Putting the Patient at the Heart of Dosage Form Design

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Research investment in the global biopharmaceutical market helps to drive innovation and development of novel therapeutic products to treat many diseases and illnesses. According to recent figures highlighted by the International Federation of Pharmaceutical Manufacturers and Associations, there are currently more than 8000 compounds in development around the world (1).

“A recent market report has shown that there was an influx of new products in the pipeline at all stages of clinical development during the 2020/2021 period (2), especially of early-stage clinical products,” notes William Chin, manager, global scientific affairs, Catalent, citing recent research studies. “Moreover, cancer, infectious diseases, and diseases of the central nervous system came up as the top areas of clinical trial activity last year. The number of people suffering from these chronic conditions is expected to rise as population growth is anticipated in many developing countries (3). The development of complex dosage forms is also expected to grow in parallel to increased diversity in the drug pipeline.”

Key trends

Over the past five to 10 years, the low water solubility of new molecular entities (NMEs) has been a major drug product development challenge, emphasizes Julien Lamps, product manager, Lonza Capsules and Health Ingredients. “Knowing the solubility performance attributes for the compound is important as it will aid selecting the right dosage technology,” he says.

“There have been numerous developments and innovations in drug delivery over the last few years to overcome challenges with products and formulations, such as biologics and complex entities like larger molecules,” adds Jnanadeva Bhat, head—formulation R&D (Pharma and Nutra), ACG Group. “Other trends that have evolved are prefilled syringes, wearable injectors, and needleless syringes, each of which have a niche market.”

Considering the route of delivery, Chin states that injectable dosage forms are dominant in the development pipeline. “The intravenous route [is] seen to offer more advantages in early-stage studies as a means to quickly deliver the desired concentration of drug to the target via systemic circulation, and to achieve the required pharmacological response,” he confirms. “However, simply having injectables may no longer be sufficient anymore because of the growing demand for more patient-friendly formats, such as oral solid dosage (OSD) forms.”

Bhat concurs that even though the sector for specialty products has witnessed growth, OSD forms have remained steady throughout the past decade. “There is demand for continuous innovation to improve efficacy, efficiency, and competence in [oral solid] dosage forms,” he says. “Developing novel and more efficient oral delivery routes also helps brands reach a larger audience. Thus, development scientists prioritize OSD forms because not only are they key to patient compliance, but they also have broad application.”

The growing demand for OSD forms has driven innovators to focus on patient-centricity early on in development, Chin continues. “This [trend] is especially true in the past year, where there has been an expectation to increase both the convenience of use and the therapeutic efficacy of the drug product, as well as ease of deployment without the need for cold-chain considerations, especially given the current focus on oral COVID-19 vaccine development,” he states.

“In biologics and small molecules, the trend shifted towards patient centricity,” adds Tatiana Nanda, director and program leader, The Center for Breakthrough Medicines. “Historically, the sole focus for drug product development was effective treatment of the disease while now additional emphasis is put on patients experience and quality of life during treatment.”

Focusing priorities

“As innovators are focusing more on solutions that allow them to develop patient-centric drug products, the priorities of drug development are expected to not only demonstrate clinical efficacy and safety in patients, but also to address key challenges such as improving usability, bioavailability, stability, and palatability, while eliminating any variability due to food effects,” confirms Chin. As a result of this shift in priorities, advanced dosage forms, such as modified-release products, multiparticulates, ODTs, or new fixed-dose combinations, are increasingly in demand, he adds.

Dosage form priorities have certainly been adjusted, Lamps specifies, with the deployment of common strategies and platforms that help to enhance drug oral bioavailability, such as cosolvents, salts, surfactants, particle size reductions, polymorphs, lipid-based systems, amorphous solid dispersions, and so on. “Additionally, it is becoming a best practice to evaluate the end dosage form earlier in the development cycle,” he adds.

