Therapeutics
decreased systemic toxicity. Moreover, because the body naturally produces peptides, peptide-based therapeutics are often well-tolerated and are less likely to elicit immune responses.
Given their attractive pharmacological profile and intrinsic properties, peptides represent an excellent starting point for the design of novel ther- apeutics, and their specificity has been seen to translate into excellent safety, tolerability and effi- cacy profiles in humans. Furthermore, peptide therapeutics are typically associated with lower production complexity compared with protein- based biopharmaceuticals and small molecules. Though peptide therapeutics offer numerous advantages, and the growth of such drugs is strong, there remains a significant gulf between ‘market actual’ and ‘market potential’. This is largely attributable to challenges with the route and method of delivery of peptide drugs. Peptides and proteins are high molecular weight biopolymers and contain both hydrophilic and hydrophobic appendages in their structure. These properties make it difficult for peptides to be absorbed by the intestine. Peptides also degrade in the stomach and duodenum, given the digestive roles of these organs, so they may not even be avail- able of absorption by the intestine. Simply said, our bodies recognise peptides as food when ingested. Given these barriers, most peptide drugs are administered parenterally, with approximately 75% given via injectable routes such as subcuta- neous, intravenous and intramuscular administra- tion. While the market for injectable proteins is strong and growing, alternative administration forms are gaining increasing traction. This trend is guided by three dynamics – patient compliance, prescriber preference and market expansion. As one can appreciate, fre- quent injections, inconsistent blood drug concen- trations and low patient acceptability make par- enteral administration of peptide-based drugs less desirable. As a result, pharmaceutical developers continue to explore alternate routes of delivery for peptide therapeutics that have the potential to maintain the drug’s potency, while enhancing the ease of administration, patient compliance and market penetration.
Against this backdrop, the oral delivery of pep- tides has caught the imagination of drug developers far and wide. The majority of drugs on the market today are given as a pill or capsule and, thus, repre- sent the form most patients are accustomed to tak- ing. Long hailed as the Holy Grail of drug delivery, orally-administered peptides offer vast potential but also present considerable development challenges.
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Challenges and opportunities in oral peptide therapeutic development Numerous technologies are currently in develop- ment that are designed to enable the oral delivery of peptides. Though each has its unique set of properties and capabilities, all must overcome key obstacles to successfully deliver peptides via the oral route. First, the oral formulation has to remain intact in the highly acidic environment of the stomach. Once through the stomach, the tablet design must then promote dissolution in the higher pH environment of the small intestine, while simul- taneously protecting the peptide payload from degradation by protease enzymes. Finally, mecha- nisms must be present which facilitate the absorp- tion of the peptide into the relatively impermeable intestinal epithelium. However, before any technology is applied to con- front these challenges, developers must first target therapeutic peptides that are appropriate for oral delivery. Practical considerations, such as whether the orally-delivered peptide will enhance patient compliance, increase treatment options and boost marketability, should have priority since, without clear medical and business advantages, there is little motivation to transition from an injectable. Yet, even if these boxes are checked, oral deliv- ery may not be an option unless one can achieve therapeutically-relevant bioavailability. Numerous factors impact bioavailability, some of which tech- nology can mitigate. However, the molecular weight of the peptide is key to ultimately determin- ing the feasibility of oral delivery, with an inverse relationship between molecular weight and bioavailability.
Illustrative of the challenges and potential of orally-delivered peptide therapeutics is the ongo- ing development of an oral leuprolide tablet for the treatment of endometriosis. Affecting approx- imately six million women in the US, endometrio- sis is one of the most common gynecological dis- orders and occurs when the endometrial lining begins to grow outside the uterus, leading to lesions. These lesions may grow on the ovaries, fallopian tubes and other areas of the uterus, caus- ing severe pain.
Leuprolide, marketed under the brand name LUPRON DEPOT® (leuprolide acetate for depot suspension), has demonstrated in the clinic and practice to be an efficacious treatment for endometriosis. However, the current parenteral route of administration limits the drug’s utilisation due to the irreversibility of the depot injection, which stays in the body for 30-90 days, and the pain and inconvenience of the injections. A daily
Drug Discovery World Fall 2017
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