Formulation science and technology have delivered a number of diverse approaches such as particle size reduction, solubilizing excipients or stabilized amorphous systems to overcome the twin obstacles of low solubility and dissolution rate limitations which would otherwise impede drug development. In preclinical development, API bulk availability is often a constraint for formulation activities and as a result, the use of bioenhanced drug delivery systems will only be assessed after simpler approaches such a coarse particle size reduction (e.g by mortar and pestle grinding), suspension preparation or salt formation have been eliminated as viable formulation options. The selection of an appropriate bioenhanced approach is usually driven by an analysis of available pharmacokinetic data from preclinical in vivo studies which can provide some insight into whether the exposure of a candidate molecule is dissolution-rate or solubility limited. This information is considered alongside the physicochemical properties of the molecule to select a suitable strategy for bioenhancement. The Biopharmaceutics Classification Scheme (BCS) is often used to categorize NCEs by virtue of solubility and permeability parameters but can be difficult to apply in an early development context as accurate clinical doses are usually unknown or span a very wide range (it is not uncommon for the possible range of clinical doses to span a few micrograms to a few hundred milligrams at this stage of preclinical development). However, the general concept of BCS has been adapted by a number of research groups to provide a framework which can be used to inform formulation selection during early development. One particular example, termed the ‘developability classification system’ (DCS), provides differentiation to the traditional BCS class II space (low solubility/high permeability) and can be used to refine the selection of suitable formulation approaches based on the biopharmaceutics of the NCE [1]. For those compounds which are deemed to be limited primarily by dissolution rate (DCS IIa), strategies such as particle size reduction by micronization (readily achieved at small-scale by bench-top jet-milling equipment) or more aggressive reduction to the nanosized region by wet-milling can be effective ways to improve the rate and extent of absorption. For compounds in the DCS IIb region, the solubility limitation predominates and strategies such as the use of solubilizing systems need to be considered. In terms of technical complexity, the type of solubilizing systems chosen can range from the use of simple co-solvent systems/solubilizing excipients (e.g. low molecular weight PEGS, propylene glycol), cyclodextrin solubilizers, to more sophisticated multi-component formulations such as SEDDS, SMEDDS or supersaturable SEDDS [2]. If adequate solubility cannot be achieved in any of these vehicles, it can be possible to exploit the usually higher kinetic solubility of the amorphous form by formulating a stabilized amorphous dispersion, often prepared at small-scale by spraydrying an organic solution of API and stabilizing polymer [3].
Predicting the Bioperformance of Preclinical Formulations
Whilst general guidance on formulation strategy can be derived by evaluating physicochemical and in vivo exposure data, it would be desirable to profile formulation performance in vitro to reduce and, wherever possible, eliminate the need for toxicokinetic testing. However, our ability to select an optimal approach based on in vitro characterization is limited by the basic nature of the predictive biopharmaceutics tools available. An important consideration is the ability of in vitro test systems to adequately reproduce the gastrointestinal environment of preclinical species. Amongst the myriad of challenges associated with achieving such a system, one key aspect comes to the fore, which is the difference in the volume of available fluid for dissolution between in vitro systems and the GI tract of the typical preclinical species used for safety assessment studies. The stark contrast between the few millilites of fluid available in the rat intestine and the volume of fluid typically used in dissolution tests is clearly a limiting factor for predicting formulation bioperformance [4]. When the challenges associated with oral drug delivery are considered in this context, the current in vitro characterization tools, such as conventional dissolution systems, simply do not replicate the rapidly changing dynamic environment of the gut lumen. As a result of these limitations, a number of non-conventional dissolution systems have been developed with an emphasis on the use of small-volume vessels to facilitate a relative assessment of in vitro performance using a few milligrams of API. For example, one such system is a small-volume system which comprises a multi-channel spectrometer providing in-line analysis by UV probes [5]. This system controls the temperature and stirring of up to 6 sample vials each with a typical dissolution volume of between 15-20ml. Whilst the small volumes required for dissolution allow experiments to be performed with a few milligrams of API, it is essentially a simple, static model which like its larger USP counterparts, is limited in its ability to accurately model the gastrointestinal environment in terms of fluid volumes, hydrodynamics and lack of an absorptive surface to replicate the membrane permeation step of absorption. However, the system does allow the intrinsic dissolution rate (IDR) of an NCE to be measured with as little as 5mg of API and a recent publication [6] which reports the use of solubility and apparent dissolution rate to predict in vivo bioavailability space in rats, illustrates the potential for IDR data to be added to early biopharmaceutics risk assessments which traditionally rely upon solubility, permeability and where available, in vivo exposure data.
