Sandra Klein

In vitro models for the prediction of in vivo performance of oral dosage forms.

Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is anticipated that the innovative in vitro biopharmaceutical tools arising from the OrBiTo project will lead to improved predictions for in vivo behavior of drug formulations in the GI tract.

The Use of Biorelevant Dissolution Media to Forecast the In Vivo Performance of a Drug

Simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of drug formulations. To reduce the size and number of human studies required to identify a drug product with appropriate performance in both the fed and fasted states, it is advantageous to be able to pre-screen formulations in vitro. The choice of appropriate media for such in vitro tests is crucial to their ability to correctly forecast the food effect in pharmacokinetic studies. The present paper gives an overview of the development and composition of biorelevant dissolution media that can be used for the in vitro simulation of different dosing conditions (fasted and fed states). In addition, the application of these media to predicting food effects is described in several case examples.

A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis

The aim of the present study was to develop a multi-unit dosage form containing 5-aminosalicylic acid (5-ASA) for the treatment of ulcerative colitis (UC), optimised on the basis of recent studies indicating that UC patients have higher intestinal pH than was previously thought to be the case. Pellets with a drug content of 77.4% were prepared by a granulation and spheronization process and then coated with a new pH sensitive poly(meth)acrylate copolymer (Eudragit((R)) FS 30D) to achieve site specific drug release close to the ileocecal valve. Dissolution tests were carried out in a paddle dissolution apparatus in media simulating pH conditions at various locations in the gastrointestinal tract. The pellets released rapidly at pH values above 7.5. Between 6.8 and 7.2 drug release was found to be zero order, while at pH 6.5 and below no release occurred. In a biorelevant medium which simulates the fasting proximal small intestine fluid it was shown that neither surfactants (sodium taurocholate and lecithin) nor changes in ionic strength trigger drug release. Compared to 5-ASA pellets coated with the well established Eudragit((R)) S, and to currently marketed products licensed for the treatment of UC, the multi-unit dosage form coated with the new polymer exhibited an in vitro dissolution profile more appropriate to the pH profile of the ileum and the colon observed in UC patients.

Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts.

To better predict food effects on the bioavailability/bioequivalence of drugs and drug products from in‐vitro data, a dissolution medium that simulates the initial composition of the postprandial stomach was developed. First, the physical parameters of two homogenized standard breakfasts often administered to assess food effects in pharmacokinetic studies were measured. These included pH, buffer capacity, osmolality, surface tension and viscosity. Subsequently, the match of the physical parameters of several commercially available liquid meals, including long‐life milk, Ensure and Ensure Plus to those of the breakfasts was evaluated. Of the three liquid meals studied, Ensure Plus had the closest physicochemical behaviour to that of homogenized standard breakfasts. By increasing the viscosity of Ensure Plus with 0.45% pectin, it was possible to obtain a medium that closely resembles the FDA standard breakfast.

Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole

The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®.

Site‐specific delivery of anti‐inflammatory drugs in the gastrointestinal tract: an in‐vitro release model

Mesalazine and budesonide are anti‐inflammatory drugs that are used to induce and maintain remission of inflammatory bowel diseases (IBD), such as Crohns disease and ulcerative colitis. Both drug substances are intended to act locally at the inflamed sites of the gastrointestinal tract. The therapeutic objective for per oral treatment with these drugs is to achieve a high concentration of the active drug at the sites of inflammation while minimizing systemic absorption. The aim of this study was to develop a test system able to reflect the changing environment that a dosage form incorporating the anti‐inflammatory agent is exposed to as it moves through the gastrointestinal tract. The USP dissolution apparatus 3 was used for all experiments. Compendial, as well as biorelevant, media were used to simulate passage through the gastrointestinal tract under various physiological conditions. Different dosage forms of mesalazine (5‐aminosalicylic acid, 5‐ASA) and budesonide available on the German market were tested. Although all dosage forms were indicated for the same therapeutic objectives, each of the dosage forms exhibited a characteristic release pattern under in‐vitro conditions simulating a passage through the fasted‐state gastrointestinal tract. Results from this test series indicate that, in the case of various dosage forms of mesalazine and budesonide used for the therapy of Crohns disease and ulcerative colitis, release patterns as the dosage form moves through the gastrointestinal tract may vary widely. As the various phenotypes of IBD have different requirements in terms of pattern of distribution of the inflamed sites, and because other aspects of gastrointestinal physiology vary within the patient population, the test methods and approach described here should be very useful in designing therapy tailored to the needs of each individual patient.

