Biomedical subjects

Martti Marvola

Publications and source records attributed to Martti Marvola.

12 recordsLinked to original sources

PubMed2006

Anthranoid laxatives influence the absorption of poorly permeable drugs in human intestinal cell culture model (Caco-2).

Interactions between widely used anthranoid laxatives and other simultaneously administered drugs are not known. In this paper, the influence of rhein, danthron, sennidins A/B, sennosides A/B, and senna leaf infusion was investigated on the permeability of furosemide, ketoprofen, paracetamol, propranolol, verapamil, digoxin, and Rhodamine 123 across Caco-2 monolayers. The effects on monolayer integrity ([(14)C]mannitol permeability, TEER) were also determined. The in vitro absorption of highly permeable drugs was not strongly affected during co-administration of the laxatives. Furosemide permeability was enhanced by rhein and danthron (3.6 and 3.0-fold), which may partly be due to opening of the paracellular spaces and/or effects on active efflux. However, the secretory permeability of digoxin and Rho 123 was not strongly affected by rhein and danthron, suggesting that inhibition of MDR1 was not responsible for the increased permeation of furosemide. The absorptive permeability of digoxin was decreased by rhein and danthron, offering evidence for effects on apical membranes. The effects on monolayer integrity were detectable, but reversible. According to presented experiments, daily use of laxatives with well-absorbing drugs would seem unlikely to affect drug permeability, but the effects on the absorption of poorly permeable drugs cannot be excluded.

Absorption↗

PubMed2005

Are chitosan formulations mucoadhesive in the human small intestine? An evaluation based on gamma scintigraphy.

Rapid passage through the proximal intestine can result in the low bioavailability of a drug substance with site-specific absorption characteristics in the upper gastrointestinal tract. To overcome this, there is increasing interest in developing gastro-retentive formulations and/or formulations that linger in the proximal parts of the small intestine, e.g. by using mucoadhesive polymers as excipients in formulations. In our recent study, we used neutron activation-based gamma scintigraphy to evaluate the gastro-retentive properties of formulations containing chitosan (Mw 150 kDa) in man. At the same time, we had an opportunity to monitor the transit of the formulations (40 or 95% of chitosan) in the small intestine. Gamma scintigraphic investigations revealed that although the chitosan studied had exhibited marked mucoadhesive capacities in vitro, retention of the chitosan formulations in the upper gastrointestinal tract was not sufficiently reproducible and the duration of retention was relatively short. In 3 volunteers out of 10, the formulation adhered to the gastric mucosa (retention times varied from 1.25 to 2.5 h) and in two volunteers to the upper small intestine (approximate retention time 45 min). In one case, the formulation adhered to the oesophagus. The system failed to increase the bioavailability of furosemide, a drug site-specifically absorbed in the upper gastrointestinal tract. As far as the kind of formulation studied is concerned, preparation of a system that is site-specific to the stomach and/or the upper small intestine seems difficult if the proposed mechanism of action is mucoadhesion. The results suggest that other mechanisms of action should also be studied.

Adhesiveness↗

PubMed2005

Pellet manufacturing by extrusion-spheronization using process analytical technology.

The aim of this study was to investigate the phase transitions occurring in nitrofurantoin and theophylline formulations during pelletization by extrusion-spheronization. An at-line process analytical technology (PAT) approach was used to increase the understanding of the solid-state behavior of the active pharmaceutical ingredients (APIs) during pelletization. Raman spectroscopy, near-infrared (NIR) spectroscopy, and X-ray powder diffraction (XRPD) were used in the characterization of polymorphic changes during the process. Samples were collected at the end of each processing stage (blending, granulation, extrusion, spheronization, and drying). Batches were dried at 3 temperature levels (60 degrees C, 100 degrees C, and 135 degrees C). Water induced a hydrate formation in both model formulations during processing. NIR spectroscopy gave valuable real-time data about the state of water in the system, but it was not able to detect the hydrate formation in the theophylline and nitrofurantoin formulations during the granulation, extrusion, and spheronization stages because of the saturation of the water signal. Raman and XRPD measurement results confirmed the expected pseudopolymorphic changes of the APIs in the wet process stages. The relatively low level of Raman signal with the theophylline formulation complicated the interpretation. The drying temperature had a significant effect on dehydration. For a channel hydrate (theophylline), dehydration occurred at lower drying temperatures. In the case of isolated site hydrate (nitrofurantoin), dehydration was observed at higher temperatures. To reach an understanding of the process and to find the critical process parameters, the use of complementary analytical techniques are absolutely necessary when signals from APIs and different excipients overlap each other.

