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Biomedical subjects

P Paronen

Publications and source records attributed to P Paronen.

At least 19 recordsLinked to original sources
PubMed1998

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.

Biological Transport↗
PubMed1997

Frictional work in double-sided tablet compression.

The aim of this study was to evaluate the friction during double-sided tablet compression. Dicalcium phosphate dihydrate and lactose were tabletted with a compaction simulator with symmetrical and asymmetrical double-sided sawtooth punch displacement profiles. The estimation of force transmission in a powder column was based on an exponential equation, including the material parameter consisting of both the friction coefficient and Poisson's ratio. This parameter was predetermined from a single-sided compression. A novel equation was derived from a previously presented equation for friction work in single-sided tablet compression. The basic assumption was drawn from the linearly decreasing movement of infinitely thin particle layers, which are produced as the compressing punch surface approaches the other punch. This calculation was also based on the assumption that the equilibrium point, where the particles do not move, is halfway between the punches in the symmetrical profile and at a distance proportional to the amplitudes of the asymmetrical upper and lower sawtooth profiles. The tensile strength of tablets compressed with single-double-sided profiles was identical, and thus the behavior of the materials studied under compression was independent of the compression profiles. The friction work values that were calculated with the proposed expression for double-sided profiles were close to the theoretical values, as estimated by calculations based on compressions with single-sided profiles. In conclusion, the novel mathematical expression opens new possibilities for the evaluation of friction in double-sided compression; for example, in rotary press tabletting.

Friction↗
PubMed1996

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 Carriers↗
PubMed1996

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.

Chemical Phenomena↗
PubMed1995

Changes in solid-state structure of cyclophosphamide monohydrate induced by mechanical treatment and storage.

The effects of mechanical treatment and various storage conditions on the structure of cyclophosphamide monohydrate were evaluated by thermal and X-ray analyses and molecular modeling. The monohydrate form of cyclophosphamide was found to convert to the anhydrous form through a metastable phase. Metastable forms were produced by mechanical treatment and by desiccation. These forms could be detected in differential scanning calometric thermograms as endothermic peaks, at approximately 39 degrees C, and X-ray powder diffractometric analysis, e.g.; by a characteristic reflection at 15.3 degrees (2 theta). Molecular modeling was used to study molecular interactions and putative metastable structures. The dehydration enthalpies of the cyclophosphamide monohydrate obtained from quantum chemical calculations and DSC analysis were 51.6 and 36.1 J/g, respectively. In a unit cell of the stable monohydrate, a water molecule is held by O(7) of the cyclophosphamide molecule and N(6)H of a neighboring cyclophosphamide molecule, with hydrogen bonds enabling existence of a water tunnel. The metastable form of cyclophosphamide is detected when a sterically formed block in the possible tunnel is removed, and the water molecules are allowed to leave the system one by one.

Calorimetry, Differential Scanning↗
PubMed1995

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.

Calcium Phosphates↗
PubMed1994

Effect of some penetration enhancers on epithelial membrane lipid domains: evidence from fluorescence spectroscopy studies.

The effect of the penetration enhancers Azone, oleic acid, 1-dodecanol, dodecyl N,N-dimethylaminoacetate (DDAA), and dodecyl N,N-dimethylaminoisopropionate (DDAIP) on epithelial membrane lipids was examined using human buccal cell membranes as a model for epithelial lipid bilayer. Buccal epithelial cells (BEC) were labeled with 1,6-diphenyl-1,3,5-hexatriene (DPH), 1-(4-(trimethylammonio)phenyl)-6- phenyl-1,3,5-hexatriene (TMA-DPH), and 8-anilino-1-naphthalene sulphonic acid (ANS) fluorophores to characterize enhancer-induced changes in the hydrophobic core, in the superficial polar head region, and on the exterior surface, respectively, with fluorescence anisotropy and fluorescence lifetimes. All the enhancers studied were found to decrease the BEC membrane lipid packing order in a concentration-dependent and time-dependent manner in the deep bilayer region, as shown by a 37-66% decrease in anisotropy. Oleic acid was also found to disrupt membrane lipids strongly in the polar head region, causing at least a 34% decrease in anisotropy values. Azone and DDAA were shown to alter molecular movement on the surface of the bilayers (24 and 19% decrease in anisotropy, respectively). The results suggest that interaction with membrane lipid domains is an important, but not the only, mode of action for the penetration enhancers studied.

Alanine↗
PubMed1993

Electrochemical characterization of human skin by impedance spectroscopy: the effect of penetration enhancers.

The electrochemical properties of human cadaver skin were studied in a diffusion cell with impedance spectroscopy as a function of time in the absence and presence of penetration enhancers dodecyl N,N-dimethylamino acetate and Azone. An improved electrochemical model of skin is presented, and combining the novel model with modern fractal mathematics, the effect of enhancers on the surface of skin is demonstrated. The enhancers appeared to open new penetration routes and increase the ohmic resistance, capacitive properties, and fractal dimension of skin, which means a rougher or more heterogeneous surface.

Administration, Cutaneous↗
PubMed1992

Interactions and comparative effects of zopiclone, diazepam and lorazepam on psychomotor performance and on elimination pharmacokinetics in healthy volunteers.

