The Shape of Dosage Forms

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It is well-known that oral solid dosage (OSD) forms remain the market leader, with recent research estimating the market size to be worth nearly $8.5 billion by 2027 (1). “OSD forms such as tablets and capsules continue to be popular dosage forms in the healthcare sector being the preferred delivery system due to them being patient friendly,” confirms Anil Kane, PhD, MBA, senior director, global technical scientific affairs, pharma services, Thermo Fisher Scientific. “However, the number of biologics and large molecules [is] growing, and this is also seen in the increase in the demand for sterile injectable dosage forms.”

Impactful trends

For Cornell Stamoran, PhD, vice-president of Strategy and co-chair of the Catalent Applied Drug Delivery Institute, a key trend impacting drug dosage forms has been the increasing complexity of drug formulations. “[This increasing complexity has been] driven by strong pipeline growth of newer modalities and mechanisms, the need for targeted delivery, and bioavailability-challenged compounds, along with more frequent use of formulations and dose forms to enable patient self-administration, or reduce the complexity of treatment regimens,” he says. “We have also seen important progress in gene therapies using adeno-associated viral (AAV) vectors and lipid nanoparticles to deliver messenger RNA (mRNA).”

“A key consideration in my view is that, with the ever-increasing diversity and complexity of novel therapeutic modalities and APIs that must be injected to achieve efficacy, the need for sterile medicines will see a corresponding rise,” states Hanns-Christian Mahler, CEO of ten23 health. It is likely, he continues, that as a result of this trend there will be a drive towards easier-to-administer (or self-administered) medicines via devices, for example, which should improve compliance and overall therapeutic success.

“Ever-changing industry dynamics in recent years have had a considerable impact on the development and use of dosage forms for drug delivery,” specifies Jnanadeva Bhat, head—Formulation R&D (Pharma & Nutra), ACG Group. “One such change has been the improvement of existing products which can offer significant advantages, such as better therapeutic efficacy, whilst at the same time minimizing development expenses and timelines.”

As a result, Bhat continues, there has been an increase in the drug dosage form portfolio in general for the industry. Additionally, more research is being performed on larger and more complex entities and biologics so that challenges, such as solubility and bioavailability issues can be overcome, he states. “Low solubility molecules have been a major dosage form development challenge,” Bhat says.

However, Bhat points out that OSD forms have remained a stable trend with continuing popularity over the years. “There is continuous competition and research in this area of pharmaceutical dosage forms to be ahead of the race, and also to reach a greater segment of the population,” he states. “In particular, capsules have a multitude of benefits in terms of easier development and administration. The significant demand we are seeing right now creates room for more innovations across product lines.”

“There is a strong desire to move from injectables to simpler oral administration; this would provide opportunities for life-cycle management as well as patient-centricity, especially in enabling technologies to allow oral delivery of biologics,” emphasizes Ali Rajabi-Siahboomi, vice-president—chief innovation officer, Colorcon. “The oral route remains the gold standard. It considers patient convenience and self-administration, in addition to dose accuracy and speed of manufacturing of tablets for oral route.”

“In 2020, oral solid products accounted for nearly 40% of the 53 novel drug products approved by the Center for Drug Evaluation and Research (CDER) (2). And of the 21 newly approved OSD products, 14 were tablets and seven were capsules,” remarks Kane. “In 2021, the total number of approved drugs was 50, of which 52% (26 products) were injectable dosage forms and 46% (23 products) were OSDs (15 tablets and eight capsules),” (3).

Stamoran concurs that OSD forms are preferential, certainly for innovator small-molecule drugs, but for biologics there is strong growth in infusion delivery. “Across both small- and large-molecule injectable launches, the use of prefilled syringes and autoinjectors is increasing,” he adds. “Also notable is a growing focus on dose forms that are most appropriate for pediatric and geriatric patients, driven in part by the increased expectations of regulators.”

A trend that has been exceptionally prevalent in 2021 is the fast launch of vaccines to combat COVID-19, which have progressed from bench to use in billions of patients at incredible speeds, Kane stresses. “A direct impact of the pandemic is the increase in demand for sterile injectable dosage forms for vaccines in vials. There are many other vaccines and injectables in development, as well as clinical trials that have resulted in increased demand on capacity for sterile injectable formats,” he says.

