Leakage of enteric (Eudragit L)-coated dosage forms in simulated gastric juice in the presence of poly(ethylene glycol).

Poly(methacrylic acid) (PMAA) and related copolymers strongly interact with poly(ethylene glycol) (PEG) in acidic fluids. Due to the in vitro experiments presented in this paper, there is a clear indication for a drug-drug interaction in vivo between PEG solutions, e.g., commercially available laxatives, and dosage forms with PMAA-based enteric-coatings (Eudragit L). In these studies, enteric-coated tablets did not fulfil the pharmacopoeias' criteria of the disintegration test if PEGs were present in the simulated gastric juice. Drug substances which are known to be unstable in acidic media or which can cause gastric irritation were released from their enteric-coated dosage forms in acidic PEG media (pH 1). Various drug dosage forms, single and multiple unit systems, were tested. They show higher and faster drug release in the presence of PEG. To get insight into the mechanism of the interaction, experiments and theoretical calculations were performed which reveal that PEGs with high molecular weight show stronger interactions with PMAA coatings indicating a contribution of hydrophobic interactions to the occurring intermolecular forces. Hydrogen bonds can be build between each monomeric unit of PEG and the acidic sequences of the copolymer.

Physico-chemical interactions between extracts of Hypericum perforatum L. and drugs.

The aim of the present study was to investigate physico-chemical interactions between extracts of Hypericum perforatum L. and drugs. The formation of nanoparticles, microparticles and precipitates in aqueous drug-free and drug-containing preparations of H. perforatum L. was investigated. In aqueous infusions of Hyperici herba only small amounts of nano- and microparticles were observed using photon correlation spectroscopy and scanning electron microscopy. In the presence of promethazine nanoparticles are formed. Between 20.3 and 5.3% of the drug is bound to nanoparticles. Maximally 4.3% of the drug is associated with precipitates. Warfarin has a negligible effect on the particle formation in aqueous infusions of Hyperici herba. In further studies dry extracts of H. perforatum were reconstituted in water. Nanoparticles and precipitates are formed in the drug-free preparations. Scanning electron micrographs show almost spherical nanoparticles with a mean diameter between 100 and 300 nm. After addition of promethazine a precipitate is formed. Maximally 12.8% of the drug is associated with the precipitate. In warfarin-containing reconstituted extracts, nano- and microparticles as well as precipitates are observed. The amount of free warfarin in solution is reduced by 36.6% maximally. A loss of the anticoagulant effect which is described in the literature may partly be caused by particle formation.

Determination of the disintegration behavior of magnetically marked tablets.

The disintegration behavior of different tablets that were marked as magnetic dipoles by the incorporation of ferromagnetic black iron oxide and subsequent magnetization was studied using a specially developed measurement setup. This novel apparatus records the magnetic induction generated by the magnetic dipole moment of the tablets during their disintegration. It was found that the observed decrease of the magnetic induction can be used for a quantitative determination of the disintegration of tablets. In particular, it could be shown that the magnetic data provide information about the disintegration mechanism. For tablets with a minor influence of swelling on the disintegration mechanism a linear decline of the magnetic fluxes was observed. After addition of swelling disintegrants (crospovidone) the decline of the magnetic flux could be fitted by an exponential function, indicating the involvement of a disintegration force. Furthermore, the data demonstrate that using modern multichannel biomagnetic measurement equipment the monitoring of the disintegration behavior of magnetically marked tablets in humans will be possible.

Magnetic marker monitoring of disintegrating capsules.

Magnetic marker monitoring was studied for its applicability to investigate the in vivo fate and behavior of disintegrating magnetically marked dosage forms. As a model, hard gelatin capsules were filled with an effervescent mixture of lactose, ascorbic acid and sodium hydrogen carbonate containing 1.3 mg black iron oxide as a magnetic label. The accuracy of the localization procedure whilst calculating all parameters of the dipole in one fitting procedure was checked in phantom experiments where the capsules were moved in well-defined paths with respect to the measurement device. The calculated position coordinates of the capsules deviated between less than 2 mm up to 8 mm from the expected position values depending on the distance between the sensor area and the capsule's path. Further experiments on the in vitro disintegration of the capsules showed that the value of the magnetic moment of the capsules can serve as a measure for their disintegration behavior. In vivo monitoring of the capsules was performed in eight experiments where a healthy volunteer swallowed each time one of the capsules. It was found that the in vivo disintegration behavior of the capsules corresponds well to their disintegration observed in water of about 37 degrees C.

Nanoparticles in plant extracts--factors which influence the formation of nanoparticles in black tea infusions.