The dissolution-permeation (D-P) system is a small-volume dissolution model which provides an absorptive surface and therefore allows the impact of permeation on dissolution rate to be studied in a single assay [7]. This two-compartment model consists of a dissolution and receiver compartment separated by a Caco-2 monolayer. The D-P system has been used to correlate the in vitro dissolution and permeation of fenofibrate, a BCS class II compound with in vivo data in rats [8]. This study screened a number of bioenhanced formulations including solid dispersion, nanoparticulate and micronized approaches and showed that the D-P system, when used with biorelevant media, could predict formulation performance in rats. However, the majority of D-P models reported in the literature are limited in their ability to reproduce in vivo relevant hydrodynamics and cannot deal with complex food materials or digestive processes. Additionally, despite their use of a biological membrane, the D-P model configuration provides a single compartment for dissolution to occur and does not mimic the dynamic range of conditions seen during gastrointestinal transit.
A number of multi-compartment dissolution models have been developed to more closely mimic the process of gastric emptying and model fluid transport from a gastric compartment to a second intestinal compartment. An example of this type of system is the artificial stomach duodenal model (ASD) which has been used to evaluate the effect of gastric emptying on API dissolution, solubilization and precipitation [9-11]. After dispersion of API or formulated drug product in the stomach chamber, contents are transferred at a controlled rate to the duodenum chamber where they are mixed with simulated intestinal fluid (SIF) allowing the dynamic processes of dissolution, precipitation, re-crystallization and re-dissolution to be followed. Fluid transport from the gastric to duodenal compartment and infusion of fresh simulated GI fluids causes a continuous variation in the concentration of drug substance in both chambers. The use of the ASD to predict in vivo formulation performance is based on observations from studies in fistulated dogs which showed that the concentration of free drug in the duodenum correlated well with formulation bioavailability [9]. The ASD has been used to assess the impact of gastric pH variability on the subsequent absorption of weak bases [12, 13]. It has also been shown to be useful for the prediction of relative bioavailability of different polymorphs [9] or solid forms [14] of nonionizable compounds. However, the design of the artificial stomachduodenum model has some limitations. Results cannot be directly correlated to bioavailability for compounds which are bioavailability limited by permeability and/or metabolism. Additionally, disintegration and dissolution in the gastric compartment may be impacted by the effective volume available (typically between 20-70ml) and the simple continuous method of stirring employed. However, the simplicity of this technique combined with biorelevant fluid transfer makes it a useful tool to understand dynamic dissolution issues for compounds, (at pharmacological doses), with a potential to precipitate following gastric transfer to the small intestine. The ability of the system to predict the bioperformance of formulations at toxicological doses is limited primarily due to the absence of an absorptive sink in this system. In summary, there are still significant challenges in applying in vitro dissolution to predict the performance of toxicology formulations and it would appear that an optimal system needs to combine facets of the systems described above (e.g. the automated control/sampling of the μDiss system, the absorptive surface provided by the D-P model and the ASD simulation of the gastric transfer process) to provide a realistic possibility of using dissolution profiles to predict formulation performance.
