Level A in vitro-in vivo correlation (IVIVC) model with Bayesian approach to formulation series.

In vitro-in vivo correlation (IVIVC) models for formulation series are useful in drug development, but the current models are limited by their inability to include data variability in the predictions. Our goal was to develop a level A IVIVC model that provides predictions with probabilities. The Bayesian approach was used to describe uncertainty related to the model and the data. Three bioavailability studies of levosimendan were used to develop IVIVC model. Dissolution was tested at pH 5.8 with basket. The IVIVC model with Bayesian approach consisted of prior and observed data. All observed data were fitted to the one-compartment model together with prior data. Probability distributions of pharmacokinetic parameters and concentration time profiles were obtained. To test the external predictability of IVIVC model, only dissolution data of formulations E and F were used. The external predictability was good. The possibility to utilize all observed data when constructing IVIVC model, can be considered as a major strength of Bayesian approach. For levosimendan capsule data traditional IVIVC model was not predictable. The usefulness of IVIVC model with Bayesian approach was shown with our data, but the same approach can be used more widely for formulation optimization and for dissolution based biowaivers.

Antihypertensive effects of clonidine.

The antihypertensive effect of clonidine given either two or three times a day with a diuretic was compared in a double-blind crossover study in 18 hypertensive patients. In 11 patients given clonidine three times a day there was better control of blood pressure, although the differences in most instances were of the order of only a few millimeters Hg. There were no differences in the frequency or severity of side effects. Clonidine twice daily with a diuretic appears to be adequate for most patients.

Alkyl-substituted silica gel as a carrier in the controlled release of dexmedetomidine.

The effect of alkyl substitution of the silica xerogel matrix on the release rate of dexmedetomidine was evaluated. Silica sol was processed by either casting or spray drying. When the reaction precursor tetraethylorthosilicate (TEOS) was partially substituted with tri- or dialkoxysilane, the release of dexmedetomidine and degradation of the matrix were decreased compared with 100% TEOS-based gel. Increasing the number or length of the organic groups attached to silicon, modified the silica gel structure and reduced the release rate of dexmedetomidine from monoliths. The release of dexmedetomidine from alkyl-substituted silica gel microparticles, however, showed a burst in drug release. Subcutaneously administered silica xerogel matrices (manufactured by casting, containing 25 mol% dimethyldiethoxysilane at two different doses of dexmedetomidine) were studied in dogs. Sustained delivery of dexmedetomidine was obtained for at least 48 h.

Effect of dosage form and formulation factors on the adherence of drugs to the esophagus.

In recent years, many case reports concerning esophageal injuries caused by drugs have been published. The primary cause has apparently been the adherence of the drug product to the esophagus. In the present study, the adherent tendency of a number of types of tablets and capsules were tested in vitro using a recently developed isolated porcine esophagus preparation. The results showed that the tendency of products to adhere to the esophageal mucosa can be modified to a great extent by shape and formulation. Products with low adherence can be obtained by film coating with aqueous dispersions or by sugarcoating. In contrast, gelatin capsules and some cellulose films appear to have a high tendency to adhere to the esophagus.

Development of a method for study of the tendency of drug products to adhere to the esophagus.

A method to determine the adherence of drugs to the esophagus was developed using isolated swine esophagi. A number of types of tablets and capsules (e.g., of doxycycline) were tested. The results showed that the tendency of products to adhere to the esophagus can be regulated by pharmaceutical properties. It was concluded that the method described is simple, inexpensive, and accurate.

Enteric polymers as binders and coating materials in multiple-unit site-specific drug delivery systems.

The aim of this study was to develop a multiple-unit, site-specific drug formulation allowing targeting of drug release in the colon. Initially, characteristics of matrix pellets containing various enteric polymers as binders were tested. An enteric coating was then added to the formulations. Ibuprofen and furosemide were used as model drugs. The former is absorbed throughout the gastrointestinal tract, the latter only from upper parts. Methacrylate copolymers, hydroxypropyl methylcellulose acetate succinates and cellulose acetate phthalate were used as enteric polymers. The properties of the products were initially tested via dissolution studies at different pHs, then via bioavailability studies in healthy volunteers. The main conclusion was that drug release can be targeted on the distal part of the small intestine and the colon by preparing film-coated matrix pellets in which enteric polymers dissolving at pH approximately 7 have been used both as binders in the pellets and as coating material. This conclusion is based on the finding that absorption of ibuprofen from the formulations developed was adequate, with a lag-time of about 2 h and tmax values at 4-5 h, where as absorption of furosemide from the analogous products was negligible. It was also found that uncoated pellets as such could represent a slow-release formulation for furosemide, a problem drug as far as modified-release products are concerned.

Morning versus evening dosing of ibuprofen using conventional and time-controlled release formulations.

