Demand for Custom Dosage Forms Fuels Innovation

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Various factors have impacted the evolution of drug dosage forms over the years, including the growing complexity of compounds entering the development pipeline, an aging population, increased focus on niche therapeutic markets, and augmented awareness on patient-centricity. Although oral solid dosage forms remain the most popular option within the industry, due to the convenience, cost-effectiveness, and ease-of-use offered by this dosage form, innovative delivery approaches are required to accommodate the rising demand for more customized solutions.

“Over the past 5–10 years, increased competition in the market, complexity of APIs, and focus on patient-centric products has led to increasing demand for custom drug delivery solutions,” confirms Andriy Kuzmov, drug delivery innovation fellow, science and technology, Catalent. “With increasing competition, it is important for new treatments to differentiate themselves from competitors by meeting the unique needs of the target patient population. This can be achieved by decreasing a patient’s pill burden, improving palatability, eliminating variability due to food effects, improving swallowability, or decreasing the frequency of administration.”

Key trends

One key trend affecting drug development has been the rise of biologics and, thus, the need to find novel ways to deliver such complex entities effectively, remarks Jeremy Drummond, senior vice-president, business development, MedPharm. “Biologics create new challenges in terms of packaging, analysis, delivery, and stability,” he says. Drawing on experiences with aptamers, Drummond adds that work has been done to demonstrate the ability of delivering biologics topically, despite the traditional issues with large molecular weight potentially impeding skin penetration (1). 

As a result of the amplified level of interest in biopharmaceuticals, there has been increased attention by industry in the development of parenteral products, comments Torkel Gren, science and technology officer, Recipharm. “Another driver for the development trend of parenterals is the increasing interest in hospital care products,” he continues. “Finally, people are beginning to see that even though parenteral administration is less convenient than oral administration, it is not that difficult. For many more serious indications, injectable dosage forms are acceptable when looking at the balance between benefit and inconvenience. The development of convenient and reliable autoinjectors is of course contributing to this opinion.”

In addition, Steve Rode, manager business development, capsules and health ingredients, Lonza, specifies that the growth of biologics as well as small molecules being delivered via alternative routes has been trending in the industry. “Innovation in larger molecules and biotech drugs has also meant increased focus in developing and delivering larger molecules such as proteins, peptides, and monoclonal antibodies orally,” he says. “So, the space is benefiting from both the sustained market focus on continuing to deliver small-molecule APIs orally while developers look to deliver high-value biologics via the same route. More recently, there has been an emergence of live biotherapeutics for which specific dosage forms are essential to ensuring stability and targeted delivery.” 

The use of more high potency compounds has led to the requirement for low-dose drug products to be developed, which has impacted both formulation development and manufacturing strategies for the targeted dosage form, explains Richard Shook, director, Drug Product Technical Services and Business Integration, Cambrex. “Formulators must utilize a holistic approach to development by integrating the appropriate excipients and ensuring that the final dosage form is stable and uniform in dosing,” he states. “During process development the manufacturing strategy must be robust while balancing efficiency and cost effectiveness.” 

Harder-to-formulate and manufacture compounds are further permeating the development pipeline, requiring new formulation and/or delivery strategies to ensure that the desired therapeutic effects are achieved, asserts Lonnie Barish, vice-president, business development and marketing, Bora Pharmaceuticals. “The demand for expertise on how to overcome challenges, such as low solubility, low permeability, or short half-life, has soared, and drug developers are increasingly seeking solutions from technical experts, such as contract development and manufacturing organizations (CDMOs), to commercialize these APIs,” he says.

In concurrence, Paul Kippax, pharmaceutical sector director, Malvern Panalytical, highlights that the move toward delivery of increasingly insoluble APIs has led to the need for evermore complex formulations and processes, even for ‘simple’ oral solid dose products. “Techniques such as API micronization or nano-milling are applied to improve the solubility of APIs,” he says. “Additionally, companies are looking to use amorphous APIs; these are inherently less stable but show higher solubility. As a result of these requirements, there has been a significant increase in the physicochemical characterization tools required to confirm the microstructure and stability of the API within a formulation.”

According to Rob Lee, president, CDMO division, Lubrizol Life Science Health, the biggest trends impacting drug dosage forms have been the rise in long-acting injectables, implants, and the use of water-insoluble molecules. “Water-insoluble compounds have always been around, but with new drug development technologies, we are better able to formulate them instead of discarding them like formulators used to a few decades ago,” he confirms. “This means that more formulation-challenged compounds stand a greater chance of making it to market and being utilized in breakthrough treatments.”

“The last few years have seen an increase in the demand for advanced dosage forms, such as controlled-release products, multiparticulates, orally disintegrating tablets, intranasal dosage forms, or new fixed-dose combinations,” adds Kuzmov. “The new dosage forms address key challenges for patients by improving adherence, ensuring proper administration of the dose, or improving the quality of life for the patient.”

