Interaction of liposomes with human skin in vitro--the influence of lipid composition and structure.

Liposomes have been suggested as a vehicle for dermal and transdermal drug delivery, but the knowledge about the interaction between lipid vesicles and human skin is poor. Therefore, we visualized liposome penetration into the human skin by confocal laser scanning microscopy (CLSM) in vitro. Liposomes were prepared from phospholipids in different compositions and labeled with a fluorescent lipid bilayer marker, N-Rh-PE (L-alpha-phosphatidylethanolamine-N-lissamine rhodamine B sulfonyl). Fluorescently labelled liposomes were not able to penetrate into the granular layers of epidermis. However, the fluorescence from liposome compositions containing DOPE (dioleylphosphatidyl ethanolamine) was able to penetrate deeper into the stratum corneum than that from liposomes without DOPE. Pretreatment of skin with unlabeled liposomes containing DOPE or lyso-phosphatidyl choline (lyso-PC) enhanced the subsequent penetration of the fluorescent markers, N-Rh-PE and sulforhodamine B into the skin, suggesting possible enhancer activity, while most liposomes did not show such enhancement. Resonance energy transfer (RET) and calcein release assay between stratum corneum lipid liposomes (SCLLs) and the phospholipid vesicles suggested that the liposomes containing DOPE may fuse or mix with skin lipids in vitro and loosen the SCLL bilayers, respectively. Among the factors not affecting stratum corneum penetration were: negative charge, cholesterol inclusion and acyl chain length of the phospholipids. In conclusion, fusogenicity of the liposome composition appears to be a prerequisite for the skin penetration.

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 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.

Water-activated, pH-controlled patch in transdermal administration of timolol. I. Preclinical tests.

Previously, transdermal patches with internal pH-controlled release were described. The aim of this study was to test the suitability of the patch design in transdermal delivery and, further, to select such transdermal patch formulations to a clinical study with timolol. In vitro release of timolol from the patches was determined as well as timolol permeation across the human cadaver skin. The effect of the skin on drug release were evaluated in vitro. In vitro data and pharmacokinetic parameters from the literature were used to construct a pharmacokinetic model for the prediction of in vivo performance of the devices. With water-activated, pH-controlled silicone reservoir devices, both the rate of drug release and the duration of constant release were controlled. The rate of timolol release was decreased when the devices were placed on human cadaver skin, and thus, the skin partly controls the rate and extent of timolol delivery to the systemic circulation in vivo. On the basis of in vitro data and kinetic simulations, devices of 10-cm(2) volume releasing timolol in vitro at the rates of 119 and 10 microgh(-1)cm(-2) were selected for human tests.

Water-activated, pH-controlled patch in transdermal administration of timolol. II. Drug absorption and skin irritation.

The feasibility of the water-activated, pH-controlled silicone reservoir devices for transdermal administration was investigated using timolol maleate as a model drug. Timolol patches were applied to the arm of 12 volunteers for 81 h, two patches per subject. Timolol absorption from patches was compared to that from a peroral timolol tablet formulation (Blocanol((R)) 10 mg). Furthermore, in vivo plasma levels of timolol were compared with those predicted by kinetic simulations. Skin irritation induced by timolol patches was assessed by visual scoring and color reflectance measurements. With water-activated, pH-controlled patches both steady-state concentrations of timolol in plasma and its duration could be controlled. However, a considerable, inter-individual variability in the transdermal absorption of timolol was observed. This is due to the high fractional skin control in timolol delivery. Timolol patches were well tolerated by subjects. Skin irritation induced by the combination of timolol with long-term occlusion was mild, and after removal of the patches, skin changes were practically reversed in 24 h. Simulation model was useful in prediction of timolol levels in plasma after transdermal administration.

Adsorption of drugs onto a poly(acrylic acid) grafted cation-exchange membrane.

