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

https://doi.org/10.1016/j.ejps.2013.08.024Get rights and content

Abstract

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.

Introduction

The research-based pharmaceutical industry is currently facing unprecedented pressures, in large part due to declining return on investment from R&D over the last decade or so.

The latest figures for new drug approvals in the USA reflect some of current challenges and how the industry is responding to these. In 2012, there were approximately 40 new drug approvals (Center for Drug Evaluation and Research, 2013), which encouragingly is the highest number in 16 years. However, the total anticipated peak sales for these new drugs is lower compared to that of new approvals in previous years (“Measuring the return from Pharmaceutical innovation, 2012 – Deloitte UK Centre for Health Solutions|Deloitte UK,” 2013). This reflects a trend towards a higher proportion of medicines being developed (or at least succeeding in reaching the market) for niche patient populations, where unmet medical need is high and the chances of getting a drug to the market is improved. As a result, for these products, the return on investment per molecule launched is somewhat lower compared to the traditional so-called “blockbuster” products where patient numbers per molecule are higher. Furthermore, a significant challenge for the introduction of innovative products in precedented therapeutic areas is the ready availability of once class-leading products in generic form. This is perhaps exemplified by the current introductions of avorstatin products, providing the prescribers with additional alternative to statins still under patent protections. Overall, these challenges make it even more difficult to justify the development of innovative products. To ensure that the industry remains commercially viable, the drug product development process needs to become more efficient.

In concordance with the recent shifts in the types of diseases being addressed by new drugs and the increase in development failures in certain indications [e.g. CNS, Oncology (Kola, 2008) ], the pipelines of pharmaceutical companies today contain a higher proportion of drugs with significant challenges in terms of drug delivery and biopharmaceutics. Looking at development pipelines of pharmaceutical industry over the past five decades (Gribbon and Sewing, 2005, Lobell et al., 2006), biopharmaceutical issues are mostly related to increasing lipophilicity and decreasing aqueous solubility. As a consequence, more development candidates exhibit poor oral bioavailability from oral drug formulations containing the crystalline form of the API. On the other hand, the lipophilicity of marketed compounds remained fairly unchanged over that time-span, indicating that the changes in the physicochemical properties of compounds in pipelines has probably been detrimental to the chances of successful development (Arrowsmith, 2011a). Reasons for the observed increase in the number of lipophilic compounds in development include:

  • (i)

    The addition of lipophilic residues to achieve an increased ligand-receptor affinity (Vieth et al., 2004).

  • (ii)

    A general broadening of chemical space, supported by the launch of combinatorial chemistry in the early 1990s (Moos et al., 1993, Patel and Gordon, 1996).

  • (iii)

    The introduction of high-through-put screening (HTS) in the early 1990s, which led to a bias towards lipophilic compounds being identified as potential leads.

Given the increasingly unfavorable biopharmaceutical properties of development candidates, formulation scientists have had to develop a variety of strategies over the past decades in order to overcome them. For instance, drugs are being formulated for oral immediate release (IR) in products that deliberately create supersaturation and/or increase of the drug’s solubility at some point in the GI tract. Such approaches are now widespread in the modern oral pharmaceutical portfolio and include solid dispersions, self microemulsifying systems, salts and cocrystals (Williams et al., 2013).

One way of building greater efficiency into the drug development process is to switch from the traditional empirical approach of product development and make greater use of predictive tools based upon a sound scientific understanding of in vivo behavior. Since lack of efficacy and safety concerns are the largest contributors to attrition (Arrowsmith, 2011a, Arrowsmith, 2011b, Kola and Landis, 2004), this scientific and predictive approach is especially important when understanding therapeutic drug targets, mechanisms causing toxicological effects and drug-drug interactions. Biopharmaceutics and pharmacokinetics (PK) are also a direct cause of attrition, although there is some evidence of improvement in recent decades (Astashkina et al., 2012). In addition, candidates with poor biopharmaceutic and pharmacokinetic properties tend to take more time and effort to progress through development, and may make safety and efficacy failures more likely (Hann and Keserü, 2012). Whilst the industry has taken on board and successfully implemented screens to remove compounds with Cytochrome P450-mediated metabolic liabilities, there are reports which suggest a shift to compounds for which the in vitro screens are not as predictive for phase II pathways, such as glucuronidation (Miners et al., 2006).

