Combination Drug Product Research Articles

Simultaneous Automated determination of Free and Total Sulfisoxazole and Sulfamethoxazole in Plasma and urine

A fully automated method for the determination of sulfisoxazole, N4-acetylsulfisoxazole, sulfamethoxazole, and N4-acetylsul-famethoxazole in human plasma and urine was developed. Untreated plasma is analyzed by automation of dialysis, hydrolysis, color development, and quantitation. The method has a sensitivity limit of 2 μg/ml of plasma and has been used successfully to determine sulfonamide levels following administration of sulfisoxazole and a combination drug product containing sulfamethoxazole and trimethoprim in humans. Samples are processed at the rate of 40 per hour, with a minimum of sample handling, data reduction, and materials.

Drop Size and Initial Dosing Frequency Problems of Topically Applied Ophthalmic Drugs

The amount and rate of drug loss through drainage, for a single drop of topically applied ophthalmic solution, increase with increasing volume of instilled solution. However, the concentration of drug in the precorneal tear film immediately after instillation of drug is higher with larger instilled volumes. Multiple drops administered at short time intervals have the advantage of increasing drug concentration in the precorneal film but the disadvantage of considerable drug loss through drainage, which for potent drugs can lead to systemic toxicity. When using radioactive technetium (99mTc) as the test substance in unanesthetized albino rabbits, it was shown that a 5-min interval between drops minimizes drainage loss of drug and the drug concentration buildup in the precorneal film as compared to the corresponding dosage regimen of drops administered at shorter time intervals. As the time interval between drops shortens to the point of one drop followed immediately by another drop, both the amount of drug lost through drainage and the tear film concentration of drug increase. Separate administration of two drugs presents a great problem as to dosage regimen. It was shown by radioactive technetium dilution and drainage studies, as well as by aqueous humor drug concentration and miosis studies, that the order of addition of drug to the eye, the volume of solution instilled, and the time of instillation of the first and second drugs all influence the ultimate activity of each drug. In general terms, the first drug administered always suffers a greater loss than the second drug and the degree of loss is proportional to the volume of each drug instilled and the time interval between drops. The implications of the present study to clinical practice are discussed. The multidrug data presented in this report constitute a strong argument for combination drug products whenever multidrug therapy is indicated.