Partition characteristics and retention of anti-inflammatory steroids in liposomal ophthalmic preparations.

Liposome preparations containing dexamethasone or its ester derivatives were formulated as eye drops. Steroids were efficiently incorporated into the liposomes; the incorporation ratio was not affected by the period of sonication or the addition of stearylamine or dicetylphosphate, but was decreased by the addition of cholesterol. The incorporation ratio appears to be governed by partition equilibrium between the lipid membrane and the aqueous phase. A theoretical interpretation of the findings was attempted by using partition theory. No release of dexamethasone palmitate from liposomes was detected, but a small portion of other steroids was rapidly released when the liposome preparation was diluted with a buffer solution. The amount of steroid released from the liposomes may also be governed by the partition equilibrium. The topical application of eye drops is a convenient and useful therapeutic method for the treatment of various ocular diseases. An ophthalmic preparation should be a clear aqueous solution to avoid temporary blurred vision and local irritation by particulate foreign matter. However, ocular drug availability as eye drops is very low due to rapid clearance of the drops from the precorneal area, and water-soluble drugs are hardly absorbed by the cornea.1) For instance, it was reported that corneal absorption of pilocarpine from a solution is terminated within only 5 min following instillation.2) Thus, an effective and safe ophthalmic preparation appears to be quite difficult to make. Many attempts to overcome these problems have been made using various delivery systems such as ointment,3) viscous solution,4) gels,5) or Ocucert.6) Recently, the use of liposomes has also been reported,7) but whether a liposomal preparation will provide any therapeutic advantage remains in question. The topical instillation of anti-inflammatory steroids is commonly carried out in the therapy of serious ophthalmic inflammation such as iritis or choroiditis. The dosage form should be an aqueous suspension since the steroids are poorly water-soluble or a water soluble derivative solution. Various problems may be encountered in making such a preparation. A higher concentration of a fluoromethorone suspension did not improve the aqueous humor drug concentration,8) and as the particle size of dexamethasone suspension increased, the drug concentration in the cornea or aqueous humor decreased.9) Furthermore, Leibowitz et al.10) reported that unless the corneal epithelium is damaged, dexamethasone sodium phosphate, a water soluble derivative of dexamethasone is not absorbed by the cornea. It thus appears that a more sophisticated preparation which increases the ophthalmic availability and prolongs the interval …