The commercial need to improve relative bioavailability for systemic-targeted inhalation therapies relates to both basic economics and safety. Increased bioavailabilities obviously translate into smaller masses of drug product per therapeutic dose and potentially lesser negative side effects. Given the relatively high delivery efficiencies achievable with the best inhaler systems, one path toward achieving higher bioavailabilities is the use of the chemical enhancers . The goal of the chemical enhancers, such as those used for marketed transdermal drug delivery systems, has traditionally been to increase the permeability of target epithelia by influencing tight junctions, plasma membrane partitioning, or some other barrier property, improving the efficiency of drug entry into the bloodstream while possibly raising questions of long-term safety, particularly severe in the case of nasally inhaled insulin . An Astra-funded clinical study  of enhancer-assisted insulin delivery through the lungs incorporated bile salts in a dry powder aerosol formulation to enhance insulin penetration. This strategy improved inhaled biopotency from 7.6% to 12.5% . More recently, PDC produced bioengineered insulin particles in dry powder form with diketopiperazine derivatives . These absorption enhancers significantly enhanced the rate of insulin absorption and the overall insulin biopotencies .
An approach published in 2001 based on research out of the Klibanov laboratory at MIT is to use ethanol . Ethanol, isopropanol, and other alcohols have long been used successfully as penetration enhancers for medical applications. Ethanol is one of the first molecules to have been used as a transdermal enhancer, because its effects are so easily and well characterized and its systemic and local toxicities are understood. It is currently contained in commercial delivery systems for estradiol  and other bioactive molecules. Ethanol and isopropanol have been used in a variety of studies based on their effects on drug transport. More applications can be found in the patent literature .
Klibanov and coworkers  showed that insulin can be stored in ethanol and delivered by nebulization to the lungs of rats. Pharmocokinetic and pharacodynamic analyses showed increased serum levels of insulin and altered glucose levels (see, e.g., Fig. 1). It was also shown that breathing nebulized ethanol had no discernible acute toxicity. Other reported advantages or attributes of delivering insulin from ethanol solutions included:
1. Ethanol can stabilize the tertiary and quaternary structure of proteins.
2. Ethanol can act as a biocide and limit microbial contamination of the suspension.
3. Higher dosing can be achieved with ethanol because the amount of drug in suspension is not limited by solubility.
4. The nonpolar nature of ethanol can allow inclusion of large quantities per volume of lipophilic drugs.
5. Ethanol can act as an enhancer of drug permeation, similar to transdermal systems.
The last point, related to degree of absorption enhancement obtained by the ethanol—if any—was not in fact clarified by this study for no positive control (i.e., insulin delivery from an aqueous solution) was performed.
Assuming ethanol can be shown to lead to substantially improved insulin absorption from the lungs, a few key questions will still need to be answered before this technology will translate into a practical therapeutic advance:
1. What are the acute and chronic toxicity limits of inhaled ethanol in humans?
2. How can an inhalation delivery system be designed to safely deliver macromolecules and other drugs for systemic administration through the lungs, given the safety profile of ethanol, while maintaining user simplicity?
3. How long after delivery of ethanol to the lungs do lung epithelia remain especially permeable?
4. What is the molecular weight or other drug molecule-specific dependence on ethanol absorption?
Whether or not ethanol proves a key to substantially improving inhaled protein bioavailabilities in humans, research related to bioavailability enhancement is likely to be followed closely by those aiming to fully exploit the commercial potential of inhaled delivery systems for systemic application.
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