irrigating solutions have been developed and are labeled to be used without the addition of any drugs, that is, not as a delivery vehicle. However, some drugs such as epinephrine are added to the irrigating solution prior to surgery and used extensively by cataract surgeons to achieve and maintain pupillary dilation, facilitating removal of the natural lens and insertion of the prosthetic intraocular lens. Use of some commercial epinephrine injections that contain sodium bisulfite in addition to their acidic pH as the source for the epinephrine additive have been reported to be the cause of intraocular toxicity, even though it is diluted as much as 500-fold before irrigation (113).
Very few injectable dosage forms have been specifically developed and approved by the FDA for intraocular use. However, the ophthalmologist uses available parenteral dosage forms to deliver anti-infectives, corticosterioids, and anesthetic products to achieve higher therapeutic concentrations intraocularly than can ordinarily be achieved by topical or systemic administration. These unapproved or off-label uses have developed over time as part of the physician's practice of medicine and include subconjunctival, retrobulbar, sub-Tenon's, and intravitreal injections.
The FDA approved intraocular injections include miotics, triamcinolone acetonide, pegaptanib sodium, ranibizumab, formivirsen sodium, viscoelastics and viscoadherents, and an antiviral agent for intravitreal injection. There are many small and large molecules currently in clinical trials that are delivered via intravitreal injection for the treatment of a variety of retinal diseases with a large area of focus on the treatment of AMD and macular edema.
Antivirals are used to treat the ocular sequelae of AIDS such as CMV retinitis. They are treated with systemic administration; but with the need for higher localized ocular therapeutic concentrations, products have been developed and approved for direct administration into the vitreous cavity.
Intraocular implants for treatment of diseases of the posterior segment have been described in the section "Delivery to the Vitreous and Posterior Segment."
Highly purified fractions of sodium hyaluronate have become an important ocular surgical adjunct because of their lubricant and viscoelastic properties. They are injected into the anterior segment of the eye during surgery for removal of cataracts and implantation of an IOL, trabeculectomy, and corneal transplantation. They are also used as a surgical aid in the vitreous cavity during retinal surgery. Their viscoelasticity provides a mechanical barrier between tissues and allows the surgeon more space for manipulation with less trauma to surrounding tissues, particularly the corneal endothelium. It is also used to coat the IOL prior to insertion and lessen the potential for tissue damage upon implantation. In posterior segment surgery, it is used to separate tissue away from the retina and as a tamponade to maneuver tissue, such as a detached retina, back into place for reattachment. The viscoelastic material is usually removed at the end of the surgery since it may take several days to be cleared from the eye and has the potential to elevate IOP.
Sodium hyaluronate is a high-molecular-weight polysaccharide, which is widely distributed throughout the tissues of the body of animals and humans. The viscoelastic materials used as ocular surgical aids are specific fractions from animal tissue, which are highly purified to remove foreign proteins and are tested to be nonantigenic and noninflammatory in the eye. The purified fraction is formulated to yield a high viscoelasticity determined by the interplay of molecular weight and concentration. The solution is packaged in disposable glass syringes, which are terminally sterilized and aseptically packaged so that they can be used in the sterile surgical field (Healon®, ProVisc®, Amvisc®).
Chondroitin sulfate (Viscoat®, Duo Vise®, DisCoVisc®) also is used in combination with sodium hyaluronate as a viscoelastic surgical aid to provide higher viscosities, which may provide additional tissue protection during the irrigation and aspiration accompanying phacoemulsification, a common means of removing the cloudy crystalline lens prior to IOL implantation.
Nonpyrogenic solutions of sterile hydroxypropyl methylcellulose are also used as ocular surgical aids similar to the viscoelastics in cataract surgery (OcuCoat®). These lubricants are sometimes classified as viscoadherents because they are used to coat the IOL prior to implantation and the tips of surgical instruments prior to deployment inside the eye. This is the same cellulosic material, but in a highly purified form, serving as a viscosifying agent in topical eyedrops and as an OTC ocular lubricant. Since it is not a natural product, it does not have the antigenic potential of the other viscoelastics. It can be stored at room temperature, whereas the sodium hyaluronate solutions must be stored in the refrigerator.
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