Most often developed as injectable formulations, a few “oral peptide” drugs have been approved in recent years. Advances in delivery technologies have contributed to growing interest, and many more are in development. Access to a contract development and manufacturing organization with established success in the development and manufacturing of oral peptide drugs can reduce the time it takes for these complex therapeutics to enter the clinic and reach the market.

Benefits of Peptide Therapies

Comprising chains of 40–50 amino acids or fewer, peptides are neither small-molecule nor biologic drug substances, but fall in between. Examples of commercial peptide drugs include Byetta, Victoza and Trulicity — glucagon-like peptide-1 (GLP-1) receptor activators for the treatment of diabetes. Other indications being targeted by peptides include oncology, inflammation and infectious diseases. There are more than 100 peptides on the market and many more in development.1

Because peptides are widely present in the body and play specific functional roles, peptide drugs outperform small-molecule  drugs with greater potency and specificity, leading to decreased side effects and greater efficacy.1 They are well tolerated by the body and exhibit reduced systemic toxicity. Peptides also offer manufacturers the advantage of being less complex to produce than most other biologic drug substances.

The one less-attractive quality of peptide drugs is their delivery method, which for the vast majority of products on the market is by injection. Peptide drugs often require frequent injections. They can also suffer from inconsistent drug concentrations. There is consequently significant interest in developing other routes of administration for peptides, including oral, nasal, buccal, pulmonary, transdermal, rectal and ocular.2

Why Oral Peptide Delivery is Challenging

Peptide drugs have been developed as injectable products because it is very challenging to achieve high bioavailability by oral administration. The upper gastrointestinal tract (GIT) is designed to digest peptides and proteins. Protective (enteric) coatings on tablets or capsules can enable passage of peptide drugs through the low pH conditions in the stomach, but resisting degradation by proteases (pancreatic and brush-border enzymes) and achieving permeability of these high-molecular-weight biomolecules through the intestinal epithelial layer are significant challenges.3 Inter- and intrapatient variability is another important factor.3

A common approach to overcoming these challenges is to use excipients, including enzyme inhibitors and permeation enhancers to prevent degradation and enhance permeability, respectively. By co-releasing these excipients with the peptide near the gut wall, a high concentration gradient can be created at the site of absorption.3

Other technologies that are being explored include mucoadhesive polymeric systems and carrier systems such as emulsions, nanoparticles, microspheres and liposomes.2 The derivatization of peptides using polyethylene glycol (PEG) to prevent degradation and improve solubility is another strategy.2 More novel tactics include the following: the use of endogeneous cell carrier systems such as vitamin B12, modified toxins and viral hemagglutinin; the use of cell-penetrating peptides hybridized with target molecules; and the preparation of peptides as prodrugs.2

Current State of Oral Peptide Drug Market

The global oral protein and peptide market is predicted by Allied Market Research to grow from $643 million in 2016 to $8.233 billion in 2028, expanding at a compound annual growth rate of 11.7% from 2022 to 2028.4 As early as 2015, companies were investigating the oral delivery of insulin, calcitonin, cyclosporine, leucine encephalin, HIV protease and other peptides.2

In February 2017, Protagonist Therapeutics presented preclinical data on two oral peptide drug candidates for the treatment of moderate-to-severe active ulcerative colitis and for moderate-to-severe Crohn’s disease.5 In May that same year, Synergy Pharmaceuticals received FDA approval for its oral peptide Trulance™ (plecanatide), a uroguanylin derivative for the treatment of chronic idiopathic constipation (CIC). The drug is also being evaluated for the treatment of chronic irritable bowel syndrome.6

In December 2017, Entrega announced a research collaboration with Eli Lilly and Company to advance its peptide delivery technology, which uses a proprietary, customizable hydrogel dosage form to control local fluid microenvironments in the GIT for enhanced absorption and reduced drug exposure variability.7 Enteris Biopharma is using its Peptelligence® oral drug-delivery platform in the development of orally delivered therapeutics that have been previously marketed as injectable-only formulations, with candidates in preclinical to phase II development stages.8

Advances in academia are also being achieved. Researchers at the University of Pennsylvania are manufacturing peptides in plant cells, where their structures are maintained and can be passed through the intestinal epithelium.9 At Kumamoto University, scientists have identified cyclic peptides that facilitate the absorption of large biomolecules in human small intestine absorption models and mouse small intestines. These peptides could potentially enable the oral administration of other peptides and proteins.10 Researchers at the Technical University of Munich have created a masked hexapeptide that exhibits the same biological effects when delivered orally as its unmasked version when injected.11

Role of the CDMO 

Because the formulation development of oral peptide drugs is so challenging, most pharmaceutical companies rely on contract development and manufacturing organizations (CDMOs) with specialized expertise in this field. 

A comprehensive understanding of the properties of each peptide is necessary to select the most effective drug-delivery system and develop an optimal drug formulation. As a result, extensive knowledge and experience are needed at the proof-of-concept stage. CDMOs that can take a project beyond this point through to commercialization offer further benefits, including elimination of the risk, time and cost associated with technology transfer and simplification of the supply chain. Effective CDMOs also offer comprehensive analytical and cGMP scale-up and commercial manufacturing services and are committed to meeting client objectives with the highest quality while maintaining the most efficient use of time and controlling costs.

Demonstrated Success

UPM Pharmaceuticals was founded as a drug formulation services company focused on oral drug delivery. Today we support clients in formulation development through final product manufacture (tablets, capsules and beads in capsules) via various processes (see Table 1). Twenty scientists work in the product development area. Our technical services group supports our manufacturing teams for dosage form production and packaging. We also have methods development and quality control/quality assurance teams. 



