Selecting oral bioavailability enhancing formulations during drug discovery and development.

Review

Selecting oral bioavailability enhancing formulations during drug discovery and development 1.

Introduction

2.

In silico chemical structures screening with biological activity for lead optimization

Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Chulalongkorn University on 12/31/14 For personal use only.

3.

Methods in preclinical drug development

4.

The selection of the early formulations in clinical pharmacology and clinical studies

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Methods to enhance solubility, dissolution rate and permeability in formulation studies of oral drug dosage forms

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Quality by design toward a biopharmaceutical quality of drug delivery systems by manufacturing processes

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Conclusions

8.

Expert opinion

Sorin Emilian Leucuta “ Iuliu Hatieganu” , University of Medicine and Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, Cluj-Napoca, Romania

Introduction: The role of chemical structure, lipophilicity, physico-chemical, absorption, distribution, metabolism, excretion, toxicity (ADMET) and biopharmaceutical properties of compounds including bioavailability are critical in drug discovery and drug dosage forms design. Areas covered: The authors discuss a number of parameters including computational approaches used for selected chemical structures with biological activity for lead optimization and chemogenomics and preclinical studies for ADMET process development of ligand properties. The authors also look at a number of other parameters including: early drug product formulations with method selection based on the biopharmaceutical classification system (BCS); in vitro--in vivo correlation (IVIVC) and different formulation strategies to enhance solubility; dissolution rate and permeability; bioavailability evaluation and quality by design as an opportunity to develop ‘safe space’ regions, where bioavailability is unaffected by pharmaceutical variations. Expert opinion: The biopharmaceutical requirements for absorption are solubility and permeability. Both are influenced by lipophilicity, but in the opposite way. The genomic methodology, coupled with combinatorial chemistry, high-throughput screening, structure-based design and in silico ADMET would yield parameters as a starting point for the biopharmaceutical properties determination in further preclinical and clinical studies. Consecutive stages in drug discovery and development are irreplaceable, but pharmacokinetics is the critical step. Selection of drug formulations based on the BCS, IVIVC are the principal aspects to enhance the solubility and dissolution rate, while a rationale management of pharmaceutical and technological factors will enhance the bioavailability. Keywords: ADMET properties, bioavailability, biopharmaceutical classification system, clinical testing, computer-aided drug design, dissolution rate, drug discovery, drug dosage form formulation, high-throughput screening, in vitro--in vivo correlation, lipophilicity, oral delivery, physicochemical properties, poorly soluble drugs, preclinical evaluation, solubility, structure-based drug design bioavailability Expert Opin. Drug Discov. (2014) 9(2):139-150

1.

Introduction

The traditional process of discovery of new therapeutics consists of two stages, drug discovery including computation, preclinical testing in absorption, distribution, metabolism and excretion (ADME) process development, clinical studies and drug dosage form development and registration. The discovery stage includes target selection, a receptor (gene or a protein), a promising molecule that can interact with the target or lead identification and validation, then its optimization by screening many similar compounds and preclinical studies of drug development focused on evaluation of the safety and efficacy of new drug candidates including preclinical 10.1517/17460441.2014.877881 © 2014 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted

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Computer-aided (in silico) approaches methodology in selected chemical structures with biological activity for lead optimization and to the choice of a new chemical entity. Chemogenomics and preclinical studies for absorption, distribution, metabolism, excretion, toxicity process development of ligands properties focus on the lipophilicity role in solubility and permeability. Early drug product formulations operate with method selection based on biopharmaceutics classification system, the biopharmaceutics drug disposition classification system, in vitro--in vivo correlations and different formulation strategies. Methods to enhance solubility, dissolution rate and permeability in formulation studies of oral drug dosage forms in preclinical and clinical preregistration stages offer the possibility to select optimum characteristics of the new chemical entity and its dosage form. Bioavailability evaluation, and quality by design policy are opportunities to develop new methods of selecting formulations with improved absorption of poor soluble, poor permeable drugs and to maintain the desired outcome of industrial phases of technology including critical characteristics of the components in a design space automated controlled. Consecutive stages in drug discovery and development are irreplaceable but the global rate of the registration will be faster reached by overcoming the bottleneck of pharmacokinetic and toxicity property evaluations in the preclinical phase or and in drug product development.