Another major trend has been the increasing complexity and risk of the drug product supply chain, asserts Thomas B. “Brad” Gold, PhD, vice-president, Pharmaceutical Development, Metrics Contract Services. “Fall-out from the pandemic, as well as other geopolitical dynamics will continue to impact the reliable supply of the many elements critical to finishing and dispensing drugs to patients,” he adds. “Managing the longer lead times necessary for obtaining critical excipients and primary packaging for example will continue to challenge contract manufacturers and have the potential to impact market timelines.”

“Many new chemical compounds have high potency and are sensitive to environmental conditions like moisture, oxygen, and heat, as well as potential interactions with other formulation components or gastro-intestinal environments, causing them to undergo oxidation, hydrolysis, or another degradation path,” emphasizes Rajabi-Siahboomi. However, advances in computing power and new capabilities in artificial intelligence (AI) are providing opportunities for accelerated innovation in drug dosage design, he specifies.

Technological advances

“Technological advancement is supporting ongoing drug development and the manufacturing innovation needed to sustain it,” continues Gold. “For example, we are seeing continuous improvement to critical processing approaches and techniques, especially handling complex and increasingly potent compounds. Equipment manufacturers are responding with system designs that integrate containment technologies to control operator exposure and prevent other issues like cross contamination.”

Moreover, as manufacturing technologies evolve, manufacturers are afforded the opportunity to introduce new and improved processes and production efficiencies, which are supported through the technology’s ability to gather process data, Gold adds. “The more data these systems provide the more useful the feedback is at improving robustness and determining if the process capable of being validated in the first place. Best practice is calling for the increased application of process analytical technologies (PAT) for example, to support continuous improvement,” he says.

“Digitization and automation can provide accurate and efficient support,” agrees Rajabi-Siahboomi, who explains that it is possible to use technological advances, such as AI, to be able to screen and identify molecules that can be progressed further through development. “AI screening has a high potential for undruggable sites—the term ‘undruggable’ is used to describe a protein that is not pharmacologically capable of being targeted; recently, however, substantial efforts have been made to turn these proteins into ‘druggable’ targets. The resulting new compounds have high potency and may potentially be unstable,” he says. “AI will enable better insight into identifying target proteins.”

Additionally, Rajabi-Siahboomi notes that three-dimensional (3D) printing technology is gaining momentum within industry, for the purposes of solid dosage manufacture. “3D printing allows the production of tablets with more than one active substance characterized by different properties and with different dissolution profiles. It has good potential, depending on the production method, as it can provide unique patient-centric dosages and improve stability by producing individual dosage forms that can be presented to patients in a short time,” he states. “This technology is still in development with some success in the nutraceuticals market and limited approvals in pharma.”

For Bhat, there are two ways in which technology has helped to shape dosage form evolution. “One aspect is related to operations and manufacturing, and the other is related to the research and development of novel dosage forms,” he says. When considering the former—operations and manufacturing—Bhat reveals that through the various innovations in equipment and techniques it has been possible to accelerate processes. “Automation improvements have also been aimed at continuous manufacturing, maximum production yield, and minimum losses,” he adds.

In terms of dosage form innovations, there are numerous novel ways to deliver, manufacture, and formulate therapeutics, Bhat continues. “For example, prefilled syringes and automated injectors for injectable dosage forms are accurate, reliable, and convenient. They reduce the need for medical supervision and facilitate easier self-administration,” he specifies. “In the case of oral delivery, nanotechnology in formulation development has emerged with many advantages in terms of increased efficacy and bioavailability of drug molecules. Thus, continuous innovation and evolution can reduce or bridge the gap between demand and developmental challenges in dosage forms.”

There have been significant advances in drug delivery thanks to innovation in materials science and manufacturing processes, explains Stamoran. “For example, development of new softgel capsules now allow these dose forms to offer inherent enteric protection and extended-release formulation,” he says. “We have also seen innovations in functional coating technology, non-glass alternatives for injectables, and new excipients, which can enhance a drug’s performance or even shift treatment regimens to less invasive routes of administration.”

Furthermore, process innovations are enabling development progression, such as the improved scale of production for therapeutic proteins thanks to breakthrough cell-line development, Stamoran points out. “Additionally, equipment and process innovations have enabled critical scale-up increases for AAVs in the field of gene therapy, while the potential implementation of continuous manufacturing in both API and dose form manufacturing also continues to progress,” he adds.

