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Driving Dosage Form Developments

Dosage forms are being shaped by numerous factors, with patient-centricity continuing to be an important driver of decisions in development.

Developing the ideal dosage form for pharmaceutical products has long been a priority for drug companies. A poor dosage form decision can lead to costly commercial errors and potentially low medication adherence by patients—an aspect that can be particularly important in the rising numbers of chronically ill patients. Not only should consideration be made to the therapeutic characteristics and potential manufacturability of the finished drug product; but also, whether the dosage form will ultimately be patient-centric and, hence, ensure optimum adherence of a treatment regimen.

“Drug dosage forms have evolved in recent years due to several factors, including the growing demand for custom drug delivery solutions, the increasing complexity of new therapeutic entities (NTEs) entering the development pipeline, and the aggressive competition in the pharmaceutical market,” reveals Ishani Maharaj, Application Development Specialist, Pharma Ingredients, Univar Solutions. “While oral solid dose (OSD) forms remain the preferred choice due to convenience and cost-effectiveness, applying innovative delivery approaches is essential to meet the unique needs of the target patient population.”

Shifting focus

“The pharmaceutical sector is propelled by radical innovations, accelerating the pace of the therapeutic process achieving the transformative shift from life science to healthcare. From personalized medicine, advanced nanotechnology to sustainable formulations, 3D printing, combination therapy, and smart drug delivery, the landscape is undergoing a profound transformation,” asserts Jnanadeva Bhat, vice president, head—Formulation R&D at ACG-Worldwide. “The growing attention to rare diseases has catalyzed a revolution in the field of drug development, reflecting the industry’s responsiveness to unmet medical needs while setting the stage for pioneering advancements.”

In concurrence, Filipe Gaspar, vice president of Technology Intensification at Hovione highlights the growing proportion of orphan drugs—and the need for leaner and accelerated drug development paths along with it—as an important trend. “The change from large volume to small volume drugs, namely by the increased prevalence of rare/orphan drugs and precision medicine, is driving substantial changes in the pharma industry and driving innovation in many areas such as drug discovery, clinical design, supply chain management, development, and regulatory paths,” he says. “A very lean, API-sparing, and accelerated CMC [chemistry, manufacturing, and controls] development approach becomes critical to prevent being the bottleneck in drug approval.”

Therefore, Gaspar continues, continuous manufacturing is being more widely adopted as it provides a more streamlined approach, avoids the need for scale-up, and facilitates debottlenecking pharmaceutical development. However, he warns that despite the advantages brought about by transitioning from batch to continuous manufacturing, there are also challenges, such as a lack of access to continuous manufacturing technology for smaller pharma companies and biotech companies.

“Most small pharma and biotech [companies] do not have [continuous manufacturing technology] as a captive technology and the limited CDMO [contract manufacturing and development organization] network is still developing the expertise and expanding their capacity,” Gaspar adds. “By relying on batch processes, these innovators may incur on additional development costs and, most importantly, delay their drugs to market, sometimes many months, which can be critical to success of many drugs.”

Focusing on manufacturing, Lisa Caralli, senior director, Scientific Advisory, Catalent, raised the matter of spray drying for biologics as an efficient and scalable alternative to the traditional lyophilization technique. “The use of more modern techniques such as spray drying has been investigated as a way to formulate lipid nanoparticles with biologic payloads into a dry powder for oral delivery, as well as optimizing particle attributes for inhalation. While additional research is still needed to validate these approaches, they represent true innovation with a potential high impact for patients,” she says.

Patient-specific requirements

For Arnaud Verhaeghe, marketing director Pharma Oral Dosage at Roquette, the most influential trend over recent years has been the expanded focus on patient-centricity. “This [trend] has manifested itself in producers putting user needs first—devising innovative ways to help patients start and adhere to treatments,” he explains. “The popularization of dosage forms like functional gummies and jellies, orodispersible powders and tablets, orally administered vaccines, and more is the best example of this attitudinal shift in action.”