This box summarizes key points contained in the article.

examination of pharmacokinetics (PK) and drug metabolism properties (or ADME process in animal studies) as part of the screening processes in the selection of drug candidates. The clinical studies and drug dosage from development stage includes pharmacological and clinical trials, because biological activity must ultimately be tested in humans, followed by registration of new drug entity and its dosage form, large-scale manufacturing and product lifecycle management [1-4]. The main reason for failure in drug research in the past decade was the lack of efficacy followed by safety and toxicity concerns, negative biopharmaceutical and PK properties of the lipophilic drug candidates in the context of the design and selection of new and better lead compounds. The attrition of promising active principle ingredients (APIs) as they progress from discovery into preclinical and then through clinical trials remains high. The attrition of drug candidates isn’t solely due to lack of efficacy or unforeseen toxicity but also due to problems and pitfalls with bioavailability. The principles of drug design aims to describe the process of drug discovery and development from the identification and selection of novel drug targets, target optimization, lead identification and lead optimization, as well as structure-based drug design (SBDD) methods and the use of computational 140

and combinatorial chemistry, for the introduction of new drugs into clinical studies. The rational design of a drug will explain the biological effect on the basis of the molecular interactions dependent on the molecular structures or physico-chemical properties of the molecules involved; various mechanisms to produce the pharmacological effects; the PK of the drug and probable relationship between biological activity with chemical structure, and pharmaceutical delivery system formulation and biopharmaceutics. Research and development (R&D) strategies presume the ability to identify, characterize new chemical entities (NCEs), which essentially possess the inherent capability and potential in the management and control of a specific disease/ailment with safer characteristics [5,6]. Many highly potent lead pharmaceutical compounds with optimized pharmacodynamic (PD) properties synthesized in pharmaceutical R&Ds with advanced combinatorial chemistry and computer-aided drug designing (CADD) approaches suffer from poor solubility- and bioavailability-related issues because of their relatively suboptimal biopharmaceutical characteristics. The drawback of lead compounds exhibiting delivery limitations due to molecular structure necessitates drug bioavailability and solubility enhancement strategies to reduce the negative impact of compounds with poor solubility on their ADME properties. Optimization of API chemical (e.g., salt formation) and physical (e.g., particle size reduction through milling) properties is often times employed to improve oral bioavailability of insoluble compounds. Computational models for ADME prediction rely heavily on aqueous solubility, metabolic stability and membrane permeability. There is a greater availability of in vitro and in situ approaches to screen compounds for intestinal permeability (as a surrogate for absorption) and metabolic stability (as a surrogate for clearance) and a variety of methods for predicting biopharmaceutical properties among which the intestinal permeability parameter is particularly important. The analysis of PK data from preclinical in vivo studies can provide some insight on the exposure of a candidate molecule being limited by dissolution or solubility [7]. 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 initiated. Both for compounds formulated for in vivo testing or commercially viable, the screening technologies should be versatile, robust and scalable. There is a need to improve the current in vitro tools to more closely simulate key aspects of gastrointestinal (GI) physiology, so that formulation decisions can be made on robust and biorelevant data. The bottleneck is no longer in basic research but in PK characteristics of lead chemical compound and in product development. Only a comprehensive design of experiments (DoE), highthroughput biopharmaceutical drug development and statistical tools can promote valuable lead compounds. Going from small-scale to large-scale manufacturing is a major

Expert Opin. Drug Discov. (2014) 9(2)


Selecting oral bioavailability enhancing formulations during drug discovery and development

undertaking in accord with strict FDA guidelines for Good Manufacturing Practices [8]. The succession of stages included in the drug discovery and development is carried out with a certain speed and like in kinetic processes, the lowest speed stage determines the global speed. The period of research until the registration of a new drug dosage form may be 10 -- 15 years. Each stage process has its peculiarities, its degree of complexity and requires discriminatory screening of chemical compound properties to comply with research objectives, namely activity, the relative lack of toxicity, PK properties, metabolism and pharmacogenomics. This is the pathway that ultimately leads to the choice of a new chemical entity, a drug substance, having properties which can be administered to humans in clinical trials, and then can be approved for marketing, having as main characteristics clinical efficacy and clinical safety. This process has several critical steps needed to choose the most appropriate characteristics of chemical compounds investigated (Figure 1). Selecting oral bioavailability enhancing formulations during drug discovery and development has to be linked to previous in vitro and preclinical stages, for the characterization of the physical-chemical and biopharmaceutical properties of chemical compounds investigated. These properties such as chemical structure, lipophilicity and solubility are essential for determining the bioavailability characteristics. Therefore, the sequence of research stages of new bioactive compounds requires selecting the appropriate chemical structures, PK properties, toxicology and pharmacogenomics as well as drug delivery system properties, to provide NCE registration as a drug and a pharmaceutical dosage form, respectively. The objective of this paper was to identify drug design strategies for lead optimization, preclinical studies for ADMET properties evaluation, early drug product formulations with method selection-based biopharmaceutics classification system (BCS), in vitro--in vivo correlation (IVIVC) and different formulation strategies to enhance solubility, dissolution rate and permeability, oral bioavailability enhancing approaches to develop safe space regions in product fabrication, where bioavailability is unaffected by pharmaceutical formulation.