Chemistry, Pharmaceutical↗

PubMed2004

Neutron activation-based gamma scintigraphy in pharmacoscintigraphic evaluation of an Egalet constant-release drug delivery system.

This paper is a report from a pharmacoscintigraphic study with an Egalet constant-release system containing caffeine and natural abundance samarium oxide. First the formulation was tested in vitro to clarify integrity during irradiation in the nuclear reactor. Then six healthy male volunteers were enrolled into the in vivo study. The in vitro release of caffeine obeyed all the time linear zero-order kinetics. The in vivo release of radioactive Sm2O3 consisted of three consequent linear phases with different slopes. The release rate was fastest while the product was in the small intestine and slowest when the product was in the descending colon. In terms of the bioavailability of caffeine, the most important factor seemed to be the residence time in the ascending and transverse colon. A long residence time in these sections led to high AUC values for caffeine.

Adult↗

PubMed2004

Gamma scintigraphic evaluation of the fate of hydroxypropyl methylcellulose capsules in the human gastrointestinal tract.

The fate (movement and disintegration) of hard novel hydroxypropyl methylcellulose (HPMC) two-piece capsules in the human gastrointestinal tract was investigated using a gamma scintigraphic imaging method. Two different prolonged-release formulations without an active ingredient were used. The capsules contained different viscosity grades of HPMC powder (HPMC K100 and HPMC K4M). The aim was to determine the main reason why the pharmacokinetic profiles of model drugs change when the diluent was changed to a higher viscosity grade. The results were compared with our previous pharmacokinetic studies with corresponding capsules containing metoclopramide hydrochloride or ibuprofen as a model drug. The first observation was that the HPMC capsules had a tendency to attach to the oesophagus. Therefore, it is recommended that the HPMC capsules as well as gelatine capsules be taken with a sufficient amount of water (150-200 ml) in an upright position and maintaining the upright position for several minutes. The viscosity grade of the HPMC did not affect the transit times of the capsules in the GI tract. The major differences between the two formulations were the complete disintegration times of the capsules and the spreading of the capsules to the large intestine. Most of the HPMC K100-based capsules were completely disintegrated during the 8h study, whereas the HPMC K4M-based capsules still exhibited plug formations in the large intestine. Also the HPMC K100-based capsules spread better to the ascending colon than the HPMC K4M-based capsules. The faster disintegration of the HPMC K100-based capsules explains the differences in the pharmacokinetic profiles of the model drugs between the HPMC K100- and K4M-based capsules in our previous studies. The main absorption site of the drugs from the capsules studied here is probably the large intestine when taken in a fasting state.

Adult↗

PubMed2004

Gamma scintigraphic evaluation of the fate of microcrystalline chitosan granules in human stomach.

In several reports of in vitro studies it has been suggested that the mucoadhesive chitosans could be of value in preparing gastro-retentive formulations. The aim of this study was to obtain direct in vivo evidence of whether microcrystalline chitosan (MCCh) formulations acted as gastro-retentive systems in humans. Neutron-activation-based gamma scintigraphy was used to study gastric residence times of MCCh granules in healthy male volunteers. Possible effects of neutron irradiation on the properties of the MCCh granules were studied in advance, in vitro. In vivo gamma scintigraphic evaluations were carried out with the subjects in a fasted state, using granules containing 95% (F1) or 40% (F2) of MCCh of molecular weight 150 kDa. Reference formulation (F3) was lactose granules. The reference granules passed rapidly from the stomach (mean t50% 0.5+/-0.3 h (n=5)). MCCh in granules prolonged gastric residence times of the formulations in only a few cases (in one volunteer in the F1 group (n=4) and in two volunteers in the F2 group (n=5)). Maximum individual t50% values were 2.1 h (F1) and 2.3 h (F2). It was concluded that the in vivo mucoadhesion of MCCh formulations is erratic, and that the formulations studied are not reliable gastro-retentive drug delivery systems.

Adult↗

PubMed2004

Scintigraphic verification of adherence of a chitosan formulation to the human oesophagus.