The influence of pH, ionic strength and the concentration of albumin in the adsorption medium as well as the charge and lipophilicity of a model drug on their adsorption onto poly(acrylic acid) grafted poly(vinylidene fluoride) (PAA-PVDF) membranes was evaluated. The PAA-PVDF membrane is a responsive porous polymer membrane that we have studied for controlled drug delivery. Sodium salicylate (anionic), flunitrazepam (neutral), primidone (neutral), desipramine (cationic) and thioridazine (cationic) were used as model drugs. The extent of drug adsorption was dependent on pH. Drug adsorption was enhanced by the dissociation of the grafted PAA chains and by a positive charge and a high lipophilicity of the drug. Increasing the ionic strength of the medium retarded the adsorption of the cationic drugs. Interestingly, the present results showing that drugs are adsorbed onto the membrane while albumin is not adsorbed onto the membrane suggest that the PAA-PVDF membrane may be suitable for separating drugs from proteinaceous substances for subsequent monitoring and evaluation.

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.

Time-dependent densification behaviour of cyclodextrins.

Understanding of volume reduction mechanisms is a valuable aid in the development of robust cyclodextrin tablet formulations. The particle and powder properties of alpha-, beta-, gamma- and hydroxypropyl (HP)-beta-cyclodextrins and their behaviour under compression were examined. The cyclodextrins studied showed big differences in particle-size distribution and particle shape. The highest densification on tapping was found for cyclodextrins having the smallest particle size. Cyclodextrins were compressed using single-sided saw-tooth displacement-time profiles at rates of 3 and 300 mm s-1 with a compaction simulator. The densification of the powders was examined by Heckel treatment, using the tablet-in-die and ejected-tablet methods. The cyclodextrins were denser at the beginning of the tableting process (at low pressures) if high rather than low velocity was used. Ranking according to their tendency toward total deformation and permanent plastic deformation was: HP-beta-cyclodextrin > beta-cyclodextrin > gamma-cyclodextrin > alpha-cyclodextrin. The ranking order in strain-rate sensitivity (SRS) of total deformation was HP-beta-cyclodextrin > > gamma-cyclodextrin > or = alpha-cyclodextrin > or = beta-cyclodextrin. On the basis of yield pressure values and the Heckel plot profiles, all the cyclodextrins were highly prone to plastic deformation. Cyclodextrins showed time-dependent consolidation behaviour manifested as increased yield pressure with decreased contact time. A ratio was defined between the SRS of fast elastic recovery and total elastic recovery. The two materials with high ratios, HP-beta-cyclodextrin and beta-cyclodextrin, were especially prone to fast elastic recovery with increasing punch velocities; gamma-cyclodextrin and alpha-cyclodextrin had low values and were less prone. On the basis of this parameter it might be possible to categorize pharmaceutical materials according to capping tendency.

Drug release from cation exchange membrane in rabbit eye.

Cations were adsorbed onto a poly(acrylic acid) (PAA) grafted poly(vinylidene fluoride) (PVDF) membrane that served as a cation exchange membrane. The aim of this study was to evaluate the effect of ionic strength of the adsorption medium on cation release from the PAA-PVDF membrane in the eye. Model cations, propranolol and timolol, were adsorbed onto the membranes in solutions with different ionic strengths (micron = 0.018 - 0.40) at pH 7.0. The circular drug-containing membranes were applied to both eyes of pigmented rabbits in the lower conjunctival sac. The membranes were well tolerated and well retained in the rabbit eye. Membranes containing either propranolol or timolol were removed from the eyes at preset time intervals, and the remaining drug content in the membranes was determined. The release rates of both propranolol and timolol decreased with increasing ionic strength of the adsorption medium. This was probably due to cationic exchange properties, as well as swelling properties of the membrane.

Effect of the new spacer-device on the deposition of the inhaled metered dose aerosol.

The effect of the new spacer-device on the in vitro and in vivo deposition of inhaled drug particles was studied. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the new pear-shaped spacer-device was evaluated with the modified cascade impactor method. For the in vivo study the disodium cromoglycate particles were labelled with a pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of a gamma camera. The new spacer-device increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper airways and mouth clearly decreased. Thus using the new spacer-device evaluated in this study the local side effects would be decreased.

Effects of inspirease holding chamber on the deposition of metered dose inhalation aerosols.

A modified cascade impaction method as well as a radiotracer technique has been used to assess the effects of the 700 ml collapsible holding chamber (InspirEase) on the in vitro and in vivo deposition of inhaled metered dose aerosols. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the InspirEase-device was evaluated with the modified cascade impactor which method imitated the human respiratory tract. For the in vivo study the disodium cromoglycate particles were labelled with pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of gamma camera. InspirEase increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper passages and mouth clearly decreased. Thus using the InspirEase holding chamber not only a better lung penetration of the inhaled drug particles can be achieved but also the local side effects would be decreased.

