Reshaping Dosage Forms

The landscape of treatment for medical conditions and illnesses has become tailored and rich thanks to advances in personalized medicine, artificial intelligence (AI), and emerging modalities. Cell and gene therapies have been joined by messenger RNA (mRNA) vaccines in pushing innovation in the field of drug dosage forms. New manufacturing trends have also spurred the drive for new ways to deliver life-saving medicines.

“A confluence of innovative technologies is reshaping the healthcare market. Among these cutting-edge approaches, [AI], data analysis and management, blockchain technology, real-world data utilization, cybersecurity, and continuous manufacturing processes stand out as driving this paradigm shift,” says Jnanadeva Bhat, vice president at ACG Capsules (R&D). “These technological catalysts are not only bolstering medication delivery but also propelling forward the entire spectrum of development, packaging, and final product distribution to end consumers. Pharmaceutical industries are making up these newer technologies for innovation in healthcare.”

Tailoring dosage forms to individual patient needs is becoming a reality, confirms Ramesh Subramanian, chief commercial officer at Aragen Life Sciences. Treatment efficacy can be improved by customizing formulations based on genetic profiles and patient-specific requirements, which may minimize side effects, he emphasizes.

A shift in patient attitudes is also influencing innovation in dosage forms, according to Arnaud Verhaeghe, marketing director Pharma Oral Dosage at Roquette. “Compared with 10, or even five years ago, consumers are far more discerning about the types of drugs or individual ingredients they allow into their bodies,” says Verhaeghe. “This [change] is reflected in the demand for improved digestibility and convenience, personalized treatments in fields such as oncology, endocrinology, and infectious diseases, and especially in the recent ‘vegan revolution.’ The latter, in particular, has had implications for established drug formats like softgels. [Because] the traditional excipient of choice—animal-derived gelatin—is unsuitable for vegan or vegetarian applications, brands have turned to cutting-edge technologies, like first-of-its-kind hydroxypropyl pea starch…Such excipients are unlocking the potential to create high performance, planet-friendly plant-based drugs that are easy for consumers to swallow—both literally and metaphorically.”

Impacts on form

Patient adherence is also making an impact on the development of dosage forms. “For decades, patient groups, including children, the elderly, and people who experience issues swallowing, have had no choice but to use medications that are inconvenient, difficult, or even dangerous to take. At best, this can lead to pill fatigue, and at worst complete non-adherence,” says Verhaeghe.

Permeability is also causing an impact on dosage form choice, according to Lisa Caralli, senior director, Scientific Advisory at Catalent. “Addressing permeability limitations for peptides and biomolecules has been an area of intense focus in recent years, with the modulation of tight junctions with excipients remaining a key approach,” she says. “First pass metabolic loss for small molecules will also drive the use of the injectable route, whereas pregastric delivery through the mouth with dosage forms such as orally disintegrating tablets remains an under-explored area to address this metabolic concern.”

Ishani Maharaj, application development specialist, pharma ingredients at Univar Solutions, also points to issues with API solubility and permeability as pushing the demand for improved formulation strategies. The use of solubility and permeation enhancing excipients allows for APIs with improved bioavailability and increased efficacy, she explains.

“To formulate these APIs as solid dosage forms, there have been promising strategies such as amorphous solid dispersions (ASDs), co-processed APIs, and lipid-based formulations (LBF),” continues Maharaj. “With the use of a lipid base delivery system consisting of a solvent, surfactant, and co-surfactant, a self-emulsifying delivery system can be formed in the digestive tract. This
[delivery system] allows improved dissolution of the drug within micelles and for better systemic absorption of the water-insoluble API. Choosing the right components of a lipid-based delivery system for a particular API can be complex. To address this, excipient manufacturers are now delivering ready-made lipid-based pre-concentrates to simplify this process for formulators.”