A randomised, placebo-controlled, double blind single-dose cross-over study was arranged to investigate possible interactions between zopiclone (7.5 mg) and two widely used benzodiazepine (BZD) anxiolytics diazepam (5 mg) and lorazepam (1 mg) during the elimination phase of drugs. Psychomotor performance was tested before and 1, 6, 8, 12 and 24 hr after the drug administration. Simultaneously, blood samples were drawn for determination of plasma drug concentrations. The elimination of each compound was not altered by coadministration of other drugs. As expected, one hour after drug ingestion, psychomotor performance was impaired. The coadministration of drugs increased the effect. During the elimination phase, 6 and 8 hr after the drug intake, only zopiclone and lorazepam in combination slightly impaired performance as compared with the pretreatment levels, but there was no difference as compared with placebo. Adverse events after active treatments were not significantly different from those after placebo. At the recommended dose of 7.5 mg, zopiclone does not alter the elimination pharmacokinetics of the BZD anxiolytics diazepam (5mg) and lorazepam (1 mg), and neither is the elimination of zopiclone affected by these BZDs. Due to the rapid elimination of zopiclone, the increase in sedation seen after concurrent administration with BZDs is of short duration.

Administration, Oral↗
PubMed1992

Pharmacokinetics in rat of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a drinking water mutagen, after a single dose.

The pharmacokinetics of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was evaluated after a single oral or intravenous administration in the rats using 14C-labelled compound. Twenty to 35% of the dose was absorbed into circulation from the gastrointestinal tract as assessed from the excretion in urine. The mean elimination half-life of the radioactivity in blood (T1/2 k10) was 3.8 hr. Traces of radioactivity remained in the blood for several days. The tissues lining the gastrointestinal and urinary tract, kidneys, stomach, small intestines and urinary bladder contained the highest radioactivity. The activity declined slowest in the kidneys. Urine was the main excretion route. Seventy-seven % of the total amount excreted appeared in urine in 12 hr and 90% in 24 hr. No radioactivity was exhaled in air suggesting that elimination through respiration did not occur. After an intravenous administration of 14C-MX, the T1/2 k10, was much longer, 22.9 hr, and the total elimination half-life (T1/2 beta), 42.1 hr. The results indicate that MX is absorbed from the gastrointestinal tract to a considerable degree and it is excreted in urine very rapidly. A fraction of MX or its metabolites is retained in blood for a longer period of time. The pharmacokinetics of MX does not suggest extensive cumulation of MX in tissues after continuous exposure.

Absorption↗
PubMed1991

Dodecyl N,N-dimethylamino acetate and azone enhance drug penetration across human, snake, and rabbit skin.

The effectiveness of the penetration enhancers, dodecyl N,N-dimethylamino acetate (DDAA) and Azone, on pretreated human epidermis for the permeation of model drugs, indomethacin, 5-fluorouracil, and propranolol-HCl, was studied in in vitro diffusion cells. Snakeskin (Elaphe obsoleta) and rabbit pinna skin were compared as possible models for human skin. The drug concentrations were analyzed by HPLC. With all skins and all model drugs, DDAA increased drug permeability at least as well as Azone, and in most cases it was a more effective permeation enhancer. The relative permeation improvements in human skin, snakeskin, and rabbit skin were 10- to 20-, 5- to 50-, and 20- to 120-fold, respectively. Tritiated water served as an indicator of skin condition. Its penetration in the skin samples was independent of the drugs used, and both penetration enhancers significantly increased the flux of tritiated water through all skins. Thus, DDAA and Azone significantly increased the permeation of lipophilic and hydrophilic model compounds. Rabbit pinna skin was a poor model for human skin in vitro, while snakeskin was much closer to human skin in terms of transdermal permeability. In most cases drug permeability decreased in the order rabbit much greater than human greater than or less than snake.

Aged↗
PubMed1991

Relative pharmacokinetics of three oral 400 mg ibuprofen dosage forms in healthy volunteers.

The pharmacokinetic properties of two solid form, 400 mg ibuprofen (IP) preparations, a soft gelatin capsule and a film-coated tablet, were compared to those obtained after the administration of liquid prepared from effervescent IP tablets. IP was absorbed rapidly (tmax 0.6-1.9 h). The fastest absorption was observed after the ingestion of the soft gelatin capsule; liquid and film-coated tablet produced 12.2-7.8 times longer absorption half-lives, 50-39% lower peak concentrations of IP in serum and 3.5-3.2 times higher tmax values. Bioavailabilities were close to similar after all products. All products were tolerated without side effects in this single-dose, crossover study on 14 healthy volunteers. The results of this study support the earlier findings that after oral administration, IP is absorbed equally well from solid formulations as from liquid form. Liquid formulations of IP often deliver slower absorption than expected probably due to incomplete dissolution of the active principle. This may have therapeutic significance, and it should be taken into account when studies on the relative bioavailability of IP from pharmaceutical drug products are planned.

Absorption↗
PubMed1991

Removal of inhaled 99mTc-labelled particles of disodium cromoglycate from the lungs.

