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Cobalamin™ - Mediated Oral Drug Delivery

Introduction

Oral administration, by which pharmaceutically-active materials formulated as liquids, tablets or capsules are taken by mouth, remains by far the most prevalent method of drug delivery. It is also preferred by the vast majority of patients. However, its successful implementation requires that the active ingredient remains largely unaltered during transit through the gastrointestinal tract and that the drug possesses the requisite physico-chemical features (typically, low molecular weight, uncharged, and at least somewhat lipophilic) that allow it to pass readily across the wall of the intestine and be delivered into the bloodstream. For many active materials, particularly peptides and proteins, oral administration is currently not an option, as the level of uptake is less than one percent of the administered dose.

There are many oral drug delivery technologies that are intended to improve the pharmacokinetic profile of active ingredients. These can be classified as either:

  1. protection systems (e.g. enteric-coated tablets),
  2. release modification systems (to control the rate/site of drug release in the intestine),
  3. muco-adhesives (to slow transit through the intestines)
  4. absorption enhancement systems.

There are many technologies which provide either (1) or (2) or (3), but these provide little or no tangible benefit unless the drug being delivered can cross the intestinal epithelium and enter the bloodstream. No absorption enhancement technology has yet been successfully incorporated into an approved product.

The Access Pharmaceuticals’ Cobalamin™-mediated oral drug delivery technology is primarily an absorption enhancement system, which can also provide drug protection. As such, it does not compete with any of the release modification technologies; in fact, many of those technologies may be complimentary, providing some added benefit in terms of controlled release of the administered formulation to the intestinal lumen.

Mechanism of Absorption

The Access technology addresses the problem of poor intestinal absorption by utilizing the body’s natural transport system. Cobalamin™ (a vitamin B12 or COBALAMIN analog) is actively transported from the gut to the blood stream by a receptor-mediated process the body normally uses for transport of vitamins.

Our scientists have found that the attachment of Cobalamin™ to drugs, polymers containing drugs, and even nanoparticles (in which drug is encapsulated) provide constructs that are co-absorbed from the intestines into the bloodstream during the uptake of the Cobalamin™. Following oral administration, the Cobalamin™ portion of the drug conjugate binds to haptocorrin in the stomach, and this complex passes into the duodenum, where the complex dissociates. Intrinsic factor (IF, a factor which is released in the stomach) binds to the Cobalamin™ portion of the liberated conjugate, and this new complex passes down the intestine, and binds to the IF receptor in the ileum. A receptor-mediated endocytotic process transfers the Cobalamin™-drug conjugate into the bloodstream.

Cobalamin Receptor

Receptor-Mediated Uptake

Initial proof-of-principle of this technology was provided using the Caco-2 cell monolayer technique. This monolayer method is well-established in drug development, and it has been shown that there is good agreement between results in the Caco-2 monolayer method and the ability of a drug to cross the cells lining the gut. Using the protein GCSF as an example; as shown in the bar chart (below), hardly any unmodified GCSF crosses the monolayer (green bar), but relatively large amounts of three different Cobalamin™-GSCF conjugates (red bars) can cross the cells by a receptor mediated process.

Cobalamin GCSF

Cobalamin™ Receptor-Mediated Uptake

As shown in the chart (below), intraduodenal administration of similar Cobalamin™-GCSF conjugates to rats resulted in significant levels of GCSF being detected in serum. In contrast, GCSF administered alone resulted in a barely detectable level of GCSF in serum.

Cobalamin Receptor Mediated

By radiolabeling it is possible to follow the biodistribution of an active material following oral administration. The bar chart (below) shows results of such a study of the oral administration of Cobalamin™-coated nanoparticles compared to uncoated nanoparticles in rodents.

Cobalamin Coated Nanoparticles

The distribution data shows that much larger amounts of radiolabeled nanoparticles were seen in the body following oral administration when the nanoparticles were coated with Cobalamin™ compared to uncoated nanoparticles, providing proof that the Cobalamin™ uptake mechanism has the capacity to transport nanoparticles, and that uptake is enhanced by utilization of this mechanism.

Oral Delivery of Insulin

The effectiveness of oral drug delivery using Cobalamin™-coated nanoparticles is demonstrated in the following graph which displays serum glucose levels following oral administration of insulin containing Cobalamin™-dextran nanoparticles compared to injected insulin. Cobalamin™-coated insulin-loaded nanoparticles given orally provide a glucose lowering effect which is slower in onset and longer in duration than i.v. insulin. When these particles are injected directly into the colon, (green plot) there is a minimal pharmacological effect as the particles are “downstream” of the IF receptors in the ileum.

Cobalamin Coated Insulin Loaded

Opportunities

Numerous pharmaceutical active ingredients cannot be delivered by the oral route because of poor absorption of the drug in the stomach and/or degradation in the GI tract. Examples include biotech products such as proteins, peptides and antibodies as well as both small and large molecules with poor membrane permeability.

Access’ proprietary technology provides a viable solution to this problem by facilitating drug absorption using Cobalamin™-mediated transport. For example, the drug can be linked to the vitamin using a degradable linker to release the free active ingredient following transport into the bloodstream. Alternatively, linking multiple copies of the drug to a polymer strand to which the vitamin is also attached provides a construct in which drug uptake is amplified. Encapsulating the drug in a nanoparticle coated with Cobalamin™ also provides drug uptake ‘amplification’, as well as protection of the drug in the GI tract. Access’ oral drug delivery technology therefore provides several alternative ways to enhance the oral absorption of active pharmaceutical ingredients which might otherwise require administration by other routes.

Summary

  • These studies confirm that oral uptake of Cobalamin™ is a receptor-mediated process.
  • Access’ proprietary technology utilizes the body’s natural vitamin transport system to facilitate the oral absorption of drugs.
  • Cobalamin™ is transported across the gut with drugs or particles attached.
  • Transportation of drugs is amplified by using nanoparticles or polymers.
  • Proof-of-principle has been demonstrated with LHRH, GCSF, EPO, Calcitonin, Interferon, and GHRP-6 (growth hormone).
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