Formulation Approaches for Early Clinical Development
Following the development of a suitable formulation to deliver the required exposure to provide adequate safety cover for clinical assessment, the formulation design for first-in-human and phase I studies can be initated. It is an emerging trend within the industry to limit formulation investment for clinical candidates until key milestones are reached (typically read-out from phase II clinical PoC studies). Equally, there is a need to advance NCEs through clinical studies as quickly and efficiently as possible. Where once companies would have committed considerable pharmaceutical development resource to design and manufacture a suitable solid dosage form for early clinical studies, companies now tend to develop fit-for-purpose approaches. The type of formulation used varies depending upon company preferences and available supply-chain/clinical infrastructure, for example, the availability of clinical research units with compounding pharmacists can be a key enabler for resource sparing approaches. Typically simple formulations are developed and can range from powder in bottle dispersions, solutions or suspensions made at the clinical study unit by extemparaneous preparation to simple powder/ API in capsule dosage forms (developing a solid dosage form is required when studies are conducted in an out-patient setting as often happens with early oncology trials). These formulation approaches facilitate rapid progression to the clinic with a reduced development time and demand for bulk API requirements. However the deferred investment in oral dosage form development until phase II means that comparability between formulations must be demonstrated and it is paramount to be able to demonstrate consistent performance in terms of clinical exposure between different formulations. Often, there is the added complexity of formulation performance in the fed state which needs to be evaluated and when these factors are considered together, the ability to characterize drug product performance in a truly biorelevant way is critical. Given the difficulties of adapting conventional USP methods to mimic the dynamic gastrointestinal environment, particularly for poorly soluble compounds, it is likely that new approaches which mimic the key elements of gastric transit, fluid hydrodynamics and dynamic digestion will offer the greatest chance of successfully predicting bioperformance for oral dosage forms [15].
Emerging Technologies for Predicting the Bioperformance of Clinical Formulations
Two new dynamic dissolution models, which have evolved from research in the nutritional area, offer the potential to accurately simulate the gastric environment and the effects of digestive processes on dosage form performance in a more biorelevant way. The first of these systems is the Modelgut (Institute for Food Research, Norwich, UK) dynamic gastric model (DGM) which was developed from insights gained from echo-planar magnetic resonance imaging studies on the gastric processing of complex meals [16-19]. The DGM is claimed to provide an accurate in vitro simulation of gastric mixing (including digestive addition around the gastric bolus), shear rates and forces, peristalsis and gastric emptying [20]. To date, a limited number of pharmaceutical applications of the DGM have been reported in the literature. One study which explored the ability of the DGM to replicate the dynamic digestion of a SEDDS formulation suggested that the DGM provided a more accurate simulation of SEDDS digestion (at least in terms of droplet size) than conventional USP II apparatus [21]. A second study assessed the relative performance of gelatin and HPMC capsules in the fed and fasted states and concluded that the capsule rupture times obtained from the DGM were similar to those observed by gamma scintigraphy in vivo studies in the fasted state and were delayed in the fed state, although the comparison to in vivo scintigraphy results in this case was affected by the impact of food on the dispersion of contents and subsequent sampling in the DGM [22]. The DGM has also been used to assess the release of a complex dosage form containing multiple APIs in immediate-release and controlled-release layers with some advantages observed for prediction of performance over conventional USP 2 dissolution apparatus [23]. Clearly more studies are required to reach a judgement on the value of this system but its ability to simulate gastric forces and meal processing should have value in accurately comparing the relative performance of clinical formulations and in particular quantifying the potential for food-effects.
