Semisolid Dosage Forms Ophthalmic Ointments and Gels

Formulation

The principal semisolid dosage form used in ophthalmology is an anhydrous ointment with a petrolatum base. The ointment vehicle is usually a mixture of mineral oil and white petrolatum. The mineral oil is added to reduce the melting point and modify the consistency. The principal advantages of the petrolatum-based ointments are their blandness and anhydrous and inert nature, which make them suitable vehicles for moisture-sensitive drugs. Ophthalmic ointments containing antibiotics are used quite frequently following operative procedures, and their safety is supported by the experience of a noted eye surgeon Ramon Castroviejo (350), who, in over 20,000 postsurgical patients, saw no side effects secondary to ointment use. No impediment to epithelial or stromal wound healing was exhibited by currently used ophthalmic ointments tested by Hanna et al. (351). The same investigators have reported that, even if these ointments were entrapped in the anterior chamber and did not exceed 5% of the volume, little or no reaction was caused (352). Ganulomatous reactions requiring surgical excision have been reported secondary to therapeutic injection of ointment into the lacrimal sac (353).

The chief disadvantages of the use of ophthalmic ointments are their greasy nature and the blurring of vision produced. They are most often used as adjunctive nighttime therapy, with eyedrops administered during the day. The nighttime use obviates the difficulties produced by blurring of vision and is stated to prolong ocular retention when compared with drops. Ointments are used almost exclusively as vehicles for antibiotics, sulfonamides, antifungals, and anti-inflammatories. The petrolatum vehicle is also used as an ocular lubricant following surgery or to treat various dry eye syndromes. Anesthesiologists may prescribe the ointment vehicle for the nonophthalmic surgical patients to prevent severe and painful dry eye conditions that could develop during prolonged surgeries. A petrolatum ointment is recognized as a safe and effective OTC emollient (21 CFR 349.14), and marketed OTC emollient products are discussed in the 12th edition of the APhA Handbook of Nonprescription Drugs.

The anhydrous petrolatum base may be made more miscible with water through the use of an anhydrous liquid lanolin derivative. Drugs can be incorporated into such a base in aqueous solution if desired. Polyoxyl 40 stearate and polyethylene glycol 300 are used in an anti-infective ointment to solubilize the active principle in the base so that the ointment can be sterilized by aseptic filtration. The cosmetic-type bases, such as the oil-in-water (o/w) emulsion bases popular in dermatology, should not be used in the eye, nor should liquid emulsions, owing to the ocular irritation produced by the soaps and surfactants, used to form the emulsion.

In an attempt to formulate an anhydrous, but water-soluble, semisolid base for potential ophthalmic use, five bases were studied and reported on (354). The nonaqueous portion of the base was either glycerin or polyethylene glycols in high concentrations. The matrix used to form the phases included silica, Gantrez® AN-139, and Carbopol® 940. Eye irritation results were not reported, but the authors have studied representative bases from that research report and found them to be quite irritating in rabbit eyes. The irritation is believed to be primarily due to the high concentration of the polyols used as vehicles.

An aqueous semisolid gel base has been developed that provides significantly longer residence time in the cul-de-sac and increases drug bioavailability and, thereby, may prolong the therapeutic level in the eye. The gel contains a high-molecular-weight, cross-linked polymer to provide the high viscosity and optimum rheological properties for prolonged ocular retention. Only a relatively low concentration of polymer is required, so that the gel base is more than 95% water.

Schoenwald et al. (355) have demonstrated the unique ocular retention of this polymeric gel base in rabbits, in which the miotic effect of pilocarpine was significantly prolonged. The use of other polymers, such as cellulosic gums, polyvinyl alcohol, and polyacrylamides at comparable apparent viscosities, did not provide a significantly prolonged effect. The prolonged effect of pilocarpine has also been demonstrated in human clinical trials, in which a single application of 4% pilocarpine HCl-containing carbomer gel at bedtime provided a 24-hour reduced IOP, compared with the usually required q.i.d. dosing for pilocarpine solution (356). As a result, some glaucoma patients can now use pilocarpine in this aqueous gel base (Pilopine® HS Gel) dosing only once a day at bedtime to control their IOP without the significant vision disturbance experienced during the day for the use of conventional pilocarpine eyedrops. The gel is applied in a small strip in the lower conjunctival sac from an ophthalmic ointment tube.