A Standardized Mini Paddle Apparatus as an Alternative to the Standard Paddle

Results from the present series of tests indicate that the mini paddle apparatus is a useful tool in characterizing drug release profiles under “standard test conditions”. Due to the possibility of using smaller sample sizes and smaller volumes of media, it offers various advantages in terms of substance, analytical, and material cost savings when evaluating release properties of drug candidates. The mini paddle setup is also a promising alternative if the analytics are not very sensitive or in the case of highly potent drugs. Because the size and shape of dosage forms can also impact drug release, the mini paddle should preferably be used for powders, multiparticulate dosage forms, and small tablets or capsules (i.e., where the paddle apparatus would be the usual method of choice). Nowadays, there are various types of mini paddle systems available on the market. However, most of these systems reflect everything but a miniaturized reproduction of the USP paddle system. For this reason, the outcome of the present study should not be generalized since changing the dimensions of the setup can quickly result in alterations of the hydrodynamics which, as has been shown in the present study, can have a huge impact on drug release from the dosage form tested. The next steps would be therefore to check, if it is possible to further downsize the setup with maintaining the significance of the compendial setup, to determine the impact of experimental settings on drug release from MR formulations and to measure/simulate flow velocities in the mini vessel.

Simplified Biorelevant Media for Screening Dissolution Performance of Poorly Soluble Drugs

8 INTRODUCTION Simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of poorly soluble drugs. Simulating small intestinal conditions with biorelevant media such as fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) has become standard practice in many dissolution laboratories (1–6). However, due to their complex composition, these media are expensive and, to date, need to be prepared on the day of the experiment. The aim of the present study was to develop media that are easier to prepare and are stable over a longer period, but can still serve the purpose of forecasting in vivo performance. Criteria for developing simplified test media also include cost-effectiveness and the ability to adequately reflect the physicochemical properties of the biorelevant media FaSSIF or FeSSIF (see Table 1). Another objective was to create mixed micelles like those formed by natural bile components. For this purpose, sodium taurocholate and lecithin were replaced with different types and concentrations of surfactants, and the physicochemical properties of the resulting mixtures were screened. Subsequently, simplified media with corresponding physicochemical properties were used for dissolution experiments. Since their oral bioavailability and dissolution rate performance have been reported to depend on the presence of dissolution enhancers (1, 3, 7–10), ketoconazole, glyburide and tamoxifen citrate were selected as model drugs for these experiments. Based on these observations, it was assumed that drug release from their formulations would be sensitive to the composition of the test media. Thus, they appeared to be optimal candidates to prove the applicability of the new set of media.

Paediatric oral biopharmaceutics: key considerations and current challenges.

The complex process of oral drug absorption is influenced by a host of drug and formulation properties as well as their interaction with the gastrointestinal environment in terms of drug solubility, dissolution, permeability and pre-systemic metabolism. For adult dosage forms the use of biopharmaceutical tools to aid in the design and development of medicinal products is well documented. This review considers current literature evidence to guide development of bespoke paediatric biopharmaceutics tools and reviews current understanding surrounding extrapolation of adult methodology into a paediatric population. Clinical testing and the use of in silico models were also reviewed. The results demonstrate that further work is required to adequately characterise the paediatric gastrointestinal tract to ensure that biopharmaceutics tools are appropriate to predict performance within this population. The most vulnerable group was found to be neonates and infants up to 6 months where differences from adults were greatest.

A comparative study of different release apparatus in generating in vitro–in vivo correlations for extended release formulations

The importance of hydrodynamics in the development of in vitro-in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state.