Recent advancements in biologics have unleashed tremendous opportunities in addressing unmet medical needs taking healthcare to new heights. Biologics have shown promising results in the treatment of debilitating conditions such as diabetes, cancer, autoimmune diseases that affect millions worldwide. The success biologics can be attributed to their high specificity and enhanced therapeutic potential over conventional small molecules. It should come as no surprise then that nearly 80% of the novel drugs approved by the US FDA in 2020 constituted of biologics. Currently, more than 800 peptide drugs are in the pipeline and around 197 peptide-based drugs have been commercialised. The global biologics market stood at an estimated USD 269,152 million in 2019 and is expected to grow at a CAGR of 14.7% to reach up to USD 464,604 million by 2023. Asia-Pacific in particular accounted for the largest market with a whopping 53.1% share of global biologics in 2019. With a high number of first-generation biologics now going off-patent, there’s immense scope for development and growth of biosimilars now. 

Biologics offer distinct advantages that small molecule drugs do not, but they are far more complex to develop and manufacture. Biologics have high molecular weight, are temperature and light sensitive, susceptible to shearing and degradation, and not as robust as small molecules. These limitations make it difficult to formulate them into conventional dosage forms such as capsules or tablets and therefore most biologics are developed into injection. However, to offer patients with a more convenient dosage form that is easier to administer and encourages greater patient compliance, non-invasive routes of administration for delivering biologics are currently being explored. Although very few of these delivery systems have succeeded commercially, the growing numbers of patents and clinical trials in this direction surely cast a light of hope for the future. This blog aims to discuss the emerging trends of the non-invasive routes for delivery of protein and peptide therapeutics and what the future may hold.  

Oral peptide delivery: Technologies driving market trends 

To aid the oral delivery of macromolecules, formulation scientists are exploring numerous advanced drug delivery strategies such as polymer conjugation, chemical modifications, nanoencapsulation, polymer nanocarriers, lipidic nanocarriers, inorganic nanoparticles, microneedles as well as hybrid carriers. Some therapeutic peptides have also successfully made it to the market as oral dosage forms. 

 Peptides with lower molecular weight (preferably less than 6000 daltons) or those possessing a cyclic structure have been found to show good chances of being delivered orally. Cyclosporin (NeoralÒ, Novartis) is one of the few commercially available oral peptide therapeutics available in the form of oral solution and liquid filled soft gelatin capsule. In aqueous condition, the formulation is converted to a microemulsion in situ. Its lipophilic nature and cyclic structure help in intestinal absorption inhibiting proteolytic degradation to a great degree. Oral octreotide, approved by USFDA for long term maintenance treatment of acromegaly, is another oral biologic that has been developed as a delayed release capsule (MYCAPSSAÒ, Chiasma Inc.). The formulation uses a unique technology called Transient Permeability Enhancer or TPE.  

 The area of novel excipients is the next big thing in the biopharmaceutical industry. Scientists all over are now looking for multi-functional excipients that can help in efficient delivery of biomolecules through the oral route. PeptelligenceÒ platform technology developed by Enteris Biopharma has been described as a “formulation toolbox” of excipients, composed of an innovative combination of GRAS category excipients. The excipient combination consists of pH lowering, membrane wetting, charge dispersal and solubilising agents which improve permeability and bioavailability of the peptide API without affecting its physicochemical properties. Emisphere Technologies Inc. has developed a unique technology called EligenÒ SNAC comprising Sodium N-[8-(2-hydroxy benzoyl) amino] caprylate which is a functional excipient designed to enhance intestinal absorption and permeability of peptides and proteins upon oral delivery.  

 Merrion Pharmaceuticals, a company dedicated towards development of orally deliverable dosage forms of drugs that are generally given via parenteral routes. They have developed novel excipients with GRAS ingredients using their proprietary GIPETÒ platform technology. They consist of patented absorption enhancers that activate micelle formation, facilitating drug absorption. Merrion has partnered with Novo Nordisk to develop oral formulations for insulin analogues. 

Another interesting technology for oral delivery of biologics has been developed by Rani Therapeutics and is called the RaniPillTM which is a robotic enteric coated capsule with a balloon like structure that inflates upon generation of carbon dioxide at higher pH due to dissolution of capsule shell. The peptide is contained in sucrose based dissolvable microneedles that pierce the intestinal wall and deliver the peptide. 

