What Is The Future Prospect Of Oral Biologics?

After decades of research and development efforts, the biopharmaceutical industry has achieved rapid development, but oral biologics technology is still far away from everyone’s vision. Today, biologics are often administered in a healthcare facility (by IV, or subcutaneously), rather than by the patient at home.

The term “biopharmaceuticals” is generally understood as complex macromolecules, ie proteins, composed of multiple hydrophobic and hydrophilic domains. However, in addition to proteins, biopharmaceuticals can also be understood more broadly to include other types of macromolecules such as antibody drug conjugates, antisense oligonucleotides, gene and cell therapy, etc. But in any case, one thing is clear: biologics are more susceptible to the environment of the gastrointestinal tract and unable to penetrate the intestinal barrier and other physiological barriers.

Biologics must be protected if they are administered orally, otherwise, they will not reach their target or exert their therapeutic effect. Approaches to protect biopharmaceuticals from the gastrointestinal tract and to help them penetrate physiological barriers include the use of penetration enhancers, lipid nanocarriers, and ingestible injectable formulations. Despite the difficulties, the topic of oral biopharmaceuticals has aroused some industry concerns—biologics require a more convenient way of administration, which is easier to achieve commercial success and has higher clinical value.

Business Potential

“The commercial potential of oral biologics is enormous,” said Dr. Weichang Zhou, President and Chief Technology Officer, Global Biopharmaceutical Development and Operations, WuXi Biologics. In Dr. Zhou Weichang’s view, although there are not many oral biological drugs that have been marketed so far, these drugs have performed well in terms of sales, including the oligopeptide diabetes treatment drug Rybelsus.

Dr. Zhou Weichang said: “Due to the convenience of oral administration and high patient compliance, Rybelsus will reach a net sales of more than 1.6 billion US dollars in 2022, highlighting the market’s demand for oral biologics. Although there is no oral antibody class However, in the past decade, the industry has seen an exponential growth in the development of novel delivery systems that can help biomacromolecules penetrate physiological barriers, thereby improving oral absorption.”

Dr. Zhou Weichang believes that oral biopharmaceuticals can also help manufacturers reduce supply chain costs. The ultimate goal of the preparation is to serve the patient until the time of actual administration, ensuring the convenience of medication and patient compliance. Most biologics are shipped under cold-chain or frozen conditions at 2-8°C and stored in airtight containers until use. Oral medications are typically dispensed to patients at a pharmacy in a room-temperature, humidity-controlled environment. Dr. Zhou Weichang pointed out that cold chain conditions enable biological agents to be distributed in pharmacies and hospitals, but it is not convenient for patients to self-administer medication, and they cannot really serve patients until the end of administration.

Technical Challenge

“Despite the many potential advantages of oral formulations, the complexity and paradoxes of biologics make it difficult to formulate oral formulations,” said Umberto Romeo, Head of R&D at CordenPharma. “Biopharmaceuticals, such as therapeutic proteins or nucleic acids, are Rapid inactivation of ‘digestion’. Currently, there is no formulation delivery system that provides sufficient oral bioavailability to effectively treat conditions, or at least does not require very high drug loading to exert limited biological effects.

CordenPharma Caponago’s core business is the production of sterile liquid preparations. According to Romeo, liquid formulation technologies, primarily injectables, are currently the only viable options for biologics.

Shaukat Ali, Ph.D., senior director of scientific affairs and technical marketing at Ascendia Pharmaceuticals, noted that in addition to formulation challenges, biologics are prone to degradation in inappropriate environments.

Technology Landscape

“Biopharmaceuticals are unstable in storage if the proper conditions are not met,” Dr. Ali said. “Biopharmaceuticals are very challenging to make into oral formulations because they cannot penetrate the mucus barrier and are unstable. Enzymatic hydrolysis is prone to occur at the physiological pH value of the intestinal tract.”

“Other reasons hindering the development of oral biologics include the elimination of large biomolecules from the body by first-pass metabolism and the short half-life in the systemic circulation. Therefore, for many biologics, the injectable route remains the most viable option.”

Scientists are still working to develop oral formulation technology for biologics. Some researchers are considering excipient formulations for the small molecule pharmaceutical industry.

Dr. Ali pointed out that there are many mature commercial formulation technologies in the field of small molecules to overcome the challenges of solubility, absorption and penetration in the gastrointestinal tract at physiological pH. The same pharmaceutical excipients can also be used in biologics development as long as they meet pharmacopeia specifications and are listed in the FDA’s Inactive Ingredient Database (IID). However, other than pharmaceutical excipients, other formulation technologies or processes for oral small molecules are unlikely to be used for commercial-scale biopharmaceutical production.

According to Dr. Ali, “For small molecules with high melting point, high fat solubility, low solubility, and low bioavailability, formulation technologies for oral tablets include spray drying, hot-melt extrusion, KinetiSol dispersion technology, and co-precipitation. Oral liquid or The preparation technology of capsule comprises solid lipid nanoparticle, nanostructure lipid carrier, microemulsion and nanoemulsion.For oral biopharmaceuticals, due to the challenges of stability and gastrointestinal permeability under the physiological pH value, in the above-mentioned technology Only a few can apply.”

According to Dr. Ali, for cell and gene therapy developers, the challenge of developing oral formulations is even greater. He emphasized: “There are currently no oral drug delivery technologies for cell and gene therapy. I don’t think there will be any oral cell or gene therapy in the short term, partly because polynucleotides and protein molecules are extremely vulnerable to enzymes in the gastrointestinal tract.” Hydrolytic effects, lack of stability.”

Dr. Ali also expects the industry to develop new excipient technologies that can protect oral biopharmaceuticals from degradation in the gastrointestinal tract and improve the transfection efficiency of DNA and RNA. These new technologies will accelerate the availability of new drugs for life-threatening and rare diseases, he said. He pointed out that Ascendia’s LipidSol is a lipid-based technology platform that can help those innovative but insoluble molecules develop suitable dosage forms, so as to develop drugs with various molecular types.

Find Another Way?

Even with all the challenges above, patient self-administration remains an important trend in biologics development, and there have been some notable advances beyond oral dosage forms. For example, in 1985, Novo Nordisk launched the first commercial insulin pen, a device that made it easier for patients to inject themselves. Other companies in the biopharmaceutical industry are now following in Novo Nordisk’s footsteps.

In fact, the novel drug delivery device is by no means limited to applications for subcutaneous administration. For example, the industry is currently developing drug delivery devices to enhance the effect of oral drug delivery. A recent article published in the Journal of Pharmaceutics pointed out that in order to meet the growing demand for oral biopharmaceuticals, researchers have been focusing on the development of devices such as intestinal patches, microneedle capsules, and particle systems [2].
The main purpose of all these research efforts is to combine biologics with a drug delivery device that is more acceptable and usable by patients. “In recent decades, there have been many successful cases in the industry in the development of biological preparations, which have truly served patients until the end of their use,” Dr. Zhou Weichang said. The concept of biological preparations is no longer limited to traditional preparation forms, but also includes Drug-device combination product preparations such as pre-filled needles and automatic injection pens are no longer limited by concentration and molecular type, and can enable the development and production of high-concentration preparations through high-throughput and computer-aided development.

Dr. Zhou Weichang believes that the drug-device combination is also an opportunity for contract manufacturing companies, “The contract development and manufacturing companies represented by WuXi Biologics have comprehensive professional knowledge and technical capabilities in formulation formulation and drug delivery systems, and can provide complete life cycle from the formulation. The one-stop service will have great development prospects in the fu