“Drug product design is more focused on meeting patient-centric target profiles and has become the goal for drug companies,” agrees Nanda. “Previously drug product profiles were a derivative of what upstream/downstream capabilities allowed. Now the selected profile and dosage form drive the required API process, needed concentration, and purity.”

The priorities of pharmaceutical companies have shifted as a result of the drive toward patient centricity, Bhat concurs, with manufacturers seeking the most patient-friendly form that supports maximum therapeutic efficacy and safety of the formulation. “Regulatory bodies also encourage patient-centric dosage forms, which fuels this new focus,” he says.

Additionally, the change of priorities for development have led to the integration of patient-centric design early on in the development cycle, Bhat continues. “The physicochemical properties of an API usually point the formulator to the most suitable route of administration, as well as dosage form. The solubility of APIs specifies approaches for dose selection, excipient selection, and stability of the final product,” he says. “Bigger challenges are observed for larger molecule oral absorption, which need to be addressed adequately by formulation scientist.”

Discussions between innovators and contract development and manufacturing organizations (CDMOs) on dosage form design are taking place relatively early on now, Chin states. Furthermore, manufacturability of the dosage form is being addressed earlier on by innovators, which is an aspect that has received less attention historically speaking, he notes. “Innovators have recognized that a druggable molecule alone does not automatically imply successful commercialization of a pharmaceutical drug product, but that there is also a need at an early stage to establish all other key considerations that will meet the target product profile covering patient and manufacturing requirements,” Chin says.

Taking patient opinions and assessments of dosage forms into consideration during design and development can also help to create user-friendly products, Bhat highlights. As patient-centricity is becoming more prominent, so too are tailored dosage forms, which directs the industry away from a one-size-fits-all approach in terms of dosage forms, he explains. “With this trend, dosage forms will perform more effectively for individuals, and this is shifting pharma R&D towards new pathways,” Bhat says.

Important innovations

For Bhat, some of the most important innovations in drug dosage forms have been seen in the area of inhalation. “Local inhalation administration delivers sufficient levels of drug to the target organ, the lungs, while minimizing systemic exposure and side effects (primarily due to the reduced drug dose needed as compared to oral administration),” he says.

“Additionally, there is mounting interest in inhalation segment, where conventional molecules are converted into inhalation formulations,” Bhat continues. “In this area, dry powder inhalation formulations via hard capsules is a trend formulators and manufacturers are showing great interest in. Capsules are not only robust and easy to use, but also help with effective delivery through the inhalation devices.”

Capsule-based dry powder inhalation (cDPI) formulations offer an affordable option that incorporate characteristics—such as reduced dosing frequency and side effects—and easy administration, which are preferable for patients, Bhat asserts. “The most impressive developments taking place in this field go beyond conventional respiratory therapeutic segments,” he says. “Many leaders are exploring cDPI for other therapeutic segments like Parkinson’s disease, migraine, tuberculosis, cystic fibrosis, and lung infection.”

Techniques, such as particle size reduction, spray-dried dispersions, and lipid-based formulation platforms, have helped overcome solubility-related issues, Lamps states. Additionally, as the techniques are complementary, they are applicable to a broad compound space, he says.

For large molecules, being able to reach high protein concentration and co-formulating with dispersion enhancers, such as hyaluronidase, has been a significant advancement, reveals Nanda. “[This innovation] allowed delivery of a high volume—up to 20 mL—of drug product as a single injection into subcutaneous space,” she stresses.

However, it is also important to consider innovation from the perspective of manufacturing, rather than just on new technologies that are centered on the discovery and development path, Chin emphasizes. “For example, one of our core expertises is in manufacturing softgel dosage forms for both immediate- and modified-release applications. The typical development option for a modified-release softgel is through the formulation of the fill content followed by the coating of the capsules,” he says. By using a proprietary modified-release softgel capsule, which combines pectin and gelatin, a separate capsule coating step can be avoided, Chin adds.