In silico chemical structures screening with biological activity for lead optimization

2.

It has been of great importance to identify protein targets, to develop targeted chemical compounds, construction of drug--target interaction network. The process of finding a drug molecule that attaches itself to the target protein in the body has moved from the lab to the computer. The screening of a large database of known molecules is a method called virtual high-throughput screening (HTS). HTS discovery helped identify countless chemical compounds with suitable properties in terms of biological action, but who had the physicochemical and biopharmaceutical inappropriate properties, a

reduced in vitro dissolution rate and permeability, which causes inadequate bioavailability [9-12]. To test pharmacological hypotheses tools such as in vivo and in vitro models were used, but in last decades computational (in silico, or CADD) methods have been applied to pharmacology hypothesis in drug discovery [13-15]. The term ‘in silico’ is used to mean experimentation performed by computer. Quantitative structure--activity relationship (QSAR) uses molecular descriptors as numerical representations of chemical structures [16]. One-dimensional descriptors encode numerically generic properties (molecular weight, molar refractivity, octanol/water partition coefficient). On the other hand, twodimensional (2D) descriptors are computed from topological representations of molecules (in 2D-QSAR models), but three-dimensional (3D) descriptors are obtained directly from the 3D structure of proteins (3D-QSAR methods) [17-22]. The virtual screening (VS) methods give a good approximation of the expected conformation and orientation of the ligand into the protein cavity (docking) and of its binding affinity (scoring) [23-25]. Molecular docking is a method to predict the predominant binding mode(s) of a ligand with a protein of known 3D structure, which is routinely used in structure-based drug discovery for hit identification (VS) and lead optimization [26]. The computational approaches have applications in all stages in the discovery and development pipeline: target identification, lead discovery, lead optimization, preclinical or clinical trials but also other objectives like synthesis route prediction, simulation of cellular or organ complex systems. The techniques in computational analysis are very different, such as VS or de novo design, quantum mechanical calculations, statistical models for metabolism and toxicity predictions [27]. Conventional approaches lead to identifying targets as proteins and modern approaches lead to the identification of thousands of new targets, expressed genes and protein coded by a particular genome [28,29]. The validation of novel molecular targets by the use of reliable animal models and gene targeting techniques are essential to prove their therapeutic value. The progression of high-throughput technologies in the areas of target discovery and lead identification determines the target validation step remaining the bottleneck in the discovery process. The lead identification as a compound that demonstrates a desired biological activity on a validated molecular target necessitates the application of combinatorial chemistry to produce molecule libraries. Some methods are used, such as VS, informatics, advances in pharmacophore mapping, high-throughput docking, nuclear magnetic resonance-based screening and chemical genetics. Drug candidate optimization is established according to molecular pharmacology properties, by the QSAR or CADD, or SBDD. This process is known as lead optimization. In a typical lead optimization process, tens of assays are run in parallel to evaluate the potency of each candidate molecule, its specificity and its ADMET properties. Computational drug design


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Reevaluation of in silico models, iterative lead optimization High throughput screening Chemistry Genomics


Bioinformatics Expression arrays Proteomics Transgenes

Target identification

Chemogenomics Microarray technology Mining databases

Phase IV clinical trails

Pharmacovigilence Large scale manufacturing Therapeutic use Safety monitoring

Target validation

Lead ptimization

Animal models Diseasemodels Computational chemistry In silico structure-based design Screening to find hits

Computational biology Cheminformatics Structure-based design for affinity and selectivity Chemical hits

Registration

Phase III clinical studies

IND/NDA

Safety, efficacy in large patient population

Lead preclinical ADMET

Animal studies Safety, pharmacokinetics Drug metabolism Dosage prediction Preformulation

Phase I – II clinical pharmacology First human exposure for efficacy, safety

Figure 1. Drug discovery and development: innovation/research-development/clinical development process.