The second dynamic dissolution model is a sophisticated multicompartmental and computer controlled model of the human upper gastrointestinal tract [24]. This system simulates the in vivo dynamic digestive and physiological processes which occur within the human stomach and small intestine and allows control of all the main parameters of digestion including temperature, pH, peristaltic mixing and transit, gastric secretion (lipase, pepsin, HCl) and small intestinal secretion (pancreatic juice, bile and sodium bicarbonate) [25]. The absorption phase is simulated by the use of a dialysis membrane which removes water and small molecules (including the products of digestion and dissolved drug substance) and allows the bioaccessibility (i.e. the amount of digested product or drug substance in solution and therefore available for absorption) to be quantified [26]. The use of a passive absorptive surface means that in vivo processes such as active transport, efflux and intestinal wall metabolism are not modeled by the system. Hydrodynamics are controlled by changes in water pressure on flexible membranes which contain the lumenal contents and enable mixing by alternate cycles of compression and relaxation, simulating in vivo muscular peristaltic contractions. Additionally, transit is regulated by opening or closing peristaltic valves that connect each compartment. This system has been used to study the absorption of nutritional materials for a number of years but limited examples of its application to pharmaceutical dosage forms are available in the literature [25-29]. Blanquet et al. [25] used this system to evaluate the impact of transit time and food on the absorption of paracetamol following administration as either the free powder form or as a sustained release tablet. This study demonstrated that the profiles of jejunal absorption found in vitro were consistent with in vivo data and a good correlation was seen with Tmax values for the immediate-release form. It was also shown that food intake (in the form of a standard breakfast) reduced the amount of paracetamol available for absorption. This was judged to be similar to clinical studies which showed a lower Cmax and delayed Tmax in the fed state compared to intake with water in the fasted state [30-33]. A further study evaluated the use of this dynamic model to improve the predictability of physiologicallybased pharmacokinetic (PBPK) simulation and modelling software for a paroxetine hydrochloride immediate-release tablet [34]. Using the bioaccessibility profile as the input rate for the drug within the in-silico absorption model, it was shown that the predicted plasma profile was improved when compared to the profile generated when USP II dissolution data were used. More recently, this dynamic dissolution model has been used to identify food-induced disintegration issues causing unexpected clinical performance for an immediate-release fosamprenavir tablet [35]. A report by Dickinson et al. [36] demonstrated that it is possible to modify this model to study formulations delivering poorly soluble compounds. In this case, the model was adapted to use a lipid membrane in place of dialysis to simulate absorption and it was shown that it was possible to predict the performance of a BCS class II compound in both fasting and achlorhydric conditions. These examples suggest that the GI-modeling system, which provides an advanced level of control over a dynamic and complex lumenal environment, may have several advantages over conventional dissolution methodologies when assessing the performance of oral formulations in either the fasted or fed states.
Conclusion
The use of in vitro dissolution to select formulations for preclinical and clinical use remains constrained by the use of equipment and methodologies originally developed to support a quality control function. There is a clear need to improve the current in vitro tools to more closely simulate key aspects of gastrointestinal physiology, so that formulation decisions can be made on robust and biorelevant data. Newer systems such as the DGM and the computerized GI model of the stomach and small intestine illustrate potential new design paths for the next generation of biorelevant dissolution systems and if current drawbacks such as sample throughput, in-line analysis and more accurate replication of the membrane permeation step can be addressed, may at last offer formulation scientists a realistic alternative to in vivo testing.
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Dr. Mark McAllister is a research fellow in the Drug Product Design group, Pharmaceutical Sciences, Pfizer, located in Sandwich, UK. He graduated in Pharmacy from Queens University Belfast in 1990 and completed a pharmaceutics Ph.D. program at Aston University with Prof. Oya Alpar. After his first industrial appointment at Hoechst-Roussel, Swindon, which provided experience working with silicone-based hormone sustained release systems, Mark moved to SmithKline Beecham where he gained experience in drug absorption profiling, biopharmaceutics and early phase candidate assessment. As a manager within the Strategic Technologies department of GlaxoSmithKline Pharmaceutical Development in Harlow, he was responsible for a number of technology development programs spanning areas such as oral modified-release and bioenhancement. Since joining Pfizer in 2008 to lead the Research Formulation drug delivery group, he has continued his research interests in biopharmaceutics and formulation support for programs from early discovery through to proofof- concept stage. More recently, he has moved into the Drug Product Design group at Sandwich and has responsibility for late-stage development projects. He currently leads the UK Academy of Pharmaceutical Scientists Biopharmaceutics focus group and is an APS board member. Mark is the deputy scientific coordinator for the Innovative Medicines Initiative ‘OrBiTo’ project which aims to develop the next generation of innovative tools for oral biopharmaceutics.