Figure 8.1. Factors that influence design of new drug delivery systems.

Irrespective of whether market pull or technology pull drives the development of new drug delivery systems, the ultimate success depends on the cost effectiveness and patient acceptability. This is exemplified by the market failure of inhalational insulin. After a decade of research, inhalational insulin was introduced in the market in 2007. However, the product did not generate revenue as expected by the manufacturer due to the complexity of the device and other issues. This eventually led to the withdrawal of the product from the market.⁶ Research in pharmaceutical companies is product- or technology-centred, while the academic research is mainly focused on understanding the basic underlying principles of drug delivery and applying that basic knowledge to develop newer systems. Thus, academic research serves as a foundation for translating scientific findings into useful products by the pharmaceutical industry.

The goal of this chapter is to provide an overview on pharmaceutics and drug delivery research for a beginner from an academic perspective. Most of the examples provided in this chapter are based on the authors’ own personal experiences and the experiences of other researchers in the field. Readers who are interested in knowing more about specific research areas in drug delivery and pharmaceutics can refer to some of the journals listed in Table 8.2. The chapter begins with a discussion on drug, disease, destination and delivery (4Ds) approach for developing new drug delivery systems followed by a discussion on the various components of a pharmaceutics research project.

Drug Delivery and Research—4Ds Approach

Drug

Pharmaceutical research is centred on design and development of drugs. A majority (40%) of the failures in new drug discovery programmes are attributed to the poor biopharmaceutics and pharmacokinetic properties.⁷ The biopharmaceutics and pharmacokinetic properties are in turn governed by the drug’s physiochemical properties. The important drug physicochemical properties include chemical structure, molecular weight, lipophilicity, aqueous solubility and stability. Different strategies can be used to address these delivery issues. An overarching goal of any new drug discovery programme is to develop an orally deliverable molecule because of the ease of drug administration and the established process for manufacturing oral dosage forms. Drug solubility and permeability are the two most important properties that govern oral drug absorption and bioavailability. On the basis of these two properties, a biopharmaceutics classification system (BCS) has been developed,⁸ which classifies drugs into four classes (Table 8.3). The BCS paradigm provides an important guideline for developing new delivery technologies to improve drug solubility and permeability.⁹ If the drugs cannot be delivered by oral route, then other routes of administration are pursued.¹⁰

As opposed to small drug molecules, macromolecules such as proteins and gene-based medicines present unique challenges due to their high molecular weight, complex structure, poor stability and poor membrane permeation characteristics.³ The landmark completion of the human genome project in 2001 and advances in basic biomedical knowledge have resulted in a plethora of proteins and gene-based medicines. There is a strong clinical and commercial need to develop new delivery systems for these challenging molecules.³ Developing new delivery systems for macromolecules requires a multidisciplinary approach to address the various delivery issues.

Table 8.2. List of representative journals related to pharmaceutics and drug delivery

^*According to the US FDA, a drug substance is considered highly soluble when the highest dose strength is soluble in <250 mL water over a pH range of 1–7.5.

^** According to the US FDA, a drug substance is considered highly permeable when the extent of absorption in humans is determined to be >90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose. (http://www.fda.gov/cder/OPS/BCS_guidance.htm).

Disease

The pathophysiology of the disease can provide several clues for the design of drug delivery systems. The physiological or cellular differences between the normal and the diseased tissues can be exploited for targeted drug delivery. For instance, the tumour vasculature is leakier than normal blood vessels. Also the tumour tissue has poor lymphatic drainage. Thsese two factors lead to enhanced permeability and retention (EPR) effect¹¹ for passive targeting of anticancer drugs. When anticancer drugs are encapsulated in small polymeric nanoparticles (100–400 nm) they pass through the tumour vasculature and are trapped inside the tumour due to the poor lymphatic drainage. On the other hand, the intact blood vessels in the normal tissues exclude these particles. Higher order targeting can be achieved by attaching ligands to the delivery system which then specifically binds to receptors expressed by the diseased tissue.¹² In case of endogenous compounds such as proteins, it is essential to understand how the endogenous levels change with the circadian rhythm. For example, the plasma levels of insulin are generally high after a meal and are secreted at basal level during other times. This has led to the development of rapidly acting and long-acting insulin formulations to address high and basal insulin demand, respectively.¹³ Therefore, a thorough understanding of the pathophysiology of the disease allows a drug delivery scientist to address the delivery issues for specific diseases.

Destination

The site where the drug needs to act can often dictate the route of drug administration. However, this may not always be possible if the site is not easily accessible or if the drug cannot be administered by a particular route because of the drug’s physicochemical properties. For example, it is logical to develop a topical product for treating skin diseases rather than administering the drug systemically. This may prevent unwanted exposure to other tissues and adverse effects. However, the remarkable barrier properties of the skin may not allow sufficient drug concentrations to reach the skin layers, which may necessitate the systemic administration. In this case, a researcher can develop strategies for increasing the drug permeation through skin.