approaches can be roughly divided into ligand-based (when structural information is missing or not fully reliable) and structure-based methods (where structural data of the target protein exist) [30]. Commercial chemical libraries for HTS (i.e., the ability to test > 500,000 compounds in an assay) are primary sources for hit identification (web service AdmetSAR), because it is a comprehensive source of chemical ADMET properties. In future development, it is necessary to establish a research pattern that is oriented by computational analyses and brings into full play chemistry, biology and other disciplines with complementary strengths. SBDD is an iterative approach and is considered as one of the most innovative and powerful approaches in drug design. It requires 3D structure of the target protein, preferentially complexed with a ligand, and subsequently, various methods to be used to design a high-affinity inhibitor either via virtual computer screening of large compound libraries or through design and synthesis of novel ligands [31]. Dynamic combinatorial chemistry is a recently introduced supramolecular approach that uses self-assembly processes to generate libraries of chemical compounds that is capable, in principle, of accelerating the identification of lead compounds for drug discovery [32]. Computational techniques assist one in searching drug target and designing drug in silico. The processes of designing a new drug using bioinformatics tools have opened a new area of research. Bioinformatics tools can provide information about potential targets and has become a major part of the drug discovery pipeline, playing a key role for validating drug targets. Bioinformatics can help in the understanding of complex biological processes and help improve drug 142

discovery. The use of computer modeling to refine structures has become standard practice in modern drug design. Drugs that are synthesized and tested by the computational techniques can contribute a clear molecular rationale modeling [33,34]. Computer-aided molecular design and SBDD help in the discovery of new classes of ligands, selection of promising lead compounds, but this is not enough to talk about them as drug substances, before the study of their interaction with receptors and their in vivo ADME characteristics. 3.

Methods in preclinical drug development

The genomic methodology, coupled with combinatorial chemistry, HTS, structure-based design and in silico ADMET would yield hundreds of candidates which will be studied not only as biologic active components, but also with their PD, PK and pharmacogenomic properties. The optimization of ligands properties (potency, selectivity and PK) toward a single macromolecular target changed organic chemistry to chemogenomics, matching the target and ligand space, identifying all ligands of all targets. Beyond understanding the nature of biological interactions in disease by these methodologies, new drug candidates will enter clinical trials [35,36]. The development part of the drug discovery follows the lead identification as biologic active compounds, with preclinical studies on the physicochemical and PK, toxicokinetic and biopharmaceutical characteristics (ADMET) of these compounds. The challenges in computer simulation of biopharmaceutical properties of small molecule compounds, so-called in silico ADMET has been particularly successful through implementation of models using predicted and measured




biopharmaceutical data. Biopharmaceutical properties have been widely predicted using molecular descriptors for the prediction of drug solubility and intestinal permeability. QSAR approaches ranging from simple multiple linear regression to modern multivariate analysis techniques, such as partial least squares are now being applied to the analysis of ADME data [37-41]. The relationships between important ADMET parameters and molecular structure have been used to develop in silico models that allow early estimation of several ADMET properties. Lipophilicity is a main factor in determining the PK properties of drug candidates. One of the well known of its qualitative estimation is the Lipinski’s rule-of-five based on the observation that most medication drugs are relatively small and lipophilic molecules [42,43]. Low bioavailability is encountered in some molecular compounds with high molecular weight (> 500), greater value of repartition coefficient or logP (> 5), greater number of hydrogen bond donors (> 5) and more hydrogen bond acceptor sites (> 10) as well as great number of rotatable bonds, on the molecule [44]. Descriptors for polar and non-polar surface area were generated, or in combination with descriptors as electrotopology, flexibility, bipolarity, polarizability and charge and were used in solubility predictions [45,46]. Accurate in silico prediction of oral absorption and distribution of a number of compounds is now possible. Computational tools have great utility in VS, in silico ADMET prediction and protein--ligand binding. Computer modeling and simulation is complementary to, but cannot replace, animal studies. The metabolism as one of the PK properties of a chemical compound depends on its lipophilicity but also on the biologic environment and software packages are not able to predict them [47]. Research and preclinical studies using animal models with a combination of in vitro assays, computer simulations and non-invasive or minimally invasive human studies (microdosing or Phase 0) were also proposed. EMA recognition of the possibility of performing in special rigorous conditions, PK studies in humans would greatly hasten the possibility of moving research from preclinical to clinical trials [48]. Supposing a drug candidate was chosen as a lead biologic active compound, it is necessary to prepare early formulations for preclinical studies in animals by different routes of administration, such as oral or intravenous, especially for PK, PD and pharmacotoxicity evaluations [49]. The key properties of interest in drug design and dosage form formulation include chemical structure and derived physicochemical and biopharmaceutical properties and in silico determinations. Solubility enhancement is necessary if solubility is < 1% (w/v) or 10 mg/ml in the aqueous or buffers, and a very small solubility can determine the use of a suspension (oral, extravasal routes), or modifying the dosage form: emulsion, nanoparticles, tablets, etc. The interests in preclinical studies refer to those compounds involved in exploratory chemistry, lead selection and optimization include in-depth activity/efficacy, PK and toxicology profiling [50].

