5.2. Novel Approaches

5.2.1. Alternate routes

Many new approaches are under investigation to improve the administration of insulin. One involves the search for an alternate route of administration. The usual method of administration by subcutaneous injection results in 80% of the dose being absorbed form the injection site. Table 5.2. compares the efficiency of different sites for administering insulin. When a protein is administered by mouth only 0.5% of the dose is absorbed intact and of that none is available to the systemic circulation as active drug. When a protein is delivered through the nasal membranes, thirty percent of the dose is absorbed, but very little is active. If an enhancer chemical is used to open up the membranes, then 10 - 15 % is available in the active form, and if a substance is used which causes the drug to stick to the nasal membranes, a so called bioadhesive, then 30% is bioavailable. This contrasts strongly with the situation in the mouth, where buccal bioavailability is a mere 0.4%, or the eye where it is only between 5 and 15%.

Table 5.2.1. Efficiency of different novel routes of administration

Route

 

 

 

% or dose absorbed

 

 

 

% of dose bioavailable

Buccal

-

0 - 0.4
Nasal (no bioadhesive)

30

0 - 2
Nasal (with bioadhesive)

-

30
Nasal (with enhancer)

-

10 -15
Oral

0.5

0
Vaginal

18

-
Subcutaneous

80

-
Ocular

-

5 - 15

When comparing different sites of administration it is useful to talk about a permeability coefficient P, defined as the mass of drug penetrating per unit area, time and concentration. This can be measured for insulin across various different membranes. In the mouth, the buccal permeability coefficient is 2 times 10-9 which translates into a total of 2.4 x 10-5 mg penetrating the membranes per minute. In the nose the permeability coefficient is between one and two times 10-6 which translates into a total of 0.0 24 mg penetrating the nasal membranes per minute. The G.I. tract has a permeability of 10 -7 which results on a penetration of 6 times 10-4 mg per minute. If one were to instill insulin into the eye, the ocular permeability coefficient is similar to the GI permeability coefficient .

Permeability Coefficient:

The values for permeability in different sites are summarized in table 5.3.

Table 5.2.2. Permeability and total amount of drug penetrating different sites
Route Permeability Coefficient

Mass penetrating (mg min-1)

Buccal 2 x 10-9 2.4 x 10-5
Nasal (rat) 1-2 x 10-6 2.4 x 10-2
G.I. 10-7 6 x 10-4
Ocular 10-7 3 x 10-3

5.2.2. Transplantation

Since it is the cells in the pancreas that are damaged in diabetes one could envision that pancreas transplantation might be a treatment option for diabetics. In 1966 the first whole pancreas transplantation was performed, but it was not successful. Since then there have been other attempts, with limited success. One of the main problems, apart from the fact that the pancreas is a very fragile organ, is that, as with any organ transplantation, there is a low availability of donor organs. Also there is a very high cost and the necessity for immune suppression to prevent rejection. In addition, diabetics often have circulating antibodies against their own islet cells, and this can lead to destruction of implanted islets.

In some cases there have been attempts to transplant only the islet cells, but again there are problems of rejection and supply. A far more promising line is to microencapsulate the islets before transplantation so that they are protected from immune attack. This will be discussed later.