Read Phase I: Advancements in oral solid dose
The industry’s tried and true dosage forms continue to evolve to keep pace with a changing industry.
“Emerging trends and innovations in oral solid dose technology are transforming the landscape of drug delivery and patient treatment,” says ACG's Rafael Costa.
Some of these trends have been ‘emerging’ for longer than others. Fixed-dose combinations (FDCs), for example, have been in existence for several decades, but have seen a resurgence in popularity and development over the last ten years. Advancements in scientific knowledge, improved formulation technologies, and a growing emphasis on personalized medicine have all contributed to the resurgence of FDCs.
FDCs are drugs that contain two or more active ingredients combined in a single dosage form. These active ingredients work together to provide synergistic effects or target different aspects of a disease or condition. While the focus on FDCs waned for some time, the pharma industry is once again recognizing the potential benefits of combining multiple active ingredients in a single dosage form. “Combination products utilizing capsules are gaining popularity, as they simplify medication regimens for patients requiring multiple medications,” says Costa.
FDCs have been particularly impactful in the treatment of diseases that have high pill burdens, such as HIV. GSK’s Combivir was one of the first FDCs to be greenlit for HIV, winning FDA approval in 2000. The drug combines two antiretroviral drugs, lamivudine and zidovudine, into a single tablet.7 By combining lamivudine and zidovudine, Combivir effectively suppresses viral replication and helps manage the progression of the disease, contributing to improved health outcomes for individuals with HIV/AIDS. Also, several single-pill triple-drug combinations are now available to treat hypertension in the U.S.
These combinations offer comprehensive approaches to managing hypertension by combining different classes of medications with synergistic effects. They optimize blood pressure control and provide convenience for patients with hypertension. Currently, the global fixed-dose combination drugs market is projected to reach a CAGR of 6.75% by 2031.
While combining multiple drugs within the same dosage form offers advantages for patients, it also comes with formulation risks. Improperly formulated FDCs can result in serious issues.
From a potential pharmacodynamic mismatch where one drug’s effects can diminish efficacy or increase toxicity to chemical non-compatibility where interactions between active ingredients cause adverse effects or reduced effectiveness, FDCs are not without obstacles. Earlier this year, Vantage Nutrition, an ACG Group company, acquired ComboCap, a technology-based startup focused on helping the industry overcome these types of challenges. ComboCap commercialized the world’s first sideby-side separated oral dose products for nutraceuticals and pharmaceuticals.
The ‘Sidebyside’ technology features a new three-piece capsule. “The third piece is the inventive introduction of a cupshaped divider membrane inside a standard off-the-shelf capsule — made from the same material as the capsule — that acts as a divider inside the body of the capsule. This enables wet and dry ingredients or incompatible actives to be housed side-by-side — together but separate in one product,” says Tobie Louw, vice president, Operations at Vantage Nutrition. The Sidebyside technology allows for the release of substances in a parallel or sequential fashion, with the ability to discharge either chamber ahead of the other based on specific requirements or demands.
The introduction of a cup-shaped divider membrane within the standard capsule offers a solution to combat pharmacodynamic mismatch or chemical non-compatibility in fixed dose combination drugs by allowing for both wet and dry ingredients or different actives to be housed side-by-side in a single product, while remaining physically separated inside the capsule. This approach allows for the co-administration of multiple active ingredients that may have different pharmacodynamic properties or chemical characteristics, which could otherwise lead to reduced efficacy or potential adverse interactions if combined in a traditional formulation. The cup-shaped divider membrane acts as a barrier, preventing direct contact between the incompatible substances within the capsule. As a result, each active ingredient maintains its effectiveness and stability, ensuring that they do not interfere with one another before ingestion.
To develop the drugs, Vantage uses a machine that utilizes a standard empty hard capsule by removing the cap, filling it with liquid, and sealing a membrane in place before replacing the cap. In the subsequent stage, powder encapsulation occurs where the cap is removed, the powder is dosed, and the cap is resealed, resulting in a completed product. The three-piece design maximizes dose volumes on both sides of the membrane while allowing for customized dose sizes through adjustable membrane positioning. Unlike the cap-in-cap design, where the outer liquid capsule dissolves before the inner powder capsule, Sidebysides dissolve both capsule shells simultaneously.
Parenteral to OSD
Parenteral drugs are administered directly into body tissues rather than through the digestive system, which offers a rapid onset of action, higher bioavailability, more accurate dosage, and better suitability for unconscious or nauseous patients. However, parenteral drug delivery poses risks as it bypasses natural body barriers like the gut and skin, making patients vulnerable to contaminants, which means ensuring high-quality and pure manufacturing standards is crucial. Parenteral drugs are also generally considered more fragile and delicate than orally administered drugs because as they travel through the bloodstream, many factors can contribute to their degradation. While biologics are traditionally administered parenterally, researchers and pharma companies have been developing technologies to deliver biologics orally.
“The other area where we are seeing trends in oral solid dose is more complex formulations or large molecules being tried in through an oral delivery,” says Anil Kane, global head of Technical & Scientific Affairs at Thermo Fisher Scientific. “These are in the broad category of enzymes, peptides, proteins, oligonucleotides, and the challenges here are designing a formulation strategy for these large molecules to withstand the rigors of an overall delivery such as gastric pH and be able to deliver at the correct site of activity for its absorption and to have optimal clinical efficacy.”
Oral delivery of biologics is difficult due to their large, complex nature and the harsh environment of the gastrointestinal tract. Digestive enzymes in the GI tract can degrade biologics before they reach their target site, reducing their effectiveness. Permeability barriers in the GI tract can restrict the passage of large molecules like biologics into the bloodstream. Additionally, the GI tract’s immune system can recognize biologics as foreign, leading to rapid clearance or neutralization. But alternative routes of administration could enhance efficacy and develop more patient-centric formulations, particularly for specific medical conditions. Currently, there is one biologic on the market that was successfully reformulated from its injectable delivery to an oral route. Novo Nordisk’s Rybelsus, an oral formulation of semaglutide for treating type 2 diabetes, represents an advancement in oral drug delivery. Rybelsus offers an alternative to subcutaneous injections for those who prefer oral medication.
Approved in the U.S. in September 2019 and subsequently in the UK, Rybelsus is the world’s first oral GLP-1 receptor agonist. It is taken daily, providing similar benefits to the once-weekly semaglutide injection. But there are downsides to the oral formulation route. Rybelsus exhibits lower bioavailability (1%) compared to its subcutaneous counterpart (over 50%). This means the tablets require larger quantities of active ingredients, potentially increasing costs that can ultimately be passed down to health care systems.
Kane highlights that once the development hurdles are surmounted, the path forward becomes clear. “Once we cross the barrier of having developed stable and scalable formulations, I think manufacturing using existing infrastructure is feasible. This does not require any new capital investment, new techniques or technologies,” says Kane.
Targeted delivery using the right polymers (or combination of polymers) in the right dosage form could allow for the delivery of biologics through the oral route, but leveraging the experience from small molecules and utilizing the infrastructure is key. Drugmakers are not only reformulating existing drugs into OSDs, but also developing new biologics only intended to be taken orally. “New molecules as well as repurposed drugs are being tried and tested using a different route of administration for different efficacy and developing more patient-centric formulations, especially for certain conditions like oncology or in different geriatric patient populations,” says Kane.
Continue reading Phase III: OSD soars: The digital metamorphosis of oral solid dose