New technologies are also making an impact on dosage form development. Manali Dalvi, lead–White Papers & Publications at ACG, points to the integration of three-dimensional (3D) printing as one of the innovations creating new capsules that can be tailored to individual patients. “This breakthrough empowers manufacturers to effectively address the unique therapeutic needs of each patient,” says Dalvi. “Moreover, capsules also offer fresh perspectives on fixed dose combinations, introducing flexibility in the composition of capsule inner content. This versatility opens the door to a wide range of potential constituents—ranging from powders and pellets to semisolids and various liquid forms (solutions, suspensions, emulsions)—to be encapsulated within,” she notes. “As the field continues to advance, it has become imperative for pharmaceutical manufacturers to stand at the forefront of this transformative shift, driving innovation and personalized care forward.”

Complex therapeutics

Developments in advanced and complex therapies have seen a surge in recent years. Bhat points to advances in genetics, molecular biology, and biotechnology as the drivers of these new treatments.

“Many researchers are eager to capitalize on these scientific breakthroughs,” asserts Bhat. “Complex therapies such as gene and cell therapies have the potential to offer advance treatment for the diseases that have been challenging to address with conventional medication. For example: cancer, heart disease, and cystic fibrosis. Many pharmaceutical companies have successfully developed and commercialized complex therapies, gaining the competitive edge in the sector, positioning themselves as leaders in medical innovation.”

Complex and advanced therapies often come with manufacturing and patient adherence challenges. How can industry meet these challenges?

The challenge of bioavailability is often seen in newly developed APIs, which exhibit poor solubility and where adequate dosing in a convenient dosage form is difficult, according to Verhaeghe. “This presents significant challenges, both in terms of manufacturing and end-user compliance,” he says. “But drug developers are fighting back with some truly ingenious approaches. One of the most exciting examples has been the expanded interest in specialized and co-processed excipients as processing aids and final-formulation ingredients. Cyclodextrins, for instance, have delivered great results in this area—their molecular encapsulation properties and affinity with complex molecules helps simplify formulations, increase solubility, and assure stability.”

Nick DiFranco, MEM, Global Market Manager, Novel Pharmaceutical Technologies at Lubrizol, agrees. “Complex therapeutics often involve challenges such as poor solubility or a high dose of drug. These challenges require efficient excipient technologies to solubilize compounds, control drug delivery without resulting in a tablet that’s too big to swallow, or avoid injections with extensive infusion times,” he says. “For example, if an oral tablet formulation is not optimized, patients may need to take tablets three or four times a day to achieve a desired therapeutic effect. Using excipients that enable high drug loading and/or control over release can increase the amount of drug per tablet while minimizing side effects, which reduces pill burden and offers huge benefits to patients. These excipient technologies don’t necessitate complex manufacturing techniques either.”

A multi-faceted approach can be used to address these challenges, according to Subramanian. “These innovations not only improve patient outcomes but also facilitate the development and commercialization of these advanced therapies,” he says. “Complex therapeutics often require specialized delivery systems, such as liposomes, nanoparticles, or microspheres that can improve drug stability, bioavailability, target specific tissues, and control release rates, enhancing the therapeutic effect.”

By way of example, Subramanian highlights nano-based formulations, 3D printing, and novel excipients as useful tools. “Nano-based formulations can enhance the therapeutic efficacy of complex drugs and reduce side effects,” he remarks. “3D printing is another technology that can help meet the dosage form requirements of complex therapies and bring formulation manufacturing closer to patients. [The technology] allows for precise control over the structure and composition of dosage forms and enables the creation of customized and patient-specific dosage forms, which is particularly valuable for complex therapies. The development of novel excipients can enhance the stability of complex therapeutics and improve their manufacturability. These excipients may be used to protect sensitive compounds or modify drug release profiles.”

Additionally, Subramanian points to quality by design as a tool in the development of complex dosage forms that uses a systematic approach to formulation to meet quality and performance requirements.

Filipe Gaspar, VP of Technology Intensification at Hovione, points to the company’s search for new technologies to deliver new modalities instead of technologies that come with limitations in formulation options, such as freeze drying. “Precise control over particle size and density, coupled with formulation design, is an enabler for high dose and low volume injections maximizing patient compliance,” he says. “At a much more mature phase is the use of respiratory delivery (inhalation and nasal) for biopharmaceuticals using spray drying technology which offers ample formulation options. Developing a highly efficient delivery device and product combination which ensures that an unskilled patient receives the intended effect is as important to address.”

