In previous pharmacokinetic studies in healthy subjects the time course of plasma concentration of prenalterol was described by a short distribution phase (alpha-phase) with a mean half-life of about 8 minutes and an elimination phase (beta-phase) with an average half- life of about two hours [1, 2]. The aim of this joint study was to check the pharmacokinetic data obtained after intravenous single dose administration with the computer program TOPFIT [3] using different compartment models and to test the predictive power of the chosen kinetic model for plasma concentration data after repetitive intravenous prenalterol dosing.

Steady state plasma levels and clinical effects of disopyramide have been compared following administration of standard capsules and controlled release (CR) tablets. Nineteen patients (29–70 years) with atrial or ventricular arrhythmias were treated for two weeks with disopyramide capsules 200 mg t.i.d. and then with CR tablets 300 mg b.i.d. for 14 weeks. After treatment either with capsules or CR tablets, plasma concentrations of disopyramide and its metabolite N-deisopropyldisopyramide were similar within 1 dosage interval. Maximum and minimum concentrations of the parent drug were 10.1±0.9 µmol/l (mean ± SEM) and 5.7±0.5 µmol/l with CR tablets, and 10.2±0.5 µmol/l and 5.6±0.5 µmol/l with standard capsules. The bioavailability of disopyramide was the same after capsules and CR tablets. Disopyramide, independent of the formulation, produced good antiarrhythmic effects. The side-effects reported on questioning were mainly of the anti-cholinergic type and there was no significant difference between the formulations with respect to their incidence, type or severity. Of 16 patients who stated a preference for one of the dosage forms, 11 prefered the CR tablets. The study confirms the good antiarrhythmic effect of disopyramide and shows that the CR preparation permits twice daily administration of disopyramide.

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.

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 (ER1(Tab), ER2(Tab) and ER3(Caps)) 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 ER1(Tab), ER2(Tab) and ER3(Caps) were 52%, 36% and 57% lower, respectively, compared with LR (P<0.01). Also at 24 h, mean total diuretic efficiency for ER1(Tab), ER2(Tab) and ER3(Caps) 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.

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.

Different compositions of in vitro dissolution fluids have been developed and used in screening experiments during the development of ethylcellulose ER-coated spheres of the model drug remoxipride. The composititons were different with respect to pH, temperature, osmotic pressure, viscosity, agitation, ionic strength, polarity of the medium, type, and concentration of surfactant. By using a chemometric methodology all the variables were varied independently at the same time, and the results were connected in a mathematical model which described the experimental domain. The most significant main effects on the amount of remaxipride released at all timepoints were caused by polarity, temperature, and agitation. The mathematical model was used to predict the in vitro condititons that was best associated with the in vivo data, obtained after administration of the formulation to sixteen volunteers. A verifying experiment showed a close connection between the predicted and experimental in vitro dissolution profile up to 4 hr, but thereafter (up to 24 hr) the profiles deviated. It is obvious that the conditions need to be further optimized. However, the present approach to stress oral dosage systems during the development phase seems very promising.

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.

The relation between the moisture sorption and compaction properties of microcrystalline cellulose, MCC, and binary mixtures of MCC with polyvinyl pyrrolidone, PVP, has been examined. PVP is a completely amorphous polymer, whereas MCC contains various fractions of amorphous structure depending not only on the quality used but also on the pharmaceutical processing. The tensile strength of tablets of MCC is shown to depend upon the relative humidity, RH, prior to compaction. At an RH of about 70%, a decrease in strength is observed corresponding to the upward shift of the moisture sorption isotherm. For a dry blend of MCC and PVP as well as for a granulation, the tensile strength is determined by the properties of MCC at humidities below 70% RH. At humidities above 70%, a reduction of the glass transition temperature of PVP below the operating temperature (20°C) is the dominating factor, resulting in a decrease in tensile strength.