Advanced Systems for oral peptide delivery 

Systems based on lipidic, polymeric, and inorganic nanocarriers have shown great potential for oral delivery of proteins and peptides. Self-nanoemulsifying systems have gained wide acceptance for delivery of proteins and peptides and have been proven to improve the intestinal permeability of certain peptides. Other lipid based nanocarriers investigated for delivery of proteins and peptides are lipid nanoparticles like solid lipid nanoparticles, nanostructured lipid carriers, lipidic micelles, nanocapsules, microemulsions and liposomes. Inherent properties of lipidic cores in such carriers include peptide protection, controlled drug release, enhanced tissue and mucus permeability, stability and biocompatibility. Select range of natural biodegradable polymers such as chitosan and its derivatives, alginates, starch and its derivatives, carbohydrates, and g-PGA based materials are being studied for oral delivery of peptides. Synthetic polymers that have been researched upon include PLGA, PGA, PCL, and PEA. There has also been a growing focus on engineering hybrid systems involving both lipid and polymer components in order to supplement the solubilising capacity of lipids with the stabilising matrix of polymers. In the inorganic category, silica nanoparticles are becoming highly popular due to their multifunctional, biocompatible and biodegradable nature. Ceramics based aquasomes are another emerging category of inorganic nanoparticles being studied for the oral delivery of proteins and peptides.  

Future perspectives 

The past decade has witnessed a huge rise in the growth of biopharmaceutical industry and the focus is now moving towards delivery of the highly sensitive biomolecules via non-invasive routes such as oral route – oral route being the most preferential due to some of the very obvious reasons like patient compliance, ease of manufacturing and reduction in cost. Thanks to innovative technologies that have made possible modulations in API, excipients, delivery carriers. However, majority of these technologies are still in their nascent stages and they have a long way to go before they are successfully launched in the market. Nonetheless, the future of oral biologics definitely looks bright. 

References 

1. Global Biologics Market Report Opportunities and Strategies. https://www.thebusinessresearchcompany.com/report/biologics-market  
2. Deb PK, Al-AttraqchiO, Chandrasekaran B,Paradkar A, Tekade RK. Chapter 16 – Protein/Peptide Drug Delivery Systems: Practical Considerations in Pharmaceutical Product Development. In: Tekade RK, editor. Basic Fundamentals of Drug Delivery. Academic Press; 2019 p. 651–84. (Advances in Pharmaceutical Product Development and Research).  
3. MoncalvoF, Martinez Espinoza MI, Cellesi F. Nanosized Delivery Systems for Therapeutic Proteins: Clinically Validated Technologies and Advanced Development Strategies. Front Bioeng Biotechnol. 2020;8 
4. Abeer MM,RewatkarP, Qu Z, Talekar M, Kleitz F, Schmid R, et al. Silica nanoparticles: A promising platform for enhanced oral delivery of macromolecules. Journal of Controlled Release. 2020 Oct 10;326:544–55.  
5. Asfour MH. Advanced trends in protein and peptide drug delivery: a special emphasis onaquasomesand microneedles techniques. Drug Deliv and Transl Res. 2021 Feb 1;11(1):1–23. 
6. Drugs@FDA: FDA-Approved Drugs https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=050715  
7. Mycapssa(octreotide) FDA Approval History [Internet]. com. https://www.drugs.com/history/mycapssa.html  
8. Learn about MYCAPSSA® (octreotide) capsules https://mycapssa.com/about-us/  
9. Peptelligence® | Oral peptide & small molecule drug delivery platform https://enterisbiopharma.com/peptelligence/  
10. Merrion Pharmaceuticals – Pharmaceutical Technology https://www.pharmaceutical-technology.com/contractors/drug_delivery/merrion-pharma/ 
11. Our Technology. Rani Therapeutics.  https://www.ranitherapeutics.com/technology/  
12. 1ZizzariAT, Pliatsika D, Gall FM, Fischer T, Riedl R. New perspectives in oral peptide delivery. Drug Discovery Today 2021 Jan 23 
13. Martins S, Sarmento B, Ferreira DC, Souto EB.Lipid-based colloidal carriers for peptide and protein delivery–liposomes versus lipid nanoparticles. Int J Nanomedicine. 2007;2(4):595–607. 
14. NiuZ, Conejos-Sánchez I, Griffin BT, O’Driscoll CM, Alonso MJ. Lipid-based nanocarriers for oral peptide delivery. Advanced Drug Delivery Reviews. 2016 Nov 15;106:337–54.   
15. Luo YY, Xiong XY, Tian Y, Li ZL, Gong YC, Li YP. A review of biodegradable polymeric systems for oral insulin delivery. DrugDeliv. 2016 Jul;23(6):1882–91.  
16. Joyce P, Schultz HB, Meola TR, Prestidge CA. Chapter 1 – Polymer lipid hybrid (PLH) formulations: a synergistic approach to oral delivery of challenging therapeutics. In:Shegokar R, editor. Delivery of Drugs. Elsevier; 2020. p. 1–27.  
17. Tan X, Liu X, Zhang Y, Zhang H, Lin X, Pu C, et al. Silica nanoparticles on the oral delivery of insulin. Expert Opinion on Drug Delivery. 2018 Aug 3;15(8):805–20. 
18. Umashankar MS, Sachdeva RK, Gulati M.Aquasomes: a promising carrier for peptides and protein delivery. Nanomedicine: Nanotechnology, Biology and Medicine. 2010 Jun 1;6(3):419–26.