Dale Meisner

Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females.

AbstractPurpose. The safety, tolerability, and pharmacokinetics of intravenous (i.v.) montelukast sodium (Singulair™, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied. Methods. This was a two-part study. Part I was a four-period study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant-rate i.v. infusions (Periods 1–3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively) or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC. Results. In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg, the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity (AUC) increased proportionately. The mean values of plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/12), and mean residence time in the body (MRTi.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg tablet of montelukast sodium, the AUC, maximum plasma concentration (Cmax), time when Cmax occurred (Tmax), apparent t1/12, mean absorption time (MAT), and bioavailability (F) of montelukast sodium averaged 2441 ng · hr/ml, 385 ng/ml, 3.7 hr, 4.9 hr, 3.4 hr, and 66%, respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the values of CL, Vss, t1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively. Following oral administration of a 10-mg tablet to females, the mean AUC, Cmax, Tmax, apparent t1/2, MAT and F were 2270 ng·hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These parameter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses. Conclusions. The disposition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated.

Liposome ocular delivery systems

Abstract Liposomes are microscopic vesicles composed of membrane-like lipid bilayers surrounding aqueous compartments. This unique feature imparts the ability of liposomes to encapsulate both lipophilic and hydrophilic compounds. Consequently liposomes have been investigated extensively as a drug carrier system by various routes of administration. One of the more recent applications is the concept of employing liposomes as drug carriers in ophthalmology. Traditional drug therapy in the eye consists of the administration of solutions and suspensions. These dosage forms are compromised in their effectiveness by several limitations including rapid nasolacrimal drainage, poor corneal penetration, nonproductive conjunctival losses and unwanted systemic exposure. The need for an ocular drug delivery system which has the convenience of a drop, but will localize and maintain drug activity at its site of action, is apparent. Liposomes offer a promising avenue to achieve this goal. The simplicity of preparation and the versatility in physical characteristics confer a unique and useful property to liposomes for use as an ocular drug deliverer. In this review, a historical account of the studies is presented to illustrate the potential of liposomes in ophthalmology. Consideration is given to methods of preparation, advantages of liposomes as drug carriers as well as some of the general issues surrounding liposomes as a pharmaceutically acceptable dosage form. Various routes of administration such as topical instillation, intravitreal, subconjunctival and systemic injection are also discussed. Significant progress has been made in these areas and a complete understanding of the liposome interaction with ocular tissues should enable the design of liposomal products suitable for ocular drug delivery.

Translymphatic Chemotherapy by Intrapleural Placement of Gelatin Sponge Containing Biodegradable Paclitaxel Colloids Controls Lymphatic Metastasis in Lung Cancer

As a means of treating lymphatic metastasis from lung cancer, the pharmacokinetics and therapeutic effects of an intrapleural (ipl) implantable drug delivery system consisting of a gelatin sponge impregnated with polylactide-co-glycolide paclitaxel (PLGA-PTX) microspheres were studied. PLGA-PTX with 7% (w/w) drug loading were incorporated into gelatin matrix. The pharmacokinetics were studied in rats with one of the following regimens: (a) Taxol 8 mg/kg by i.v. injection; (b) Taxol 8 mg/kg ipl; (c) PLGA-PTX (100 mg/kg) ipl; (d) sponge containing PLGA-PTX (100 mg/kg) ipl. PTX concentrations in lymph node and plasma were determined by liquid chromatography mass spectrometry, and the area under the curve (AUC) was calculated. Therapeutic efficacy was assessed in an orthotopic lung cancer model with tumor resection 14 days following tumor implantation. Animals were randomized to ipl placement of PLGA-PTX sponge, placebo sponge, or no treatment. Lymph node metastases were examined at 32 d. The results show that the mediastinal lymph node AUC was significantly higher with ipl. placement of PLGA-PTX sponge compared with i.v. and ipl administration of Taxol. This represents 100- to 400-fold increase of lymphatic drug exposure compared with i.v. dosing. Peak plasma concentration was significantly reduced in the PLGA-PTX sponge group compared with i.v. dosing. PLGA-PTX particles were microscopically identified in lymphatic tissue and resulted in an 80% reduction of lymphatic metastasis compared with controls. Translymphatic-targeted drug delivery significantly decreases lymphatic metastasis in an orthotopic lung cancer model. This effect may be attributable to the improved distribution of PTX to the lymphatic system.