Are European marketed acyclovir 5% cream products similar? Comparison with EU and US reference product.

OBJECTIVE: The aim was to perform a comparative evaluation of composition and in vitro release performance of multisource acyclovir 5% creams. SIGNIFICANCE: The outcome was analyzed in relation with the principles of the Topical drug Classification System (TCS). METHODS: The in vitro drug release testing (IVRT) was based on selection of an inert artificial membrane and a medium providing sink conditions, and utilizing the vertical diffusion cells. US and European innovator products, with marked difference in excipients, were used as references for the assessment of the in vitro release similarity. The qualitative composition of the topical semisolid products was inventoried, with no quantitative details being available. A Principal Component Analysis was applied by either dichotomy ranking or grouping the individual excipients into categories according to their functional role. RESULTS: The results confirmed the sensitivity and discriminative characteristics of IVRT with respect to the qualitative composition, as well as its relevance in the comparative assessment of multisource drug products beyond the current strict requirements of Q1 and Q2 similarity. CONCLUSIONS: This is in line with the principles of the TCS and with the central role assigned to IVRT.

Rheological and in vitro release measurements of manufactured acyclovir 5% creams: confirming sensitivity of the in vitro release.

Previous evaluation of marketed acyclovir 5% creams using in vitro release testing (IVRT) and its correlation with the qualitative composition confirmed the discriminative characteristics of this methodology. This was in line with the principles of Topical drug Classification System (TCS). For the current research, experimental formulations were designed and prepared by applying controlled changes in manufacturing process, sources of raw materials, and amount of the excipients. The topical semisolids were representative for the four classes of TCS. The outcome of the IVRT and rheological assessments was evaluated in relation with the nature of the change and the functional role of the excipients. The variations in propylene glycol content from 5% to 40% impacted both the in vitro release rates (gradual decrease from 16.23 to 8.97 µg/cm2/min0.5) and the microstructural characteristics (proportional increase of yield stress from 17.98 to 46.40 Pa). The inert excipients e.g. cetostearyl alcohol or white soft paraffin altered majorly the rheological behavior, as their functionality is mainly related to vehicle properties. IVRT was discriminative for the microstructural differences induced by both categories of excipients according to TCS dichotomy. This simple, reliable, and reproducible test reflected the impact of difference in quantitative composition and characteristics of excipients.

Commonality between BCS and TCS.

Both biopharmaceutics classification system (BCS) and topical drug classification system (TCS) are based on sound scientific principles with the aim of providing biowaiver and reducing regulatory burden without lowering the quality requirements and standards of approval for the drug products. BCS is based on the solubility and permeability properties of the active pharmaceutical ingredient (API, or drug substance) whereas the TCS is based on the qualitative and quantitative composition of the dosage form and the in vitro release rate of the active ingredient as key decision tools. Both BCS and TCS take drug release and dissolution as their guiding principle for providing biowaiver, increasing the availability and affordability of safe and effective medicines to the consumers and at the same time maintaining the drug product quality.

The forgotten or underestimated relevance of biopharmaceutical-based assessments for the oral absorption studies of oxime reactivators.

INTRODUCTION: The absorption, distribution, metabolism, excretion and toxicity (ADME(T)) of oxime reactivators have been assessed with respect to their polarity, a fundamental requirement for their specific mechanism of action in the intoxication with organophosphorous compounds. The limitations of the therapeutic outcome have been associated not only with the severity of intoxication and to particularities of the toxicants, but also to the reduced lipophilicity and consequent restricted permeability across biological barriers. AREAS COVERED: This article inventories the plethora of mnemotic rules developed throughout the years for defining chemical spaces where drugs share one or more structural and ADME(T) characteristics. Their applicability to oxime is analyzed, especially in relation to intestinal absorption and brain distribution. Other aspects of oximes for antidotal outcome are also reviewed. EXPERT OPINION: The drugability rules are not applicable to oxime reactivators, because the increase in lipophicity and consequent improved permeability across biological barrier comes together with amplified (neuro)toxicity and reduced reactivating capacity. The available data suggest a high solubility and reduced metabolism, assigning the quaternary oximes to the fourth class of Biopharmaceutical Classification Systems. Reliance upon oral absorption data for designing safe centrally acting oximes can be of potential value, with adequate characterization of uptake-influx transporters interplay.

A science based approach to topical drug classification system (TCS).

The Biopharmaceutics Classification System (BCS) for oral immediate release solid drug products has been very successful; its implementation in drug industry and regulatory approval has shown significant progress. This has been the case primarily because BCS was developed using sound scientific judgment. Following the success of BCS, we have considered the topical drug products for similar classification system based on sound scientific principles. In USA, most of the generic topical drug products have qualitatively (Q1) and quantitatively (Q2) same excipients as the reference listed drug (RLD). The applications of in vitro release (IVR) and in vitro characterization are considered for a range of dosage forms (suspensions, creams, ointments and gels) of differing strengths. We advance a Topical Drug Classification System (TCS) based on a consideration of Q1, Q2 as well as the arrangement of matter and microstructure of topical formulations (Q3). Four distinct classes are presented for the various scenarios that may arise and depending on whether biowaiver can be granted or not.

In vitro and in vivo evaluation of three metronidazole topical products.

