Review articleInherent formulation issues of kinase inhibitors
Graphical abstract
Introduction
Small molecular Kinase Inhibitors (smKIs) form a promising and rapidly expanding class of drugs [1], [2]. The drugs target specific parts of Kinase receptor proteins that play an important part in the intracellular growth signaling pathways in tumor and immune cells [3], [4], [5]. After the first drug approval by the United States Food and Drug Administration (FDA) of Imatinib in 2001 [6], [7], the number of drugs approved by both the FDA and European Medicines Agency (EMA) are now nearing 30, listed in Table 1. Many more smKIs are being investigated in clinical trials and are expected to be approved in the coming years. A range of small molecular inhibitors have proven to be useful in the therapy of certain types of cancer. Additionally, smKIs may be prescribed as alternatives when other therapeutic options have failed or are deemed inappropriate [8]. A few compounds are (also) applied in the therapy of immunomodulated diseases [9], [10], [11], [12] and may even have a future in the therapy of diseases such as diabetes mellitus [13].
All of the smKIs are without exception administered orally. This has great advantages in terms of patient convenience and cost reduction [14], [15], [16]. It presents however serious difficulties for compounds with a low solubility and/or permeability. These drugs are hindered by a reduced and variable bioavailability. This may cause drug plasma concentrations to be ineffectively low or toxically high with all due consequences [17]. Understanding and controlling the parameters of solubility and permeability can therefore have a profound influence on patient plasma drug levels.
The smKIs have been designed using high-throughput screening and combinatorial chemistry from which the intricate structures and inherent solubility issues originate [18]. These means are used in the drug discovery of other drug classes as well, e.g. drugs acting on the central nervous system that also experience a problematic solubility [19].
Drug solubility and the dissolution process are affected by a plethora of factors with clinical implications. A number of these factors are inherent to the smKI structure and function. It follows that, as drug dissolution is most often the primary determinant for the smKI bioavailability, there is an apparent link between the high specificity of the smKIs and their impaired absorption into the systemic circulation.
This article will first present the overall problematic biopharmaceutical properties of the smKI drug group. Secondly, it will discuss the characteristic structural elements that are responsible for the solubility behavior of the smKIs. It will continue by reviewing the current commercial formulations along with alternative investigational formulations. This article aims to underline that although high specificity can, in many cases, place a challenging strain on drug solubility and bioavailability, different and innovative formulation techniques may present possible solutions to some of these issues. Literature offers several reviews that address (pre)formulation challenges for poorly soluble drugs in general [20], [21], [22]. This article focuses on smKIs in particular. To the authors' knowledge, this review is the first to combine literature and patent research on the solubility and formulation of smKI compounds from a pharmaceutical perspective.
Section snippets
Bioavailability
In the process of reaching the therapeutic target, the first step after oral administration and the disintegration of the dosage form is always the dissolution of the drug substance [75]. The second step, absorption, only takes place with the dissolved portion of the drug. Thus, poor drug solubility can be one of the main causes for a low and variable uptake of a drug into the systemic circulation, i.e. a low and variable bioavailability. This is generally true for the smKIs, as listed in Table
Essential structures
In the past few decades the role of signal proteins in the homeostasis of tumors became more and more apparent [80], [81]. The advancement of the diverse techniques and possibilities of molecular modelling have led to a therapeutic target-based drug discovery regime [82], [83]. With it, structure-activity relations for inhibitory molecules for these proteins were assessed. Key in these relations is the binding of the lead drug molecule to the receptor and the inhibitory action thereon [84]. The
Formulations
Partly as a consequence of the before-mentioned factors, the solubility of a drug salt polymorph can be described thermodynamically. The following combined equation illustrates this [137]:X, dissolved molar fraction; ΔHf, latent heat of fusion (heat absorbed during melting); R, gas constant; T, temperature; T0, melting point of solute; V, molar volume of liquid solute; Φ, volume fraction of the solvent; δ, solubility parameter (expression of cohesion
New formulations in literature and patents
Patents and exclusivities are still covering all of the smKIs, except for Imatinib [184], [185]. While registered and approved alternative formulations are a long way off, there is a limited body of research published and patented at the time of writing. This section will briefly discuss the most frequently reported and patented oral formulation types.
Discussion
The currently approved smKIs have important places in clinical practice for registered indications. A large fraction of these compounds is under investigation for additional indications. The new and upcoming smKIs target many of the same kinases and are designed in a similar fashion as the already marketed ones. Their general physicochemical properties might not differ significantly from those of the older smKIs. A low and variable bioavailability is an enormous problem and may also lead to
Conclusions
Due to the very distinct targeting of the smKIs, biocompatible physicochemistry is driven to the edge. This places a strain upon bioavailability and presents challenges to formulation scientists.
‘Classical’ physical mixtures may work to achieve a relatively high bioavailability for some compounds, namely Imatinib, Ruxolitinib and Dabrafenib. This is certainly not the case for the majority of smKIs however. Bearing patents and exclusivities in mind, the past experiences can lead to new and
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