For drugs that are presently given by injections, there is a tremendous potential to develop non-invasive delivery systems to reduce the pain and discomfort associated with injections. Vaccines represent one such class of drugs where non-invasive delivery can have huge implications for routine immunisation and mass vaccination programmes. Irrespective of the route of administration, the drug has to cross several biological barriers before it can reach the site of action. Therefore, it is important to understand the transport of drugs across biological membranes vis-à-vis use that knowledge to design drug delivery systems. For example, prodrugs can be designed by attaching endogenous compounds such as amino acids to drugs, which can then be ‘ferried’ across the biological membrane by amino acid transporters.¹⁴ Similarly, the local environment at the target site can be used to deliver the drug to the desired site. For colonic diseases, a polymeric system or azo bonding (e.g. sulfasalazine) that is specifically broken down by bacteria in the colon can be used to target and release the drug for local action.¹⁵ Therefore, a researcher working in drug delivery should have a good understanding of the anatomical and physiological aspects of the target site.

Delivery System

The delivery system, which is the main focus of pharmaceutics research, should integrate the 3Ds (drug, disease and destination). Apart from the drug, a delivery system involves several components such as polymers, stabilisers and preservatives. In this regard, it is essential to consider the properties and safety of the non-drug additives before developing a delivery system. On the other hand, new carriers can be designed to overcome the issues with the existing carriers such as payload capacity, safety, etc. In addition to materials, some devices are also used in drug delivery such as iontophoretic devices or metered dose inhalers. A drug delivery approach used for one disease may be optimised for another disease condition. Sometimes the drug may have toxicity issues associated with a particular route of administration and this must be examined early in the development phase. For instance, in transdermal drug delivery, it is important to ensure that the drug by itself does not cause any skin irritation. Most importantly, there should be a strong rationale for developing a new delivery system. To name a few, the rationale may be improved patient compliance or reduced dosing frequency or reduced adverse effects, or overcoming the limitations of conventional therapies.

Basic Principles for Pharmaceutics Research

A research endeavour is expected to address some questions and raise more questions for further research. This cycle of questioning and reasoning (Figure 8.3) continues till satisfactory answers are obtained by the researcher.¹⁶ The elements of pharmaceutics or drug delivery research are not any different from the basic elements of scientific research. For more discussion on basics of research, see Chapters 1 through 5. In this chapter, pharmaceutics or drug delivery examples are discussed pertaining to different components of a research project.

Figure 8.3. The research cycle of ‘questioning’ and ‘answering’.

Research Idea/Theme/Problem

The human mind has to first construct forms, independently before we can find them in things.

(Einstein)

A research project stems from an interesting idea that is generated based on the scientific background of the researcher. An idea or a research problem can stem from several sources such as the literature, by talking to colleagues or listening to seminars, or getting clues from other fields. In this regard, patents are also useful resources for new ideas. The patents can be easily accessed through the Internet (www.uspto.gov; www.wipo.int/pctdb/en/). Robert Langer, who is a world-renowned drug delivery scientist from MIT, invented the concept of delivering multiple drug molecules using a microchip.¹⁷ He got this idea while watching a television programme on how computer chips were made.¹⁷

There is a general perception, particularly among beginners, that research is discovering ‘something new from scratch’. More than often not, research involves refining or optimising an existing model or system, albeit answering new questions. For example, it is generally known that larger particles are rapidly cleared by blood macrophages by phagocytosis. However, the influence of particle shape on phagocytosis was not known until recently.¹⁸ This would allow us to take advantage of the shape, in addition to the particle size for designing an efficient particulate delivery system. In pharmaceutics, the research ideas are centred on improving the deliverability of drugs through different routes of administration by developing new delivery systems or modifying existing systems (Table 8.4). Product development issues in the pharmaceutical industry can also be excellent research topics for academic scientists.

Table 8.4. Representative list of core research themes in pharmaceutics/drug delivery

It is helpful to have a handy notebook to write down the so-called ‘bright ideas’. Fredrick Banting always used to have a notebook on his bedside. One day he woke up in the middle of the night to write down the idea of isolating insulin from the pancreas. This bright idea revolutionised the field of medicine and later got him the Nobel Prize in medicine (http://nobelprize.org/nobel_prizes/medicine/laureates/1923/banting-bio.html). For a beginner, it is not unusual to ‘passively’ read and understand the literature, but with experience, one should ‘actively’ read the literature and raise new questions. Once a researcher identifies a research problem, he or she should subject it to unbiased and vigorous scrutiny by brainstorming with colleagues, and searching the literature for validity, feasibility and the availability of funds to carry out the research.

A reductionist approach is helpful to breakdown a bigger problem into smaller ones. Sometimes simple cartoons or flow diagrams can be helpful. It provides a means to express and visualise an abstract idea. Helmut Ringsdorff, a well-known polymer scientist, is famous for his cartoon on multifunctional polymeric drug delivery systems involving a targeting ligand, drug and a release modifier. Although this was just a theoretical concept in the early 1970s, it led to a new field of polymer therapeutics later.¹⁹

Objectives

The objectives or goals of the research project are measurable outcomes to test the research hypothesis. The goals should not be a list of experiments, but rather well-defined measurable outcomes. All the goals should be logical and complement each other to test the hypothesis. It is important to ensure that the goals are achievable within the proposed timeline and budget. Every goal or objective should be justifiable on its own merit and should be based on a sub-hypothesis. If all the sub-hypotheses are supported, then the central hypothesis is automatically supported. For example, the transdermal delivery of a drug X is based on a hypothesis that the transdermal drug delivery can lead to controlled drug delivery for up to a week to treat hypertension. To test this hypothesis the goals can be set as follows:

1. To study the skin permeation of drug X through excised guinea pig skin using ethanol and propylene glycol as solvents

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