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Effective solutions for overcoming the high molecular weight, hydrophilicity, and instability of large biomolecules have yet to be identified.
Oral delivery of drugs is the preferred route of administration by both patients and manufacturers. Ease and convenience are the greatest requirements for patients, which leads to higher medicine adherence. Production costs for oral dosage forms also tend to be lower than for other options and offer the greatest versatility with respect to optimization of drug delivery.
For biopharmaceuticals, however, oral administration has been limited to a few relatively smaller molecules, including peptide products such as desmopressin and cyclosporine for systemic treatment, and a number of other products for local treatment. Many attempts have been made to develop oral insulin and other treatments for diabetes, but none have yet been successfully commercialized. Novo Nordisk, for example, halted development of its oral insulin product in October 2016.
The difficulty lies in the physical and chemical properties of large biomolecules and the physiology of the gastrointestinal (GI) tract. Overcoming these fundamental characteristics is challenging. “Numerous approaches have been explored to enable the oral delivery of biologic APIs. These range from using permeation enhancers to support permeation through the tight junctions of the epithelium, to nanocarriers to force active transport while protecting the biologic API from the gut, to making pro-drugs of the biologic APIs to enhance passive permeation,” observes David Lyon, director of research at Capsugel’s Bend, OR facility. He notes that each of these approaches has had modest success in animal models, but has yet to develop into a commercial product.
The greatest challenge to the oral delivery of biologic APIs is absorption across the GI tract, according to Ronak Savla, scientific affairs manager, Catalent Pharma Solutions. Most oral drugs are absorbed in the small intestine, which has the highest permeability compared to the large intestine and stomach. Characteristics of the GI tract that influence absorption include the surface area and mucosa permeability of the particular segment; the pH; the presence of food, bile, enzymes, and bacteria; and the number of structures such as Peyer’s patches and lacteal ducts.
For biomolecules, however, their large size and polar surface make it difficult for them to diffuse across the epithelial layer. “Molecules with molecular weights of less than 700 Daltons are relatively easily absorbed, which does include peptidomimetics; while those above 1000 Daltons, regardless of size, are not typically absorbed to any extent,” Savla says. In addition, most biologic molecules, including peptides, violate Lipinski’s Rule of Five, which is used to determine if a drug molecule has physicochemical properties that will allow it to be therapeutically active when orally administered. “Drug lipophilicity has the strongest correlation with oral bioavailability; there appears to be a minimum degree of lipophilicity required for oral absorption,” Savla adds.
A second important issue for biologic APIs is their susceptibility to enzymatic and chemical degradation in the GI tract. “Specifically, the physicochemical delivery challenges include hydrolytic sensitivities of the molecules to the acidic media in the gut, as well as the enzymatic activity of the intestine,” explains Lyon. Once the active is absorbed, there are additional opportunities for degradation inside both intestinal epithelial and liver cells, which in the latter is referred to as the hepatic first-pass effect.
The main consequence of the poor absorbance and degradation of biologic APIs administered orally is low bioavailability. In some cases, this issue can be overcome by using higher doses, but doing so raises concerns about both potential side effects and excessive costs.
Drug formulation efforts focus on overcoming the various physicochemical challenges to increase bioavailability. Permeation enhancers and enzyme inhibitors are commonly used. Encapsulation and/or the use of protective (enteric) coatings can help prevent chemical and enzymatic degradation. Modification of the biologic API structure through either covalent or non-covalent bonding with lipophilic substances is another approach.
The stability of biologic drug substances must also be considered when developing formulations. For instance, some techniques used for the production of small molecules--such as those that introduce heat or organic solvents--may not be suitable for biologic products. In addition, according to Savla, the prevention of aggregation upon storage can be a challenge, particularly for biologic products in solution. “Temperature, pH, and--in some cases--light can have an important impact on protein structure during manufacturing, which can lead to a delicate balance between the formulation, process conditions, and stability of the biologic API,” Lyon comments.