Many functions of the human body vary considerably during a day. These variations can lead to changes in drug plasma concentrations. In the study on healthy volunteers described here it was determined whether ibuprofen plasma levels following single oral doses of immediate-release and press-coated time-controlled release tablet formulations depend on time of drug administration (08:00 or 22:00 h). The difference between morning and evening dosing of the immediate-release formulation was minimal. The results with the press-coated formulation were unexpected having regard to results of previous studies on non-steroidal anti-inflammatory analgesics. Time to peak concentration was 6 h after morning administration, 4 h after evening administration. Both the rate and extent of bioavailability of ibuprofen were lower when dosing took place at 08:00 h than when dosing took place at 22:00 h. The influence of food on the pharmacokinetic profile of an evening dose of the press-coated formulation was also studied. When tablets were administered with a meal the ratio C(max)/AUC and t(max) and AUC values indicated that bioavailability was reduced. The main conclusion was that the chronopharmacokinetic behaviour of the press-coated ibuprofen tablet is related to the formulation, not the drug substance as such.

Development of level A, B and C in vitro-in vivo correlations for modified-release levosimendan capsules.

The aim of this study was to investigate the possibility of developing different levels of correlation between in vitro release and in vivo absorption rate for four modified-release levosimendan capsule formulations. Differences and similarities in the in vitro dissolution curves were compared with pharmacokinetic parameters describing absorption rate. Formulations F, G, H and I differed in the amounts of the delaying excipients alginic acid and HPMC. In vitro release rate was studied by the USP basket method using the following conditions: pH 5.8 or 7.4 and a rotation speed of 50 or 100 rpm. In vivo bioavailability was tested in nine healthy male volunteers and the fractions absorbed were calculated by the Wagner-Nelson method. Dissolution conditions pH 5.8 and a rotation speed of 100 rpm predicted best the similarities and differences in absorption rates among different formulations, and levels C and B correlation coefficients were 0.85 and 0.97, respectively. For formulation H level A correlation (r=0.997) was found when in vitro lag time was 0.2 h and time scale factor 1.9. This study indicated that dissolution tests developed can be used as a surrogate for human bioequivalence studies, for development processes of final commercial products, to ensure batch to batch bioequivalence and in the future in possible scale-up and post approval change cases for modified-release levosimendan formulation H.

Extrusion-spheronization of pH-sensitive polymeric matrix pellets for possible colonic drug delivery.

The aim of this study was to investigate extrusion-spheronization pelletization for preparing pH-sensitive matrix pellets for colon-specific drug delivery. The effects of three independent variables (amounts of Eudragit S, citric acid and spheronizing time) on pellet size, shape (roundness and aspect ratio), and drug release were studied with central composite design. The pellets contained ibuprofen as a model drug, citric acid as a pH-adjusting agent, Eudragit S as a pH-sensitive binder and microcrystalline cellulose (MCC). The pellets were prepared with Nica extrusion-spheronizing equipment and subsequently enteric-coated using an air-suspension technique. Eudragit S as a pH-sensitive matrix former in pellets increased the pellet size and influenced pellet roundness. In small amounts Eudragit S increased pellet roundness but in larger amounts pellet roundness was reduced. Citric acid promoted the pelletization process resulting in a narrower area distribution. The pH-sensitive matrix pellet failed to delay the drug release. The combination of citric acid and enteric coating, however, delayed the drug release for 15 min in a pH 7.4 phosphate buffer.

Organic acids as excipients in matrix granules for colon-specific drug delivery.

Interest exists in developing site-specific systems for release of a drug in the lower part of the small intestine or in the colon. The aim of this study was to investigate whether drug release rates from enteric matrix granules could be influenced by using organic acids as excipients. Ibuprofen was used as a model drug and Eudragit S and Aqoat AS-HF as enteric polymers. The dissolution rates of the drug were investigated at different levels of pH (5.8, 6.8 and 7. 4). Drug absorption was studied in bioavailability tests in healthy volunteers. In vitro/in vivo correlation was also investigated. It was concluded that although inclusion of an organic acid in a formulation retarded in vitro release of the model drug, no corresponding effect was evident in in vivo studies. Bioavailability tests are therefore important early on during development of new dosage forms or formulations. Although no correlation between in vitro and in vivo results was generally evident correlation could be demonstrated for individual formulations following mathematical transformation of data.

Citric acid as excipient in multiple-unit enteric-coated tablets for targeting drugs on the colon.

