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New approaches seek to address formulation and delivery challenges for these complex molecules.
Since the first recombinant protein therapeutic, human insulin, was approved by FDA in the early 1980s (1), there have been significant advances in the biopharmaceutical market. The industry is currently witnessing the emergence of protein and peptide therapeutics across a multitude of indications, such as oncology, infectious diseases, endocrinology, and immunology. The high selectivity and specificity of these macromolecules offer increased treatment efficacy while also potentially reducing the side effects and toxicity that are sometimes present with alternative therapeutic options (2).
“There is enormous therapeutic potential in proteins and peptides,” says Rashmi Nair, senior scientist, Formulations at Dr Reddy’s. “Major benefits that they offer over conventional small molecules could be attributed to their structural and functional similarities to endogenous biochemicals in the human body. This similarity translates into better drug targeting, lesser side effects, and new treatment options for various diseases where complex chemistry is restricted in small molecules.”
Susanne Joerg, head of formulation development, Drug Product Services, Lonza Pharma & Biotech adds, “Protein and peptide therapeutics have the potential to provide safer and more targeted therapies. They consist of amino acids and can interact with target receptors or ligands to convey their pharmacologic action. As they specifically have the potential of a more targeted interaction with receptors or ligands, they thus have a lower risk for off-target toxicity, a characteristic of many chemical molecules. An example is chemotherapy agents (such as cisplatin) being used for cancer treatment, versus targeted antibodies that block and prevent specific cell growth.”
Yet, despite the therapeutic advantages these macromolecules offer, they are also associated with several notable disadvantages, such as limited bioavailability as well as physical and chemical instability. These disadvantages have proven problematic for developers looking to create the best formulation and delivery method for these compounds and have limited their use.
As reported by Cleland and Langer more than 20 years ago, “The success of most peptide and protein drugs is dependent upon the delivery of the biologically active form to the site of action” (3). To achieve this, Cleland and Langer stressed that developing the most stable formulation possible is a requirement, and consideration of multiple routes of administration is important for future formulation development (3).
Production considerations. Producing protein or peptide therapeutics is highly complex and can include many more critical process steps than those required for a small-molecule drug (4). Additionally, manufacturers typically use living cells or organisms to synthesize the macromolecules, which can impact the characteristics of the final product (4). Research into protein-engineering strategies during drug development aims to address complex manufacturing processes (4).
“Structural modification with PEGylation, cyclization, chemical conjugation, use of enzyme inhibitors, absorption enhancers, encapsulated carriers, and so on, are all being employed to address the challenges of stability and delivery of protein and peptide therapeutics,” adds Nair. “A combination of approaches is often required that takes into consideration the route of administration and required target bioavailability.”
Direct structural modification, such as cyclization, PEGylation, and chemical conjugation, are considered to be key strategies in improving bioavailability and stability of peptide therapeutics (5). Co-administration techniques, such as with enzyme inhibitors, absorption enhancers, and encapsulated carriers are being assessed to improve the ability to deliver the macromolecules.
For Joerg, the most appropriate formulation development is vital in overcoming stability issues with these complex drug products for parenteral administration. “While freeze-drying usually provides the best stability, liquid dosage forms are preferred due to lower complexity for use and administration,” she says.
“To ensure appropriate product quality during manufacturing, integrated approaches for drug substance and drug product processing are critical, including the evaluation of ultrafiltration/diafiltration approaches, the composition of drug substance and product, and thorough evaluation of all drug substance and drug product manufacturing unit operations and operating ranges,” Joerg continues. “For example, the choice of a wrong fill pump can render a whole batch of protein product instable and non-compliant.”
Administration route considerations. Drug delivery challenges posed by protein and peptide therapeutics are many. Not only are the molecules large in size but they are hydrophilic, cannot easily cross biological barriers, are degraded by enzymes, rapidly leave the circulation system, and are highly charged, all of which complicate the delivery strategy. Commonly, as a result of these challenges, parenteral formulations and routes of administration have generally been the ‘go-to’ for these promising therapeutic options.
“Two major drug delivery routes are oral and parenteral,” states Nair. “While parenteral delivery is more commonly used, it has its own challenges with a short half-life of the drug resulting in frequent drug dosing and eventually less patient compliance.”
Joerg adds, “The size and hydrophilicity of proteins make it difficult to achieve sufficiently large and robust bioavailability without parenteral administration, which includes intravenous, intra-arterial, subcutaneous, intramuscular, intrathecal, and intravitreal/intraocular administration. All these routes of administration have specific challenges in terms of allowed volume for administration, pH, and osmolality requirements, and, of course, all parenteral preparations must be sterile and compliant with regards to endotoxin and particle requirements, for example.”