A common theme across current approaches is the use of functional excipients such as permeation enhancers. “The larger size and hydrophilicity of biologic molecules hinders their passage across cells. Permeation enhancers are typically used to increase the space between epithelial cells in the GI tract lining,” Savla explains. Common enhancers include bile salts, fatty acids, surfactants, salicylates, chelators, chitosans, and zonula occludens toxin (1). Use of these excipients does, however, have the potential to cause damage to the mucosa and to allow absorption of other substances, such as other prescribed APIs in patients taking multiple drugs or even gut bacteria and their toxins.
Enzyme inhibitors are also used to prevent degradation of biologic APIs by enzymes in various parts of the GI tract, according to Savla. Examples include sodium glycocholate, bacitracin, and soybean trypsin inhibitor (1).
In addition to the use of functional excipients as formulation solutions, common approaches to increasing the oral bioavailability of biologic APIs include modifying the drug molecule and/or the biological system.
A range of technologies have been explored for modifying the structure of biomolecules, including the use of polymers, the formation of nanoparticles, and their inclusion in lipid systems. In many cases, all three approaches are employed. “Each technology has its pros and cons and may be more suitable for certain molecules or applications over others. Lipid systems are interesting because there have been a lot of studies completed with small molecules and they can both increase the permeability of biologic molecules and protect them against hydrolysis and enzymatic degradation,” says Savla. Examples of lipid systems include liposomes, archaesomes, and emulsions.
Encapsulated biologics often exist as nanoparticles. Encapsulation protects the active against degradation, while the size of nanoparticles allows for better penetration through the stomach lining, according to Savla. In addition, tailored receptors that target the GI tract lining for enhanced absorption can also be attached to encapsulated proteins. Polymers used for the preparation of such nanoparticulate formulations include chitosan and chitosan derivatives and other polymers commonly used for the preparation of small-molecule drugs (1).
More exotic solutions include “robotic” pills, such as those being developed by Rani Therapeutics. Tiny needles comprised of a permeation enhancer, which are pushed by self-inflating balloons that function under specific conditions in the intestine, deliver the biologic active through the intestinal wall.
Actual modification of the protein structure through conjugation with lipophilic compounds (fatty acids) or oligomers such as polyethylene glycol (PEG) has also been investigated. Crystallization of proteins can improve oral delivery, but typically is quite difficult for most biologics (1).
“Manipulation of the structure of biologic drug substances using any of these approaches must be pursued with caution, however, given the fact these structures are not only complex but crucial to the efficacy and safety of the drug product,” Savla asserts.
In addition to modifying the structure of the biologic API, some approaches focus on manipulation of bacteria that are commonly found in the intestine. Many of these bacteria are designed to tightly bind to the intestinal mucosa. Through genetic engineering it is possible to create versions of these bacteria that can produce and secrete protein APIs and deliver a high concentration to the absorption mucosa, avoiding the possibility of degradation, according to Savla. In addition, these bacteria can deliver the biomolecules throughout their lifetimes in the intestine. This technology can be combined with modification of protein structures to increase lipophilicity and resistance to degradation.
There are also promising oral technologies being developed by companies such as Applied Molecular Transport (AMT) that use poorly immunogenic transporter proteins covalently linked to biologic APIs to actively transport them across the epithelium, according to Lyon. AMT’s Transint platform provides targeted delivery of peptides and proteins to cells in the GI tract or liver using the non-toxic portion of the protein cholix toxin, which delivers a toxic compound produced by Vibrio cholera across the gut epithelium. The carrier protein is covalently bound to the biologic API for delivery to the GI tract, while a linker inserted between the two allows delivery to the liver following enzyme cleavage.
“These types of approaches are elegant at delivering peptides and proteins, but still require protection of the construct from the stomach and intestinal environments,” Lyon says. He notes that the combination of such a transporter technology and Capsugel’s intrinsically enteric capsule technology, or enTRinsic drug delivery technology, may prove effective for providing both physicochemical protection and permeation. “Our enTRinsic drug delivery technology, which uses an enteric polymer in the capsule shell thereby avoiding the need for enteric coating and the high temperatures associated with coating processes, provides acid-, water-, and enzyme-impermeable capsule characteristics that allow the cargo to be delivered intact to the site of absorption while protecting the active molecules,” Lyon explains.
