Selecting the optimal dosage form is a critical part of any drug development programme; and whereas sometimes the best choice is self-evident, this is not always the case explain Catalent's Andriy Kuzmov and Steven Winling
Multiple factors need to be considered, including feasibility and cost; but, for a successful marketed product, a dosage form that meets both delivery and patient requirements is essential.
The growing complexity of the nature of active pharmaceutical ingredients (APIs) in the past decade has led to increased demand for custom drug delivery solutions.
This corresponds with a surge in interest in developing products that are more patient-focused, improve patient compliance and stand out in a crowded marketplace.
There are many ways in which an oral dosage form can be differentiated from its competitors to improve the patient experience.
Something as simple as reducing the patient’s pill burden can have a huge impact, whether by cutting the frequency of dosing or the number of pills that need to be taken.
In addition, a pill that is easier to swallow or is more palatable will certainly be more appealing to patients, as will one for which food effects have been minimised or eliminated, giving patients increased control of their daily routine.
As the demand for more creative dosage forms is not limited to on-patent medicines, both branded and generic products can benefit from these tactics.
Controlled release products, fixed dose combinations, orally disintegrating tablets (ODTs) and multiparticulate formats can all prime a product for greater success.
It is important to consider which factors can impact the success of a given dosage form. It is critical to ensure that the intended dosage form can achieve the necessary bioavailability and exposure.
The final dosage form should also ensure ease of administration and promote patient adherence. Selecting the simplest, least invasive dosing regimen that limits the number of daily doses is also important.
Delivery strategies may be required to solve inherent API issues. If a drug is extensively metabolised during the first pass effect of the liver, for example, then a delivery strategy that promotes pregastric absorption, such as an ODT, might be required.
Polymorph stability concerns can be addressed by delivering and maintaining the API in a solubilised state with the use of lipid-based formulations.
Controlled release technologies can be used to mitigate toxicities caused by high peak levels of drug in the bloodstream (Cmax) by reducing the amount of the API released at one time and providing a slower rate of absorption.
Of course, if a dosage form cannot be made reproducibly and at scale, then it is unlikely to succeed. A robust manufacturing process is essential, with the critical process parameters being well characterised via a Quality by Design (QbD) approach.
Ideally, the manufacturing process will be simple, scalable and will use established techniques; but, if it needs to be more complex, then the commercial viability and feasibility of the process must be carefully considered at the outset if the entire project is not to be delayed.
These factors in particular can be addressed during dose design and may improve a patient’s experience with a given drug regimen: pill burden, dosing frequency, dosing unit size and avoiding food-associated restrictions each poses its own unique formulation challenges.
Reducing the number of pills a patient needs to take at once requires an understanding of the API characteristics that ultimately require the patient to take multiple tablets.
If low solubility is limiting absorption and requires administration of a higher dose, dissolution enhancing formulation strategies can improve the API’s solubility and bioavailability, and reduce the dose required to achieve the same exposure.
It may also reduce the volume of excipients that need to be incorporated into the formulation, resulting in a smaller tablet.
If the pharmacokinetic profile of a simple tablet requires multiple doses per day to achieve exposure, once-daily dosing might be achieved with a controlled release formulation; but, employing this strategy requires developing a good understanding of how the API will behave as it travels through the gastrointestinal tract.
The drug will need to be sufficiently soluble across the whole physiological pH range and be absorbed in both the small intestine and the colon.
Food-associated restrictions can prove particularly onerous for patients. Some APIs need to be given on an empty stomach to maximise bioavailability, whereas others may need to be given with food.
If a drug has a positive food effect, there are several mechanisms that lead to its increased exposure when dosed with food. Once the mechanisms are understood, scientists can select formulation approaches to mitigate or eliminate the positive food effect.
Often, this can be achieved by administering the drug in a lipid-based formulation delivered in soft gelatine capsules.
Despite the challenges, user-friendly dosage forms play a critical role in fixing the adherence problem. In an ideal world, all patients would take every single dose of their prescribed medication exactly on schedule and in the correct way for the duration of the course.
Although there are many reasons why they do not, factors relating to the drug and its formulation weigh heavily.
One of the leading causes of therapeutic failure in chronic conditions is patient non-adherence, with estimates reaching 50% in developed countries and often times higher rates in developing countries.1,2
Sometimes, the regimen is just too complicated and patients may get fed up with protracted treatment times or give up in the light of failed treatments in the past. But there are various aspects that clever formulation can solve.
If the drug tastes bad, for example, then taste masking strategies can be employed. Patient-friendly doses should be remembered at the start of the development process to increase the likelihood of a positive outcome.
It is, of course, important to account for the needs of the target patient population as each disease presents a unique set of challenges.
The Catalent Applied Drug Delivery Institute, for example, has done patient surveys alongside the Lung Cancer Alliance in lung cancer patients, and with the Ernest Mario School of Pharmacy at Rutgers University in paediatric patients.
Both research studies asked questions to better understand the patients’ needs and to help ensure that both patient and molecule challenges are considered during the development process.
To help bring products to their patients, pharma companies of all sizes often engage specialist formulation companies to overcome challenges when creating the ideal dosage form.
The relationship between the partners should be open and collaborative, with all parties working to deliver a safe and effective treatment for patients.
A company with a broad base of formulation knowledge will be able to offer a wide range of potential dosage forms and work with the pharma company to assess exactly which one meets the patients’ needs while considering the inherent properties of the molecule.
By leveraging the expertise of a partner with a wide range of dosage form experience and formulation technologies in the early stages of development, formulators can develop phase-appropriate dosage forms to progress from preclinical to GLP toxicology and on to early clinical studies.
As a project matures, they can then seamlessly transition programmes to the next stage of development, saving time during the scale-up process.
An integrated CDMO can also add value by implementing a comprehensive and phase-appropriate QbD approach whereby multiple or all stages of development are conducted within the same network.
This can reduce the risks of disconnects and complex logistics when too many partners are handling progressive development stages.
As with all areas of science and technology, this field is not static and new dosage forms and improved versions of existing ones will continue to be developed.
In coming years, one can expect new formulation types that provide further options for difficult molecules, particularly those for which solubility and bioavailability are suboptimal … and perhaps even successful non-invasive alternatives for the delivery of biologics.
Either way, it is essential that the patient remains at the heart of the development process if a formulation is ultimately to prove successful.