Evaluation of a novel cellulose powder as a filler-binder for direct compression of tablets.

A novel form of cellulose powder was evaluated as a filler-binder in tablets. The particle, powder, flow and binding properties of this experimental cellulose material were compared with those of two commercial microcrystalline celluloses, Avicel PH 101 and Emcocel. The effect of various storage conditions on the physical stability of tablets compressed from celluloses was also evaluated. The particle size and shape of experimental cellulose powder differed markedly from those of microcrystalline celluloses. Experimental cellulose contained mainly large and roughly spherical agglomerates of particles, among which were few smaller regularly shaped particles. Because of spherical particle shape, the experimental cellulose powder flowed better than microcrystalline celluloses, which consisted of much more irregularly shaped particles. Experimental cellulose formed stronger tablets than microcrystalline celluloses. It also acted more effectively than microcrystalline celluloses as a binding material in tablets containing poorly compressible ascorbic acid and acetaminophenone. This may be due to the extensive surface area of the particles of experimental cellulose powder. The specific surface area of this material was over 50 times as great as that of microcrystalline celluloses. This indicates an extremely porous structure of cellulose agglomerates. Tablets containing experimental cellulose powder were able to resist a permanent loss in tablet strength at different storage conditions better than tablets containing microcrystalline celluloses. According to the results of this study an experimental agglomerated form of cellulose powder is a very advantageous material as a filler-binder for direct compression of tablets.

Predicting plasticization efficiency from three-dimensional molecular structure of a polymer plasticizer.

PURPOSE: In polymeric coatings, plasticizers are used to improve the film-forming characteristic of the polymers. In this study, a computerized method (VolSurf with GRID) was used as a novel tool for the prediction plasticization efficiency (beta) of test compounds, and for determining the critical molecular properties needed for polymer plasticization. METHODS: The film-former, starch acetate DS 2.8 (SA), was plasticized with each of 24 tested compounds. A decrease in glass transition temperature of the plasticized free films (determined by differential scanning calorimeter (DSC)) was used as an indicator for beta. Partial least squares discriminant analysis was used to correlate the experimental data with the theoretical molecular properties of the plasticizers. RESULTS: A good correlation (r2 = 0.77, q2 = 0.58) between the molecular modeling results and the experimental data demonstrated that beta can be predicted from the three-dimensional molecular structure of a compound. Favorable structural properties identified for the potent SA plasticizer were strong hydrogen bonding capacity and a definitive hydrophobic region on the molecule. CONCLUSIONS: The VolSurf method is a valuable tool for predicting the plasticization efficiency of a compound. The correlation between experimental and calculated glass transition temperature values verifies that physicochemical properties are primary factors influencing plasticization efficiency of a compound.

Thermophysical properties of some pharmaceutical excipients compressed in tablets.

PURPOSE: Thermophysical properties of three tableting excipients; microcrystalline cellulose, lactose and dicalcium phosphate dihydrate were observed to evaluate their ability to resist temperature induced changes in tablet form. METHODS: Two thermophysical parameters, thermal diffusivity and specific heat, were measured by a pulse heating method. The materials were also evaluated by differential scanning calorimetry (DSC). RESULTS: Microcrystalline cellulose in tablet form was found to be rather insensitive to heating and cooling treatments, even though the tablets seemed to remain in a stressed state four weeks after tableting. This stress, indicated by low temperature anomalies, was observed by the pulse method, but not by DSC. When magnesium stearate was incorporated as a lubricant within the microcrystalline cellulose powder, the thermophysical parameters indicated that the internal structure of the tablets changed with heating and cooling. Magnesium stearate eliminated the low temperature anomalies as well. The heat treatment changed the thermophysical properties of tablets made of the crystalline excipients lactose and dicalcium phosphate dihydrate, permanently causing irreversible structural changes. CONCLUSIONS: The melting of the lubricant together with enhanced stress relaxation in the structure of microcrystalline cellulose most probably caused the improved thermal diffusivity. The observed thermophysical changes with the crystalline excipients were due to changes in tablet's structure and material. The combination of methods used was found to be an accurate and reliable way to obtain useful information on the structural changes and material relaxations of intact tablets during temperature treatment and age-related changes in material properties.