Routes of administration and absorption enhancement

Routes of administration and absorption enhancement

1- The Parenteral Route of Administration
Parenteral administration defined as administration where a needle is used including intravenous(IV), intramuscular (IM), subcutaneous (SC) and intraperitoneal (IP) injections.
- It suffices here to state that the blood half-life of biotech products can vary over a wide range. For example, the circulation half-life of t-PA is a few minutes, while monoclonal antibodies (MAb) reportedly have half-life’s of a few days.
- One reason to develop modified proteins through site directed mutagenesis is to enhance circulation half-life. A simple way to expand the residence time for short half-life proteins is to switch from IV to IM or SC administration. One should realize that by doing that, changes in disposition may occur, with a significant impact on the therapeutic performance of the drug. These changes are related to:

1- The prolonged residence time at the IM or SC site of injection compared to IV For instance, diabetics can become “insulin resistant” through high tissue peptidase activity. Other factors that can contribute to absorption variation are related to differences in exercise level of the muscle at the injection site and also massage and heat at the injection site. The state of the tissue, for instance the occurrence of pathological conditions, may be important as well.
2- Differences in disposition
Upon administration, the protein may be transported to the blood through the lymphatics or may enter the blood circulation through the capillary wall at the site of injection. The fraction of the administered dose taking this lymphatic route is molecular weight dependent. Lymphatic transport takes time (hours) and uptake in the blood circulation is highly dependent on the injection site.


2- The Oral Route of Administration

Advantage
Oral delivery of protein drugs would be preferable, because
- It is patient friendly
- No intervention by a healthcare professional is necessary to administer the drug.

Disadvantage
-Oral bioavailability usually very low. The two main reasons for this failure of uptake are:

1- Protein degradation in the gastrointestinal (GI) tract. In the stomach, pepsins are secreted and its active at pH between 3 and 5 and lose activity at higher pH. Pepsins are endopeptidases capable of cleaving peptide bonds distant from the ends of the peptide chain.
- Other endopeptidases are active in the GI tract at neutral pH values, e.g., trypsin, chymotrypsin, and elastase. They have different peptide bond cleavage characteristics.

2- Poor permeability of the wall of the GI tract in case of a passive transport process
High molecular weight molecules such as proteins do not readily penetrate the intact epithelial barrier if diffusion is the sole driving force for mass transfer. Their diffusion coefficient decreases with increasing molecule size, therefore it does not allow us to use the oral route for therapeutic proteins if high bioavailability is required.
- For oral immunization, only a (small) fraction of the antigen (protein) has to reach its target site to elicit an immuneresponse. The target cells are lymphocytes and antigen presenting accessory cells located in Peyer’s patches.
These Peyer’s patches are macroscopically follicular structures located in the wall of the GI tract. Peyer’s patches are overlaid with microfold (M) cells that separate the luminal contents from the lymphocytes. These M cells have little lysosomal degradation capacity and allow for antige.n sampling by the underlying lymphocytes.


Alternative Routes of Administration
-Parenteral administration has disadvantages (needles, sterility, injection skills) compared to other possible routes.
-Therefore, systemic delivery of recombinant proteins by alternative routes including nose, lungs, rectum, oral cavity, and skin have been selected as potential sites of application.
- The nasal, buccal, rectal, and transdermal routes all have been shown to be of little clinical relevance if systemic action is required, and if simple protein formulations without an absorption enhancing technology are used.
- In general, bioavailability is too low and varies too much. The pulmonary route may be the exception to this rule.

The first pulmonary insulin formulation was approved by FDA in 2006 (Exubera). Pulmonary inhalation of insulin is specifically tested for meal time glucose control. Uptake of insulin is faster than after a regular SC insulin injection (peak 5–60 minutes versus 60–180 minutes). The reproducibility of the blood glucose response to inhaled insulin was equivalent to SC injected insulin, but patients preferred inhalation over SC injection.

Dry powder inhalers and nebulizers are being tested. The fraction of insulin that is ultimately absorbed depends on:
(i) The fraction of the inhaled/nebulized dose that is actually leaving the device
(ii) The fraction that is actually deposited in the lung
(iii) The fraction that is being absorbed, i.e.,

TO % total relative uptake = % uptake from device x % deposited in the lungs x % actually absorbed from the lungs.
TO % for insulin is estimated to be about 10% .

The fraction of insulin that is absorbed from the lung is estimated to be around 20%.
These figures demonstrate that insulin absorption via the lung may be a promising route;