ABSTRACT
Reformulation of metered-dose inhalers (MDIs) without the use of chlorofluorocarbon (CFC) propellants presents numerous obstacles because there are no alternative propellants that can serve as immediate replacements for pharmaceutical use. Hydrofluorocarbons (HFCs), hydrochlorofluorocarbons (HCFCs) and hydrocarbons (HCs) are all under consideration as possible alternatives for CFC propellants. However, no single propellant or combination of propellants has been identified with all of the physical-chemical properties of CFCs. Based on their zero ozone depletion potentials, relatively low global warming potentials, non-flammabilities, densities, and vapor pressures, HFA-134a and HFA-227 are the most attractive replacement propellants identified to date. Yet, their use in MDIs will still require: (1) identification of a metering valve with propellant and formulation-compatible gaskets, (2) use of current suspending agents at levels much lower than in present MDIs or identification (and characterization) of new suspending agents, and (3) modification of existing manufacturing technologies. Demonstration of acceptable final product stability, safety and efficacy will be necessary prior to submission to worldwide registration authorities.
Subject(s)
Aerosol Propellants/standards , Hydrocarbons, Fluorinated/standards , Nebulizers and Vaporizers/standards , Administration, Inhalation , Aerosol Propellants/chemistry , Equipment Design , Humans , Hydrocarbons, Fluorinated/chemistryABSTRACT
Theoretical models for percutaneous penetration are described, and a diffusion apparatus useful in the evaluation of transport kinetics of drugs applied to skin is discussed. Experimental data are presented for: (a) the flux of diflorasone diacetate through hairless mouse skin, (b) the percutaneous penetration profile of propylene glycol, (c) the effects of vehicle concentrations of polyoxypropylene 15 stearyl ether and propylene glycol on the percutaneous flux of diflorasone diacetate, (d) skin--vehicle partition coefficients of diflorasone diacetate, (e) the solubility profile of diflorasone diacetate as a function of solvent concentration, and (f) the alteration of the skin's resistance to the penetration of diflorasone diacetate due to propylene glycol. Excess solvent in a vehicle caused a decrease in the percutaneous flux of diflorasone diacetate. Formulations containing 0.05 and 0.1% diflorasone diacetate had similar penetration rates when the solvent concentration was optimized for each percentage of diflorasone diacetate.
Subject(s)
Anti-Inflammatory Agents/metabolism , Polymers/pharmacology , Propylene Glycols/pharmacology , Skin Absorption/drug effects , Administration, Topical , Animals , Anti-Inflammatory Agents/administration & dosage , Betamethasone/analogs & derivatives , Female , Glucocorticoids , In Vitro Techniques , Kinetics , Mice , Mice, Nude , Models, Biological , Ointments , Pharmaceutical Vehicles , SolubilityABSTRACT
The kinetics of uptake and release of desmosterol, cholesterol, and beta-sitosterol by Burkitt lymphoma cells at 26 degrees, pH 7.3, and isoosmotic conditions were quantitatively and mechanistically interpreted. The data are in agreement with the model involving the passive transport of the unbound sterol across the rate-determining plasma membrane, with rapid distribution within the heterogeneous cell interior. Effective permeability (P-e) and partition (K-e) coefficients of the sterols were inversely proportional to the serum concentration in the external media due to sterol-serum binding. These results are consistent with the mechanism in which only the unbound solute in the external solution participates in the membrane transport process. At all serum levels, P-e and K-e increased with increasing sterol polarity: desmosterol greater than cholesterol greater than beta-sitosterol.
Subject(s)
Cell Membrane Permeability , Cholesterol/metabolism , Desmosterol/metabolism , Sitosterols/metabolism , Animals , Burkitt Lymphoma , Cattle , Cells, Cultured , Fetus , Kinetics , Models, Biological , Permeability , Regression AnalysisABSTRACT
General physical models are derived for the diffusional transport of drugs across membranes of mammalian cells in culture suspension. These models represent different sets of possible physical processes taking place during the transport of a drug molecule. Once the diffusing species reaches the cell barrier, it may gain entrance to the cell kinetically by one of the principal quasisteady-state mechanisms, all of which assume the cell membrane to be an integral part of the total barrier.
Subject(s)
Cell Membrane Permeability , Biological Transport , Cell Membrane , Cells, Cultured , Diffusion , Models, Biological , Pharmaceutical Preparations/blood , Subcellular Fractions/metabolismABSTRACT
Mass transport studies with three cardiac glycosides in the Burkitt lymphoma cell system have provided significant examples of the factorization and quantification of the influences of serum-drug binding, membrane-drug binding, cell interior binding, and intrinsic membrane permeability upon the uptake and release kinetics of drugs in living cell systems. All of the data from the glycosides are in agreement with the general physical model involving the rapid equilibration of the solute within the cell after permeation through the rate-determining plasma membrane barrier. The transport of digitoxin was influenced by membrane and serum binding and that of digoxin was influenced by membrane binding. There was no binding of ouabain to the plasma membrane and serum. The variables in the uptake and release kinetic studies at pH 7.3 included the use of viable and heat-inactivated cells, fetal bovine serum levels, and temperature.