Despite the high level of interest in formulating biologic drugs for oral delivery, it remains uncertain when commercial products will eventually be available. “Several programs have reached and failed in Phase III. While there are a few current programs in Phase II and III clinical trials, it is difficult to predict whether these trials will be successful. Most of these programs face competition from injectable formulations--a high bar to match or surpass,” Savla observes.
Lyon is more hopeful when it comes to biologic APIs that treat local gut disease states, such as Crohn’s diseases and irritable bowel syndrome, and expects that oral delivery for these drug substances will be fairly common within the next five years. Although he notes that great progress continues to be made translating “IV drugs to oral,” he says that significant breakthroughs have yet to be made if currently marketed biologic APIs are to be converted without covalent modification from IV delivery to drug products delivered orally.
To tackle this challenge, Catalent is taking a parallel screening approach. “We understand that there is no one-size-fits-all solution and it is difficult to predict oral bioavailability a priori. We first assess a molecule’s permeation through the oral and sublingual/buccal routes using the permeation enhancer sodium caprate. If the molecule demonstrates potential for one of these routes, we work on developing formulation candidates,” Savla explains.
The Catalent Applied Drug Delivery Institute’s Non-invasive Macromolecule Delivery Consortium also brings together academic and industry experts from a variety of disciplines to discuss and develop possible ways to address challenges faced by everyone in the area, according to Savla. The Institute organized a conference focused on routes of non-invasive macromolecule delivery in February 2017 in San Diego. The conference was designed to bring together leading experts from academia and industry to discuss challenges, share results, and pave the path for the next steps in the field.
“As a specialized contract service provider with a focus on product design,” says Lyon. “Capsugel has invested in technologies that solve some of the challenges associated with the non-invasive delivery of biologic APIs, including oral solutions.” As mentioned above, the company’s enTRinsic drug delivery technology overcomes the need to protect biologic APIs from the GI tract environment. “The enTRinsic technology can be used in conjunction with standard biologic APIs and pro-drugs for either systemic or local gut delivery, and we have ongoing development and clinical programs with a number of pharmaceutical and biopharmaceutical partners,” Lyon notes.
The oral delivery of biologic APIs--mainly peptides and proteins--has been a “holy grail” of pharmaceutical drug delivery for the past several decades, according to Lyon. “Oral delivery remains the preferred route for delivery of medicines. Biologic APIs are growing faster as a class of molecules than traditional small molecules and have enjoyed shorter development times and approval times over the past decade. While the driving factor is improved therapies, biotherapeutics also provide innovative companies with increased differentiation in their product lifecycle strategies. It is reasonable to expect that the interface of these two areas will remain an exciting and active area of research and investment in the coming years,” he states.
One potentially exciting direction of research for Savla is the intentional design of orally administered biologic APIs. “Given that most biologic drugs are injected, there is no guidance or rules of thumb for oral delivery. To date the focus has been converting existing biologic APIs initially developed specifically for parenteral administration to alternative oral delivery formulations. It is certainly possible that better success with oral delivery can be achieved if the biologic APIs are designed from the start to function effectively within the intestinal tract. Of course, there are significant risks in taking this approach given the numerous issues with the absorption and degradation of large biomolecules in the GI tract. It may in fact take initial successes with modified existing APIs before someone is willing to develop and orally administered biologic drug from scratch,” he concludes.
1. Catalent Applied Drug Delivery Institute, Non-invasive Macromolecule Drug Delivery Guide (Somerset, NJ, 2015).
Vol. 41, No. 3
When referring to this article, please cite it as C. Challener, “Oral Delivery of Biologic APIs: The Challenge Continues," Pharmaceutical Technology 41 (3) 2017.