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Biomedical subjects

C Graffner

Publications and source records attributed to C Graffner.

At least 19 recordsLinked to original sources
PubMed2002

The influence of caprate on rectal absorption of phenoxymethylpenicillin: experience from an in-vivo perfusion in humans.

The aim of this in-vivo perfusion study in humans was to investigate the influence of a penetration enhancer, sodium caprate, on the rectal absorption of phenoxymethylpenicillin and antipyrine. Six subjects, 3 male and 3 female, were included in two separate studies using perfusion solution of different pH (T1 and T2, respectively). Each in-vivo rectal perfusion investigation lasted for 200 min and consisted of two periods of 100 min, the first serving as a control, and sodium caprate being added in the second period in both T1 and T2. The concentrations of phenoxymethylpenicillin, antipyrine and sodium caprate in the outlet perfusate were assayed by HPLC, as was the plasma concentrations of phenoxymethylpenicillin. At pH 6.0 (0-100 min) the fraction absorbed (f(abs)) and effective permeability (P(eff)) of phenoxymethylpenicillin were 0.3% and 0.06 x 4 cm s(-1), respectively, and remained unaffected by the addition of sodium caprate. When the same subjects were perfused at pH 7.4, the f(abs) and P(eff) of phenoxymethylpenicillin were 2.4% and 0.11 x 10(-4) cm s(-1) (0-100 min), respectively, also remaining unchanged by addition of sodium caprate (100-200 min). It was possible to determine the plasma AUC of phenoxymethylpenicillin after addition of sodium caprate in three subjects at both pHs; this was in the range of 14.0-62.8 and 56.4-231 (min micromol L(-1)) at pH 6.0 and 7.4, respectively. Interestingly, there was a correlation between P(eff) for sodium caprate and the individual plasma AUC and C(max) of phenoxymethyl-penicillin, which indicates that the permeability of the enhancer in the tissue upon which it should act is crucial for achieving an effect. The f(abs) and the P(eff) of antipyrine were not affected at either pH when sodium caprate was added to the perfusion solution. In conclusion, the plasma pharmacokinetics of phenoxymethylpenicillin suggested a slightly increased rectal absorption at pH 7.4 in subjects where sodium caprate was transported into the rectal tissue. However, the increased P(eff) for phenoxymethylpenicillin wastoo small to detectfrom the outlet perfusate, which suggests that sodium caprate alone has a limited effect on the permeability in-vivo across the rectal epithelium when it is presented in a solution.

Administration, Rectal↗
PubMed2000

Influence of neutron activation factors on matrix tablets for site specific delivery to the colon.

The impact of the neutron activation procedure, i.e. incorporation of samarium oxide (Sm(2)O(3)) and neutron irradiation, on the compression properties (including the crushing strength) and in vitro dissolution of potential colonic delivery systems based on matrix tablets of amidated pectin (Am.P) or two types of hydroxypropyl methylcellulose (HPMC) was investigated. The neutron activation factors did not influence the compression properties of the tablets. Replacement of magnesium stearate with samarium stearate in directly compressed Am.P tablets to achieve both radiolabelling and lubrication resulted in a greater extent of concentration-dependent reduction of the crushing strength. Dissolution tests demonstrated that irradiation increased the release of the model drug ropivacaine from the tablets. The extent of this increase was unexpectedly low considering the previously observed degradation of the polymer expressed as an irradiation-induced viscosity reduction in solutions prepared from the polymers. Delayed-release coating with Eudragit L 100 protected the HPMC tablets against the release-increasing effect of irradiation until the late phases of release. Sm(2)O(3) retarded the release to a varying extent depending on particle characteristics. Incorporation of Sm(2)O(3) in the coating layer did not influence the release. However, one-third of the radioactivity leached from the coating within 60 min in 0.1 M HCl.

Amides↗
PubMed2000

Development of pectin matrix tablets for colonic delivery of model drug ropivacaine.

The objective of this work was to develop pectin-based matrix tablets for colonic delivery of the model drug ropivacaine, with the future perspective of radiolabelling the system by neutron activation technique for a gamma-scintigraphic study. The aim was to investigate some formulation factors that could reduce the release of the drug in the simulated gastric and intestinal fluids, increase the release in the simulated cecal fluid (with pectinolytic enzymes) and improve the poor compactibility of pectins. For dissolution studies, the flow-through apparatus with sequential dissolution liquids simulating the mouth-to-colon conditions was used. The effect of two pectin types, the incorporation of ethylcellulose as a dry matrix-additive and water or ethanol as granulation liquids were investigated in a study designed as a D-optimal mixture. Amidated pectin (Am.P) produced harder tablets than the calcium salt of pectin (Ca.P) and was more susceptible to enzymatic degradation. Addition of ethylcellulose increased the tablet strength and the dissolution rate. Furthermore, directly compressed Am.P tablets were produced by addition of coarse or micronised qualities of ethylcellulose. The latter improved the crushing strength markedly imposing a marginal release-reducing effect. Coating this formulation with Eudragit((R)) L 100 reduced the release in the simulated upper GI conditions without interference with the subsequent enzymatic activity.