According to Mahler, it can appear that there is limited innovation in the area of sterile products, as a result of the reliance of pharmaceutical products on prior use to ensure safety and regulatory compliance. “Lyophilization remains the drying method of choice for products that require drying; primary containers are typically made of glass; there aren’t really any novel formulation excipients,” he notes.

“At the same time, technology has advanced very significantly,” Mahler asserts. “And whilst innovation may not be apparent at first sight, it surely is on the second: the understanding of stabilization mechanisms has significantly grown, we now understand the role of some excipients like polysorbates in the formulation, we understand the various interactions between the process and the formulation and the packaging components. Hence, development of sterile medicines has become much more informed, enabled by analytical technologies.”

Kane believes that there will be a notable change in the dosage forms under development thanks to technological advances and improved understanding of processes. Areas of particular interest for Kane are biologics in OSD forms and the oral delivery of human microbiome and probiotics.

“Increased knowledge of technology and processes such as lyophilization, cryo-protection, targeted drug delivery, [and] in-vitro simulation models coupled with unprecedented recent developments in materials such as surfactants, permeation enhancers, polymers, muco-adhesive materials, and so on, are propelling advances in these areas and are likely to make oral delivery of biologics, microbiome, and probiotics a clinical reality,” Kane says. “Advances in specialized processes such as spray drying and lyophilization will help formulating peptides, oligonucleotides, enzymes, and proteins into stable solid or liquid states that can be formulated into capsules or tablets.”

Impactful solutions

Prominent technological advances, such as AI, additive manufacturing, blockchain, and other Industry 4.0 technologies, are impacting various aspects of drug development confirms Rajabi-Siahboomi. For example, AI is providing industry with more efficient ways of isolating potential clinical candidates and continuous manufacturing is offering cost and time-efficient production of therapies, he states.

Extrusion technology is an invaluable resource to help developers enhance material properties so that innovative manufacturing techniques, such as 3D printing, may be employed, Rajabi-Siahboomi continues. “Hot melt extrusion (HME), which enhances material properties, is emerging as a key technology for the continuous manufacture of drugs within the pharmaceutical industry. One notable advantage is the ability to produce a variety of formulations, such as solid dose forms, which improve drug bioavailability,” he says.

“Also, inline PAT tools can be integrated with the HME process to support a quality-by-design (QbD) approach to continuous manufacturing,” Rajabi-Siahboomi explains. “HME extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier, increasing dissolution rates and bioavailability. The most common difficulty encountered in producing such dispersions is the stabilization of amorphous drugs, which prevents them from recrystallization during storage. Advances in both materials and equipment have increased the development of equipment and chemicals for specific use with HME.”

Digitized solutions that can provide useful information, such as digital pills, smart pill, smart medicine, and on-dose authentication, are considered to be of importance by Kane. Digital pills—where an ingestible sensor is embedded in a pill—can be used for the provision of data on the administration of the therapy as well as the physiological condition of the patient, he explains. “Ingestible sensors in smart oral drug delivery dosage forms such as tablets and capsules will revolutionize diagnostics, clinical monitoring, data collection, and data analytics in the health care industry,” Kane adds.

“Smart medicines are a digitized form of traditional medicines. There are typically two components required to digitize a medicine—a target and a sensor,” Kane continues. “With smart medicines, the target is applied directly to the medicine via a coating or ink, and the sensing device (a cell phone application) is used to read the medicine and convert the signal into a digital format in a matter of seconds.”

On-dose authentication technologies can help to monitor patients and their administration of a therapeutic regimen, as well as ensure the medicine is authentic. The technology incorporates identification, such as bar codes and spectral images, on the dosage form, Kane specifies.

“A variety of formulation and manufacturing strategies are supporting more accurate, controlled OSD delivery to improve efficacy and patient outcomes,” emphasizes Gold. By way of example, he highlights how mini-tablets are emerging as a format that can provide an increased patient-centered dosing experience. “Configurable in single- or multiple-unit oral forms, mini-tablets have enormous potential to promote dosing flexibility and target dose forms to meet the unmet needs of different patient populations, like children or patients who have trouble swallowing,” Gold says. “Because of their size, usually less than 3 mm or less, these forms can be used to accomplish a number of oral drug delivery strategies.”