The growth of the biologics market and patient-centric dosage forms have promoted the development of parenteral formulations and long-acting injectable products, according to Maharaj. “Injectable dosage forms are adequate when assessing the balance between benefit and inconvenience. The pursuit of convenient and reliable devices that can simplify injection procedures and give autonomy to patients can be a promising strategy to deliver such complex medicines in a patient-friendly way. Wearable devices such as a microneedle autoinjector could be a good candidate for delivering these larger molecules such as proteins, peptides, and monoclonal antibodies,” she says.

Delivering high-value biologics orally, however, will be a priority for the industry, continues Maharaj, because it is non-invasive. Delivery methods for biologics that are not readily absorbed after oral administration, however, will also be explored, she remarks.

“For example, monoclonal antibodies (mAbs) have a variety of potential therapeutic applications in autoimmune diseases and cancers. The dosage form remains a major obstacle for mAbs as frequent intravenous administration can reduce patient adherence,” says Maharaj. “Subcutaneous administration promises improved patient convenience and compliance due to the possibility of self-administration by patients, less visits to the hospital, and low healthcare costs.”

A push from regulators to develop advanced therapies also gives incentive for sponsor companies to invest in technologies and processes for complex therapies. FDA’s Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME) allows for agency review of novel excipients, which “will foster development of excipients that may be useful in scenarios in which excipient manufacturers and drug developers have cited difficulty in using existing excipients” (1).

“Novel excipients can be the key to producing products with improved bioavailability and reduced side effects,” says Caralli. “For example, surfactant excipients are often used to solubilize molecules with low aqueous solubility, or to form emulsions. However, some of these excipients are known to cause a hypersensitivity reaction in some patients, therefore, by using alternative forms that do not induce this reaction could provide a better and safer patient experience. Another area is innovation in polymers used for amorphous systems: highly crystalline drug substances can be transformed into their amorphous state, and stabilized with polymers to improve in-vivo solubility, and therefore, bioavailability. Novel polymer systems that can be used at lower processing temperatures in hot melt extrusion may reduce drug degradation and improve processability.”

A dose of technology

Technologies being adopted in laboratory hardware and data analytics are accelerating the development of dosage forms, according to Gaspar. “[Laboratory hardware] enables fast optimization, and [data analytics] transform the continuous accumulation of data (experience) into knowledge that can be multiplied for every new drug under development,” he says.

Gaspar points to continuous manufacturing of oral dosage forms as an example of a way to utilize data analytics because of the rich data environment and sophisticated process equipment and process analytical technology. “Scientists and engineers can interact with such a broad data environment and build sophisticated models that are normally used in control strategy definition, while also monitoring the manufacturing process not just with a few selected process parameters, but potentially with the full process data that can be analyzed by multi-variate methods to inform potential faults in real-time,” he notes. “During drug product development, it facilitates execution of extremely fast [design of experiments] and exploration of a design space.”

Caralli believes AI will play a pivotal role in drug dosage design. “[AI’s] ability to quickly synthesize current research will dramatically increase the speed of bringing new ideas into reality. [AI] could assess current dose design trends, based on patient populations and indication, allowing the optimization of drug administration, and ultimately increasing the rate at which drugs advance into the clinic,” she says.

However, Caralli cautions that AI-generated information may not be completely reliable. “Firstly, it may be detrimental to true innovation as it becomes easier to build on the ideas of others rather than generate new ones; and additionally, there is a need to override the natural impulse to publish studies showing what has been successful, versus what has not to avoid generating a biased data set. The industry may find itself becoming too trusting in the seemingly confident answers generated by AI, that it may not apply human skepticism, which is an important part of the scientific method,” she summarizes. “However, as the ability to identify trends through AI improves, the safety benefits to patients may ultimately outweigh the risks to innovation.”

Reference

1. FDA. Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME). FDA.gov (accessed Feb. 14, 2024).

About the author

Susan Haigney is lead editor at Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 48, No. 3
March 2023
Pages: 12-14

Citation

When referring to this article, please cite it as Haigney, S. Reshaping Dosage Forms. Pharmaceutical Technology 2024 48 (3).