To help drive this much needed switch to more efficient development, and to encourage synergies between pharmaceutical companies in Europe, IMI [Innovative Medicines Initiative (“Home|IMI – Innovative Medicines Initiative,” 2013)] has implemented 37 public–private partnerships with more to come. These are research collaborations between Pharmaceutical Companies, Universities, Patient Organizations, Medical Agencies etc., focusing on the most urgent bottlenecks in Pharmaceutical R&D. Of these, the Oral Biopharmaceutics Tools (OrBiTo) project aims to create new and optimized laboratory tests and computer models that will better predict the biopharmaceutical performance of drugs and formulations in patients as well as providing suggestions for the most rational use of novel and existing methods. The aims and objectives of OrBiTo also relate well to the FDA’s Quality by Design (QbD) initiative, which is designed to encourage a better understanding of new products during development, including developing and understanding in vivo behavior (ICH Expert Working Group, 2009, Yu, 2008).

In light of the OrBiTo IMI initiative, this article is a review and gap analysis of current knowledge in the biopharmaceutical field, with special emphasis on in vitro tools to predict in vivo performance of pharmaceutical formulations.

While many innovative options for delivering low solubility drugs have been developed, novel and reliable in vitro tests to predict the in vivo dissolution, precipitation and/or absorption of the drug from these formulations are in need of further development. Traditional dissolution using the paddle or basket apparatus is normally utilized to assess product quality and to predict changes in drug release that may impact the in vivo performance of oral products, but has not changed radically since the 1970s. Limitations of the traditional approach to dissolution are of particular relevance to low solubility drugs with their challenging biopharmaceutical properties.

More than a hundred years ago, the importance of dissolution testing to in vivo performance had already been recognized. Quoting C. Caspari in 1895

…it would seem that prompt action of certain remedies must be considerably impaired by firm compression. The composition of all compressed tablets should be such that they will readily undergo disintegration and dissolution in the stomach.” (C. Caspari, A treatise on Pharmacy 1895, Lea Bros. Philadelphia p. 344.)

As described by Krämer (Dressman and Krämer, 2005), the evolution of suitable methods to establish links between in vitro and in vivo product performance had to be put on hold until reliable analytical methods were developed in the 1950s. In that era, vitamin products and enteric coated tablets came under closer scrutiny, and failure to disintegrate was linked to poor clinical results by greats such as John Wagner, the leading pharmacokineticist of the day. In the 1970s, as generic drug products became common, interest in linking in vitro with in vivo performance intensified and in 1973 a correlation between dissolution and absorption rates was demonstrated for digoxin tablets (Shaw et al., 1973). This paved the way for the field of in vitro in vivo correlation (IVIVC). In the 1970s and 1980s, many attempts were made to establish IVIVCs for various types of drug products, as summarized by Welling (Welling et al., 1991). At that time, Welling reported that “to the writer’s knowledge, there have been no studies that have accurately correlated in vitro and in vivo data to the point that the use of upper and lower limits for in vitro dissolution parameters can be confidently used to predict in vivo behavior and therefore to replace in vivo testing”. However, both the pharmaceutical industry and the regulatory authorities persisted with the IVIVC concept, holding workshops and drafting chapters on IVIVC during the 1980s (Pharmacopeial Forum, 1988; “PMA comments on USP Stimuli to the revision process. In vitro-in vivo correlations for extended release oral dosage forms,” 1988; PMA Joint Committee on Bioavailability, 1985, Skelley et al., 1990). IVIVC had to wait, however, until 1995 to be included in the United States Pharmacopeia. In USP Chapter 1088, it was stated that “the goal of the pharmaceutical scientist is to find a relationship between an in vitro characteristic of a dosage form and its in vivo performance” (US Pharmacopoeia, 1995). By that time, it was recognized that an IVIVC can be more readily defined for MR than for IR dosage forms. In 1997, guidance issued by the FDA described the application of IVIVC in the development and evaluation of extended release (ER) dosage forms (Malinowski et al., 1997). Two years later, IVIVC was mentioned in the corresponding European Note for Guidance (“GMP Guideline Quality of Modified Release Products Section I (Quality) CPMP/QWP/604/96,” 2013). Over the following decade, the IVIVCs generated have predominantly been for MR dosage forms, which is not unexpected as by definition dissolution should be rate determining for the PK profile.

With more poorly soluble drugs being developed as oral dosage forms, it was recognized in the 2000s that, since the dissolution is often an important restriction to their absorption, IVIVC might be possible for drug products containing poorly soluble drugs, even if the product was intended for “immediate” release.