For Manuel Leal, business development director, Idifarma, the biggest trend in drug dosage forms has been the development of hybrid drugs, involving the re-purposing of existing molecules into new indications or dosage forms. “These drugs take advantage of the hybrid regulatory pathways enabled by FDA-505(b)(2)-and the European Medicines Agency (EMA)-10(3),” he explains. “This trend uses innovative technologies to achieve the required dosage form, and can be very beneficial to certain groups of patients (pediatric and geriatric), and can also help sustain healthcare systems.”

Other areas of change for drug developers is the expansion of the orphan drug market, which is anticipated to be twice that of the overall prescription drug market by 2024 (2), due in part to the implementation of FDA’s orphan drug modernization plan. “Personalized medicine principles are being applied ito tailor treatments to individual patients or to their subpopulation to minimize side effects and to achieve the best possible therapeutic effect,” notes Barish. “Genetic profiling and epigenetics, the study of heritable phenotype changes, are providing insights into different patient populations and the pharmacokinetic and pharmacodynamic effects of various drugs. With these understandings, it is hoped that doctors can be more selective in their choice of pharmaceutical products for their patients, taking into consideration their efficacy in certain subsets of the population.”

“Development pipelines are moving away from blockbuster drugs with one-size-fits all dosage forms into more personalized medicines,” agrees Frederique Bordes-Picard, manager business development for innovative products, Capsules and Health Ingredients, Lonza. “More targeted actives are the focus in areas like oncology, thus addressing more specific and smaller patient populations.”

Furthermore, increased regulatory scrutiny has amplified the industry’s efforts into risk-based approaches and increased the need for integration of quality-by-design methodology during drug development, stresses Shook. “To apply this methodology appropriately, a clearer determination of the critical quality attributes of a dosage form and what factors impact those attributes is needed,” he adds.

Investing in innovation

“To help meet the demand for complex drug delivery solutions, manufacturers have been investing in the infrastructure and capacity to successfully produce, at scale, the novel dosage forms that are required by next generation treatments,” says Kuzmov. “Along with capital investments, manufacturers need to ensure they have the right personnel and expertise within their network to handle a variety of development projects.”

There has been continuous improvement of existing development approaches over the years, asserts Gren, with devices offering an excellent example of advancements. “Inhalation devices have been around for decades; however, new devices are much easier to use. The same is true for injection devices,” he notes. “Many technologies for modified release, such as coated pellets, were also developed decades ago but are now easier to use as we have more experience in how to apply them.” 

Bordes-Picard adds that there has also been the wider use of personal devices, such as mobile phones and wearables, to improve treatment management and support patient compliance in a number of therapeutic areas. “There’s also been greater exploration of nasal, pulmonary, and transdermal routes as alternatives to injection and oral dose innovation as manufacturers look to develop increasingly patient-centric doses,” she states.

Excipient development has also impacted formulation approaches, with novel excipients and innovative technologies aiding formulation scientists in the development of better injectable dosage forms for insoluble compounds, confirms Lee. “Innovations in excipient development have had a significant impact on low-dose drug products,” adds Shook. “Formulators can identify critical material attributes of the drug substance and work with manufacturers to ensure that excipient specifications align with those attributes.”  

Additionally, functional excipients have been made available that improve stability and solubility of biopharmaceutical compounds or that enable targeted delivery, which has removed some of the potential barriers to oral bioavailability, reveals Rode. “To improve the opportunities and potential for drug candidates with low solubility or bioavailability, we’ve seen increased utilization of techniques such as spray dried dispersions,” he continues. “There’s also been a greater adoption of equipment that more accurately fills neat API into capsules allowing developers to speed up first-in-human clinical studies.”

According to Leal, innovative technologies, such as spray drying, have been instrumental for the development and repurposing of many drugs with solubility problems. “Spray drying is one of the most suitable technologies to improve the solubility, and hence the bioavailability of low soluble compounds,” he says. “Solving this complex problem opens a wide range of potential applications and innovations.”

For Barish, the use of extrusion spheronization offers even and predictable distribution and transportation of API in the gastrointestinal tract. “Because of its simple and fast processing and its ability for high drug loading capacity, this manufacturing technology is gaining more attention,” he asserts. “It is incredibly versatile so that pellets composed of different drugs can be blended and formulated together to deliver two or more APIs to the same or different sites in GI tract in a single capsule.”  Additionally, the technique can improve the safety and efficiency of the API and help increase the APIs bioavailability by controlling or modifying the release characteristics.  The technique has been widely utilized to formulate sustained and controlled release delivery systems as well. 