Amides↗
PubMed1999

Influence of neutron activation factors on the physico-chemical properties of suppositories and their excipients.

The effect of the neutron activation factors, i.e., admixture of samarium oxide (Sm2O3) and irradiation time, on the physico-chemical properties of the raw materials and the in vitro dissolution and disintegration of hydrophilic and lipophilic suppositories was investigated. It was possible to expose the pure bases and the model drugs (5-aminosalicylic acid [5-ASA] and ropivacaine hydrochloride) to 1 min of neutron irradiation in a flux of 1.1.1013 n cm-2s-1. The dissolution and disintegration of the corresponding suppositories showed that the physico-chemical properties and the fraction of incorporated drug together with the lipophilic/hydrophilic nature of the base were important factors. Sm2O3 increased the disintegration time of hydrophilic suppositories containing 5-ASA, while the dissolution of both drugs from these formulations remained unchanged. Sm2O3 did not alter the disintegration time of the lipophilic formulations, but it reduced the dissolution of both drugs from these suppositories. Irradiation induced different behaviour in the different bases.

Amides↗
PubMed1999

The influence of frusemide formulation on diuretic effect and efficiency.

AIMS: Changes in drug delivery rate may result in clinically important changes in drug effects. For the loop diuretic frusemide, it would be desirable to develop controlled release preparations, that could maintain an effective urinary excretion rate over a prolonged period of time. The aim of this study was to investigate the influence of frusemide formulation on frusemide recovery, diuretic effect and efficiency. METHODS: Twelve subjects were given 60 mg of four different frusemide controlled release formulations in a single-dose, double-blind, randomized 4-way cross-over design. The formulations were three study drugs with different extended dissolution rates (ER1Tab, ER2Tab and ER3Caps ) and one reference drug (LR). Urinary volume and contents of frusemide in urine were measured in samples collected over 24 h. RESULTS: Substantial differences in frusemide recovery and diuretic efficiency were observed between LR and all other formulations. At 24 h, mean total frusemide recoveries of ER1Tab, ER2Tab and ER3Caps were 52%, 36% and 57% lower, respectively, compared with LR (P<0.01). Also at 24 h, mean total diuretic efficiency for ER1Tab, ER2Tab and ER3Caps was 83%, 31% and 135% higher, respectively, compared to LR. The rapid dissolution and absorption of LR resulted in a high diuretic response from 0 to 3 h after dosing. However, from 0 to 24 h, there were no differences in diuretic response between the formulations. CONCLUSIONS: Controlled release formulations of frusemide with a low and extended rate of dissolution lead to a more prolonged absorption and subsequent diuresis, but still maintain a similar cumulative response, due to their higher diuretic efficiency.

Adolescent↗
PubMed1999

Effects of thermal neutron irradiation on some potential excipients for colonic delivery systems.

Different excipients, which are currently being studied for colon delivery systems, were examined with respect to their stability toward neutron irradiation as a potential method of radiolabeling the formulations for gamma-scintigraphic studies. Three different pectin and four different hydroxypropyl methylcellulose (HPMC) types, in addition to two types of polymethacrylate films, were exposed to 1, 2, and 3 min of thermal neutron irradiation in a flux of 1.1 x 10(13) n cm-2 s-1. The physicochemical characteristics of pectins and HPMCs and the mechanical properties of the polymethacrylate films were examined after the radioactivity of the samples had declined to background levels. Methods included ultraviolet (UV) and Fourier transform infrared (FTIR) spectroscopy, pH measurements, loss on drying, thermogravimetric analysis (TGA), viscosimetry, gas chromatographic (GC) analysis of pectin monosaccharides, and tensile strength testing of the films. The results suggest that pectins and HPMCs undergo degradation, as expressed by a significant reduction in the dynamic and intrinsic viscosities of the samples. Generally, HPMCs were more sensitive than pectins to neutron irradiation. However, calcium pectinate proved to be the most sensitive among all the investigated polymers. Both polymethacrylate films (Eudragit L and S) resisted loss of mechanical properties following 1 and 2 min of neutron irradiation, whereas irradiation for 3 min implied significant changes in the appearance and the mechanical properties of Eudragit L films. As a conclusion, neutron irradiation results in dose-dependent degradation of the investigated polysaccharides and polymethacrylates. The consequences on the in vitro behavior of a formulation containing such polymers are discussed.

