Clinical Relevance of Dissolution Testing in Quality by Design

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound

Characterization of NF-κB reporter U937 cells and their application for the detection of inflammatory immune-complexes

Our study tested the hypothesis that immunoglobulins differ in their ability to activate the nuclear factor-κB pathway mediated cellular responses. These responses are modulated by several properties of the immune complex, including the ratio of antibody isotypes binding to antigen. Immunoassays allow the measurement of antigen specific antibodies belonging to distinct immunoglobulin classes and subclasses but not the net biological effect of the combination of these antibodies. We set out to develop a biosensor that is suitable for the detection and characterization of antigen specific serum antibodies. We genetically modified the monocytoid U937 cell line carrying Fc receptors with a plasmid encoding NF-κB promoter-driven GFP. This clone, U937-NF-κB, was characterized with respect to FcR expression and response to solid-phase immunoglobulins. Human IgG3, IgG4 and IgG1 induced GFP production in a time- and dose-dependent manner, in this order of efficacy, while IgG2 triggered no activation at the concentrations tested. IgA elicited no response alone but showed significant synergism with IgG3 and IgG4. We confirmed the importance of activation via FcγRI by direct stimulation with monoclonal antibody and by competition assays. We used citrullinated peptides and serum from rheumatoid arthritis patients to generate immune complexes and to study the activation of U937-NF-κB, observing again a synergistic effect between IgG and IgA. Our results show that immunoglobulins have distinct pro-inflammatory potential, and that U937-NF-κB is suitable for the estimation of biological effects of immune-complexes, offering insight into monocyte activation and pathogenesis of antibody mediated diseases

Novi kopolimerni zwitterionski matriksi za polagano oslobađanje verapamil hidroklorida

Stable co-polymer [vinyl acetate-co-3-dimethyl(methacryloyloxyethyl)ammonium propane sulfоnate, p(VA-co-DMAPS)] latex of different compositions has been synthesized for the first time by emulsifier-free emulsion copolymerization. The unusual “overshooting” behavior of the co-polymer tablets has been explained by the formation of specific clusters from the opposite oriented dipoles zwitterionic species. The change of their concentration with the DMAPS unit fraction (mDMAPS), pH and ionic strength has been considered responsible for the differences observed in the swelling kinetics. The results obtained prove that mDMAPS and ionic strength could be used to control the swelling degree of the p(VA-co-DMAPS) matrices. In this way, p(VA-co-DMAPS) matrices could be effectively used to control the sustained release of drugs with basic properties like verapamil hydrochloride from model tablets.Metodom emulzijske polimerizacije sintetiziran je novi stabilni kopolimer [vinil acetat-ko-3-dimetil(metakriloiloksietill)amonijev propan sulfоnat, p(VA-co-DMAPS)] lateks promjenjivog sastava. Neobično “overshooting” ponašanje tableta pripravljenih iz tog kopolimera objašnjava se stvaranjem specifičnih klastera suprotno rijentiranih dipola zwitterionskih specija. Proučavan je utjecaj udjela DMAPS jedinica (mDMAPS), pH i ionske jakosti na kinetiku bubrenja. Dobiveni rezultati dokazuju da se promjenom mDMAPS i ionske jakosti može kontrolirati stupanj bubrenja p(VA-co-DMAPS) matriksa i oslobađanje verapamil hidroklorida iz tableta pa se ti matriksi mogu upotrijebiti za polagano oslobađanje bazičnih lijekova srodnih verapamilu

Nep en namaak Viagra en Cialis tabletten: trends en risico's voor de volksgezondheid - Een overzicht van de analyses uitgevoerd bij het Rijksinstituut voor Volksgezondheid en Milieu in de periode 2000 - 2004