Preclinical development activities in the drug development process is crucial because chemical compounds are evaluated for their characteristics, that is, the likelihood that they will be successful drugs, such as easy formulation, exposure (solubility, metabolism, bioavailability, PK properties), toxicity (reactive metabolites, effects on organs, drug interactions).

The selection of the early formulations in clinical pharmacology and clinical studies

4.

The oral route of administration is one of the most useful and convenient for patients. Oral bioavailability of drugs is dependent on the physicochemical and biopharmaceutical properties of the drug substance, the nature, quantity and reactivity of the excipients in dosage form, the technological factors used in the preparation of the drug dosage form and physiological factors. For the first-in-man in clinical pharmacology studies, we need to develop some pharmaceuticals with new bioactive compound for administering the volunteer subjects, healthy and patients, in Phase I and II studies, respectively, as well as for the large number of patients in Phase III controlled clinical studies. Some key methods for selecting oral bioavailability enhancing formulations during pharmacological and clinical studies are the BCS, the Biopharmaceutics Drug Disposition Classification System (BDDCS) and IVIVCs [12,54]. A BCS has categorized hit compounds, based on their aqueous solubility and intestinal permeability. The BCS is a useful tool for decision making in the discovery and early development of new drugs. The regulatory agencies and health organizations have utilized this classification system to allow in vitro dissolution to be used to establish bioequivalence for highly soluble and highly permeable compounds [51-53]. Because there is a strong correlation between the intestinal permeability rate and the extent of metabolism, BDDCS was proposed as a means to predict the drug disposition characteristics of new molecular entities, during the early stages of drug discovery and development [54]. Studying BDDCS for > 900 compounds, it was found few drugs with metabolism between 30 and 70%, most drugs being very highly metabolized (> 70%) or very poorly metabolized (< 30%) [55]. BDDCS also allows potential drug development, drug--drug interactions to be predicted and also predicting the effect of high-fat meals on the extent of bioavailability [56]. One of the challenges of biopharmaceutics research is correlating in vitro drug release information of various drug formulations to the in vivo drug profiles to shorten the drug development period, to reduce the number of human studies during the development period, to serve as a surrogate for in vivo bioavailability, to support biowaivers as well as in quality control for certain scale-up and post-approval changes [57]. IVIVCs could be referred to as the relationship between appropriate in vitro release characteristics and in vivo bioavailability parameters [58]. Five correlation levels have been defined in the IVIVC FDA guidance [59].


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Level A correlation is the highest category of correlation and represents a point-to-point relationship between in vitro dissolution rate and in vivo input rate of the drug from the dosage form. A level B IVIVC utilizes the principles of statistical moment analysis. In this level of correlation, the mean in vitro dissolution time (MDTvitro) of the product is compared with either mean in vivo residence time or the mean in vivo dissolution time (MDTvivo). In level C correlation, one dissolution time point (t50%, t90%, etc.) is compared with one mean PK parameter such as area under the curve, time to Cmax after drug oral administration or maximum plasma drug concentration. Level D correlation is a rank order and qualitative analysis and serves as an aid in the development of a formulation or processing procedure. BCS is a fundamental guideline for determining the conditions under which IVIVCs are expected [60]. Comparison between dissolution profiles in vitro could be achieved using a difference factor (f1) and a similarity factor (f2), which originates from simple model independent approach [61]. The similarity factor is a measurement of the similarity in the percent dissolution between the two curves of in vitro dissolution of two formulations with the same drug in the same dose. The determination of f2 can evaluate whether or not the two formulations are similar in the in vitro dissolution profile. Waivers were originally designed only for class 1 drugs. Recently, EMA allows biowaivers for BCS class 3 drugs in specific cases if > 85% of the drug dissolves in 15 min. The FDA, WHO and EMA allowed a BCS-based biowaivers for drug products containing BCS class 1 drugs when the drug products exhibit rapid dissolution [62-64]. There are different formulation strategies of selecting the investigational drug dosage forms based on BCS [65]. For BCS class 1 or 3 drugs, formulations are designed with a simple strategy. However, for BCS class 2 or 4 drugs, deliberate formulation designs based on both the physico-chemical and biopharmaceutical properties of the drugs are required to obtain sufficient and reproducible bioavailability after oral administration. The bioavailability of a BCS class 2 drug absorption is rate limited by its dissolution; an enhancement of the dissolution rate of the drug is a key factor for improving the bioavailability. The bioavailability of BCS class 3 (high solubility and low permeability) drugs is rate limited by the membrane permeability in the GI tract. The intrinsic lipophilicity of a drug is determined by its chemical structure; therefore, it is necessary to return to the lead optimization phase to increase the permeability via the transcellular route. BCS class 4 drugs exhibit challenging molecular properties such as low solubility and low permeability, both are rate-limiting steps for absorption; it would be considered that physiological factors highly influence the absorption of BCS class 4 drugs. FDA’s BCS is an attempt to rationalize the critical components related to oral absorption and utilization of these principles for selection of a suitable technology to serve the interests of the early stages of drug discovery [66-69]. 144

