Pharmacokinetic advantage of intrapericardially applied substances in the rat.

Intrapericardial application of therapeutic agents may open perspectives for target-directed therapy of the diseased heart. This study was performed to investigate whether intrapericardial drug application is beneficial from a pharmacokinetic point of view. Male Wistar rats were provided with intrapericardial and intravascular catheters for substance administration and sampling.

In vivo evaluation of controlled-release products.

A theoretical investigation has been conducted to understand the deconvolution method used for evaluating the in vivo release rate of an oral controlled-release product from the plasma drug concentration versus time profile. The theory is based on well-accepted pharmacokinetic compartmental models. The cumulative amount of drug released from a dosage form can be partitioned into two parts: the amount already absorbed and the amount released but still remaining at the absorption site in the gastrointestinal tract.

Nifedipine gastrointestinal therapeutic system.

Convenient once-a-day dosage regimens are highly desirable in general, and especially for the treatment of asymptomatic diseases such as essential hypertension. Nifedipine is an insoluble, short-acting calcium channel blocker that presents a difficult technical challenge for formulation in a constant 24-hour delivery dosage form. Once-a-day dosage forms have been developed based on the gastrointestinal therapeutic system (GITS) push-pull osmotic pump configuration in three strengths with different drug delivery rates (mg/hour) per dose (mg), as 1.

Osmotic delivery systems for the beta-adrenoceptor antagonists metoprolol and oxprenolol: design and evaluation of systems for once-daily administration.

The essential features and mode of action of oral osmotic drug delivery systems (Oros) for metoprolol fumarate and oxprenolol succinate are described. Critical aspects in the development of systems for once-daily administration of both drugs are discussed, and methods for evaluating in vitro release characteristics are presented. In vitro testing confirmed that drug delivery corresponded closely to the theoretical release behaviour predicted from the physicochemical and membrane permeability characteristics for both oxprenolol and metoprolol systems.

Elementary osmotic pump for indomethacin.

Based on the principles of an elementary osmotic pump, systems were designed to deliver indomethacin in solution at a constant rate, Z, to contain a total amount of drug, Mt, and to deliver 80% of their content at time t80. To allow selection of the optimal delivery rate into the body, three different prototypes were prepared with respective values for Z, Mt, and t80 of: 7 mg/hr, 85 mg, 11 hr; 9 mg/hr, 85 mg, 8 hr; and 12 mg/hr, 85 mg, 6 hr. These systems were found to deliver 70% of each system's contents at zero-order rates.

Evolution and design of 'rate controlled' osmotic forms.

A new type of therapeutic system, the precision release osmotic form, has recently been developed. This new dosage form has been referred to in other publications as the gastro-intestinal therapeutic system (GITS). Its action is based on the principles of osmosis as a means of delivering precise amounts of drug over prolonged periods of time.

Kinetics of osmotically controlled indomethacin delivery systems after repeated dosing.

Two osmotically driven, controlled-release dosage forms of indomethacin were evaluated in a multiple-dose crossover study in 12 healthy subjects. Following equivalent daily doses, less frequent dosing of both controlled-release forms resulted in plasma concentration profiles that are more uniform than those following capsule regimens. After the first day, morning predose plasma levels wer significantly higher for the controlled-release treatments.

Time course and disposition of methazolamide in human plasma and red blood cells.

Methazolamide was determined in plasma, whole blood, and urine by a GLC-mass spectrometric method. Temporal patterns of methazolamide concentrations in plasma and red blood cells were obtained following single- and multiple-dose oral administration of the drug. The nonlinearity in the binding of the drug to the red blood cell carbonic anhydrase was evident from a comparison of plasma and red blood cells concentrations.

Acetazolamide binding to two carbonic anhydrase isoenzymes in human erythrocytes.

Acetazolamide binding to high activity and low activity carbonic anhydrase isoenzymes in red blood cells was studied. Inhibitory constants of 0.041 and 2.

Gastrointestinal therapeutic system for acetazolamide. Efficacy and side effects.

Acetazolamide has been formulated in a new gastrointestinal therapeutic system that delivers the drug at an essentially constant rate of 15 mg/hr (GITS 15/125). We compared the therapeutic effect, magnitude of plasma concentration fluctuations, and incidence of side effects produced by the GITS 15/125 with conventional 250-mg acetazolamide tablets on eight glaucomatous patients randomly assigned to a different regimen each week. One or two GITS 15/125 twice a day (bid) were found as effective in reducing intraocular pressure as one 250-mg acetazolamide tablet.

Dosage form index: an objective criterion for evaluation of controlled-release drug delivery systems.

A dimensionless parameter, the dosage form index (DLtau) is proposed for evaluating the performance of drug delivery systems. The index is defined as the ratio of the maximum to minimum concentrations of the drug in plasma within each interdose interval (in hours), tau, during repetitive administration of the dosage form in the quasisteady state. Dosage form indexes can be averaged among subjects or within subjects at successive time periods to arrive at a mean value.

Programmed diffusional release rate from encapsulated cosolvent system.

The programmed diffusional release rate of an active agent through a rate-controlling membrane from a cosolvent system is discussed. At initial conditions, the drug is present below saturation in solution in a solvent mixture, enclosed by the rate-controlling membrane; the solvent is composed of the main solvent and a consolvent, which increases the drug solubility in the main solvent. During operation, the active agent and cosolvent diffuse from the capsule at a rate controlled by the membrane.

Elementary osmotic pump.

The elementary osmotic pump is a new delivery system for drugs or other active agents; it delivers the agent by an osmotic process at a controlled rate. Control resides in the: (a) water permeation characteristics of a semipermeable membrane surrounding the formulated agent, and (b) osmotic properties of the formulation. In its simplest embodiment, the system is constructed by coating an osmotically activie solid agent with the rate-controlling, semipermeable membrane.