“The capsule technology allows innovators to design the delayed-release profile to be incorporated directly into the softgel capsule shell, thereby making a separate capsule coating step unnecessary,” Chin continues. “This [innovation] reduces manufacturing time and yield loss and eliminates potential quality issues associated with coated softgels.”

Market drivers

“An important driver that could steer the dosage form market is the increasing demand for solutions that could overcome cold supply chain bottleneck constraints, especially given the current focus on vaccine development for COVID-19, as most vaccines are available as solution for injection that require ultra-cold chain storage,” Chin asserts. “A lot of effort and investment will be made to develop an alternative dosage form that could effectively deliver such biomolecules via the oral route. If this alternate dosage form could not only overcome enzymatic and permeability barriers, but also ensure stability and biological activity without the need for ultra-cold storage solutions, this could be expected to positively impact the global pipeline in the coming years.”

A rising demand for tailored or customized formulations and precision medicine will greatly impact drug dosage form development in the near future, according to Bhat. “The increased focus on patient centricity will certainly lead the development pipelines away from a generalized approach to more individualized treatments,” he stresses. “[This shift] will also allow for the creation of more innovations in combination delivery to achieve better dose compliance by minimizing the number of medicines that need to be taken separately.”

For example, combining dosage forms in one hard capsule is a possible option, Bhat adds. “Pellet technology, or minitablets, are a great example of converting conventional technology into personalized solid oral dosage form,” he says. “Minitablets can be filled in capsules as it is relatively easy to blend them together to attain combinations of multiple drugs in accurate doses and with different release profiles, if required. This solution is customized and user-friendly as it will reduce the dose regime.”

In Lamps’ opinion, lipid-based formulations will continue to impact dosage form developments in the future by addressing the solubilization challenge. “As [the technology] maintains solubilization during the dispersion/digestion step in the gastrointestinal lumen, it’s favoring efficient diffusion through the mucus layer to reach the intestinal epithelium,” he explains.

Additionally, amorphous solid dispersions (ASDs), which dissolve rapidly to higher concentration than crystalline forms and maintain supersaturation in the intestine, promoting drug absorption, will impact dosage forms in the future, Lamps continues. “[ASDs] broad applicability, flexibility, and quenching rates makes them amenable for high-dose compounds,” he says.

A high priority effort for many drug developers is the creation of an appropriate dosage form for cell and gene therapies (CGT), Nanda specifies. “Formulation and manufacture of CGT drug products represents specific challenges not encountered by small molecules and biologics,” she says. “Early-phase clinical trials for advanced therapies are rather complex and include wide dose ranges. It becomes extremely important to introduce a proper, robust formulation for CGT therapies early on, to be able to accommodate an intended route of administration, indication, and dose level.”

Although CGTs are still only administered in a clinical setting, the requirement for an optimal dosage form is just as critical as it is for therapies (large and small molecule) that are administered at home, Nanda emphasizes. “Both healthcare professionals and patients greatly appreciate using a therapy that allows a streamlined and simple administration, reduces the number of doses, or does not require specialized surgical instrumentation for delivery,” she says. “CGTs will require significant development in the container closures most suitable for efficient storage and shipment and convenient withdrawal for administration. Continued innovation of novel devices and adaption of existing platforms will also help enable advanced (tissue specific) therapy delivery.”

References

1. IFPMA, “The Pharmaceutical Industry and Global Health: Facts and Figures 2021,” ifpma.org (April 2021).
2. K. Sedo, “2020 Global Drug Delivery & Formulation Report: Part 4, The Drug Delivery and Formulation Pipe-line,” PharmaCircle LLC (June 2021).
3. PricewaterhouseCoopers, “Chronic Diseases and Conditions Are On the Rise,” pwc.com [Accessed July 12, 2021].

About the Author

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Article Details

Pharmaceutical Technology
Vol. 45, No. 8
August 2021
Pages: 16–20

Citation

When referring to this article, please cite it as F. Thomas, “Putting the Patient at the Heart of Dosage Design,” Pharmaceutical Technology 45 (8) 2021.