The influence of different factors on the formation of nanoparticles in freshly brewed tea extracts was investigated. A black tea infusion was observed during cooling using photon correlation spectroscopy (PCS). The mean particle size and the number of the nanoparticles increase with decreasing temperature. In the presence of caffeine more particles are formed within the infusion. To study the influence of slight structural differences between methylxanthines, the effect of the addition of caffeine to solutions of freshly prepared decaffeinated tea was compared to that of theophylline and theobromine. In the case of theophylline fewer nanoparticles were formed. Molecular modelling calculations were performed to evaluate the most probable geometries for caffeine-polyphenol complexes. A parallel position and a congruent orientation of the 6-membered ring of caffeine and the aromatic galloyl group is the most probable geometry.

Lean production of taste improved lipidic sodium benzoate formulations.

Sodium benzoate is a highly soluble orphan drug with unpleasant taste and high daily dose. The aim of this study was to develop a child appropriate, individually dosable, and taste masked dosage form utilizing lipids in melt granulation process and tableting. A saliva resistant coated lipid granule produced by extrusion served as reference product. Low melting hard fat was found to be appropriate as lipid binder in high-shear granulation. The resulting granules were compressed to minitablets without addition of other excipients. Compression to 2mm minitablets decreased the dissolved API amount within the first 2 min of dissolution from 33% to 23%. The Euclidean distances, calculated from electronic tongue measurements, were reduced, indicating an improved taste. The reference product showed a lag time in dissolution, which is desirable for taste masking. Although a lag time was not achieved for the lipidic minitablets, drug release in various food materials was reduced to 2%, assuming a suitable taste masking for oral sodium benzoate administration.

Lipid-based intravesical drug delivery systems with controlled release of trospium chloride for the urinary bladder.

The overactive bladder (OAB) is a common disease with an overactivity of the detrusor muscle in the bladder wall. Besides peroral administration of anticholinergic drugs and bladder irrigations, there is a need for a sustained release formulation in the urinary bladder. In order to realise a local long-term treatment of the overactive urinary bladder, lipidic drug delivery systems were prepared. Requirements for an intravesical application are a long-term controlled release of trospium chloride, a high drug loading and small sized drug carriers to permit an insertion through the urethra into the urinary bladder. The drug delivery systems were manufactured by using compression (mini-tablets), solid lipid extrusion (extrudates) and a melting and casting technique (mini-moulds) with different amounts of trospium chloride and glyceryl tristearate as matrix former. Drug release depended on the drug loading and the preparation method. Mini-tablets and lipidic extrudates showed a drug release over five days, whereas that from mini-moulds was negligibly small. The appearance of polymorphic transformations during processing and storage was investigated by using differential scanning calorimetry and X-ray diffraction. In contrast to mini-tablets and mini-moulds, lipidic extrudates showed no polymorphic transformations. In summary, lipids are suitable matrix formers for a highly water-soluble drug, like trospium chloride. Despite a drug loading of up to 30%, it was feasible to achieve a drug release ranging from several days up to weeks. In addition, small dosage forms with a size of only a few millimetres were realised. Therefore, an insertion and excretion through the urethra is possible and the requirements for an intravesical application are fulfilled.

Swallowing dysfunction and dysphagia is an unrecognized challenge for oral drug therapy.

There is evidence that swallowing issues and dysphagia are an increasing problem of the aging population in the coming decades that is affecting oral medication administration. There is a variety of clinical expressions of swallowing dysfunction caused by aging, acute or chronic disease conditions, decline in physiological functions and adverse drug reactions. About one third of patients in long term care facilities experience serious difficulties with swallowing solid oral dosage forms (SODF). Manipulations of the solid oral drug products occur frequently in nursery homes leading to medication errors and potential changes in drug product performance. The alteration of the drug products is performed with the best intention of the care giver to help the patients but bears concerns about safety and lawfulness. Alternative SODF and drug delivery technologies should be considered in the development of new and generic products and their prescription to overcome medication administration problems in patients with swallowing difficulties of SODF.

Orally disintegrating mini-tablets (ODMTs)--a novel solid oral dosage form for paediatric use.

The new European regulations on paediatric medicines and recent WHO recommendations have induced an increased need for research into novel child-appropriate dosage forms. The aim of this study was the development of orally disintegrating mini-tablets (ODMTs) as a suitable dosage form for paediatric patients. The suitability of five commercially available ready-to-use tableting excipients, Ludiflash, Parteck ODT, Pearlitol Flash, Pharmaburst 500 and Prosolv ODT, to be directly compressed into mini-tablets, with 2 mm in diameter, was examined. All of the excipients are based on co-processed mannitol. Drug-free ODMTs and ODMTs with a child-appropriate dose of hydrochlorothiazide were investigated. ODMTs could be produced with all investigated excipients. ODMTs with a sufficient crushing strength >7 N and a low friability <1% could be obtained, as well as ODMTs with a short simulated wetting test-time <5 s. ODMTs made of Ludiflash showed the best results with crushing strengths from 7.8 N up to 11.8 N and excellent simulated wetting test-times from 3.1 s to 5.0 s. For each excipient, ODMTs with accordance to the pharmacopoeial specification content uniformity could be obtained. The promising results indicate that orally disintegrating mini-tablets may serve as a novel platform technology for paediatrics in future.

