The Effect of the Toxic Reaction of the Retina by Liposome-encapsulated Tobramycin in Normal Rabbits

To determine whether liposome-encapsulated tobramycin is less toxic than commercial tobramycin and the threshold dose of liposome-encapsulated tobramycin required to produce toxic reactions when it was injected intravitreally in rabbit, we used liposome-encapsulated tobramycin, tobramycin in PBS, mixture of tobramycin and liposome-encapsulated saline, liposome-encapsulated saline and normal saline respectively. After those were injected, we examined the histologic findings and the functional changes of the retina. The final results are summarized as follows; 1. When tobramycin was injected intravitreally alone, there was no toxic reaction of the retina histologically and functionally with dosage 500 micro gram of commercial tobramycin, but dosage more than 750 micro gram produced toxic reaction. 2. When liposome-encapsulated tobramycin was injected intravitreally, there was toxic reaction of the retina histologically and functionally with dosage 1500 micro gram of tobramycin. 3. When a mixture of tobramycin and liposome-encapsulated saline was injected intravitreally, there was similar toxic reaction as tobramycin used alone with dosage more than 750 micro gram of tobramycin. Liposome-encapsulated saline and normal saline did not produce toxic reaction. The above results indicate that liposome encapsulation markedly reduces the ocular toxicity of tobramycin and that as mnch as dosage 1000 micro gram of liposome-encapsulated tobramycin may be tolerated by the intravitreal route in the rabbit eye. Therefore, the results of this study offer some hope that we may use the method of intravitreal injection of liposome-encapsulated tobramycin safely and effeciently for the treatment of bacterial endophthalmitis in near future.

Pharmacokinetics of intravitreally injected liposome-encapsulated tobramycin in normal rabbits

Bacterial endophthalmitis, which is a devastating complication of intraocular surgery or eye trauma, has a poor prognosis. Intravitreal injection of antimicrobial agents has become a part of the standard treatment of endophthalmitis. The authors investigate the pharmacokinetics of intravitreal liposome-encapsulated tobramycin as a possible method of prolonging the duration of therapeutic concentrations. Tobramycin was encapsulated into liposomes of phosphatidylcholine, phosphatidic acid, and alpha-tocopherol by the reverse phase evaporation method. The final liposomal suspension contained tobramycin, 7.0 mg/ml, 60.5% encapsulated. One eye received an intravitreal injection of either liposome-encapsulated tobramycin (LET), tobramycin phosphated-buffered saline (TS) or a mixture of tobramycin and liposome-encapsulated saline (TEL), and the results were as follows: 1. Concentrations of free tobramycin were significantly lower with LET than with TS or TEL at 1 hour after intravitreal injection. 2. Concentrations of free and total tobramycin were significantly higher with LET than with TS or TEL at 5 and 8 days after intravitreal injection. Concentrations of free tobramycin with TS were lower than the minimal inhibitory concentration(MIC) of tobramycin for Pseudomonas aeruginosa at 8 days after intravitreal injection, while those with LET were higher than the MIC of tobramycin for Pseudomonas aeruginosa 18 days after injection.

Concentration of Tobramycin in the Cornea and Sclera After Subconjunctival Injection of Negatively-charged Liposome Encapsulated Tobramycin in Rabbits

Bacterial keratitis is a common ophthalmic disease. Recently, topical and subconjunctival therapy were equally effective in reducing the number of viable bacteria in experimental corneal ulcers. Subconjunctival injection produced high but transient concentrations followed by persistent low levels. In contrast, eyedrops produced moderate but sustained concentrations throughout the treatment period. Liposomes are small, biodegradable lipid vesicles with an aqueous core. Incorporation of drugs into liposomes provides a convenient way to retard their release from a relatively inert depot without changing the intrinsic characteristics of the agents.