During the last years de Dutch market has been flooded with falsifications of Viagra. and Cialis.. Both products are used for the treatment of erectile dysfunction. This report is about the trend of these falsifications during the years 2000 - 2004. The risks of these products to public health are surveyed and also described. The following conclusions are drawn: There is a trend towards products containing other active compounds than sildenafil and tadalafil, the compounds of Viagra. and Cialis.. There is a trend towards the addition of (unknown) active compounds to herbal products. Falsifications are a risk to public health: they are produced without adequate quality control; they mislead the users concerning manufacturer and composition. The risk to public health is much higher if unknown, chemical compounds are added to herbal products. The effects and side effects of these compounds are unknown. Besides, herbal products are often considered to be natural and therefore harmless. In order to detect trends and new risks in the future, an ongoing survey of the legal and illegal market by analysing samples is needed. The trend analysis and risk survey are based on the analytical results of about 400 samples. These samples were sent in by governmental inspectorates for chemical analysis. The samples give an insight into the developments of the illegal market. However, they may not be representative for the market supply.De Nederlandse markt is de afgelopen jaren overspoeld met vervalsingen van Viagra. en Cialis. Beide producten worden gebruikt voor de behandeling van erectiestoornissen. Dit rapport gaat over een trendanalyse van deze vervalsingen over de jaren 2000 - 2004. Ook de risico's van deze producten voor de volksgezondheid zijn geinventariseerd en beschreven. De volgende conclusies zijn getrokken: Er is een trend naar producten, die andere actieve verbindingen bevatten dan sildenafil en tadalafil (de verbindingen, die in Viagra en Cialis zitten). Er is een trend naar het toevoegen van (onbekende) actieve verbindingen aan kruidenproducten. Vervalsingen zijn een risico voor de volksgezondheid: ze worden geproduceerd zonder adequate kwaliteitscontrole; ze misleiden de gebruiker wat betreft de fabrikant en de samenstelling. Het risico voor de volksgezondheid is veel groter als er onbekende, chemische verbindingen aan kruidenproducten worden toegevoegd. Van deze verbindingen zijn de werking en bijwerking niet bekend. Bovendien worden kruidenproducten vaak gezien als natuurlijk en dus ongevaarlijk. Om in de toekomst trends en nieuwe risico's te kunnen vaststellen moeten de legale en illegale markt voortdurend gevolgd worden door monsters te analyseren. De trendanalyse en de risico-inventarisatie zijn gebaseerd op de analyseresultaten van circa 400 monsters. Deze monsters zijn door de overheidsinspecties ingezonden voor chemische analyse. De monsters geven inzicht in de ontwikkelingen van de illegale markt, maar zijn daar mogelijk geen representatieve afspiegeling van

Humaniteit en doelmatigheid in de zorg: twee kanten van dezelfde medaille?

Dag in, dag uit verlenen artsen, verpleegkundigen, mantelzorgers en vrijwilligers geweldige zorg. Ook ontstonden er de afgelopen jaren prachtige initiatieven om de zorg te verbeteren. Tegelijkertijd bestaat er bij veel zorgverleners en patiënten frustratie en onbegrip over het zorgbeleid van verschillende overheden. Deze bekijken de zorg eenzijdig als kostenpost. Hun relatie met partijen in de zorg verandert in een machtsstrijd die gewonnen moet worden. Dit roept veel weerstand op, verspilt energie, ontmoedigt en remt de positieve ontwikkelingen. Het alternatief voor de zorg legt die twee werelden naast elkaar en bepleit een perestrojka voor de zorg. Het doet een klemmende oproep aan de overheden en alle partijen in de zorg om de blik op zorg te verbreden en zich te richten op het ontketenen en faciliteren van de overvloedig aanwezige positieve krachten. Het alternatief voor de zorg dient zich immers allang aan. Het boek eindigt met richtinggevend manifest: ‘Beroepseer + zorg op maat = het alternatief’

Nep en namaak Viagra en Cialis tabletten: trends en risico's voor de volksgezondheid - Een overzicht van de analyses uitgevoerd bij het Rijksinstituut voor Volksgezondheid en Milieu in de periode 2000 - 2004