Additionally, Verhaeghe notes that due to the fact the success of such oral dosage forms, as mentioned earlier, hinges on a pleasant taste and texture, there have been good strides forward in the field of taste-masking as well.

“Continuous improvement in elevating traditional dosage forms to increase therapeutic efficacy, improve patient compliance, and enable more patient-centric options are becoming more practical with advanced technologies, innovative medical device designs, and new functional excipients,” Maharaj specifies. “From a formulator’s perspective, tablets and capsules are tunable and can achieve different release profiles, including immediate or modified release, fixed-dose combinations (FDCs), orally disintegrating tablets (ODTs), and other types of release profiles. This [flexibility] creates a lot of opportunity to develop oral dosage forms that are adapted for certain patient groups. ODTs have gained significant traction as they eliminate the need to swallow a pill and offer ease-of-use for the elderly and pediatric population.”

Commenting further on FDCs, Uwe Hanenberg, head of Product Development in Oral Solid Dose, Recipharm, iterates that this dosage form option has gained substantial popularity in recent times. “These formulations combine multiple APIs into a single dosage form, often utilizing advanced modified-release technologies,” he says. “By controlling the release of each API into the bloodstream, these combinations minimize side effects and extend the therapeutic effect in patients—reducing the number of daily doses required, which minimizes patient burden and enhances patient compliance with therapy.”

“The growing interest in oral medication has highlighted the importance of both personalized medication and FDC therapies as influential trends in the development of drug dosage forms,” confirms Manali Dalvi, lead white paper and articles at ACG-Worldwide. “[Additionally], FDC has provided the option to develop potential proprietary drugs, which offer greater savings compared to the NCE or their generic version. This strategic approach not only provides manufacturers with reinforced intellectual property support but also empowers them to prolong their market exclusivity.”

Repurposing existing active ingredients can also be leveraged to improve patient-centricity is enabled by FDA’s 505(b)(2) pathway, remarks Nick DiFranco, MEM, Global Market Manager, Oral Drug Delivery, Lubrizol. “The 505(b)(2) pathway accelerates drug product development by allowing companies to leverage the existing safety/toxicity data of a drug when developing improved formulations or changing dosage forms. This might include developing extended-release formulations that reduce the pill burden on a patient or creating smaller-sized tablets or granules that can be dosed directly for either a child or geriatric patient with difficulty swallowing,” he says. “Alternatively, it could be creating a long-acting injectable or utilizing altnernative excipients with reduced side effects. Particularly for poorly soluble APIs, the desire for patented formulations and advancements in delivery technologies, create opportunities for differentiated and optimized dosage forms.”

The movement of the industry toward a more patient-centric model has been key in driving innovation in dosage form design, stresses Caralli. “However, as a formulator, this puts a spotlight on bioavailability enhancing formulations, which often need to do more than improving aqueous solubility,” she states.

Overcoming solubility and bioavailability issues

“Approximately 60% of APIs under development, and more than 40% of those in reformulation, are poorly water soluble—meaning the pipeline is full of insoluble drug products,” emphasizes DiFranco. “If we want to continue bringing small molecules to market, we need new tools for formulation because traditional excipients aren’t always going to yield viable products. This is especially true in the oncology field, where the pipeline comprises many challenging classes of APIs, such as proteolysis-targeting chimeras (PROTACs).”

Ramesh Subramanian, chief commercial officer, Aragen Life Sciences, points to the investments being made into the development of novel drug delivery systems, such as liposomes, nanoparticles, and microspheres. “These systems help overcome the challenges of drug solubility, bioavailability, and targeted delivery, improving therapeutic outcomes,” he adds.

In Gaspar’s experience, amorphous solid dispersions (ASDs) are becoming the predominant platform to overcome poor bioavailability, leveraged by spray drying. “In turn, this has led to significant advances on the formulation of amorphous materials, namely in material and analytical sciences, the development of novel (sometimes enabling) excipients, and the need for appropriately formulated dosage forms,” he says.

