In Vitro Methods for Evaluating Drug Release of Vaginal Ring Formulations-A Critical Review.

The vagina is a promising site for both local and systemic drug delivery and represents an interesting administration route for compounds with poor oral bioavailability. Whereas most of the currently marketed dosage forms were designed as immediate release formulations, intravaginal rings (IVRs) offer the possibility of a controlled vaginal drug delivery over several weeks or months. For a long time, the development of IVRs was limited to steroid-releasing formulations. Recently, IVRs have witnessed a surge of new interest as promising delivery systems for microbicides. Therefore, various novel IVR designs have been introduced. To ensure that only safe and effective IVRs will be administered to patients, it is important to properly distinguish between IVRs with desired and undesired release performance. In vitro methods for evaluating drug release of IVRs that present with sufficient predictive capacity for in vivo drug release, and discriminatory power with regard to IVRs quality, are an essential tool for this purpose. The objective of the present review article is to present the current status of in vitro drug release testing of IVRs and to critically discuss current compendial and non-official in vitro drug release methods with regard to their discriminatory power and in vivo predictivity.

Maize Inoculation with Microbial Consortia: Contrasting Effects on Rhizosphere Activities, Nutrient Acquisition and Early Growth in Different Soils.

The benefit of plant growth-promoting microorganisms (PGPMs) as plant inoculants is influenced by a wide range of environmental factors. Therefore, microbial consortia products (MCPs) based on multiple PGPM strains with complementary functions, have been proposed as superior, particularly under challenging environmental conditions and for restoration of beneficial microbial communities in disturbed soil environments. To test this hypothesis, the performance of a commercial MCP inoculant based on 22 PGPM strains was investigated in greenhouse experiments with maize on three soils with contrasting pH, organic matter content and microbial activity, under different P and N fertilization regimes. Interestingly, the MCP inoculant stimulated root and shoot growth and improved the acquisition of macronutrients only on a freshly collected field soil with high organic matter content, exclusively in combination with stabilized ammonium fertilization. This was associated with transiently increased expression of AuxIAA5 in the root tissue, a gene responsive to exogenous auxin supply, suggesting root growth promotion by microbial auxin production as a major mode of action of the MCP inoculant. High microbial activity was indicated by intense expression of soil enzyme activities involved in C, N and P cycling in the rhizosphere (cellulase, leucine peptidase, alkaline and acid phosphatases) but without MCP effects. By contrast, the MCP inoculation did not affect maize biomass production or nutrient acquisition on soils with very little Corg and low microbial activity, although moderate stimulation of rhizosphere enzymes involved in N and P cycling was recorded. There was also no indication for MCP-induced solubilization of Ca-phosphates on a calcareous sub-soil fertilized with rock-phosphate. The results demonstrate that the combination of multiple PGPM strains with complementary properties as MCP inoculants does not necessarily translate into plant benefits in challenging environments. Thus, a better understanding of the conditions determining successful MCP application is mandatory.

Predicting local drug availability of locally acting lozenges: From method design to a linear level A IVIVC.

Lozenges are commonly applied in the treatment of sore throat. They often contain drugs intended to exert their effect locally in the oral cavity and throat. In the recent past, an increasing interest in development of generic products for locally acting lozenges could be noted. However, it was not clear, if therapeutic equivalence of locally applied, locally acting lozenges can be predicted based on results from in vitro studies. The aim of the present study was to determine an in vitro model that enables the assessment of local availability and bioequivalence of locally acting lozenges. Two novel in vitro dissolution setups (prototypes I and II) developed for simulating parameters relevant to drug release in the oral cavity, were screened for their biopredictivity. In the first step of the respective study in vitro mass loss and drug release of two marketed flurbiprofen lozenge formulations was determined. Then, an in vivo sucking study was performed to determine in vivo mass loss of the lozenges in 12 healthy volunteers. In the final step in vivo mass loss was correlated with in vitro mass loss resulting in a point to point (level A) correlation both lozenge formulations when using in vitro data obtained in the prototype II-based in vitro setup indicating biopredictivity of this in vitro model.

Bioequivalence of locally acting lozenges: Evaluation of critical in vivo parameters and first steps towards a bio-predictive in vitro test method.

Locally-acting lozenges are among the most common types of solid dosage forms applied in the oral cavity. Since no guidance on the in vitro demonstration of local bioequivalence is available, we wanted to develop a new bio-predictive test method for dissolution of lozenges based on a set of physiological parameters relevant to lozenge dissolution in the oral cavity. An in vivo sucking study determining the impact of different lozenge (candy) bases and flavours on sucking times, saliva osmolality and salivary flow rates was performed in 6 volunteers. In vivo sucking times were compared with in vitro dissolution times observed in experiments with official dissolution methods. In vitro dissolution times of all formulations were significantly longer than average in vivo sucking times (20-30 vs. <5 min) indicating that official test methods are not applicable for predicting in vivo dissolution of lozenges. Therefore, we developed and evaluated a novel test apparatus enabling the simulation of forces applied by tongue and hard palate during sucking. Results obtained in a first set of in vitro experiments came very close to those obtained in vivo. This novel in vitro approach is thus very promising in terms of predicting the bioequivalence of locally-acting lozenges.

In vitro dissolution testing of parenteral aqueous solutions and oily suspensions of paracetamol and prednisolone.

The number of intramuscularly applied dosage forms has been continuously increasing during the last decades. However, up to date no in vitro dissolution test method for parenteral dosage forms has been described in the Ph. Eur. or USP. It was the aim of this study to investigate dissolution test setups based on the compendial flow-through cell and the reciprocating holder for this purpose. Both apparatuses were equipped with dialysis membranes to accommodate the drug formulation. The suitability of the dissolution method was evaluated by comparing release profiles with blood level curves that were obtained previously in an in vivo study in rats by our group. Aqueous solutions and oily suspensions of paracetamol and prednisolone were tested in vitro that were also applied in the in vivo study. In the case of the aqueous solutions in which no formal dissolution occurs, transport from the applied depot across a dialysis membrane was investigated. While the drug transport across the dialysis membrane of both drugs in aqueous solution was similar in all applied test methods, differences in the release behavior of paracetamol and prednisolone as an oily suspension were observed. This was mainly due to sedimentation of the particles within the oily depot.