It is well known that adherence of a drug product, e.g. a gelatine capsule, to the oesophagus can cause oesophageal injury, which can be severe if the medicinal agent has corrosive properties. In a recent study we investigated by means of gamma scintigraphy whether chitosan granules dispensed in gelatine capsules had gastro-retentive properties. In one of ten volunteers the formulation lodged in the oesophagus. This case is reported here. The capsule adhered initially to the distal oesophagus. The capsule shell had started to disintegrate within 5 min, with some radioactivity detectable in the stomach. However, about two thirds of the radioactivity remained detectable in the oesophageal region for 1.75 h. This could be explained on the basis that there had been adherence not only of the gelatine shell but also of chitosan granules to the oesophageal mucosa. In evaluating potential for causing oesophageal injury it is not enough to consider only the mucoadhesive properties of the outermost layer of a drug product, because the filler may also have such properties. When new excipient materials are introduced, evaluation of their mucoadhesive tendencies is important.

Adhesiveness↗

PubMed2003

Evaluation of microcrystalline chitosans for gastro-retentive drug delivery.

In vivo absorption studies were carried out in human volunteers to evaluate whether microcrystalline chitosan (MCCh) granules would be gastro-retentive. Furosemide, which is site-specifically absorbed from the upper gastrointestinal tract, was used as model drug. The rate of release of furosemide in vitro could be prolonged by increasing the molecular weight (M(w)) or amount of MCCh (150 to 240 kDa; 80 to 95%) in the granules, and also by addition of acidic excipients to the formulations. No marked changes in the in vivo absorption rate (t(max)) were noted, but the amounts of furosemide absorbed (AUC(0- infinity ) and C(max)) decreased as the in vitro release rate decreased, although this was not statistically significant in the case of AUC. The highest AUC(0- infinity ) (3050 micro g l(-1) h) for furosemide (40 mg) was achieved with granules containing 80% MCCh of 150 kDa M(w). With MCCh of 240 kDa M(w) AUC(0- infinity ) was 1890 micro g l(-1) h. This kind of pharmacokinetic profile of furosemide suggests that the gastric retention time of the granules is too short in relation to the release rate, and a large amount of the drug passes its "absorption window" before being released. The in vivo study produced no evidence that the chitosan formulations studied can be used as mucoadhesive gastro-retentive drug delivery systems. The results of in vitro mucoadhesion studies did not predict the results of in vivo studies.

Absorption↗

PubMed2002

Removal of acetaldehyde from saliva by a slow-release buccal tablet of L-cysteine.

High alcohol intake is an independent risk factor for upper gastrointestinal (GI)-tract cancers. There is increasing evidence that acetaldehyde, the first metabolite of ethanol, might be responsible for ethanol-associated carcinogenesis. Especially among Asian heavy drinkers with the ALDH2-deficiency gene, i.e., a genetic inability to remove acetaldehyde, the risk of digestive tract cancers is markedly increased. Local acetaldehyde production from ethanol either by oral microbes, mucosal cells or salivary glands is a plausible carcinogenic agent in the saliva. The aim of our study was to examine whether is it possible to bind carcinogenic acetaldehyde from saliva with L-cysteine, which is slowly released from a special buccal tablet. Nine healthy male volunteers took part in our study, and each subject served as his own control. A placebo or L-cysteine-containing tablet was fastened under the upper lip. Thereafter the volunteers ingested 0.8 g/kg of body weight of 10% (v/v) ethanol, and saliva samples were collected at 20 min intervals for 320 min. Salivary acetaldehyde and ethanol levels were analysed by headspace gas chromatography. The mean reduction of acetaldehyde concentration of the saliva with the L-cysteine tablet compared to placebo was 59% (CL(95%) 43%, 76%). Area under the curve (AUC(0-320min)) with the L-cysteine and placebo tablet were 54.3 +/- 11 microM x hr and 162 +/- 34.2 microM x hr (mean +/- SEM), respectively (p = 0.003). After alcohol intake, up to two-thirds of carcinogenic acetaldehyde can be removed from saliva with a slow-releasing buccal L-cysteine drug formulation. Thus, a buccal cysteine tablet could potentially be used to prevent upper GI-tract cancers, especially among high-risk individuals.

Acetaldehyde↗

PubMed2002

Effect of synthesis parameters of the sol-gel-processed spray-dried silica gel microparticles on the release rate of dexmedetomidine.