Chromatography, Gas↗
PubMed1998

Critical dissolution tests of oral systems based on statistically designed experiments. II. In vitro optimization of screened variables on ER-coated spheres for the establishment of an in vitro/in vivo correlation.

The study was designed to optimize the effects of the screened in vitro dissolution variables agitation, temperature, osmolality, and polarity on the release of the neuroleptic compound remoxipride from extended release coated spheres. The variables were varied independently by means of a fractional factorial design. The in vitro tests were performed with the Basket method (USP). The polarity and the osmolality of the medium had significant effects on the dissolution rate of remoxipride. A statistical model was calculated based on the obtained dissolution in vitro. The model was then used to predict the in vitro conditions that most closely correlated with the dissolution rate of remoxipride in vivo, after administration of the formulation to 16 volunteers. The predicted in vitro conditions were experimentally verified, and an excellent association with the in vivo behavior of the formulation was found. Validation of the optimal in vitro conditions was performed on another batch of the formulation. The dissolution profile obtained showed a significant association with the corresponding dissolution profile in vivo. The use of statistically designed experiments in the development of critical dissolution tests for the establishment of in vitro/in vivo correlations seems to be a useful working approach, and supports further application to other oral solid systems.

Antipsychotic Agents↗
PubMed1998

Critical dissolution tests of oral systems based on statistically designed experiments. III. In vitro/in vivo correlation for multiple-unit capsules of paracetamol based on PLS modeling.

The main aims of the present study were to establish an in vitro/in vivo correlation for multiple-unit capsules of paracetamol by means of statistical prediction models and to investigate the effect of a number of in vitro variables on the discussion rate of paracetamol from the formulation. A fractional factorial screening design was used to investigate the effects of the variables agitation, pH, osmolality, viscosity, and the presence of bile salt on the dissolution rate of paracetamol. The effects were evaluated in two separate partial least-squares models, in which the responses were expressed as the cumulative percentage of paracetamol dissolved at specified time-points (model I) and as the shape (beta) and scale (eta) parameters according to the Weibull function (model II). It was concluded that agitation and viscosity had significant effects on the dissolution rate of paracetamol. Statistical models based on the responses from models I and II were then used to predict the in vitro conditions most closely correlated with the in vitro dissolution of paracetamol after administration of the formulation to 10 healthy volunteers. The predicted optimal in vitro conditions were similar for the two models and not too far from what is expected from the gastrointestinal tract. The experimental verification of the in vitro conditions showed that both models were equally good, and contributed to high degrees of correlation with the in vivo dissolution behavior of the formulation during 9 hr. The relationships obtained when plotting the percentage dissolved in vitro versus in vivo were y = 1.1x (r2 = 0.98) and y = 1.1x (r2 = 0.94) for models I and II, respectively. Based on these results, it is difficult to state a preference for one of the models. Finally, the use of statistical prediction models to develop critical in vitro tests is a successful approach in the establishment of associations between dissolution behavior in vitro and in vivo for oral extended-release systems.

Acetaminophen↗
PubMed1998

Water-solid interactions. IV. Influence of moisture sorption on the compaction of film-coated particles.

The effect of moisture sorption on the compaction properties of model modified-release (MR) pellets coated with ethyl cellulose/hydroxypropylcellulose film has been studied for the MR pellets alone and in binary mixtures with microcrystalline cellulose, lactose alpha-monohydrate, or lactose 9% amorphous. The in vitro dissolution rate prior to and after compaction was used as an indirect method of evaluating the effect of exposing the MR pellets to a compaction force. Moisture sorption as well as the glass transition temperature (Tg) using differential scanning calorimetry (DSC) were determined as a function of humidity for cast film conditioned at different humidities using a climate test chamber. The compaction properties of lactose and microcrystalline cellulose were altered by the addition of MR pellets, resulting in a robust tablet mass and a tensile strength of the tablet masses that was less sensitive to moisture. The amount of moisture sorbed was found to have little influence on the formation of cracks or on the rupturing of film-coated MR pellets during compaction. This was probably a result of both the small depression in the Tg for the film system at increasing RH and the robustness of the film chosen. The results also showed that the volume reduction properties of the tableting excipients were of importance for reducing damage to the film coating. Lactose had a higher protective effect on the film-coated MR pellets compared to microcrystalline cellulose.