However, there remains a need for the pharmaceutical industry to develop reliable IVIVCs and in silico methods for predicting the rate and extent of complex GI absorption, the bioavailability and the plasma concentration--time curves for orally administered drug products.

Methods to enhance solubility, dissolution rate and permeability in formulation studies of oral drug dosage forms

5.

One of the key parameters of the biological quality of a drug dosage form is its bioavailability. For poorly soluble drugs, the principal aspects are to enhance the solubility and dissolution rate in order to enhance the bioavailability. The official definition is: “Bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action” [70,71]. It is more practical to define the bioavailability as the extent and the rate to which a drug substance or its active moiety is delivered from a pharmaceutical form and becomes available in the general circulation, because the site of action is unknown for many drugs and it is often impossible to assay drug concentrations at the site of action. A correlation exists between plasma and biophase drug concentrations. The biophase bioavailability can be realized by the systemic bioavailability following common routes of administration, or directly the site-specific biophase bioavailability for the formulations capable of cellular internalization, where the drug release only will take place, with the aid of nanoparticulate drug delivery systems [72-74]. In some cases, preparing nanopharmaceutical delivery systems may improve oral bioavailability [75]. The solubility of a drug substance depends on the nature and intensity of the forces present in solute and the solvent, as well as the resultant solute--solvent interaction. The nature of the energies interaction and the interplay of the electronic and steric factors in determining the solubility of substances in various solvents was presented [76]. The solubility can be increased using soluble salts of the drug [77], co-solvents [78], hydrotropic adjuvants [79] or soluble cyclodextrin complexes [80]. Dissolution is defined as a dynamic process by which a material is transferred from solid state to solution per unit time. The dissolution rate is described in the Noyes--Whitney equation [81]. There are different methods to enhance the solubility and dissolution rate of the poorly soluble drugs permitting the selection of the desired drug or dosage form [82-84]. One of the most important domains of research in pharmaceutical technology is focused on maximizing dissolution rates or equilibrium solubilities of drug particles with poor solubility and permeability. Mostly, the three types of formulation strategies are used to enhance the dissolution rate: physical, chemical and technological methods. Physical approaches includes solubility enhancement by particle size reduction (Table 1) [85-90]. Chemical approaches involve partial chemical modification by formation of salts, ester prodrugs and ionic




complexes with poorly water-soluble drugs (Table 2) [76,77]. Technological tactics uses solubilizing agents, technologies for colloidal dispersions of the drug and especially nanotechnologies in order to increase drug solubility, dissolution rate and bioavailability (Table 3) [91]. Permeability enhancement for poorly permeable drugs is a key objective in the screening of NCE. Different permeability enhancement techniques for poorly permeable drugs in order to prevent or restrict presystemic degradation and poor penetration across the gut wall should be used [92,93].

Quality by design toward a biopharmaceutical quality of drug delivery systems by manufacturing processes

6.

The FDA and EMA are encouraging the use Quality by Design (QbD) in the development of drug products. The principle is outlined in the ICH guidelines Q8 (Pharmaceutical Development), Q9 (Quality Risk Management), Q10 (Quality System) and Q11 (Manufacture). In November 2009, the FDA published the final ICH Q8 (R2) Guidance on Pharmaceutical Development [94]. These documents offer a lifecycle approach to continual improvement to drug manufacturing. A process is well understood when all critical (direct impact) or key (indirect impact) sources of variability are identified and explained (so-called control space). Variability is managed by the process design and monitoring. Product quality attributes are accurately and reliably predicted over testing of extreme combinations of all operating parameters for process, equipment and facilities (so-called design space, safe space). When a QbD approach is selected, robust product formulation and manufacturing processes should be designed to achieve desired product performance and also relate to desired clinical performance. QbD is partially based on the application of multivariate statistical methods and statistical DoE strategy for the determination of the process and product design spaces and for the development of both analytical methods and pharmaceutical formulations. Process analytical technology (PAT) comprises designing, analyzing and controlling processes by measuring on line critical process parameters and quality attributes. However, the PAT initiative is only one topic within the broader FDA initiative of ‘Pharmaceutical cGMPs for the 21st century -- a risk-based approach’ [95]. If product performance is within the design space, dissolution testing may not be needed as a routine test for a finished product specification or could be replaced by other surrogate testing (e.g., near infrared) [96,97]. The QbD associated with the BCS and IVIVC allows for fast development and increases quality when properly conducted. 7.