The objective of this study was to evaluate the possibilities to control the release rate of dexmedetomidine (DMED) from different spray-dried silica gel microparticle formulations. Microparticles were prepared by spray drying a silica sol polymer solution containing the drug. Drug release was investigated both in vitro and in vivo. The influence of sol-gel synthesis parameters, like pH and the water/alkoxide ratio (r) of the sol, on the release behaviour of the drug was studied. Silica gel microparticles had a smooth surface. Microparticles prepared from diluted sol, however, were more aggregated and clustered. The drug release conformed to zero order release from microparticles prepared near the isoelectric point of silica (pH 2.3 and pH 3) and to the square root of time kinetics from microparticles prepared at pH 1 and pH 5. The release also showed a dual-phasic profile with an initial burst and after that a slower release period. The dexmedetomidine release conformed to zero order kinetics from microparticles prepared at water/ alkoxide ratios between r = 6 and r = 35 (at pH 2.3). The release rate was the slowest from microparticles prepared with water/ alkoxide ratio 35. The bioavailability of dexmedetomidine in dogs showed that the release was sustained from silica gel microparticles as compared with a subcutaneously administered reference dose of 0.1 mg.

Analgesics, Non-Narcotic↗

PubMed2002

Bioavailability and in vitro oesophageal sticking tendency of hydroxypropyl methylcellulose capsule formulations and corresponding gelatine capsule formulations.

The overall aim of the present study was to widen our knowledge about the biopharmaceutical behaviour of novel hydroxypropyl methylcellulose (HPMC)-based two-piece capsules by comparing them with the classic hard gelatine capsules. Firstly, the tendency of the HPMC capsules to stick to isolated porcine oesophageal preparation was evaluated. The force needed to detach the HPMC capsules from the oesophagus was significantly lower than that for the gelatine capsules (P<0.001), which is evidently an advantage of this new dosage form. The second aim was to investigate the possibility of preparing sustained-release capsules using different powdered HPMCs as diluents (K100, K4M and K15M) and the effect of the molecular weight of HPMC powder on the in vitro and in vivo behaviour of the capsules. In addition to peroral drug administration also rectal dosing was applied. Two groups of eight healthy volunteers participated in randomised, cross-over, single-dose studies. One group was administered capsules orally and the other rectally. There were no marked differences in the bioavailability properties of either the oral or rectal HPMC capsules containing ibuprofen as model drug as compared with corresponding gelatine capsule formulations. Using different viscosity grades of HPMC powders as diluents it was possible to control the absorption rate of the model drug both from gelatine and HPMC capsules as far as the oral route was concerned. After rectal administration there were no statistically significant differences between the formulations containing different grades of HPMC powder. Only partial correlation was observed between the results of the bioavailability studies and the in vitro dissolution studies. From a biopharmaceutical point of view these two shell materials can be regarded as interchangeable.

Administration, Oral↗

PubMed2002

In vitro evaluation of microcrystalline chitosan (MCCh) as gel-forming excipient in matrix granules.

Although much research has been carried out into the effects of chitosan and its chemical properties on drug release, less attention has been paid to the effects of its physical properties. The aim of this study was to characterize microcrystalline chitosan (MCCh) as a gel-forming excipient. Matrix granules containing chitosans of differing physicochemical properties (crystallinity, molecular weight, degree of deacetylation) and ibuprofen or paracetamol as model drugs were prepared. Gel formation by the chitosans in the granules and subsequent effects on drug release were studied at pH 1.2 and pH 5.8. The chitosan granules acted as slow-release formulations in the case of ibuprofen (a class-II drug in the Biopharmaceutics Classification System) but with paracetamol (class-I) no controlled-release formulation could be developed. Microcrystalline grades of chitosan had the most marked retardant effects on drug release, with the efficacy of gel formation by MCCh explaining the results. The kinetic constant for ibuprofen release (at pH 5.8) ranged from 22%.h(-1) (MCCh) to 31%.h(-1) (unmodified chitosan). The release rate was easily controlled by varying the amount or molecular weight of MCCh, and to a lesser extent by the degree of deacetylation. The effects were most pronounced when pH was markedly acidic, suggesting that MCCh granules might be particularly useful in preparing stomach-specific slow-release dosage forms.

Chemistry, Pharmaceutical↗