Low bioavailability and metabolic liability have also limited the oral administration of protein and peptide therapeutics (5–7). “Proteins and peptides do not sustain the rigor of the gastrointestinal tract. Chemical degradation in gastric fluids, extensive metabolism in luminal spaces, and first pass metabolism are major concerns with oral delivery of proteins and peptides,” says Nair.
However, oral delivery is considered to be the preferred route of administration due to the benefits it offers-patient convenience and acceptance, which in turn leads to increased patient compliance (6,7). “Even in the few examples where peptides have sufficient bioavailability after oral or inhalation administration for systemic use, there are various other challenges to be managed and overcome, such as cost-of-goods, safety, or toxicity of the compounds and variability in patients,” continues Joerg. “The numerous attempts to try and overcome parenteral administration have seen very limited success-primarily due to the inherent complexity of structure, hydrophilicity of the molecule, and the fact that our bodies have been designed to digest proteins through the oral route.”
Yet, she notes an advance in a more patient-centric approach to delivery that has been garnering increasing attention lately is the use of autoinjectors, syringes, or pens as delivery devices. “For example, monoclonal antibody therapies for subcutaneous administration often are used with syringes or even large-volume patch pump devices,” she adds. These techniques, along with improved focus on formulation evaluation and using a more systemic approach of following quality by design for process unit operations, are all helping to progress delivery, she further explains.
“However, appropriate product design and thorough planning of clinical (or patient) use, adequate in-use testing, and instructions for use (IFUs) are of utmost importance,” Joerg cautions. “For example, syringes and autoinjector systems can often facilitate self-injections of patients. But, a properly designed IFU and appropriate training of the patient is required to ensure compliance.”
Over the past 30 years, there has been extensive research into improving the stability and delivery of protein and peptide therapeutics. The success of this work is being reflected in the fact that increasing numbers of these therapies are being approved by regulatory bodies (8) and, in terms of delivery, the growth of the oral peptides and proteins market (9).
In the near future, Joerg anticipates that more attention will be put on the integrated development of the drug substance and product and more systemic evaluations of all parameters. “There is an increasingly considerable demand coming from the industry for an integrated solution from a sole vendor who has a combination of scientific and regulatory experience,” she says. “As we see pipelines moving to progressively complex biologics-for example, antibody drug conjugates, bispecific antibodies, fusion proteins, and other second-generation antibody therapies-the question of drug product becomes even more pertinent. Many companies are therefore looking for expertise that they may not have internally to solve these challenges.”
In terms of drug delivery, Joerg notes that, even though there have been numerous attempts at progressing alternatives to parenteral administration, injections or infusions remain, at this moment in time, the primary option. “In order to facilitate administration, devices will play a key role,” she continues, “with increasing connectivity to the Internet of things.”
For Nair, the past decade has been particularly encouraging for proteins and peptides. “Many new drug design tools, in-silicoscreening software, and predictive simulations have helped drug development programs. Stably folded, cell-penetrating proteins and peptides have advanced in clinical studies. Carrier-mediated drug delivery with microspheres and liposomes has enabled the commercialization of many promising drugs,” she adds.
In the coming decade, Nair predicts that there will be more development into the use of polymers for drug delivery, which could protect proteins and peptides from physical and chemical degradation and also help to sustain the drug release profile through depots or prolonged blood circulation times. “But, an important point,” Nair concludes, “is the consideration of integrated drug substance and drug product projects in drug development programs. Through this, overcoming the challenges of protein and peptide drug delivery will be increased as this is essentially a multidisciplinary science that requires an understanding of organic chemistry, biochemistry, pharmaceutical technology, and physical chemistry.”
1. D.V. Goeddel et al., Proc. Natl Acad. Sci. USA76 (1) 106–10 (1979).
2. C. Cao, Pharm.Tech. 40 (11) 22–24 (2016).
3. Cleland and Langer, Formulation and Delivery of Proteins and Peptides ACS Symposium Series (American Chemical Society, Washington, DC, 1994).
4. H.A.D. Lagassé et al., F1000 Research 6 (F1000 Faculty Rev) 113 (2017).
5. B.J. Bruno, G.D. Miller, and C.S. Lim, Therapeutic Delivery 4 (11) 1443–1467 (2013).
6. J.H. Hamman, G.M. Enslin, and A.F. Kotze, BioDrugs 19 (3) 165–177 (2005).
7. J. Shaji and V. Patole, Indian J. Pharm. Sci. 70 (3) 269–277 (2008).
8. B.G. de la Torre and F. Albericio, Molecules 23 (3) 533 (2018).
9. MarketWatch, “Oral Proteins and Peptides Market,” Press Release, May 8 2018.
Volume 43, Number 1
When referring to this article, please cite it as F. Thomas, "Considering Protein and Peptide Delivery," Pharmaceutical Technology 43 (1) 2019.