The carbomer polymeric gel base itself has been used successfully to treat moderate to severe cases of dry eye (keratoconjunctivitis sicca) (357). The dry eye syndrome is usually characterized by deficiency of tear production and, therefore, requires frequent instillation of aqueous artificial tear eyedrops to keep the corneal epithelium moist. The gel base applied in a small amount provides a prolonged lubrication to the external ocular tissues, and some patients have reduced the frequency of dosing to control their symptoms to thrice a day or fewer.

Sterility and Preservation

Since October 1973, FDA regulations require that all U.S. ophthalmic ointments be sterile. This legal requirement was a result of several surveys on microbial contamination of ophthalmic ointments, and followed reports in Sweden and the United Kingdom of severe eye infections resulting from use of nonsterile ointments. In its survey published in 1973, the FDA found that of 82 batches of ophthalmic ointments tested from 27 manufacturers, 16 batches were contaminated, including 8 antibiotic-containing ointments. The contamination levels were low and were principally molds and yeasts

(358). The time lag in imposition of a legal requirement for sterility of ointments compared with solutions and suspensions was due to the absence of a reliable sterility test for the petrolatum-based ointments until isopropyl myristate was employed to dissolve these ointments and allow improved recovery of viable microorganisms by membrane filtration. Manufacturers found that, in fact, many of their ointments were sterile, but revised their manufacturing procedures to increase the assurance of sterility.

A suitable substance or mixture of substances to prevent growth of, or destroy, microorganisms accidentally introduced during use must be added to ophthalmic ointments that are packaged in multiuse containers, regardless of the method of sterilization employed, unless otherwise directed in the individual monograph or unless the formula itself is bacteriostatic in accordance with the USP (771), Ophthalmic Ointments. Schwartz

(359) has commented that a sterile ointment cannot become excessively contaminated by ordinary use because of its consistency and the fact that in a nonaqueous medium microorganisms merely survive, but do not multiply. Antimicrobial preservative effectiveness of ophthalmic ointments is evaluated by use of the USP (51).

Packaging

Historically, ophthalmic ointments were packaged in small tin collapsible tubes, usually holding 3.5 g. The tin tube was compatible with a wide range of drugs in petrolatum-based ointments; however, epoxy-phenolic-lined aluminum tubes are becoming more widespread. Plastic tubes made from flexible LDPE resins have also been considered as an alternative material, but do not collapse and tend to suck back the ointment. The various types of metal tubes are sealed using an adhesive coating covering only the inner edges of the bottom of the open tube to form the crimp, which does not contact the product. Laminated tubes are usually heat sealed. The crimp usually contains the lot code and expiration date. Filled tubes may be tested for leaks by storing them in a horizontal position in an oven at 60°C for at least 8 hours. No leakage should be evidenced except for a minute quantity that could only come from within the crimp of the tube or the end of the cap. The screw cap is made of polyethylene or polypropylene. Polypropylene must be used for autoclave sterilization, but either material may be used when the tubes are gas sterilized. A tamper-evident feature is required for sterile ophthalmic ointments, and may be accomplished by sealing the tube or the carton holding the tube such that the contents cannot be used without providing visible evidence of destruction of the seal.

The tube can be a source of metal particles and must be cleaned carefully before sterilization. The USP (751) metal particles in ophthalmic ointments is a test procedure that sets the limits of the level of metal particles in ophthalmic ointments. The total number of metal particles detected under 30 times magnification that are 50 |im or larger in any dimension is counted. The requirements are met if the total number of such particles counted in 10 tubes is not more than 50, and if not more than one tube is found to contain more than eight such particles.

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