Bror Svarfvar

Transport of drugs across porous ion exchange membranes

Porous ion exchange membranes have potential applications for drug delivery systems. Permeability of these membranes can be controlled by environmental factors like pH and ionic strength but also the drug properties have an important role in the permeation process. In this paper the influence of the drug charge, lipophilicity and molecular weight on the diffusional drug flux is demonstrated. The membranes under study were poly(acrylic acid) (PAA) grafted porous poly(vinylidene fluoride) (PVDF) membranes which are cation selective due to the partial ionization of carboxyl groups in grafted PAA chains. At low pH the membrane pores are open and the drugs can diffuse through the membrane quite easily. However, at pH 7 the grafted chains partially block the pores and the diffusional flux of bigger drug molecules (Mw9400) decreases five orders of magnitude and also the flux of smaller molecules is clearly reduced. When the influence of the drug charge on the diffusion of the drugs across the membranes was studied, it turned out that the PAA-PVDF membranes facilitate the transport of cationic drugs and repel anionic ones. The presented mathematical model, based on Donnan drugs equilibrium and measured transport number data, predicted the observed trends reasonably well.

Drug release from poly(acrylic acid) grafted poly(vinylidene fluoride) membrane bags in the gastrointestinal tract in the rat and dog.

Stomach-specific drug delivery systems would be of value in treating diseases of the upper gastrointestinal tract. The present study measured in vitro and in vivo drug release from pH-sensitive membrane bags, constructed of poly(acrylic acid) grafted onto a poly(vinylidene fluoride) (PAA-PVDF) membrane, which might be suitable for stomach-specific drug delivery. The used model drugs were propranolol-HCl (1.0 mg) and FITC-dextran MW 4400 (1.0 mg). Drug release in vivo was studied by inserting membrane bags into the stomach and proximal duodenum of anesthetized rats and dogs. At 30 and 180 min, the bags were removed from the lumens and residual drug content was determined. The release of either propranolol or FITC-dextran were comparable in both stomach and duodenum, showing that in vivo drug release did not depend on environmental pH. In vitro results suggested that these results could be explained by interactions between PAA and the mucous layers of the stomach and duodenum.

Drug release from a porous ion-exchange membrane in vitro

The effect of environmental ionic strength on the rate of drug release from a cation exchange membrane was evaluated. Cationic propranolol-HCl, timolol, sotalol-HCl, atenolol and dexmedetomidine-HCl and neutral diazepam were adsorbed onto a porous poly(vinylidene fluoride) (PVDF) membrane that was grafted with bioadhesive poly(acrylic acid) chains (PAA-PVDF). Despite its porosity, the PAA-PVDF membrane acted as a cation exchange membrane. The release of adsorbed drug from the PAA-PVDF membrane was investigated by using a USP rotating basket apparatus. Adsorption of cationic drugs onto the PAA-PVDF membrane tended to increase with increasing lipophilicity of the drug. A decrease in the ionic strength of the adsorption medium increased the amount of the cationic drugs adsorbed onto the membrane, but had no effect on diazepam adsorption. The release of cationic drugs from the PAA-PVDF membrane was greatly affected by the ionic strength of both the adsorption medium and the dissolution medium, while ionic strengths did not affect diazepam release. Our results suggest that the ionic strength of both the adsorption and dissolution media substantially affects the release rate of a drug that has been adsorbed onto the ion exchange membrane, primarily via electrostatic interactions, while ionic strength has no effect on the release of a drug which has been adsorbed onto the membrane via non-electrostatic forces.

Drug permeation through a temperature-sensitive poly(N- isopropylacrylamide) grafted poly(vinylidene fluoride) membrane

Abstract Poly( N -isopropylacrylamide) (poly(NIPAAm)) is a temperature sensitive polymer, which has been used in the development of thermally controlled devices. In the present study, poly(NIPAA)m grafted poly(vinylidene fluoride) (PVDF) membranes were prepared by an irradiation method and fluxes of model compounds across the various grafted membranes were measured. The effectiveness of various grafted membranes to control drug fluxes by temperature was studied using FITC-dextrans (molecular weights 4400–50 600) and mannitol as model compounds. Also, the effect of environmental conditions on the LCST of the membrane was evaluated. The fluxes of bigger molecules across a temperature sensitive, porous poly(NIPAA)m–PVDF membranes were effectively controlled by temperature, environmental ionic strength and degree of grafting of the membrane, while flux of the smaller molecules was not controlled thermally even at high degree of membrane grafting. These result indicates that the studied membranes are useful in controlling the permeation of high molecular weight compounds such as polynucleotides, peptides and proteins.

Influence of ionic strength on drug adsorption onto and release from a poly(acrylic acid) grafted poly(vinylidene fluoride) membrane

Ion exchange resins have several applications in pharmacy for controlled or sustained release of drugs. In the present study, effects of the ionic strengths of adsorption medium and dissolution medium on drug adsorption onto and release from a acrylic acid grafted poly(vinylidene fluoride) (PAA-PVDF) were studied. Despite their porosity, PAA-PVDF membranes act reasonable well as cation exchange membranes. It was observed, that ionic strength of adsorption medium, degree of grafting and concentration of propranolol-HCl in adsorption medium affect propranolol-HCl adsorption onto the membrane. The fluxes of smaller molecules (MW < 500) across the membrane decreased with ionic strength of buffer solution, whereas the fluxes of the large molecules (FITC-dextran, MW 4400) increased with ionic strength. Release rate of adsorbed propranolol-HCl from the membrane into phosphate buffer was greatly affected by ionic strength of adsorption medium. These results can be explained by a cation exchange process between membrane and cations present in the buffer solution and swelling behavior of the grafted PAA chains.

Preparation of poly[ethylene-g-(vinylbenzyl chloride)] and functionalization with bis(phosphonic acid) derivatives

Abstract Poly[ethylene- g -(vinylbenzyl chloride)] ( 1 ) film was prepared and used as an intermediate for the synthesis of polymer supported bis(phosphonic acid) derivatives. ( 1 ) was synthesized by preirradiation grafting of vinylbenzyl chloride (VBC) on polyethylene film. A reaction time of 29 h gave ( 1 ) with a chlorine capacity of 4.7 mmol Cl/g. As shown by energy dispersive X-ray analysis, the depth of the graft modification can be varied from surface to bulk modification by controlling the reaction time. The gel content of the film was found to increase with increased extent of grafting. A 28% VBC grafted film was found to have a gel content of 91%. The swelling of the Poly[ethylene- g -(vinylbenzyl chloride)] ( 1 ) film in toluene or THF was rapid A 145% VBC grafted film swells 260 area % within 2 min in refluxing toluene. Tetraisopropyl methylene-bisphosphonate ( 2 ) or tetraethyl ethane-1,1-bisphosphonate ( 3 ) were reacted with NaH and used for nucleophilic substitution of chlorine in the poly[ethylene- g -(vinylbenzyl chloride)] film. Forty-six percent of the chlorine groups were substituted within 24 h using the sodium salt of tetraisopropyl methylenebisphosphonate ( 2 ) in a 10-fold excess in refluxing toluene. Under the same reaction conditions, using the sodium salt of tetraethyl ethane-1,1-bisphosphonate ( 3 ) gave 50% substitution. Energy dispersive X-ray analysis showed that the substitution reaction proceeds throughout the film at the same rate, which implies that the reaction is not mass-transfer controlled. Hydrolysis of the polymer supported bisphosphonate in hydrochloric acid to yield the bis(phosphonic acid) form gave a film which swells 60 area % in water at room temperature and 100 area % at 100°C.