Disodium cromoglycate particles were labelled with 99mTc by spray-drying technique. The in vitro dissolution profile as well as the leakage of radioactivity from the drug particles were determined using a through-flow cell method. The radioactive drug particles were mixed with a lactose carrier and inhaled from a dry powder device by five healthy volunteers. The removal of the inhaled drug particles from the lungs was evaluated by a gamma camera. A close relationship between the dissolution of the drug as such and the leakage of radioactivity was noted. Gamma scintigraphy indicated a biphasic exponential removal of radioactivity from the lung region. The slow component with the halftime of about 55 min was mainly due to the dissolution of drug particles in the lungs. The halftime of the fast component describing mucociliary clearance was less than 10 min. This process was the dominating one for the removal of the drug from the lungs. The experiment thus showed that the main fraction of the inhaled dose was deposited in the tracheobronchial region. Accordingly, only a small portion of the dose initially deposited in the lung can be absorbed and induce a therapeutic effect.

Aerosols↗
PubMed1991

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.

Administration, Inhalation↗
PubMed1991

Nasal distribution of radioactive drug administered using two dosage forms.

The deposition patterns of 99mtechnetium labelled disodium cromoglycate particles administered either from a metered dose aerosol with a conventional nasal adaptor or from a dry powder nasal inhaler were studied using gamma camera. Disodium cromoglycate particles were firstly labelled with 99mTc using the spray drying technique. Both the metered dose aerosol and the dry powder dosage form were formulated using these radioactive drug particles. Seven healthy volunteers inhaled either three aerosol doses or one dry powder dose unit into one nostril. The drug dose reaching nasal cavity after administration from these two dosage forms was about the same. The deposition patterns as well as the changes in distribution due to the mucociliary transport were monitored by a gamma camera equipped with a low energy all purpose collimator. Initially drug doses deposited in a wider area of the nasal cavity when disodium cromoglycate particles were administered as a dry powder dosage form. In addition, retention index (%) which illustrates the movements of drug particles by mucociliary transport from the initial area of application seemed to be slightly higher for a metered dose aerosol than for a dry powder dosage form. At the end of the 30 minutes measuring period the area of the mucosal layer covered by radioactive drug particles was clearly wider for the dry powder dosage form than for the metered dose aerosol. Thus it is well possible to administer drug particles effectively into the nasal cavity as a dry powder dosage form.

Administration, Inhalation↗
PubMed1991

In vitro inhalation behaviour and therapeutical response of salbutamol particles administered from two metered dose aerosols.

In this study the particle size, as well as the in vitro deposition and the immediate bronchodilating effect on asthmatic patients, of two salbutamol inhalation aerosol preparations (Ventoline, Glaxo, UK, and salbutamol inhalation aerosol, Orion Pharmaceutica, Finland) were compared. The in vitro deposition study was performed using the modified Sierra Andersen cascade impactor. The bronchodilating effect of inhaled aerosol doses were monitored by measuring peak expiratory flow (PEF) values. In the clinical study, the pulse and blood pressure of the patients, as well as the side effects, were also recorded. Due to the anatomy and physiology of human lungs, the accepted optimum size for inhaled drug particles is under 5 microns, and preferably under 2 microns. Over 95% of the drug particles in both aerosol preparations were under 5 microns. 30% of the salbutamol particles in the Ventoline inhalation aerosol were under 2 microns, whereas in Orion salbutamol aerosol 14% of the drug particles were under 2 microns. Respectively 23% of Ventoline and 19% of the Orion salbutamol preparation penetrated into the therapeutically most significant imitated alveolar stages of the modified cascade impactor. Both salbutamol aerosols showed a clear clinical efficacy in the bronchodilating test. In addition, no significant differences existed in the bronchodilating effect of these inhalation aerosols. In conclusion, although there seemed to be a slight difference in the particle size distribution and in the in vitro inhalation behaviour, this variation did not have any effect on the clinical response.

Adult↗
PubMed1991

In vitro deposition and clinical efficacy of two sodium cromoglycate inhalation powders.

In this study, the in vitro deposition as well as the clinical efficacy of two dry powder inhalation preparations containing 20 mg of disodium cromoglycate were evaluated. The preparations were Blacil and Lomudal administered either with I.S.F. or Spinmatic powder inhalers, respectively. The in vitro inhalation study was performed using the cascade impacted method. During the in vitro test, similar fractions of the drug doses were retained in both inhalation devices. A remarkably larger proportion of the pelletized drug powder from the Lomudal preparation was deposited in the imitated upper airway than from the Blacil preparation consisting of the mixture of micronized disodium cromoglycate particles and lactose as a carrier. On the other hand, a larger fraction of the drug dose was deposited in the imitated lung area after the administration of the Blacil preparation than from Lomudal. The clinical study was performed as an exercise test in sixteen asthmatic patients. The preparations tested were statistically equally effective. The decrease in all the values of the pulmonary function parameters (PEF, FEV1) was, however, smaller after the administration of disodium cromoglycate from Blacil than from Lomudal preparation. According to the results of this study, the cascade impaction test seems to be valuable for predicting the efficacy of inhalation powders.

Administration, Inhalation↗