De Nederlandse markt is de afgelopen jaren overspoeld met vervalsingen van Viagra. en Cialis. Beide producten worden gebruikt voor de behandeling van erectiestoornissen. Dit rapport gaat over een trendanalyse van deze vervalsingen over de jaren 2000 - 2004. Ook de risico's van deze producten voor de volksgezondheid zijn geinventariseerd en beschreven. De volgende conclusies zijn getrokken: Er is een trend naar producten, die andere actieve verbindingen bevatten dan sildenafil en tadalafil (de verbindingen, die in Viagra en Cialis zitten). Er is een trend naar het toevoegen van (onbekende) actieve verbindingen aan kruidenproducten. Vervalsingen zijn een risico voor de volksgezondheid: ze worden geproduceerd zonder adequate kwaliteitscontrole; ze misleiden de gebruiker wat betreft de fabrikant en de samenstelling. Het risico voor de volksgezondheid is veel groter als er onbekende, chemische verbindingen aan kruidenproducten worden toegevoegd. Van deze verbindingen zijn de werking en bijwerking niet bekend. Bovendien worden kruidenproducten vaak gezien als natuurlijk en dus ongevaarlijk. Om in de toekomst trends en nieuwe risico's te kunnen vaststellen moeten de legale en illegale markt voortdurend gevolgd worden door monsters te analyseren. De trendanalyse en de risico-inventarisatie zijn gebaseerd op de analyseresultaten van circa 400 monsters. Deze monsters zijn door de overheidsinspecties ingezonden voor chemische analyse. De monsters geven inzicht in de ontwikkelingen van de illegale markt, maar zijn daar mogelijk geen representatieve afspiegeling van.During the last years de Dutch market has been flooded with falsifications of Viagra. and Cialis.. Both products are used for the treatment of erectile dysfunction. This report is about the trend of these falsifications during the years 2000 - 2004. The risks of these products to public health are surveyed and also described. The following conclusions are drawn: There is a trend towards products containing other active compounds than sildenafil and tadalafil, the compounds of Viagra. and Cialis.. There is a trend towards the addition of (unknown) active compounds to herbal products. Falsifications are a risk to public health: they are produced without adequate quality control; they mislead the users concerning manufacturer and composition. The risk to public health is much higher if unknown, chemical compounds are added to herbal products. The effects and side effects of these compounds are unknown. Besides, herbal products are often considered to be natural and therefore harmless. In order to detect trends and new risks in the future, an ongoing survey of the legal and illegal market by analysing samples is needed. The trend analysis and risk survey are based on the analytical results of about 400 samples. These samples were sent in by governmental inspectorates for chemical analysis. The samples give an insight into the developments of the illegal market. However, they may not be representative for the market supply.IG

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol.

Literature data related to the Biopharmaceutics Classification System (BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, and atenolol in the form of BCS-monographs. Data on the qualitative composition of immediate release (IR) tablets containing these active substances with a Marketing Authorization (MA) in the Netherlands (NL) are also provided; in view of these MA's the assumption was made that these tablets were bioequivalent to the innovator product. The development of a database with BCS-related data is announced by the International Pharmaceutical Federation (FIP)

Disintegration of Highly Soluble Immediate Release Tablets: A Surrogate for Dissolution

The purpose of the work was to investigate correlation between disintegration and dissolution for immediate release tablets containing a high solubility drug and to identify formulations where disintegration test, instead of the dissolution test, may be used as the acceptance criteria based on International Conference on Harmonization Q6A guidelines. A statistical design of experiments was used to study the effect of filler, binder, disintegrating agent, and tablet hardness on the disintegration and dissolution of verapamil hydrochloride tablets. All formulation variables, i.e., filler, binder, and disintegrating agent, were found to influence tablet dissolution and disintegration, with the filler and disintegrating agent exerting the most significant influence. Slower dissolution was observed with increasing disintegration time when either the filler or the disintegrating agent was kept constant. However, no direct corelationship was observed between the disintegration and dissolution across all formulations due to the interactions between different formulation components. Although all tablets containing sodium carboxymethyl cellulose as the disintegrating agent, disintegrated in less than 3 min, half of them failed to meet the US Pharmacopeia 30 dissolution criteria for the verapamil hydrochloride tablets highlighting the dependence of dissolution process on the formulation components other than the disintegrating agent. The results identified only one formulation as suitable for using the disintegration test, instead of the dissolution test, as drug product acceptance criteria and highlight the need for systematic studies before using the disintegration test, instead of the dissolution test as the drug acceptance criteria