Conclusions

The drug discovery and development process is a long and expensive one. It starts from target identification, validation

of the targets and identification of the lead compounds, mainly with computational methods. Preclinical studies are designed to investigate the ADMET properties of novel lead compounds. The ultimate goal is to minimize the potential for clinical risk and maximize the efficacy. Correlating in vitro drug release information of various drug formulations to the in vivo drug profiles and focusing BCS as an indicator of developing a predictive IVIVC give the importance of drug dissolution and permeability on selecting formulations with good bioavailability. Optimization of pharmaceutical dosage forms for a great and reproducible bioavailability, lead the registration of the NCE. Maintaining the critical attributes of the drug and dosage form in a safe space during manufacturing assures these quality attributes relative to clinical performance, to offer a better quality product to the patient. 8.

Expert opinion

In drug discovery and development research, there are consecutive periods in which selecting oral bioavailability enhancing formulations have their importance, giving the opportunity to the next stage of screening that ultimately lead to the choice of a new chemical entity. The genomic methodology, coupled with combinatorial chemistry, HTS, structure-based design and in silico ADMET would yield many hundreds or thousands of candidates which will be studied not only as biologic active components, but some of them, also with their PD, PK and pharmacogenomic desired properties. The computational approaches as skills in drug design have applications in all stages in the discovery and development pipeline, from target identification to lead discovery, from lead optimization phases to preclinical or clinical trials. Simulations of complex systems at the cellular and organ level, synthesis route prediction and prodrugs development are also important fields in which computation can play a key role. The progression of high-throughput technologies in the areas of target discovery and lead identification determines the target validation step remaining the bottleneck in the discovery process. The drawback of lead compounds exhibiting delivery limitations due to molecular structure necessitates drug bioavailability and solubility enhancement strategies to reduce the negative impact of compounds with poor solubility on their ADME properties. There is a need to improve the current in vitro tools to more closely simulate key aspects of GI physiology, so that formulation decisions can be made on robust and biorelevant data. The bottleneck is no longer in basic research of lead chemical compound but in ADME preclinical studies and in product development and only a comprehensive DoE, high-throughput biopharmaceutical drug development and statistical tools can promote valuable lead compounds. The attrition of promising APIs as they progress from discovery into preclinical and then through clinical trials


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Table 1. The physical approaches to enhance dissolution rate of drug particles. Physical approach

Particularities

Comminution, micronization Cocrystal technology Solid dispersions

Jet mill, rotor-stator colloid mills and nanosuspension Crystalline API and excipient, stoichiometric ratio, hydrogen bonds Amorphous transformation of the API, drug in a hydrophilic carrier matrix (polyvinylpyrrolidone, polyethyleneglycol 6000, etc.), melt-mixing method, solvent evaporation method or SC fluid technology, dissolving then recrystalizing API from SC solvent (carbon dioxide, etc.) API, polymer, solvent, spraying technique Drug, polymer, extrusion technique, drug in amorphous state Injection device, cryogenic liquid (hydrofluoroalkanes) and various drying processing (freeze drying, lyophilization) of amorphous drug


Closed spray drying Hot melt extrusion Cryogenic techniques

API: Active principle ingredient; SC: Supercritical.