Table 1:

UPM Process Capabilities Useful for Oral Peptide Drug Production

  • Dry blend, low/high energy
  • Fluid bed coating
  • Encapsulation, hard shell
  • Compression
  • Pan coating
  • Roller compaction
  • Milling


With respect to oral peptides, UPM was involved in the formulation development of two of the very few FDA-approved products. We invested in large-scale manufacturing capacity specifically for the commercial production of the second product we developed. Currently three additional oral peptide drugs are at the Investigational New Drug (IND)  stage. Products include both immediate- and delayed-release formulations.

Our knowledge of many different excipients has enabled the development of effective oral peptide formulations. Specialty excipients (see Table 2) can address stability and solubility issues and provide the desired controlled-release rate. For water- and moisture-sensitive peptides, they can be used to achieve both internal and external desiccation. Antioxidants prevent degradation due to exposure to oxygen.



Table 2:
 
Selected Specialty Excipients Used in Oral Peptide Drug Formulation

  • Divalent ions
  • Lipids
  • Water-soluble polymers
  • Proteins
  • Enteric polymers
  • Absorption enhancers
  • Solubilizers
  • Polymeric inert sugars
  • Dessicants, internal and external
  • Antioxidants


Identifying the appropriate excipients for a given oral peptide formulation requires the performance of extensive compatibility studies to ensure that none impact the stability of the API. Because many peptides are high-potency compounds requiring low microgram dosages, issues of content uniformity must also be addressed. In addition, some peptides require solubilization to achieve drug distribution as a molecule rather than a particle, which can create additional challenges with respect to stability. 

While for most processing steps conventional equipment can be used, because many peptides are water- and moisture-sensitive, it is necessary to provide a controlled environment during manufacturing. UPM has low-humidity suites designed for this purpose. In some cases, dehumidification is achieved locally; in others, a low-humidity environment is provided in the entire suite. 

We also have low-humidity solutions in our packaging area and use heavy (thick)-wall bottles to protect final products from the external environment during storage. Nitrogen purging, external desiccants selected after extensive performance studies and antioxidants are also used for this purpose.

Analysis of peptides requires special expertise as well. UPM has knowledge of the latest chromatography column technology available for peptides and has worked closely with the ultra-performance liquid chromatography (UPLC) instrument manufacturer to ensure that our instruments and columns are appropriate. We have, for instance, replaced the stainless-steel tubing on instruments for peptide analysis with polyetheretherketone (PEEK) tubing to avoid potential interactions. We have developed proprietary methods using a quality-by-design (QbD) approach to ensure that the most appropriate, robust techniques and methods are developed for each specific peptide and that they are readily transferrable to commercial operations. UPM also has an established network of partners that can provide any analytical capabilities not available in-house.

Tackling Formulation Challenges

UPM’s demonstrated success in oral peptide drug development and manufacturing provides security to our pharmaceutical partners in the peptide market. UPM currently manufactures 72 commercial SKUs with 47 R&D projects in development. With two commercially approved oral peptide products on the market that we developed and three additional oral peptide products currently in development at UPM, we have gained considerable experience and technical expertise. We now have a platform of technologies available for application to additional oral peptide drugs from development through commercialization.

We also recognize at UPM that the drug development process is unpredictable. Each peptide is unique and presents its own set of development challenges. We have therefore built in flexibility to overcome the hurdles presented by oral peptide drugs and to respond rapidly to the unexpected.

UPM’s scientists are eager to apply their existing knowledge for the rapid development of highly effective, customized, innovative solutions for new oral peptide products. In fact, we enjoy the formulation and analytical development challenges presented by oral peptide drug delivery and are energized by the science behind these complex and promising therapies. 

References

  1. Shields, Paul. “Oral Peptide Therapeutics — a holy grail or quixotic quest?” Drug Discovery World. Fall 2017. Web.
  2. Muheen, Abdul et al. “A review on the strategies for oral
    delivery of proteins and peptides and their clinical perspectives.”
    Science Direct. 16 Jun. 2014. Web.
  3. Brayden, David J. “The Cautious Comeback of Oral Peptides.” The Medicine Maker. Aug. 2015. Web.
  4. Shaikh, Sohail, Pallavi Jaiswal. “Oral Proteins and Peptides
    Market by Drug Type (Linaclotide, Plecanatide, Calcitonin, Insulin and Octreotide) and Application (Gastric & Digestive Disorders, Bone Diseases, Diabetes and Hormonal Disorders).”
    Global Opportunity Analysis and Industry Forecast, 2017–2028. Mar. 2018. Web.
  5. “Protagaonist Therapeutics Presents Data on Oral Peptide
    Drug Candidates at European Crohn’s and Colitis Organization (ECCO) Congress.”
    PR Newswire. 17 Feb. 2017. Web.
  6. Karounos, Denise. “A New Peptide Drug Is Approved.” Peptides International. 15 May 2017. Web.
  7. “Entrega To Receive $5 Million Investment from Lilly to Advance Proprietary Oral Delivery Technology for Peptides.” Business Wire. 19 Dec. 2017. Web.
  8. “Pipeline.” Enteris Biopharma. 2018. Web.
  9. Hernandez, Randi. “Are Oral Peptide Drugs on the Horizon?” Pharmaceutical Technology. 14 Jul. 2016. Web.
  10. “Small intestine permeable peptides facilitate digestive tract absorption.” Kumamoto University. 21 Sep. 2017. Web.
  11. “The ‘Holy Grail’ of peptide chemistry: Making peptide active agents available orally.” Technical University Munich.
    22 Feb. 2018. Web.