Adsorption↗
PubMed1996

Water-solid interactions. III. Effect of glass transition temperature, Tg, and processing on tensile strength of compacts of lactose and lactose/polyvinyl pyrrolidone.

The effect of moisture sorption at different relative humidities on the tensile strength and the physical stability of compacts of crystalline and partly amorphous lactose, alone and in binary mixtures with PVP, has been studied. Furthermore, the role of moisture as a plasticizer and its effect on the glass transition temperature, Tg, are related to the compactibiltiy. Samples were conditioned for 2 hr using a climate test chamber at different relative humidities. Moisture sorption was determined, the radial crushing strength for compacts was measured immediately and after storage, and the tensile strength was calculated. The glass transition temperature, Tg, was determined using DSC. The tensile strength of the compacts was found to depend on both the conditioning humidity and the humidity during storage. An increase in humidity to a level at which the glass transition temperature, Tg, fell below the operating temperature, T, resulted in transition from a rigid glassy state to a mobile rubbery state. For compacts of partly amorphous lactose, an increase in the tensile strength was observed during storage of tablets, due to recrystallization of the amorphous regions above Tg. Tablets of mixtures of lactose and PVP exhibit a sharp decrease in tensile strength at humidities above 70% RH, due to the glass-to-rubber transition of PVP.

Calorimetry, Differential Scanning↗
PubMed1993

In vivo validation of the release rate and palatability of remoxipride-modified release suspension.

Remoxipride, a D2-dopamine receptor antagonist, is well tolerated and completely absorbed after oral administration. Because of its extremely bitter taste, an oral palatable suspension was developed by using a taste-masking microencapsulation. The bioavailability of remoxipride was investigated in two studies in healthy volunteers after administration of a 100-mg dose in suspension. The first study used a capsule as reference, and the second study a plain solution. Taste assessment was carried out in the second study. The extent of bioavailability was the same when comparing the oral suspension to a capsule and to a plain solution. However, the rate of absorption is delayed, and Tmax was 3.0 hr after the suspension, 1.0 hr after the oral solution, and 1.6 hr after the capsule. The release rate in vitro from the suspension was determined by applying the USP-paddle method. By using numerical convolution and deconvolution, the release rates in vivo and in vitro were shown to be similar when using water with 0.5% sodium lauryl sulfate as dissolution liquid. The taste-masked oral suspension is suitable for full-scale production, with good control of the encapsulation process and of the preparation of a suspension.

Adult↗
PubMed1992

Investigation of the applicability of a tensile testing machine for measuring mucoadhesive strength.

The applicability of a tensile testing machine (M30K, JJ Lloyd Instruments Ltd, GB) is investigated for measuring mucoadhesive strengths. A sample of an aqueous dispersion of a polymer with expected mucoadhesive properties is placed between two homemade discs of polyoxymethylene. The upper disc is mounted on a movable part of the machine while the lower disc is fixed on the stationary frame. A tensile force is submitted and the maximum detachment force at fracture and the adhesion work are estimated from the force displacement curve recorded. In some experiments, native mucous tissue of the large intestine of pigs was glued to the upper disc. Four polymers polycarbophil (Carbopol EX-55), carboxypolymethylene (Carbopol 934P), hydroxypropylmethylcellulose (Methocel K4M), and sodium alginate, are used in five different concentrations. At least three measurements are made of each polymer and concentration. Viscosity and osmolality are determined. By standardizing the time of sample equilibration and the run rate before measurement, it is possible to get good reproducibility of the tensile values. Based on the maximum nominal breaking force and the work consumed, it is concluded that the tensile strength is dependent both on the concentration and the type of polymer. The conclusions are the same independent of whether mucous pig tissue is used, or not. The same rank order in adhesive properties of the polymers is achieved as from using modified surface tensiometers.

Adhesiveness↗
PubMed1992

Optimization of a matrix tablet formulation using a mixture design.

The simplex centroid design was applied to the optimization of a modified release tablet formulation. A base granulation was made with the active ingredient naftidrofuryl. The variables investigated included fractions of the excipients microcrystalline cellulose, lactose and dicalcium phosphate dihydrate. The release rate, crushing strength, friability and weight variation were determined as response parameters. Mathematical models were fitted to the data obtained by the lattice method, described by Scheffé and by means of multiple linear regression. Regression analysis indicated a relatively good fit of the models. On the basis of the regression models, contour plots were constructed. An increase in the amount of dicalcium phosphate caused lower release rate and increased weight variation. An increase in the content of lactose showed lower strength and increased friability, whereas an increase in the amount of microcrystalline cellulose had the opposite effect.