Table 2. Chemical approaches to enhance dissolution rate of drugs. Chemical approach Soluble salts or pH adjustment Prodrugs strategy Complexation method

Particularities Soluble salts of acids and bases poorly soluble, or pH adjustment to increase solubility of acids and bases Chemical derivatization of the drug (esterification) to introduce ionizable function lead to a prodrug soluble and in vivo bioconversible into active moiety Forming a water-soluble drug--ligand (cyclodextrin) complex

Table 3. Technological tactics to enhance dissolution rate of drugs. Technological approach

Particularities

Preparation of colloidal drug delivery system

Nanotechnologies The most important types of nanoparticles are: liposomes, niosomes, solid lipid nanoparticles, inorganic nanoparticles, carbon nanotubes, metallic colloid nanoparticles The polymer therapeutics: drug--polymer conjugates, protein--polymer conjugates, polymer micelles, dendrimers Surfactants

remains high. The attrition of drug candidates isn’t solely due to lack of efficacy or unforeseen toxicity but also due to problems and pitfalls with bioavailability. One of the key parameters of the biological quality of a drug dosage form is its bioavailability. For poorly soluble drugs, the principal aspects are to enhance the solubility and dissolution rate in order to enhance the bioavailability. The biopharmaceutical requirements for chemical compound absorption are solubility and permeability, both being influenced by lipophilicity, but in the opposite way. Few papers have also investigated their PK properties, although poor PK properties are one of the main reasons for terminating the development of drug candidates. This is the reason for in silico 146

Emulsions, microemulsions, self-microemulsifying drug delivery systems and self-microemulsifying drug delivery systems or suspensions, micro- and nanosuspensions Incorporating micromolecular drugs as well as biomolecules or biomacromolecules, including molecules as interference RNA or oligonucleotides. Matrix or reservoir-type systems Especially for cellular or subcellular targeting Increasing the solubility by hydrophilization of micellar solubilization

approaches to assess not only the VS, but also the ADME properties of compounds at the early stages of discovery/lead optimization, including in silico ADME/T prediction, and advanced methods for determining protein--ligand binding. These parameters are interconnected with in vitro lead validation and optimization, but also are a starting point for the biopharmaceutical properties determined in further preclinical and clinical studies. Consecutive stages in drug discovery and development are irreplaceable but the global rate of the registration will be faster reached by overcoming the bottleneck of PK and toxicity property evaluations in the preclinical phase. There are limitations of preclinical testing like extrapolation of toxicity data from animals to humans.




The human micro-dosing was admitted by the EMA and this should be a promising direction of obtaining human PK data early in the preclinical stage, while this would provide an answer to the growing public demand for a reduction in the use of animals for pharmaceutical development. Early formulation development is an integral part in drug discovery and development. The dosage form formulations are prepared mostly for drug compounds at both discovery stage and preclinical stages. Hence, early formulations are also known as animal formulations or preclinical formulations. Some of the most important methods used for the selection of drug formulations are based on the BCS, IVIVC which facilitate the increase bioavailability by increasing drug solubility. These methods allow in some classes biowaivers approvals by the registration organisms. It is not the case for poorly soluble drugs, where the principal aspects are to enhance the solubility and dissolution rate in order to enhance the bioavailability. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest The authors declare that they have no conflict of interest and have received no payment in the preparation of their manuscript.

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Sorin Emilian Leucuta Professor, “Iuliu Hatieganu”, University of Medicine and Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, Str. Victor Babes nr.8, 400023, Cluj-Napoca, Romania Tel: +40 264575841; E-mail: [email protected]

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Modulating Drug Release and Enhancing the Oral Bioavailability of Torcetrapib with Solid Lipid Dispersion Formulations.

Comparative oral bioavailability advantage from curcumin formulations.

Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects.

Bioavailability and bioinequivalence of drug formulations in small animals.

Systematic development of solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the oral bioavailability and intestinal lymphatic uptake of lopinavir.

Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles.

Bioavailability and Bioequivalence in Drug Development.

'Stealth' lipid-based formulations: poly(ethylene glycol)-mediated digestion inhibition improves oral bioavailability of a model poorly water soluble drug.

Exploring the potential of self-assembled mixed micelles in enhancing the stability and oral bioavailability of an acid-labile drug.

Drug development and discovery: challenges and opportunities.

Advancing the drug discovery and development process.

Safety Pharmacology in Drug Discovery and Development.

Comparative bioavailability of rifampicin and isoniazid in fixed-dose combinations and single-drug formulations.

Enhanced Dissolution and Oral Bioavailability of Piroxicam Formulations: Modulating Effect of Phospholipids.

Addressing toxicity risk when designing and selecting compounds in early drug discovery.

The bioavailability of ofloxacin from several formulations.

Bioavailability study of two different verapamil formulations.

Selecting targets from eukaryotic parasites for structural genomics and drug discovery.

Bioavailability and dissolution of proprietary and generic formulations of phenytoin.

In silico tools used for compound selection during target-based drug discovery and development.

Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy.

Bioavailability and dissolution of different formulations of oxytetracycline preparations.

Eudragit E100 nanostructures for enhancing oral bioavailability of carvedilol.

Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery.