Development of Oral Therapeutics for Diabetes
There have been extensive efforts to develop alternative drug delivery strategies, particularly for peptides like insulin used to treat endocrine disorders, specifically diabetes. This is because protein and peptide therapeutics require parenteral (delivery by the intravenous route) administration, which serves as a barrier or deterrent to adherence to medication regimes. Oral delivery is therefore desirable, but it is challenged by several barriers related to the organization and physiological function of the gastrointestinal tract.
Why Is There a Need for Oral Routes of Administration in Diabetes?
Oral therapeutics for diabetes sit under the umbrella term
of biologic therapeutics, which include large proteins, antibodies, hybrid
fusion proteins, therapeutic peptides common tie, and antibody and drug
conjugates. These therapies are administered via injection as they are poorly
bioavailable via the oral cavity.
Consequently, research has explored the feasibility of
delivering proteins via alternative routes with oral, nasal, pulmonary, buccal,
ophthalmic, and transdermal administration being considered. Oral drop delivery
is particularly attractive for patients due to its widespread use and
convenience. However, the use of oral therapeutics is hampered by the
anatomical structure and function of the gastrointestinal system. The
challenges to efficient oral absorption of peptides are as follows:
- The mucus barrier: the gastrointestinal tract has evolved a lining complete with a sophisticated set of cellular and mucosal barriers to restrict the access of enteral microbiota, toxic agents, and pathogens
- Gastrointestinal enzymes
- Protein lumenal export or degradation
- Intracellular environment
What Approaches Have Been Developed to Overcome the Permeability Barrier for Oral Therapeutics for Diabetes?
Paracellular approaches are designed to facilitate the
movement of a peptide-based drug through transient disruption of cellular
junctions. In contrast, transcellular approaches enable the movement of peptide
drugs through the cytoplasm of enterocytes, which are secreted into the
lymphatic or systemic circulation.
Technologies that have been employed for the absorption of
peptides along different regions of the gastrointestinal tract Among these
strategies, the most notable types include permeation enhancers; and a
permeation enhancer has recently been used in the approved oral formulation of
semaglutide –an anti-diabetic medication used for the treatment of type 2
diabetes.
Permeation Enhancers
Permeation enhancers the target of the transcellular route
by facilitating the movement of non-degraded peptides through the epithelial
cells. Alternatively, permeation enhancers operate via the paracellular route,
interfering with the intercellular junction adhesion proteins.
Enhancers must be able to transiently disrupt the intestinal
epithelium to enable peptide absorption while ensuring an acceptable safety
profile without any local minimal or systemic toxicity. Permeation enhancers
with different modes of action can be combined at low doses to minimize cell
toxicity while still working synergistically to enhance permeation's efficacy.
Among them, very few have shown sufficient efficacy and safety to be able to
progress from preclinical to clinical trials.
Two permeation enhancers, sodium caprate and sodium
N-caprylate (also known as SNAC) are examples of two that have been used in
proprietary delivery platforms for several years. Sodium caprate is a
medium-chain fatty acid that occupies an ionized soluble says and shows
detergent capacity at the pH value of the small intestine. It affects both the
transcellular and paracellular roots. SNAC is classified as "generally
recognized as safe" (GRAS) and operates predominantly via the
transcellular mode of transit through the epithelium.
There are several concerns associated with permeation
enhancers, namely the potential for the increased likelihood that noxious
agents, including pathogenic organisms, will penetrate the barrier, along with
the potential for the development of immune responses or disruption to the gut
microbiome. As of yet, no such toxicities have emerged; for example, the
largest trial to date, which examines the safety of oral insulin, has
demonstrated that when subjects are treated with an insulin analog encapsulated
with sodium caprate.
Only a small number of patients developed human anti-insulin
and cross-reacting antibodies. This, therefore, precluded any significant
conclusions about the significance of these antibodies from being drawn.
Alongside this, the largest trial of oral semaglutide, which examined the
long-term cardiovascular safety of oral semaglutide, co-formulated with SNAC,
demonstrated no serious adverse events.
Modulation of pH
The low pH of the stomach presents a significant barrier to
the oral delivery of peptides. However, tablets that contain oral therapeutics
for delivery can be coated with an acid-stable enteric coat. This thereby
prevents them from dissolving in the stomach. After leaving the stomach, the
oral therapeutic reaches the upper intestine, where the elevation in pH enables
dissolution of the enteric coat, with subsequent release of the tablet
contents. This approach has been used to develop an oral formulation for
calcitonin, a treatment for Paget's disease of bone or hypercalcemia of
malignancy.
To overcome the degradation by intestinal and pancreatic
enzymes, citric acid is included in the tablet to produce a local transient
decrease in pH. This is because the optimal pH for these gastrointestinal
enzymes is neutral to basic, so citric acid inhibits resident peptidases. The
coadministration of citric acid can also achieve this with oral formulations to
enhance absorption.
Direct Enzyme Inhibition
Enzyme inhibition can circumvent the barrier of got enzyme
activity. Inhibitors include aprotinin, soybean trypsin inhibitor, and
leupeptin. The most clinically advanced example of this direct enzyme
inhibition mean of administration is an oral insulin formulation which includes
a soybean trypsin inhibitor and a curating agent that scavenges calcium. This
functions to sequester calcium, a cofactor from a protease. Despite this
approach being diploid, the utility and safety of enzyme inhibition as a general
strategy for improving the absorption of oral peptides are unknown.
Peptide Cyclization
Cyclization strategies remove exposed termini from the N and
si ends of peptides particularly vulnerable to cleavage by enzymes. A cyclic
structure is traditionally a naturally occurring feature of small peptides.
There have been two successfully developed for oral administration; the
immunomodulatory drug cyclosporin and desmopressin, which is an analog of the
peptide hormone vasopressin, which exhibits greater resistance to degradation
relative to vasopressin. Despite this, the extent of its feasibility as a
generalizable strategy for oral peptide absorption is not promising. The
majority showed limited oral bioavailability in a study of physical-chemical
parameters and oral absorption properties of 125 cyclic peptides.
Other strategies include:
- Mucus-penetrating agents: This enables the drug to get past the mucus barrier. In the context of oral therapeutics for diabetes, insulin delivery in preclinical studies has been achieved through the development of cell-penetrating peptide (CPP)–insulin conjugates encapsulated in mucoadhesive N-trimethyl chitosan chloride-coated PLGA nanoparticles. However, safety and efficacy remain to be validated in large clinical trials
- Cell-penetrating peptides (CPPs) are generally efficient at translocating the membrane as they are derived from viruses that can do this. Alternatively, they may be non-viral proteins or smaller molecules. CPPs can interact with membrane components such as amino glycans and traverse endocytotic pathways whereby they can deliver their protein cargo into systemic circulation via exocytosis. Energy-dependent and energy-independent pathway mechanisms have been identified as facilitators of CPP and cargo entry. Although they have been explored for anti-cancer and antimicrobial therapy, their utility in enhancing oral absorption of peptide therapies, like diabetic therapy, has not yet been validated in the clinical setting.
- Intestinal patches enable a small reservoir of the drug to be physically protected from local degradation and position the drug close to the epithelium, where it is absorbed. An example of this is a mucoadhesive patch capable of adhering to the small intestine mucosa in pigs and rats, where it was shown to release calcitonin, which was detected in systemic circulation and achieved its indication of reducing blood calcium. More recently, an adhesive patch that disrupts intestinal tight junctions to facilitate drug transport via the paracellular route has been reported in the context of insulin delivery into systemic circulation in rats via electric current-mediated entry and did not show evidence of structural impairments to the gut mucosa. Although promising in preclinical studies, chemical proof of concept is yet to be demonstrated
- Hydrogels: these contain water across linked polymer and a peptide-based cargo drug, alongside mucoadhesive polymers. Together these facilitate prolonged retention and increase the time that the peptide resides in the gut while providing resistance to enzymatic degradation
- Microneedle devices and mini-posts: these encompass device-based delivery technologies. An example of this is an enteric-coated capsule for the delivery of biological therapeutics, including peptides such as insulin. The capsule undergoes pH-dependant dissolution in the small intestine, with the concomitant release of carbon dioxide used to inflate a small balloon that positions a microneedle-based device next to the epithelium. This enables the injection of the therapeutic cargo through the mucosa. Another two technologies include a luminal unfolding microneedle injector (LUMI) and an orally ingested self-orienting millimeter-scale applicator (SOMA). LUMI includes poly(methacrylic acid-co-ethyl acrylate) and PEG coating of multiple drug-loaded microneedles; the coating dissolves at the pH of the small intestine. SOMA is capable of adhering to the gastric mucosa and delivers pharmaceutical products such as insulin via injection. This does not require puncturing the outer layer of the stomach
The Current State of Oral Therapeutics for Diabetes
Insulin itself has been formulated with several permeation
enhancers for oral delivery. SNAC has not been as high concentrations of SNAC
can interfere with the glucose drink property of insulin. By contrast, sodium
caprate has been extensively studied; for example, a long-acting insulin analog
delivered in a tablet containing sodium caprate for once-daily administration
was compared against a once-daily subcutaneous injection of insulin, insulin
glargine, over 8 weeks elect phase two trial of 50 patients with type 2
diabetes.
