Absorption rate boost for
transdermal applications
LTS Lohmann Therapie-Systeme has developed a product that has an increased
absorption when released to the skin compared to natural isotope methods.
Although the transdermal application of drugs has great
advantages, its downside is that the amount of the
drug absorbed via the skin is limited. Thus, when the
therapy of dermal application began, attempts were made to find
a way of increasing the capacity of drugs to penetrate the skin.
The development of penetration enhancers, which are added to
the dosage for dermal application, was regarded as the solution
for this problem. However, these substances change subjacent
skin structures, at least for a short time, and can result in
undesired side effects. Furthermore, the toxicity of components,
such as Azone®, is not yet fully understood and no transdermal
delivery system containing Azone has been approved by
authorities worldwide. Therefore, the substitution of very polar
active pharmaceutical ingredients (API) by their derivatives has
been investigated. These approaches are known under the
technical term ‘prodrugs’.
The dermal application of prodrugs seems an interesting
alternative. In this case, structural elements of a drug considered
unfavourable for dermal absorption are derivatised or esterified.
The characteristic feature of a chemical modification of
prodrugs is that the derivatised element is extremely unstable so
that the drug underlaying the prodrug is quickly and completely
formed in vitro. However, it is recognised that this concept can
only rarely be realised in practice, since the intended quick and
complete metabolic degradation does not take place in vivo. Thus,
some toxicological questions arise with respect to the prodrugs
which still require extensive pharmacological studies.
Toxicological qualification
In general, a prodrug has to be identified as a new chemical entity,
and include all necessary work for its toxicological qualification.
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Figure 1. Infrared spectra of Salbutamol. |
Consequently, chemical procedures must be found for derivatives
of APIs containing one or more O-H and/or N/H groups that can
be easily converted to its prodrug and vice versa. The hydrogen
atom in those functional groups can be easily substituted by
deuterium and vice versa. Because intermolecular forces created
by D-O/N are weaker than H bridge bonds, it was suggested that
the exchange of hydrogen against its isotope deuterium might
create products feasible for transdermal absorption. The exchange
under in vivo conditions takes place quickly.
Hydrogen always represents an isotopic mixture of 1H, 2D
and 3T. For this reason, all chemical compounds compared
with hydrogen are always present as a mixture of deuterated
and non-deuterated compounds, with the proportion of 2D
amounting to about 0.015%. Due to its high level of exchangeable
hydrogen items, Salbutamol was chosen as a model API.
Experimental qualification
For the production of deuterated Salbutamol, 0.5g of
Salbutamol was dissolved with heat in 20g of deuterium
oxide. Because the substance does not crystallise,
evaporation under vacuum at room temperature is carried
out. This resulted in the following:
- a yield of 0.5g
- a melting point of 149.8°C (the melting point of
Salbutamol is 153.4°C)
- infrared spectra of educts and product (Figure 1).
During skin permeation studies experiments were
conducted with exercised guinea pig skin fixed in a
Franz-Diffusion cell. Physiological saline solution was
used as the acceptor medium and the determinations of
contents were carried out by HPLC. Here, 200g each of
Salbutamol and deuterated Salbutamol were dissolved in a
blend of 800mg deuterated or undeuterated oleic acid and
2g of 2-Butanone. After completion of the solution the
2-Butanone was removed under vacuum.
The denaturated Salbutamol penetrated the guinea pig
skin by a factor of more than two. Therefore, the exchange
of active hydrogen against deuterium might be a good
approach in enhancing the permeability of APIs.
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