Martin Kuentz

Lipid-based formulations for oral delivery of lipophilic drugs

In the last decade there has been a growing interest in lipid-based formulations to deliver challenging compounds such as lipophilic drugs. Following a brief clarification of the nomenclature, this review stresses the different mechanisms of how lipid-based excipients and formulations interact with the absorption process. Case studies are presented in which enhanced bioavailability was demonstrated in vivo using this pertinent formulation approach. It is emphasized that lipid-based delivery of challenging drugs requires a development in consecutive steps. Such a structured formulation development is crucial for optimal allocation of resources. Thus, lipid-based excipients are first evaluated in view of drug solubility, phase behavior, as well as with respect to known biological effects. Mixtures can be screened in simple dilution tests and are subsequently studied in more advanced biopharmaceutical tests. Once a lipid-based formulation principle is identified, different technologies are presented to encapsulate the fill mass either in soft or hard capsules. It is also possible to formulate lipid-based systems as a solid dosage form. Even though such solid lipid technologies seem very attractive, one has to assure that the final dosage form does not impair the biopharmaceutical potential of the lipid formulation principle.

Comparison of in vitro tests at various levels of complexity for the prediction of in vivo performance of lipid-based formulations: Case studies with fenofibrate

The objectives of this study were to characterise three prototype fenofibrate lipid-based formulations using a range of in vitro tests with differing levels of complexity and to assess the extent to which these methods provide additional insight into in vivo findings. Three self-emulsifying drug delivery systems (SEDDS) were prepared: a long chain (LC) Type IIIA SEDDS, a medium chain (MC) Type IIIA SEDDS, and a Type IIIB/IV SEDDS containing surfactants only (SO). Dilution, dispersion and digestion tests were performed to assess solubilisation and precipitation behaviour in vitro. Focussed beam reflectance measurements and solid state characterisation of the precipitate was conducted. Oral bioavailability was evaluated in landrace pigs. Dilution and dispersion testing revealed that all three formulations were similar in terms of maintaining fenofibrate in a solubilised state on dispersion in biorelevant media. During in vitro digestion, the Type IIIA formulations displayed limited drug precipitation (<5%), whereas the Type IIIB/IV formulation displayed extensive drug precipitation (~70% dose). Solid state analysis confirmed that precipitated fenofibrate was crystalline. The oral bioavailability was similar for the three lipid formulations (65-72%). In summary, the use of LC versus MC triglycerides in Type IIIA SEDDS had no impact on the bioavailability of fenofibrate. The extensive precipitation observed with the Type IIIB/IV formulation during in vitro digestion did not adversely impact fenofibrate bioavailability in vivo, relative to the Type IIIA formulations. These results were predicted suitably using in vitro dilution and dispersion testing, whereas the in vitro digestion method failed to predict the outcome of the in vivo study.

Drug Absorption Modeling as a Tool to Define the Strategy in Clinical Formulation Development

The purpose of this mini review is to discuss the use of physiologically-based drug absorption modeling to guide the formulation development. Following an introduction to drug absorption modeling, this article focuses on the preclinical formulation development. Case studies are presented, where the emphasis is not only the prediction of absolute exposure values, but also their change with altered input values. Sensitivity analysis of technologically relevant parameters, like the drug’s particle size, dose and solubility, is presented as the basis to define the clinical formulation strategy. Taking the concept even one step further, the article shows how the entire design space for drug absorption can be constructed. This most accurate prediction level is mainly foreseen once clinical data is available and an example is provided using mefenamic acid as a model drug. Physiologically-based modeling is expected to be more often used by formulators in the future. It has the potential to become an indispensable tool to guide the formulation development of challenging drugs, which will help minimize both risks and costs of formulation development.

Advancing in-vitro drug precipitation testing: new process monitoring tools and a kinetic nucleation and growth model

Objectives  Poorly soluble weak bases often precipitate during intestinal passage, potentially leading to incomplete drug absorption. The underlying in‐vivo and in‐vitro drug precipitation mechanisms are not well understood. Thus, new analytical tools and a kinetic nucleation and growth model were introduced to in‐vitro drug precipitation testing in biorelevant media.

Study of a Standardized Taurocholate- Lecithin Powder for Preparing the Biorelevant Media FeSSIF and FaSSIF

The properties of taurocholate–lecithin powder (SIF Powder) and the biorelevant media FeSSIF and FaSSIF prepared from the powder were investigated using various techniques. The powder is stable and shows no change in the physical or chemical characteristics for at least 12 months in the original container stored at 2–8 °C. FeSSIF and FaSSIF were stable with respect to hydrolysis for at least 48 h at 37 °C. Oxidation in FeSSIF was detected at a very low level and to an even lower extent in FaSSIF. FaSSIF comprises a complex mixture of colloidal aggregates including rod-like, spherical, disc-like mixed micelles and vesicles. Consistent particle size was achieved by equilibrating the medium at room temperature (RT) after preparation. In comparison, FeSSIF only comprises smaller mixed micelles and requires no equilibration. The dissolution rates of three poorly water-soluble model drugs tested in FaSSIF media differing in average particle size controlled at 30 nm and 50 nm were not statistically different. However, differences in the average particle size can affect visual clarity: FaSSIF is generally slightly opalescent above an average size of approximately 50 nm and appears clear below approximately 50 nm. Challenge tests showed that FaSSIF is more susceptible to microbial spoilage than FeSSIF. Reproducible FeSSIF and FaSSIF can be made conveniently from the powder by employing standard preparation methods at RT.