The primary endpoint, which was reductions in fasting
glucose, was similar in both treatment arms, and the rates of adverse events
what's similar between both groups. Despite the promising results, mechanical
development of the permeation-enhanced insulin was discontinued due to low
bioavailability (between 1.5 and 2%).
Another oral form of oral therapeutics for diabetes is an
insulin analog formulated with sodium caprate, which contains a
methoxy-trimethylene-glycol-propionyl moiety linked to the Lys-β29 amino group
formulated to act quickly to reduce postprandial hyperglycemia. Dose
proportional increases in plasma insulin and reductions in blood glucose
following administration of 10 to 30mg tablets were found.
In addition to permeation enhancers and protein delivery
strategies, insulin-containing nanoparticles have been used for oral
therapeutics for diabetes. These nano-articles showed greater epithelial uptake
and are less likely to be targeted to lysosomes for intracellular degradation.
Moreover, insulin nanoparticles undergo enhanced
transmucosal passage relative to the non-modified insulin. 'Bubble' carriers
composed of diethylenetriamine pentetic acid dianhydride and sodium bicarbonate
can incorporate insulin in the form of bubbles.
Sodium dodecyl sulfate, also included in the bubble
carriers, increases the dispersion of insulin molecules, stabilizes the
carriers, and acts as both an inhibitor of proteases and enhances permeation.
The paracellular transport of insulin has been enhanced when insulin
preparations have been formulated with choline; this also reduces enzymatic
incineration and decreases the thickness of the gastrointestinal mucus layer to
enhance bioavailability.
Most current oral therapeutics for diabetes target the
stomach and small intestine at present. However, the colon has been viewed as a
favorable region to YouTube faster rates of transit, a pH closer to neutral,
decreased levels of decorative enzymes and increased susceptibility to
permeation enhancers. To achieve this colonic targeting, insulin has recently
been co-formulated with modified nanoparticles, amphipathic chitosan
derivatives, and a series of CPPs. These facilitate transcellular transmucosal
passage.
Despite the promise and attractiveness of oral therapeutics
for diabetes, there are still several bioavailability roadblocks in oral
insulin delivery systems. This is coupled with a high cost of manufacturing
recombinant insulin, which would mean that competitive price marketing oral
therapeutics for diabetes could prove challenging. The discontinuation of
permeation-enhanced insulin has illustrated this.
Reference:
Drucker DJ. (2020) Advances in oral peptide therapeutics.
Nat Rev Drug Discov. doi: 10.1038/s41573-019-0053-0.
Banerjee A, Ibsen K, Brown T, et al. (2018) Ionic liquids
for oral insulin delivery. Proc Natl Acad Sci U S A. doi:
10.1073/pnas.1722338115.
Eldor R, Arbit E, Corcos A & Kidron M. (2013)
Glucose-reducing effect of the ORMD-0801 oral insulin preparation in patients
with uncontrolled type 1 diabetes: a pilot study. PLOS ONE.
Geho WB, Rosenberg LN, Schwartz SL, et al. (2014) A
single-blind, placebo-controlled, dose-ranging trial of oral hepatic-directed
vesicle insulin add-on to oral anti-diabetic treatment in patients with type 2
diabetes mellitus. J Diabetes Sci Technol. doi: 10.1177/1932296814524871.
Wu S, Bin W, Tu B, et al. (2014) A Delivery System for Oral
Administration of Proteins/Peptides Through Bile Acid Transport Channels. J
Pharm Sci. doi: 10.1016/j.xphs.2019.01.027.
Guo F, Ouyang T, Peng T, et al. (2019) Enhanced oral
absorption of insulin using colon-specific nanoparticles co-modified with
amphiphilic chitosan derivatives and cell-penetrating peptides. Biomater Sci.
doi: 10.1039/c8bm01485j.
No comments