Delivery of drugs to the large bowel has been extensively investigated during the last decade. The aim of this study was to investigate whether enteric-coated tablets could be made from enteric-coated matrix granules and drug release targeted to the colon. Whether in vitro drug release rate and in vivo absorption could be delayed by adding citric acid to the granules and/or to the tablet matrix was also studied. Ibuprofen was used as model drug because it is absorbed throughout the gastrointestinal tract. Eudragit S and Aqoat AS-HF were used as enteric polymers. Drug release rates were studied at different pH levels and drug absorption was studied in bioavailability tests. The conclusion was that citric acid retarded in vitro drug release when used in multiple-unit tablets. In vivo absorption of ibuprofen was markedly delayed when citric acid was included in both granules and tablet matrix. Further studies are needed to determine the optimal amount of citric acid in formulations.

In vivo evaluation of matrix granules containing microcrystalline chitosan as a gel-forming excipient.

Interest in drug delivery to the gastrointestinal tract by means of chitosan has been increasing. In the study reported, the biopharmaceutical properties of granules containing microcrystalline chitosan (MCCh; molecular weight 150 kDa, degree of deacetylation 75%) were evaluated via bioavailability tests in human volunteers. Ibuprofen and furosemide were used as model drugs. With ibuprofen, granules containing 40% of MCCh behaved as a slow-release formulation (t(max) 2.9 h). With furosemide, the most marked difference between a conventional dosage form and granules containing 40% MCCh was a marked lag time (0.5 h) before absorption from the latter. This difference was reflected in t(max) values for furosemide. Despite the lag time, AUC values for furosemide were high, indicating that the granules containing MCCh had remained in the stomach and that drug release had taken place in the stomach rather than in the intestine. The results of the bioavailability studies indicate that MCCh matrix granules allow a simple preparation of slow-release and perhaps stomach-specific dosage forms. Use of model drugs differing in relation to sites of absorption in the gastrointestinal tract aided identification of sites of absorption of drugs from the granules. Further studies, including gamma-scintigraphic evaluations, will be performed on how the granules behave in the stomach.

In vitro release of dexmedetomidine from silica xerogel monoliths: effect of sol-gel synthesis parameters.

Dexmedetomidine, an alpha 2-agonist, was incorporated as a hydrochloride salt into silica xerogel in order to evaluate the effect of sol-gel synthesis parameters: pH of the sol, water/alkoxide molar ratio, drug concentration and size of the device on the drug release rate and degradation rate of the matrix. This study showed that diffusion controlled the release of dexmedetomidine from silica xerogel prepared between pH 1 and pH 5. The drug release was, however, slowest near the zero charge of silica xerogel (pH 2-3). The burst of dexmedetomidine, a lipophilic, but in the form of hydrochloride salt water-soluble drug, was increased from the matrix prepared either below or above the isoelectric point. It follows that the optimum pH for preparing a drug delivery device for dexmedetomidine, is near the zero charge of silica xerogel, where the degradation of the matrix was also slowest. In addition to processing pH, the release rate of drugs can be controlled by changing the water/alkoxide molar ratio of the sol.

Assessment of bioavailability of experimental single-unit sustained release tablets of verapamil hydrochloride using the stable isotope technique.

A stable isotope technique has been used to assess the bioavailability of sustained release verapamil products. The test formulations were tablets with a core containing 90 mg of verapamil hydrochloride coated with ethylcellulose film, the permeability of which was controlled using different amounts of hydroxypropyl methylcellulose. A product containing ethylcellulose 75% hydroxypropyl methylcellulose 25% w/w gave a single-unit sustained release tablet of verapamil hydrochloride that allowed a dose interval of 24 h. There was no loss in bioavailability, even though verapamil had extensive first-pass metabolism.

The effects of some sweetening agents and osmotic pressure on the intestinal absorption of sulfafurazole in the rat.

The effects of some sugars and osmotic pressure have been examined on the absorption of sulfafurazole in the rat. Statistically significant correlations were found among the hypertonic solutions between the reciprocal of osmotic pressure and AUC0--infinity or Cmax. In addition, negative correlation existed between plasma concentrations at 15 min and osmotic pressure. No significant correlations were noted among the hypotonic solutions. More attention should be paid to the osmotic pressure of formulations. The osmotic pressure of hypertonic solutions, especially, might affect absorption of drug from its dosage form.

Citric acid as a pH-regulating additive in granules and the tablet matrix in enteric-coated formulations for colon-specific drug delivery.

Colon-specific drug-delivery systems have been extensively investigated over the last decade. The aim of the study reported here was to investigate whether times of commencement of drug liberation and absorption could be controlled by varying the amount of citric acid in granule cores or in the tablet matrix in enteric-coated multiple-unit tablets. One of the most important aims was to determine the optimal amounts and locations of citric acid in formulations intended as drugs targeted at the colon. Ibuprofen was used as the model drug. Drug release rates were studied in phosphate buffer at pH 6.8 and 7.4. A gradient dissolution study at pH 1.2, 6.8 and 7.4 was undertaken with two formulations. Drug absorption was studied by means of bioavailability tests. We concluded that the drug release rate could be controlled in vitro by changing the amount of citric acid in granule cores or the tablet matrix. In vivo tests confirmed that between 10 and 15% citric acid in the tablet matrix delayed the commencement of drug absorption most. This kind of formulations could be suitable for preparation of colon-specific dosage forms. It is probably unnecessary to include citric acid in granule cores. No logical correlation between in vitro and in vivo results was obtained.

