Patient-centric drug design to improve therapeutic outcomes

Pharmaceutical companies put enormous amounts of time and money into developing drugs that are both safe and effective. Yet, all this effort comes to nothing if the patient fails to take the medication as instructed. Taking the patient’s view into consideration early on in the drug development process can greatly improve compliance rates, says Catalent

The leading cause of therapeutic failure in chronic conditions is patient non-compliance. The proportion of patients who fail to take their prescribed medications in accordance with instructions rises from nearly 40% after 6 months to almost 70% after a year.

The cost of non-adherence in North America alone was estimated to be $337 billion in 2013, so addressing the underlying issues that lead patients to give up on their medicines should be a priority.

There are several factors that affect patient compliance, including route of administration, pattern and frequency of dosing, length of treatment and drug side-effects.

There is also the physical and mental status of the patient to take into consideration; recent FDA guidance demonstrates a correlation between difficulty in swallowing certain dosage forms and a reduction in patient compliance, with a complete discontinuation of therapy in some cases. Studies have also shown that as the number of medications taken per day increases, adherence begins to decrease.

The aim of all pharmaceutical companies is to provide the best products to treat the most patients safely and effectively; but, at the same time, they also need to make the drug development process as quick, efficient and cost-effective as possible. This begs the question of whether patient-centric drug development can be mutually beneficial both to patients and to pharmaceutical companies.

According to respondents of the 2015 Drug Delivery Landscape Survey, while the pharma and biopharma industries can appreciate the role that the intelligent design of drug substances, drug products and packaging can play in patient adherence and outcomes, there is little evidence that it has been successful in implementing patient-centric drug design.

Formulation scientists and R&D managers from the pharma/biopharma industries responded that patient adherence is an important factor in developing a drug formulation; yet, when they were asked to rate the significant factors in drug development, elements such as patient adherence, patient dosing convenience and impact on the patient’s likely drug regimen all received low rankings.

A combination approach

There is a definite need for a drug delivery strategy that not only overcomes formulation challenges but also meets patient demands. For example, creating the smallest tablet or capsule formulation with the highest possible drug concentration may help to achieve better patient adherence.

Fortunately, there are advanced drug formulation and delivery technologies employed today that can not only solve formulation challenges, but are also likely to generate better outcomes — for patients, payers and innovators alike.

For success in this area, patient-centric design needs to be intentional, rather than implicit, and as the concept of intelligent design reaches maturity, pharma companies are beginning to consider patient-friendly dosage forms as early as possible. The sooner this happens, the less costs are incurred, but the survey results indicate that changes in design tend to occur at these later stages (Figure 1).

Figure 1: Patient-centric product design changes

Outsourcing partners will be of increased importance as companies begin to embrace patient-focused drug design, as innovators seek the experience of companies that understand the principles of patient-focused design, have a proven history of success generally, and can implement them in specific disease states.

Traditionally, oral dosage forms taken once a day have been accepted as the most suitable option for patients but the “appeal” of new products to patients is now being considered by drug innovators much earlier in the development process too, so that a once-a-day medicine is also easier to take, or perhaps that side-effects are minimised with the use of modified release technologies within that one dose.

There are many factors and options to consider during early drug formulation and dosage form development. A science-based approach that focuses on the drug’s ability to treat diseases through enhancements in bioavailability and to better address patient-specific needs such as ease of administration, food effects and less frequent dosing, is the ultimate goal for a patient-centric approach to formulation development.

Looking ahead, the continued use and development of predictive and in silico tools that integrate the chemical and clinical/patient aspects of drug substance and drug product design will enable more rapid, efficient and effective patient-focused design of drug substance and formulation.

Continuing investment in dose form and device innovation — such as oral peptide delivery, non-invasive delivery of large molecules and shifts from infused to non-infused biologics — will create new opportunities to improve finished dose aspects of drug products.

Overcoming solubility issues

The most widely challenging issue with many drug molecules in development is poor solubility or poor dissolution rates in the human gastrointestinal tract. This can result in inadequate absorption into the bloodstream and, thus, low bioavailability (the ability of the drug to reach its site of action in the body), so the drug can produce its desirable effect/response. Currently, three of the most widely used strategies for improving solubility and dissolution rate are particle size reduction, amorphous solid dispersion (hot melt extrusion [HME] and spray-dried dispersions) and lipid-based technologies.

Particle size reduction is used to increase the surface area of the drug particle and thus increase the dissolution rate. As the size is further reduced, there could also be an increase in solubility. This can result in better bioavailability for drugs administered via the oral and pulmonary routes. Other benefits of size reduction are better content uniformity, enhanced suspension stability (reduced sedimentation) and a better texture of oral, topical or ocular formulations.

HME has the ability to generate physically stable and easy-to-process solid dispersions of amorphous APIs. HME processing systems disperse APIs in the polymer matrix at the molecular level to form solid dispersions or solid solutions. Relative to crystalline APIs, amorphous solid dispersions improve bioavailability in more than 80% of cases.

Spray-dried dispersions utilise the concept of drug-polymer molecular association to prevent the drug from crystallising. The drug remains in a kinetically stable amorphous state. The key to stabilising the inherently unstable amorphous state is the judicious selection of polymer, and the appropriate ratio of drug to polymer. The drug and polymer are solubilised in a solvent system, and spray dried into a powder form.

Lipid-based formulation technologies can be used to solve complex formulation and development challenges, including improvement of solubility, permeability or both, to enhance bioavailability. Each of these enabling technologies can be employed to improve the bioavailability of many poorly soluble drugs, and in the case of lipid-based formulations, poorly permeable drugs as well.

Partner for success

Choosing a development partner that is not only experienced in a range of drug delivery technologies, but is also familiar with the realities of successfully launching products to a global market — for example, helping with network supply strategies and helping to overcome unforeseen problems — is key for developers, and ultimately benefits the patients for whom the products are designed. Catalent offers many innovative dosage forms that solve a range of challenges, including

Controlled release technology: Across a number of dosage forms, such as tablets, capsules and other formulations, there are several technologies that can be employed for sustained/modified drug substance release to increase a drug’s efficacy and reduce the patient’s pill burden.

Patient preferred softgel solutions: Developments in softgel technology to accommodate patient-centric design include coated softgels, which provide optimal drug release profiles, helping to enhance both therapeutic performance and the patient experience. Different types of coatings can help enable targeted delivery, modified release, reduced side-effects, better API stability and even fixed dose combinations. Developments such as OptiGel Bio allow for the delivery of macromolecules, whereas OptiGel Micro technology uses an innovative manufacturing process to produce smaller, spherical capsules that are ideal for patient populations for which swallowing may pose difficulties.

Zydis orally disintegrating tablets (ODTs): These fast-dissolving, freeze-dried tablets disperse in the mouth, typically in less than 3 seconds and with no water required. Zydis fast dissolve enhances pharmacokinetics, improves patient compliance and can offer a marketing advantage for a valued brand.

OptiShell soft capsule technology: Bioavailability and solubility issues can be overcome using a patented shell derived from plant polysaccharides, which goes beyond conventional softgel technology. Allowing higher temperature fill formulations and a wider pH range for semi-solid and highly viscous fill formulations, as well as accommodating a wider range of compatible fill excipients for enhancing drug bioavailability and stability, the technology also has the potential to modify or extend the release of compounds from softgels.

Taken as a whole, the benefits to innovator companies that include patient-centric drug development as a key factor in their clinical trials, scale-up and manufacturing plans, are numerous. Early adopters of this strategy will see many benefits to this approach ... now and into the future. They will also be ready to take advantage of future technologies and processes as they become available and use them to their benefit.