Chemistry, Pharmaceutical↗
PubMed1990

Plasma concentrations of remoxipride and the gastrointestinal transit of 111In-marked extended-release coated spheres.

To explore the oral absorption of remoxipride, spheres of remoxipride were labeled with indium-111 colloid before coating with a release-controlling ethylcellulose membrane. Since the labeling remained inside the coating, it was suitable as a marker. Eight healthy volunteers were given a single dose of 100 mg remoxipride in 111In-marked spheres as a multiple-unit capsule. The radioactivity and the position of the spheres (microcapsules) were followed externally for 30 hr by gamma scintigraphy. Parallel to this, plasma concentrations were drawn for 48 hr to confirm the extended dissolution and absorption of remoxipride. The hard gelatin, multiple-unit capsule released the microcapsules within the stomach. These were then rapidly emptied into the small intestine, within 0.5-1 hr. There was then an immediate distribution in the upper small intestine before collection in the lower portion, within 2-5 hr. After passing into the large intestine, there was again extended distribution of the microcapsules. A mean Cmax of 2.7 microM remoxipride was achieved 4 hr after drug administration and a mean AUC of 26.1 mumol.L-1.hr was achieved. Judging from the absorption versus time profile, calculated according to the Wagner-Nelson method, and the scintigraphic images, it is concluded that the main absorption occurs from the small intestine. Data from four volunteers, however, indicated a comparatively good absorption also from the large intestine. Due to the good absorption properties, it is reasonable to expect a low variation in the extent of bioavailability of remoxipride after administration in an extended-release, multiple-unit capsule formulation.

Administration, Oral↗
PubMed1989

Comparative dissolution studies of rectal formulations using the Basket, the Paddle and the Flow-Through methods. I. Paracetamol in suppositories and soft gelatin capsules of both hydrophilic and lipophilic types.

The applicabilities of the Paddle, the Basket and the Flow-Through methods have been investigated for seven different rectal compositions of hydrophilic and lipophilic type. The formulations were studied with respect to in vitro dissolution rate and behaviour in the different techniques. It was found that the composition has a considerable influence on the behaviour of the dosage form and this must be taken into account when judging the applicabilities of the three dissolution tests. The Paddle, the Basket and the Flow-Through methods are considered to be equivalent methods for the dissolving suppositories tested. The Flow-Through method is applicable for all the seven compositions tested; however, a low flow rate (8 ml/min) is necessary to use for soft gelatin capsules when both the coefficient of variation and the behaviour of the dosages within the techniques is taken into consideration.

Acetaminophen↗
PubMed1986

Tolerance and pilot pharmacokinetics of amiflamine after increasing single oral doses in healthy subjects.

Oral doses of 1 to 100 mg amiflamine, a new reversible monoamine oxidase type A-selective inhibitor, were given for the first time in humans to six healthy men. No apparent pharmacologic effects were recorded until the 80 mg dose. After 100 mg, one subject developed symptoms indicative of an overdose. Amiflamine is extensively metabolized by two consecutive N-demethylations. The biotransformation patterns in plasma and urine were found to correlate with the debrisoquin metabolic ratio.

Adult↗
PubMed1986

Pressor response of oral tyramine in healthy men given amiflamine and placebo.

During two baseline challenge tests, oral tyramine (50 to 400 mg) was given to 12 healthy men to find each individual's cardiovascular pressor response. All 12 subjects "tolerated" 200 mg oral tyramine, but three of the 12 developed an increment in systolic blood pressure greater than 30 mm Hg when given a dose of 400 mg. Thereafter, amiflamine, 5 mg bid (n = 8), or placebo, 1 capsule twice a day (n = 4), were given in a double-blind fashion for 7 days, and oral tyramine challenge tests (12.5 to 400 mg) were given on days 5 to 7. During dosing with amiflamine or placebo, no subject tolerated 400 mg oral tyramine and no difference between the two regimens was found with regard to tyramine response. Plasma concentrations of amiflamine and two of its metabolites were measured on days 4 to 7. Steady-state concentrations were reached within 4 to 5 days. Plasma concentrations of tyramine after 400 mg tyramine showed a positive correlation with the increase in systolic blood pressure (P less than 0.001).

Administration, Oral↗