A statistical experimental design was chosen for comparing the in vitro release properties of ethyl cellulose-coated extended release spheres with remoxipride. Two compositions with different plasticizer were tested since these were shown to cause significantly different absorptions rates of the compound after administration to healthy volunteers. The experimental variables investigated were pH of dissolution media, amount of non-ionic surfactant, agitation in the in vitro technique and composition of the spheres. The experiments were performed in both the Paddle and the Flow-Through technique.The release rates were constantly higher by the Flow-Through at all the conditions tested and the effects of the variables were also more pronounced, A statistically significant correlation was found between the release curve and the absorption curves during three different in vitro conditions i.e. at pH 1.2 using an agitation of 100 rpm in the Paddle or a flow of 16 ml/min in the Flow-Through and in a buffer of pH 7.2 at a flow of 16 ml/min. The similarity, however, did not give enough support to choose any of these conditions for a discriminating method in the quality control.

Moisture sorption and desorption have been characterized for active (naproxen and paracetamol) and inactive pharmaceutical solids by using a climatic test chamber. The relative humidity (RH) of the climatic test chamber was varied in the range from 15 to 90%. Equilibrium moisture content was achieved within a period of 2 h for slightly hygroscopic and moderately hygroscopic substances. For very hygroscopic substances equilibrium was reached within 2 h at low RH(< 60%), whereas more than 24 h were needed at high RH (> 60%). Moisture sorption isotherms were characterized by using the climatic test chamber and were found to be identical with moisture sorption isotherms characterized by desiccators.

The flow-through cell at a flow rate of 16 and 8 ml/min has been used to investigate how the amount of paracetamol and codeine phosphate, in relation to the total weight of a lipophilic suppository, influences the in vitro dissolution rate. Two in vivo studies explored how the rate and extent of bioavailability in humans varied as a function of fraction of drug substances. Despite an approx. 20-fold difference in aqueous solubility between paracetamol and codeine phosphate, the lipophilicity controlled the in vitro release and bioavailability. Decreasing the amount of paracetamol and codeine phosphate in relation to total suppository weight and increasing the size of the suppository resulted in a faster absorption rate and an increased extent of bioavailability. This was more pronounced for paracetamol. The flow-through cell was found to produce dissolution profiles which were in agreement with the plasma concentration profiles obtained, indicating that the lower flow rate reflected the in vivo situation more correctly than the higher flow rate. The intra-individual variation when administering one composition on two different occasions was found to be relatively small for five of the subjects who participated in both studies.

The flow-through cell has been used to investigate whether it is possible to discover any relationship between the in vitro dissolution rate of paracetamol from suppositories and the plasma concentrations reached after administration to eight healthy volunteers. A rectal solution was used as a reference. Three suppository compositions were varied with regard to amount of drug substance in relation to total suppository weight and size. The in vivo study was designed to explore the use of statistical moment analysis and convolution/deconvolution in the association of in vivo data and in vitro dissolution results. An increase in both rate and extent of bioavailability was observed when decreasing the fraction and increasing the size, but it was not explained to what degree each of these factors contributed. The flow-through method using a 22.6 mm cell, primarily developed for oral dosage forms, was found to produce dissolution profiles which associated well with the plasma concentration profiles obtained both when a statistical moment analysis and the convolution method was applied. The most optimal flow rate studied was 28 ml/min which reflected the in vivo situation better than a lower or a higher flow rate.

The release properties of calcium alginate minimatrices were studied in media of various compositions. Three drugs with different aqueous solubility (paracetamol, theophylline and chloramphenicol) were incorporated as model substances and their release rates were investigated in 0.1 M HCl and water. The theophylline release was also studied in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), 0.034 M NaCl and 0.1 M NaCl. Additionally, the simultaneous liberation of calcium ions from the carrier material into the different media was analysed and illustrated by means of calcium release curves. Only when pure water was applied as release medium were the matrices able to extend the release of the two least soluble model drugs, theophylline and chloramphenicol. In all other media the drug release proceeded much more rapidly, due to various transformations in the carrier material. The cross-linking calcium ions were rapidly discharged from the matrices in the presence of acid, and the carrier material was converted to alginic acid. Although the transformation did not change the morphology or the swelling behaviour of the matrices, it destroyed their ability to provide retarded drug release. In the NaCl solutions and SIF, the calcium ions were partly exchanged by the non-gelling sodium ions or sequestered by the phosphate. This caused swelling and, in the latter case, dissolution of the matrices, and induced a rapid release of the encapsulated drug. Due to the pronounced sensitivity towards the composition of the release medium and the rapid drug release in media of physiological relevance, it was concluded that the minimatrices do not seem applicable as an oral controlled release system.