Time-controlled release pseudoephedrine tablets: bioavailability and in vitro/in vivo correlations.

In chronopharmacotherapy, circadian changes in disease symptoms are taken into account. Press-coated, time-controlled release tablets containing pseudoephedrine hydrochloride as a model drug have been formulated and the suitability of this highly soluble drug in relation to the new drug delivery system was evaluated. Hydroxypropylmethylcellulose was used in the coat of the tablet to adjust drug release. If such a formulation was administered in the evening it would have maximal effect in the early morning, and would be useful for the treatment of nocturnal symptoms. Two cross-over, single-dose bioavailability studies were carried out on eight healthy volunteers. A dissolution test method was developed to establish level A and level C in vitro/in vivo correlation for four formulations. With a low viscosity grade of polymer, peak concentrations were achieved after five hours. The drug was absorbed much more slowly from tablets containing a high viscosity grade polymer, with a plasma peak at ten hours. For further development of the drug delivery system described, a dissolution test method at pH 7.2 at a rotation speed of 150 min-1 is recommended on the basis of level A in vitro/in vivo correlation.

Is one paracetamol suppository of 1000 mg bioequivalent with two suppositories of 500 mg.

A common belief is that one tablet or suppository containing, e.g. 100 mg of a drug can be substituted, without any changes in the therapeutic effect, with two units of the same brand containing 50 mg of the drug. In the present study a single dose of paracetamol was administered to healthy volunteers as (a) two tablets of 500 mg, (b) two suppositories of 500 mg, and (c) one suppository of 1000 mg. There were statistically significant differences in all bioavailability parameters (t(max), C(max) and AUC) between the three treatments. The relative bioavailability of the 500 mg suppositories was 77% and that of the 1000 mg suppositories 66%. The absorption rate from suppositories was markedly lower than from the tablets. Especially low absorption rate was obtained with the suppository of 1000 mg. The two strengths, although having the same trade name, were not therefore bioequivalent.

Biopharmaceutical evaluation of time-controlled press-coated tablets containing polymers to adjust drug release.

This paper deals with press-coated modified release tablets in which the drug dose is situated in the core or is divided between the core and the coat. The coat contains polymer (sodium alginate or hydroxypropylmethyl cellulose, HPMC) to control drug release. The main objective was to investigate how the pharmacokinetic profile of the model drug could be modified by altering the proportion of the drug between the core and the coat. The effect of the amount of the polymer in the coat was also studied. Bioavailability tests were carried out on healthy volunteers. In the absorption curves of the tablets containing 50%, 67% and 80% of the drug in the core and 180 mg HPMC in the coat a bimodal profile was observed. No bimodal release pattern in the in vitro dissolution studies was found. If the whole dose was incorporated in the core the absorption curve has only one clear t(max) value at about 10 h. Doubling the amount of HPMC in the coat dramatically decreased drug absorption. It was concluded that, if a slightly reduced t(max)-value was required, the viscosity grade of HPMC used should be lowered.

Effects of pH regulators used as additives on the bioavailability of ibuprofen from hard gelatin capsules.

In our previous study the reasons for fast absorption of ibuprofen from sodium bicarbonate based hard gelatin capsules stayed unclear. These were not investigated using pH regulators (aluminium hydroxide, calcium carbonate, tartaric acid) with different chemical and physical properties. Ibuprofen absorption was much slower with aluminium hydroxide capsules (MRT 5.3, Tmax 3.1 h, Cmax 25.6 mg l-1, lag time 37.5 min) than with sodium bicarbonate capsules of the previous study (MRT 2.6 h, tmax 0.4 h, Cmax 51.4 mg l-1), lag time 0 min). The corresponding values for calcium carbonate and tartaric acid capsules were: MRT 3.7 h and 3.9 h, Tmax 1.7 h and 2.0 h, Cmax 32.2 mg l-1 and 30.8 mg l-1 and lag time 3.1 min and 7.6 min. No differences were noted in the AUC values. A rank order correlation existed between dissolution parameters and the in vivo parameters reflecting the rate of bioavailability. It was concluded that the rapid absorption of ibuprofen from capsules containing sodium carbonate is due to enhanced in vivo disintegration of the capsule, enhanced in vivo dissolution of the drug and enhanced gastric emptying rate.