Section snippets

Disintegration

The disintegration test is performed to determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium at 37 °C using the disintegration apparatus and experimental conditions proposed by the Pharmacopeia (The European Pharmacopoeia, 2011, United States Pharmacopoeia Convention, 2012). According to the Pharmacopeias, disintegration is defined as that state in which any residue of the unit, except from fragments of insoluble coating or capsule shell,

Overcoming the limitations of pharmacopoeial setups – recent advances and current challenges

In general, the pharmacopeia have provided the industry with reliable QC dissolution methods for various types of oral dosage forms. However, in terms of both the apparatus and the media used, these compendial systems are far from optimized for dosage form development and predictive evaluation. As they are designed for easy implementation in most laboratory settings while providing sink conditions for drug release, compendial media serve the purpose of QC well. When the paradigm shifts from QC

In vitro models for predicting drug absorption: the future

As oral drugs continue to be the largest segment of new drug approvals, with more than half of the newly approved medicines in the USA 2012 being delivered orally (“New Drug Approvals,” 2013), novel, biorelevant in vitro tools for the prediction of oral dosage form performance in vivo have a key role in making drug product development more efficient. Novel biopharmaceutical tools could lead to:

  • (i)

    Preventing potential development compounds from being falsely discarded in the preclinical development

Integration of in vitro models with PBPK modeling

Although results of biorelevant dissolution release tests have proven useful for qualitatively, and in some cases quantitatively predicting in vivo drug performance (Fang et al., 2010, Sunesen et al., 2005), the dissolution release test cannot capture all processes that may affect the in vivo performance. For example, gastric emptying, permeability through the intestinal membrane, transit time, pH and fluid volume in each segment of the GI tract, first pass metabolism and excretion can all play

Concluding remarks

Methods for characterizing drug release from oral pharmaceutical products have evolved substantially since they were first introduced as quality control tools. Although the classical quality control methods can detect variations in manufacturing procedures, they may or may not be relevant to the in vivo performance of the drug product. As we have gained deeper insight into gastrointestinal physiology from the pharmaceutical perspective over the last 20–25 years, it has become possible to develop

Acknowledgements

This work has received support from the Innovative Medicines Initiative Joint Undertaking (http://www.imi.europa.eu) under Grant Agreement No. 115369, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.

References (232)

  • J. Bevernage et al.

    Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues

    Int. J. Pharm.

    (2013)
  • S.N. Bhattachar et al.

    Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus, TM simulations to predict absorption

    J. Pharm. Sci.

    (2011)
  • J. Brouwers et al.

    Intraluminal drug and formulation behavior and integration in in vitro permeability estimation: a case study with amprenavir

    J. Pharm. Sci.

    (2006)
  • J. Brouwers et al.

    Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability?

    J. Pharm. Sci.

    (2009)
  • J. Brouwers et al.

    Food-dependent disintegration of immediate release fosamprenavir tablets: in vitro evaluation using magnetic resonance imaging and a dynamic gastrointestinal system

    Eur. J. Pharm. Biopharm.

    (2011)
  • P. Buch et al.

    IVIVC in oral absorption for fenofibrate immediate release tablets using a dissolution/permeation system

    J. Pharm. Sci.

    (2009)
  • S.R. Carino et al.

    Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model

    J. Pharm. Sci.

    (2006)
  • S.R. Carino et al.

    Relative bioavailability of three different solid forms of PNU-141659 as determined with the artificial stomach-duodenum model

    J. Pharm. Sci.

    (2010)
  • F. Carriere et al.

    Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans

    Gastroenterology

    (1993)
  • N. Castela-Papin et al.

    Drug interactions with diosmectite: a study using the artificial stomach–duodenum model

    Int. J. Pharm.

    (1999)
  • A. Christiansen et al.

    Effects of non-ionic surfactants on in vitro triglyceride digestion and their susceptibility to digestion by pancreatic enzymes

    Eur. J. Pharm. Sci.

    (2010)
  • S. Clarysse et al.

    Postprandial evolution in composition and characteristics of human duodenal fluids in different nutritional states

    J. Pharm. Sci.

    (2009)
  • J.F. Cuiné et al.

    Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs

    J. Pharm. Sci.

    (2008)
  • A. Dahan et al.