The most impactful dosage form technology for Anita Solanki, lead—White Papers, Formulation R&D (Pharma and Nutra), ACG Group, has been fixed-dose combinations (FDCs). “Combining two or more drug molecules can offer improved efficacy, as opposed to increasing the dose of a single drug—this is known as the synergistic effect,” she specifies. “To sum up, minimized drug resistance, maximized patient centricity, and the synergistic effect are the advantages for FDC in drug delivery.”

“For small molecules, the most significant changes in the time I have been involved in drug delivery are the advances in characterizing and addressing bioavailability challenges for oral delivery, which have become increasingly prevalent in the industry’s pipeline compounds,” states Stamoran. “Starting with better assessment tools to predict bioavailability characteristics, to a more comprehensive technology toolkit to solve the issues noted, the path to addressing these challenges today is far easier than in the past.”

In the case of large molecules, Stamoran highlights three developments as being most impactful: “the advances made in design, manufacture, and use of AAVs for gene therapy, including increasing understanding of patient safety-related factors of high-dose therapies; the large-scale clinical validation of lipid nanoparticle-based delivery of mRNA (COVID-19 vaccines); and the emerging opportunity for linkers and a site specific bioconjugation technology, with a wider therapeutic window and improved manufacturability of antibody-drug conjugates,” he says.

Trends for the future

“There is a conspicuous move in the direction of personalization and customization of treatment for the coming decade. 3D printing techniques are important in the field of pharmaceutical applications because of the possibility of faster formulation of tailor-made medicines which can be employed in personalized treatment,” notes Solanki. “Patient-centered dosage forms could be developed via 3D printing. Not only personalized dosage forms, but also different drug combinations, shapes, and release patterns can be achieved with 3D printing technologies.”

Inhalation as a drug delivery route is undergoing extensive research and will remain a hot topic for the future as it is no longer restricted to respiratory disorders alone, remarks Solanki. “Capsules based dry powder inhalation formulations are one of the preferred choices, because of their affordability in comparison to other inhalation dosage forms. Inhalation device and product combination will make sure that an unskilled patient receives the intended effect, whilst also being easy to handle and carry,” she says.

Gold expects there to be two trends in particular that will be influential on dosage forms and formulation over the course of the next decade. He believes that medicinal chemists will be increasingly able to understand the genetic resistance (or lack thereof) to certain compounds and that it will be possible to rebuild lost tissue, treat joint and bone pain, and many other diseases and conditions, thanks to advances in autologous and allogenic regenerative stem cell therapies.

“The continuing evolution of emerging modalities will continue to push delivery technology innovation needs, to deliver to specific targets, enhance safety profiles, and ensure manufacturability and patient usability,” stresses Stamoran. “Sustainability continues to grow in importance, both in terms of raw material production/green chemistry, and the operation of development and manufacturing activities. Finally, there are active legislative proposals in the [United States] that may establish an FDA pathway for new platform technology review, providing a smoother route for rapid adoption of innovation.”

Smart medicines and, more specifically, on-dose authentication, will be trending in the future, according to Rajabi-Siahboomi. Through these novel technologies, not only is it possible to deter counterfeiters, but it is also possible to help patients engage better with their medicines, he specifies. “In other words, ‘smart’ medicines not only bring authentication closer to the patient but also help them feel more comfortable with how they take the medicine,” Rajabi-Siahboomi states. “Non-adherence is a huge challenge for healthcare systems and patients may have many reasons for not taking their medicine. All patients can benefit from greater information and support that ultimately improves safety and adherence.”

For Mahler sustainability should be a primary consideration. “My perception is that many companies have excused a lack of product sustainability focus with the need to treat the patient(s). In my view, both aspects should not be mutually exclusive,” he summarizes. “Cradle-to-grave considerations for modern dosage forms are required to be embedded early in development. And this should and has to go way, way beyond CO₂ emission calculations and offset.”

References

1. Maximize Market Research, Oral Solid Dosage Pharmaceutical Formulation Market: Industry Analysis and Forecast (2021–2027) by Dosage Form, Drug Release Mechanism, Distribution Channel, and Region, Report (September 2021).
2. FDA, Advancing Health Through Innovation: New Drug Approvals 2020, Report (January 2021).
3. FDA, Advancing Health Through Innovation: New Drug Approvals 2021, Report (January 2022).

About the Author

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Article Details

Pharmaceutical Technology
Vol. 46, No. 3
March 2022
Pages: 16–20

Citation

When referring to this article, please cite it as F. Thomas, “The Shape of Dosage Forms,” Pharmaceutical Technology 46 (3) 2022.