“More lipid-based delivery solutions, solubility, and permeability increasing excipients are coming onto the market to enable formulators to improve the solubility profile of those lipophilic, hard-to-formulate APIs within an oral dosage form,” notes Maharaj. “This [market dynamic] alleviates numerous challenges with formulating Class II/IV drugs, resulting in increased therapeutic efficacy, but improved manufacturing efficiency, shortened development timelines, and reduced overall costs.”

Another option to help overcome bioavailability is nasal administration, Maharaj continues. “Nasal dosage forms such as nasal sprays, powders, suspensions, and gels have been on the market for years. However, this dosage form type can offer an ideal route and improved bioavailability for some drug types, particularly for central nervous system disorders. This offers immense potential for nasal dosage forms with innovation focused on delivery devices,” she states. “Excipient and process selection to produce the desired API particle size is critical for optimal deposition and absorption via the nasal cavity route.”

Biopharmaceutical escalation

“The rise of biopharmaceuticals and biosimilars has led to innovations in formulation development,” specifies Subramanian. “These complex molecules require specialized formulations to maintain stability and ensure consistent therapeutic performance.”

Growth within the biologics sector is expected to continue at an impressive rate, which, according to Hanenberg has also spurred further advancements in OSD technology. “Although biologics have traditionally been administered parenterally due to the sensitive nature of their active ingredients, recent development work on some of these molecules, such as insulin, has allowed them to be formulated for oral delivery,” he says. “This shift enhances patient centricity by offering the convenience of OSD while introducing new formulation challenges for large-molecule drugs. As a result, we can expect more developers to turn their attention to such advancements in drug delivery.”

The notable shift in industry’s focus toward the development of protein and RNA therapies has been apparent over recent years, Caralli adds. “The investigation of nanoparticle delivery exploded after the COVID-19 pandemic: one such method involves using nanoparticles to deliver mRNA vaccines via the gastrointestinal tract, as researched by Robert Langer and his team at the Massachusetts Institute of Technology (1). These vaccines would not be constrained by the cold-chain restrictions of the injectable versions, allowing for the easier distribution of drugs to developing countries and rural areas,” she remarks.

Orally administered and other non-parenteral vaccines are great examples of ways in which patient compliance can be improved by pharma companies, stresses Verhaeghe. “Not only do these dosage forms remove the meticulous cold chain required for the use of liquid biologics—making them less susceptible to supply chain disruption—but they have been shown to be more attractive to patients, not least because of the elimination of off-putting needles.”

A remarkable evolution

It is estimated that one in six people will be over the age of 60 years by 2030 (2), meaning that there will be a greater proportion of patients who may have difficulties with dexterity and swallowing, asserts Hanenberg. “OSD developers will have to reformulate their drugs to cater to these evolving patient needs, designing their tablets to be smaller and easier to swallow and packaging to be more accessible. They must also consider the needs of pediatric patients, catering their administration to counter bitter-tasting medicines with more palatable flavors and mouthfeel,” he says.

Assessment of whether or not a dosage form is appealing and satisfactory to the target patient population impacts drug adherence, which is just as important as ensuring the right excipients for the active are selected to facilitate optimal drug delivery and product stability, Maharaj confirms. “Patient-centricity is a trend that will continue to be a key driver in developing novel drug dosage forms in the future,” she emphasizes.

“The industry has witnessed a remarkable evolution in drug dosage forms, driven by a convergence of scientific breakthroughs, patient-centric approaches, and regulatory incentives,” concludes Bhat. “As we stand at the intersection of innovation and healthcare, it has become exciting to delve into the trends that are shaping the future of drug delivery.”

References

1. Kim, H.; Kirtane, A.R.; Kim, N.Y.; et al. Gastrointestinal Delivery of an mRNA Vaccine Using Immunostimulatory Polymeric Nanoparticles. AAPS J. 2023, 25, 81.
2. WHO. Ageing and Health. WHO.int, Fact Sheet, Oct. 1, 2022.

Source – Pharmatech