“One key innovation over the past 10 years has been the growing acceptance by regulators of in-vitro physicochemical analysis methods for assessing bioavailability and/or bioequivalence,” says Kippax. “Application of these methods provides a possible means of avoiding complicated clinical studies to show equivalence for complex dosage forms. This has been a significant enabler for the development of complex drug products by generic companies.”

Further to opportunities within the field of generics, the in-vitro approaches can offer development opportunities for novel drug products, Kippax continues. Combining physicochemical analysis with the application of new modeling approaches and digital design tools, it is possible to predict the drug product properties that will be required to achieve bioavailability. “This can be an enabler in the selection of the most appropriate dosage form, and in ensuring the development of a robust processing route,” Kippax says.

Particularly focusing on locally acting products, Drummond adds that major advances have been seen in the use of in-vitro models that are based on fresh human tissue, which can optimize the activity of drug formulations. “These models are now used not only to measure permeation but also monitor the activity of formulations and de-risk the decision to enter clinical trials through the use of fresh human tissue,” he notes.

Trends driving demand

As access to healthcare increases, so too will demand for all kinds of therapeutics, exclaims Barish. “There is already a greater demand for the treatment of more novel and niche diseases, prompting even more development of new modalities, techniques, materials, and excipients to ensure the safety, efficacy, and stability of future challenging drug substances,” he says. 

Patient-centricity and the increasingly complex nature of molecules in the development pipeline are drivers for demand in advanced dosage forms and formulation techniques, confirms Kuzmov. “The trend of patient-centric dosage forms will continue in the development of parenteral formulations as well through the development of long-acting injectable products or the use of devices to simplify injection procedures for patients,” he notes. “At the same time, researchers will continue the push to develop non-invasive methods for the delivery of biologics and other treatments that are not readily absorbed after oral administration.”

The growth in biologics is a big driver for Lee. “With more biologics on the market, the preferred delivery routes for those could reshape the status quo. There is already more interest in long-acting injectables for biologic compounds, and this is expected to continue,” he says. However, oral dosage forms will continue to grow in the marketplace, although there may be further exploration into alternative delivery routes, such as nasal, facilitated by regulatory pathways like FDA’s 505(b)(2), Lee adds. 

Having the ability to dose active molecules with precision while minimizing adverse systemic impact on patient is an important future trend according to Shook. “The further development of modified-release dosage forms will enable the delivery of active molecules to a specific site of treatment,” he says. “This will ensure that the therapy is introduced and actively initiated at right time and place to disrupt the disease with precision and minimal impact to the patient.”

Personalized medicines are anticipated to drive change in how companies approach dosage forms. “In my opinion, it is likely that the industry will continue to move away from a high volume, one-dosage-form-fits-all approach towards smaller, fully customized dosage forms,” reveals Bordes-Picard.

This drive toward precision medicines for smaller patient populations could have many implications, adds Gren. “Three-dimensional printing is a technology that may allow a very high degree of individual adaption of the medicine. However, a number of issues regarding quality assurance and cost may limit the use of 3D printing over the next 10 years,” he continues. “Instead, adapting conventional manufacturing technology, making it more flexible and allowing smaller batches may be very useful.”

Changes in how companies select candidate drugs will be prominent for Kippax, who believes that companies will seek to select drugs that reduce risks associated with scale-up and manufacture. “The paradigm is shifting from the development of specific processes designed to create a single drug product, towards the application of standardized continuous-manufacturing approaches. Selection of candidate APIs and formulations will therefore increasingly be based on their fit with these processes,” he explains.

Furthermore, Kippax highlights the fact that additive manufacturing approaches are being employed in the design of new dosage forms. “These are exciting developments, perhaps providing a means of delivering truly personalized dosage forms, created to simplify the dosing regimens required to meet a patient’s needs,” he says. “Achieving this will require greater understanding of the link between API and formulation physical properties and the requirements for safe, effective drug delivery.”

“An important trend in the future is undoubtedly going to be the combination of dosage form delivery with technology, whether that be for monitoring the patient or in aiding the delivery,” summarizes Drummond. “It is an exciting time in the drug development industry, and the COVID-19 pandemic has focused the attention on the value that innovation can bring to patients, as well as the value governments and populations place on health and wellbeing.” 

References

1. J.D. Lenn, et al., J. Invest. Dermatol., 138 (2) 282–290 (2018).
2. Evaluate Pharma, “Orphan Drug Report 2019,” info.evaluate.com, Market Report, April 2019. 

Article Details

Pharmaceutical Technology 
Vol. 44, No. 7
July 2020
Pages: 16–20, 33

Citation 

When referring to this article, please cite it as F. Thomas, “Demand for Custom Dosage Forms Fuels Innovation,” Pharmaceutical Technology 44 (7) 2020.