The influence of the calcium concentration, the amount of drug added and the characteristics of the alginate on the encapsulation and release of theophylline from minimatrices made of calcium alginate were studied. The combined effects of the calcium concentration used for gelation and the amount of drug added during matrix production was investigated by means of a central composite design. Both factors influenced the drug encapsulation and drug release rate in water. The response surfaces for the release parameters t(50%) and T-d showed that the slowest release was obtained from matrices prepared using intermediate levels of the two factors. The retardation was, however, relatively small, and t(50%) and T-d did not exceed 1.5 and 2.8 h, respectively. Drug release in 0.1 M HCl was very rapid from all the formulations tested. It was only slightly affected by the amount of drug added during matrix production and was not influenced by the calcium concentration. A high G alginate was used as carrier material in the matrices investigated during the central composite design. Alginates containing fewer G residues gave matrices with a lower encapsulation efficiency and a faster drug release rate in both dissolution media. An increase in the mean molecular weight of the alginate from 200 000 to 270 000 did not affect the release properties.

The rectal bioavailability of propoxyphene has been investigated in an explorative study on six volunteers after administration of hydrophilic and lipophilic suppositories with and without a mucoadhesive. A tablet formulation was used as reference. The in vitro dissolution characteristics of the four different rectal compositions were studied by using the basket, paddle and flow-through techniques in order to determine whether these methods could be used to predict the plasma concentration vs time curves. The results indicate that rectal administration of dextropropoxyphene napsylate reduces first-pass elimination of the drug. By choosing a hydrophilic suppository base it was possible to achieve the same rate of absorption and a 60% greater extent of bioavailability of propoxyphene than after oral administration. The basket method was the most suitable technique to predict a ranking between the different compositions.

Small calcium alginate matrices were prepared by ionotropic gelation of droplets of an alginate solution containing dispersed theophylline, followed by air-drying of the gel beads. The effect of various production factors on the size, composition and drug release properties was investigated in two separate studies. A 23 factorial design and a 2V5−1 fractional factorial design were applied. The size of the matrices was controlled mainly by the coaxial airstream applied during droplet production. However, the alginate concentration and the calcium concentration used for gelation also appeared to have a significant influence. The latter two factors, together with the amount of drug dispersed, determined the matrix drug content. The calcium concentration and the amount of drug affected matrix calcium content the most. The amount of drug also affected the moisture content. The calcium and alginate concentrations, the gelling time, the drug addition and the alginate G content affected the drug release rate in water. An increase in the level of all these factors caused a retardation in release. Several synergistic two-factor interactions were also observed.

The influence of compaction pressure on the technical characteristics, and on the release rate of naftidrofuryl from a mixed xanthan gum/guar gum matrix tablet, has been investigated. The crushing strength increased with increasing compaction pressure, and the friability, the porosity and the release rate decreased at the same time. The release rate studies were performed in different media with various agitation rate of the paddles. Tablets made at 50 MPa compaction pressure eroded relatively fast, giving a more rapid drug release than tablets made at higher pressure. The dependence of release rate on compaction pressure and agitation speed indicates that the penetration of liquid into the matrix, as well as the erosion of the hydrated matrix, control the release of drug into the bulk solution.

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.

Pilot investigations of a small-scale method for production of calcium alginate matrices containing the model drug theophylline were performed. Gel beads of calcium alginate were produced by dripping a sodium alginate solution containing dispersed drug into a calcium chloride bath. Subsequent drying produced small matrices in which the drug crystals were embedded. Various factors connected with droplet formation, gelation, washing and drying of the product were investigated and shown to influence the size, the composition and the release properties of the matrices. The encapsulation method offers an effective incorporation of theophylline only when the gelling and washing solutions are saturated with drug. Increasing the calcium concentration used for gelation reduces the encapsulation efficiency and gives a lower drug content of the matrices. By decreasing the calcium concentration of the gelling solution from 0.20 M to 0.05 M, or by removing more of the unbound calcium from the gel beads by more extensive washing, a slower drug release from the matrices is induced. The drying method and the drying temperature determine the appearance, the moisture content and the physical state of the drug in the matrices. The drug release is markedly more rapid from freeze-dried than from air-dried matrices.