    The effect of different lipid based formulations on the oral absorption of lipophilic drugs: the ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats

    Eur. J. Pharm. Biopharm.

    (2007)
  • M. Erceg et al.

    In vitro vs. canine data for assessing early exposure of doxazosin base and its mesylate salt

    Eur. J. Pharm. Biopharm.

    (2012)
  • D.G. Fatouros et al.

    In vitro-in vivo correlations of self-emulsifying drug delivery systems combining the dynamic lipolysis model and neuro-fuzzy networks

    Eur. J. Pharm. Biopharm.

    (2008)
  • S. Fernandez et al.

    Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol, medium chain glycerides and PEG esters

    Biochim. Biophys. Acta

    (2007)
  • N. Fotaki et al.

    In vitro versus canine data for predicting input profiles of isosorbide-5-mononitrate from oral extended release products on a confidence interval basis

    Eur. J. Pharm. Sci.

    (2005)
  • N. Fotaki et al.

    Canine versus in vitro data for predicting input profiles of L-sulpiride after oral administration

    Eur. J. Pharm. Sci.

    (2005)
  • N. Fotaki et al.

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

    Eur. J. Pharm. Biopharm.

    (2009)
  • K.J. Frank et al.

    Amorphous solid dispersion enhances permeation of poorly soluble ABT-102: true supersaturation vs. apparent solubility enhancement

    Int. J. Pharm.

    (2012)
  • G. Garbacz et al.

    Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses

    Eur. J. Pharm. Biopharm.

    (2008)
  • G. Garbacz et al.

    Comparison of dissolution profiles obtained from nifedipine extended release once a day products using different dissolution test apparatuses

    Eur. J. Pharm. Sci.

    (2009)
  • Y. Gargouri et al.

    Kinetic assay of human gastric lipase on short- and long-chain triacylglycerol emulsions

    Gastroenterology

    (1986)
  • M.J. Ginski et al.

    Prediction of dissolution-absorption relationships from a dissolution/Caco-2 system

    Int. J. Pharm.

    (1999)
  • K. Goodman et al.

    Assessing gastrointestinal motility and disintegration profiles of magnetic tablets by a novel magnetic imaging device and gamma scintigraphy

    Eur. J. Pharm. Biopharm.

    (2010)
  • P. Gribbon et al.

    High-throughput drug discovery: what can we expect from HTS?

    Drug Discov. Today

    (2005)
  • C.-H. Gu et al.

    Using a novel multicompartment dissolution system to predict the effect of gastric pH on the oral absorption of weak bases with poor intrinsic solubility

    J. Pharm. Sci.

    (2005)
  • H.R. Guzmán et al.

    Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations

    J. Pharm. Sci.

    (2007)
  • L. Hendeles et al.

    Food-induced dose dumping of once-a-day theophylline

    Lancet

    (1984)
  • E. Jantratid et al.

    Designing biorelevant dissolution tests for lipid formulations: case example – lipid suspension of RZ-50

    Eur. J. Pharm. Biopharm.

    (2008)
  • E. Jantratid et al.

    Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form

    Eur. J. Pharm. Sci.

    (2009)
  • M. Kakhi

    Classification of the flow regimes in the flow-through cell

    Eur. J. Pharm. Sci.

    (2009)
  • L. Kalantzi et al.

    The delayed dissolution of paracetamol products in the canine fed stomach can be predicted in vitro but it does not affect the onset of plasma levels

    Int. J. Pharm.

    (2005)
  • L. Kalantzi et al.

    In vitro methods can forecast the effects of intragastric residence on dosage form performance

    Eur. J. Pharm. Sci.

    (2008)
  • M. Kataoka et al.

    Effect of food intake on the oral absorption of poorly water-soluble drugs: in vitro assessment of drug dissolution and permeation assay system

    J. Pharm. Sci.

    (2006)
  • M. Kataoka et al.

    Estimation of P-glycoprotein-mediated efflux in the oral absorption of P-gp substrate drugs from simultaneous analysis of drug dissolution and permeation

    Eur. J. Pharm. Sci.

    (2011)
  • B. Abrahamsson et al.

    A novel in vitro and numerical analysis of shear-induced drug release from extended-release tablets in the fed stomach

    Pharm. Res.

    (2005)
  • G.L. Amidon et al.

    A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability

    Pharm. Res.

    (1995)
  • M.U. Anby et al.

    Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems

    Mol. Pharm.

    (2012)
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