Rapid assessment of sedimentation stability in dispersions using near infrared transmission measurements during centrifugation and oscillatory rheology

We used the LUMiFuge) 114 particle separation analyser to investigate the sedimentation kinetics of bentonite/xanthan gum mixtures through pH 2-7 during centrifugation. This new technique monitors timed near infrared transmission profiles of different samples in the centrifugal field. Statistical analysis of the data then identifies the formulations with minimal clarification tendency. All mixtures were characterised by rotational and oscillatory rheology. Various rheological parameters correlated with the LUMiFuge clarification data, most notably the relaxation exponent, n and loss tangent, tan delta. We devised a combined desirability function for the different mixtures, defining maximal desirability as the minimal values for the two oscillatory parameters. The results matched those of separation analysis in the centrifugal field.We conclude that the experimental design is suitable for selecting formulations with optimal sedimentation stability whether combined with LUMiFuge analysis or oscillatory measurements. The method can be used to screen formulations for optimal long-term stability test performance, with significant potential savings and minimal sedimentation risk after prolonged storage.

Determination of the optimal amount of water in liquid-fill masses for hard gelatin capsules by means of texture analysis and experimental design

The aim of this study is to use texture analysis as a non-destructive test for hard gelatin capsules filled with liquid formulations to investigate mechanical changes upon storage. A suitable amount of water in the formulations is determined to obtain the best possible compatibility with the gelatin shell. This quantity of water to be added to a formulation is called the balanced amount of water (BAW). Texture profiling was conducted on capsules filled with hydrophilic polymer mixtures and with formulations based on amphiphilic masses with high HLB value. The first model mixture consisted of polyethylene glycol 400 and polyvinylpyrrolidone K17 with water and the second type consisted of caprylocaproyl macrogol glycerides (Labrasol) with colloidal silica (Aerosil 200) and water. The liquid-fill capsules were investigated by measuring changes on mass and stiffness after storage under confined conditions in aluminium foils. Capsule stiffness was investigated also as a parameter in a response surface analysis to identify the BAW. Polyvinylpyrrolidone did not show a great influence on the BAW in the range of 10-12% (w/w) for the first model mixture. Capsules with the less hydrophilic Labrasol formulations, however, kept their initial stiffness after storage best with only half of that amount, i.e. 5-6% (w/w) of water in the compositions. From this study it can be concluded that texture profiling in the framework of an experimental design helps to find hydrophilic or amphiphilic formulations that are compatible with gelatin capsules. Short-term stability tests are meaningful if capsule embrittlement or softening is due to water equilibration or another migration process that takes place rapidly. Long-term stability tests will always be needed for a final statement of compatibility between a formulation and hard gelatin capsules.

Drug-Excipient Compatibility Testing Using a High-Throughput Approach and Statistical Design

The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of ~ 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40°C/50°C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.

The apparent solubilizing capacity of simulated intestinal fluids for poorly water-soluble drugs

Drug solubility testing in biorelevant media has become an indispensable tool in pharmaceutical development. Despite this importance, there is still an incomplete understanding of how poorly soluble compounds interact with these media. The aim of this study was to apply the concept of the apparent solubilization capacity to fasted and fed state simulated intestinal fluid (FaSSIF and FeSSIF, respectively). A set of non-ionized poorly soluble compounds was studied in biorelevant media prepared from an instantly dissolving complex (SIF™ Powder) at 37°C. The values of the solubilization capacity were different between FaSSIF and FeSSIF but correlated. Drug inclusion into the mixed micelles was highly specific for a given compound. The ratio of the FeSSIF to FaSSIF solubility was in particular considered and discussed in terms of the apparent solubilizing capacity. The apparent solubilization concept appears to be useful for the interpretation of biorelevant solubility tests. Further studies are needed to explore acidic and basic drugs.

Comparison of high-resolution ultrasonic resonator technology and Raman spectroscopy as novel process analytical tools for drug quantification in self-emulsifying drug delivery systems.

Self-emulsifying drug delivery systems (SEDDS) are complex mixtures in which drug quantification can become a challenging task. Thus, a general need exists for novel analytical methods and a particular interest lies in techniques with the potential for process monitoring. This article compares Raman spectroscopy with high-resolution ultrasonic resonator technology (URT) for drug quantification in SEDDS. The model drugs fenofibrate, indomethacin, and probucol were quantitatively assayed in different self-emulsifying formulations. We measured ultrasound velocity and attenuation in the bulk formulation containing drug at different concentrations. The formulations were also studied by Raman spectroscopy. We used both, an in-line immersion probe for the bulk formulation and a multi-fiber sensor for measuring through hard-gelatin capsules that were filled with SEDDS. Each method was assessed by calculating the relative standard error of prediction (RSEP) as well as the limit of quantification (LOQ) and the mean recovery. Raman spectroscopy led to excellent calibration models for the bulk formulation as well as the capsules. The RSEP depended on the SEDDS type with values of 1.5-3.8%, while LOQ was between 0.04 and 0.35% (w/w) for drug quantification in the bulk. Similarly, the analysis of the capsules led to RSEP of 1.9-6.5% and LOQ of 0.01-0.41% (w/w). On the other hand, ultrasound attenuation resulted in RSEP of 2.3-4.4% and LOQ of 0.1-0.6% (w/w). Moreover, ultrasound velocity provided an interesting analytical response in cases where the drug strongly affected the density or compressibility of the SEDDS. We conclude that ultrasonic resonator technology and Raman spectroscopy constitute suitable methods for drug quantification in SEDDS, which is promising for their use as process analytical technologies.