Two 1% and one 0.75% metronidazole cream products were approved as bioequivalent products. These products were evaluated for their in vivo cutaneous penetration characteristics by dermatopharmacokinetic (DPK) and dermal microdialysis (DMD) sampling methodologies. The same three products were also evaluated for their rheological and in vitro drug release (IVR) properties. Structural differences were observed in the resulting flow curves. However, similar IVR profiles were obtained for the two topical semisolid dosage forms containing 1% metronidazole. For the lower strength product, a higher IVR rate was associated with the lower DPK profile. All three products exhibited similar values of area under the curve when investigated by DMD. This in vitro evaluation corroborated the divergent penetration characteristics found using in vivo methodologies.

New insights on the consequences of biotransformation processes on the distribution and pharmacodynamic profiles of some neuropsychotropic drugs.

The metabolic processes frequently trigger highly complex pharmacokinetic (PK) and pharmacodynamic (PD) characteristics for the coexisting entities, parent drug and its active or inactive metabolites. The interpretation of both individual and cumulative profiles, frequently used in the therapeutic drug monitoring procedures, must take into consideration the biological coherence of the changes of the molecular descriptors characterizing the metabolites versus the parent drugs, and further qualitative and quantitative consequences on permeability processes across highly specialized biological barriers (e.g. blood-brain barrier [BBB]). This paper analyzes the correlation of molecular descriptor differences and the PK/PD consequences for three representative psychotropic drugs (risperidone, clozapine and tramadol) and their active metabolites, underlying the safety and efficacy concerns of using the products of metabolic processes as potential new drugs. The minimal structural changes are correlated with the predicted or experimental penetrability across the biological membranes, with a special emphasis on BBB penetration, as the limiting phase for the effect at central nervous system level. The PD characteristics related to the active metabolites are compared to the ones reported for the parent drugs, concerning mainly the affinity for cerebral receptors and the type of activity at a specific level. For the neuropsychotropic substances, with BBB penetrability as a sine qua non condition, the comparative analysis of PK/PD properties for the parent drug and its metabolites generates a complete and highly complex image of the consequences of their coexistence, since these entities must be conceived and analyzed not separately, but by inclusion of usually complementary properties generating a unique therapeutic profile.

Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review.

Undoubtedly, the use of oximes represents real progress in counteracting intoxications with organophosphates (OP), through potentiating antidotal effects of atropine. The penetration extent of these compounds through the blood-brain barrier (BBB) to significantly reactivate phosphorylated or phosphonylated acetylcholinesterase (AChE) in the brain still remains a debatable issue. Penetration of biological barriers by oximes was investigated mainly through determination of several quantitative parameters characterizing digestive absorption and BBB penetration. A weak penetration of biological barriers could be concluded from the available experimental data. The functional parameters/therapeutic effects following the penetration of oximes through BBB, more precisely the antagonism of OP-induced seizures and hypothermia, prevention of brain damage and respiratory center protection, leading to the final end-point, the survival of intoxicated organisms, are of high interest. It seems obvious that oximes are weakly penetrating the BBB, with minimal brain AChE reactivation (<5%) in important functional areas, such as the ponto-medullar. The cerebral protection achieved through administration of oximes is only partial, without major impact on the antagonism of OP-induced seizures, hypothermia and respiratory center inhibition. The antidotal effects probably result from synergic effects of other PD properties, different from the brain AChE reactivation process. Oxime structures especially designed for enhanced BBB penetration, through potentiating the hydrophobic characteristics, more often produce neurotoxic effects. Certainly, obtaining oximes with broad action spectrum (active against all OP types) would make a sense, but certainly, such a target is not achievable only through the increase in their penetrability in the brain.

The toxicokinetics and toxicodynamics of organophosphonates versus the pharmacokinetics and pharmacodynamics of oxime antidotes: biological consequences.

This paper presents basic data on organophosphonate (OP) mechanisms of action, especially by toxicokinetic/toxicodynamic (TK/TD) process correlations. It is generally accepted that at least during onset of OP biological systems interaction, blood and tissue cholinesterase's inhibition represents OP exposure marker and initiating mechanisms for toxicodynamic effects, characteristic for cholinergic crisis. OP penetrability of various biological barriers conditioning TK characteristics are determined by a series of physico-chemical properties. Non-cholinergic effects, direct interactions with cellular structures and subsequent effects (excitotoxicity) triggered by cholinergic crisis are also briefly presented. Opposed to these OP TK/TD characteristics, the authors analysed the pharmacokinetic/pharmacodynamic (PK/PD) characteristics and their correlations for oximes, as basic OP antidotes, besides atropine and anticonvulsants. Phosphorilated cholinesterasis reactivators are mono or bispyridinium derivatives with quaternary ammonium atoms, high water solubility, ionized at physiological pH, distribution in extra-cellular space, very low digestive absorption and blood-brain barrier (BBB) penetrability. OP nerve gas acute toxicity is correlated with anti-acetylcholinesterase (AChE) activity and partition coefficient. The toxicity rank seems to be determined by lipophilicity, besides their specific AChE inhibitory property. It has the effect that acute toxicity is the resultant of a TD process closely linked and dependent in vivo upon molecular descriptors determinant for the TK process. For cholinesterasis reactivators, molecular and PK characteristics limit their effects, especially to the peripheral level. The absent or much reduced BBB penetrability allowed some researchers to suggest that reactivators' penetration and presence at central level are not necessary. The study of PK/PD correlations, molecular descriptors and biological membrane permeability of oximes can better define their antidotal effects mechanisms and, maybe, open a new perspective for field development.