Prediction of intestinal drug absorption properties by three-dimensional solubility parameters.

PURPOSE: The purpose of this study was to investigate the use of solubility parameters for the prediction of gastrointestinal absorption sites and absorption durations of drugs. METHODS: Three-dimensional solubility parameters of drug substances were calculated using an advanced parameter set based on the group contribution methods of Fedors and Van Krevelen/Hoftyzer. The results of the calculations were illustrated via Bagley diagram and related to absorption data reported in the literature. RESULTS: Solubility parameters of drugs which are known to be absorbed over a long period in human's digestive tract were found in a limited area within the Bagley diagram. From the three-dimensional solubility parameters of these substances, a region for optimal absorption with the centre coordinates delta(v)=20.3 (J x cm(-3))(0.5) and delta(h)=11.3 (J x cm(-3))(0.5) could be derived. Drugs with absorption sites along the whole gastrointestinal tract were found in this area. Drugs which are preferably absorbed from upper parts of the intestine are located in another typical region with partial solubility parameters delta(h) of more than 17 (J x cm(-3))(0.5). CONCLUSIONS: The method which is presented in this paper appears as a simple but effective method to estimate the absorption behaviour of new substances in drug research and development.

Interactions between aqueous Hypericum perforatum extracts and drugs: in vitro studies.

Physico-chemical interactions between drugs and plant extracts can result in the formation of nanoparticles, microparticles and precipitates. The extraction method may have an influence on the components of the plant preparations and the interactions between drugs and plant extracts. In this study the particle formation in different drug-containing preparations of Hypericum perforatum L. was compared. The formation of nanoparticles was investigated by PCS and scanning electron microscopy. Precipitates were separated from nanoparticles by centrifugation or filtration. The particle formation in drug-containing infusions and reconstituted methanolic extracts of Hypericum perforatum L. was different. In reconstituted dry extracts 21.5% 17alpha-ethinylestradiol and 36.6% levonorgestrel was bound to precipitates, in aqueous Hypericum infusions less than 4% of the hormones was bound. In infusions containing desipramine nanoparticles were formed while the formation of nanoparticles in desipramine-containing reconstituted extracts was negligible. Up to 10% of desipramine was bound to precipitates in reconstituted extracts, but only 4% was associated with the precipitate of infusions. The interactions between extracts of Hypericum perforatum L. and drugs depended on the extraction method. Reconstituted methanolic extracts showed a more intensive binding with oral contraceptives than aqueous infusions.

Mechanistic study on the opposite migration order of clenbuterol enantiomers in capillary electrophoresis with beta-cyclodextrin and single-isomer heptakis(2,3-diacetyl-6-sulfo)-beta-cyclodextrin.

Opposite migration order was observed for the enantiomers of the chiral beta2-adrenergic drug clenbuterol (CL) in capillary electrophoresis (CE) when resolved with native beta-cyclodextrin (beta-CD) and heptakis (2,3-diacetyl-6-sulfo)-beta-CD (HDAS-beta-CD). The possible mechanisms of the affinity reversal of the CL enantiomers depending on the structure of the CD were studied using 1H-nuclear magnetic resonance (1H-NMR) spectrometry and one-dimensional rotating frame nuclear Overhauser and exchange spectrometry (1-D ROESY). Significant differences were observed between the structure of the (+/-)-CL complexes with beta-CD and HDAS-beta-CD.

Effect of organic solvent, electrolyte salt and a loading of cellulose tris (3,5-dichlorophenyl-carbamate) on silica gel on enantioseparation characteristics in capillary electrochromatography.

The effect of the amount of the chiral selector, cellulose tris(3,5-dichlorophenylcarbamate) (CDCPC) on the separation characteristics of enantiomers of some charged and neutral analytes was studied in capillary electrochromatography (CEC). For better understanding of the effect of the loading of the chiral selector on the particles and pore size of the packing material, laser-beam particle size analyzer and scanning electron microscopy (SEM) were used. As shown in this study, CDCPC can be used for CEC enantioseparations of a wide range of chiral charged and neutral analytes with high efficiency. The loading of the polysaccharide derivative on the surface of silica materials even in high amounts does not markedly affect the particle size and porous structure of the packing material. The separation characteristics are strongly affected by the loading of CDCPC onto silica gel in both CEC and capillary liquid chromatography (CLC).