Mucosal drug delivery: beyond buccal

Several products have already been launched on the market that rely on muco-adhesion principles, generally delivering drugs via the oromucosal route. Examples include buccal tablets or patches that can be placed in the cheek or on the gums and fast-dissolving tablets that are placed under the tongue.

The advantage of this approach is that absorption through the oromucosal lining can improve the bioavailability of drugs that have a high first-pass metabolism in the gastrointestinal tract. In other words, they are metabolised to a large extent by the liver before they enter the bloodstream.

Other advantages include rapid absorption and onset of action, and these characteristics have made oromucosal delivery a popular route of administration for medicines such as painkillers, nausea treatments and drugs for acute symptoms such as angina (see table).

A key restriction of oromucosal delivery, however, is the limited number of compounds that can be administered in this way. Larger molecular-weight molecules, in particular, cannot generally be absorbed effectively via the mouth, and this has encouraged researchers to look at the ways muco-adhesive formulations can be used elsewhere in the body.

One scientist recognised for his pioneering work in muco-adhesion and drug delivery is Dr Vitaliy Khutoryanskiy, reader in pharmaceutical materials at the University of Reading's School of Chemistry, Food and Pharmacy in the UK.

A polymer chemist by education, in recent years he has started to look at biological applications of materials and won the 2012 McBain Medal for his work in the field of colloid, polymer and interface science.

“Despite several decades of research, muco-adhesion is still not fully understood,” he told PME.

“Current efforts are focused on the design of materials with improved performance, and the development and validation of new physical techniques to study muco-adhesion and formulation of new dosage forms for mucosal administration.”

Getting muco-adhesive formulations that work for oral delivery – bypassing the mouth and being absorbed in the Gastrointestinal (GI) tract – has proved far more challenging and there are still no products on the market, despite decades of research.

“There has been fantastic in vitro work for several decades on muco-adhesive formulations for oral drug delivery, but in vivo results have generally been disappointing,” according to Khutoryanskiy, who noted that, in earlier cases, the muco-adhesive properties have meant that the tablet is retained in the stomach rather than the lower intestine.

“The tablets that are supposed to stick somewhere in our GI tract simply don't, so this is still a theoretical concept for drug delivery,” he said.

Despite setbacks, work still goes on, spurred by the promise of being able to develop orally bio-available formulations of biologic drugs that are currently delivered via injection.

Towards the end of last year, researchers from China, Hong Kong and Singapore presented in vivo data on a two-stage delivery system that suggests it may be possible to deliver even large molecular-weight molecules such as insulin. The two stages are based on an enteric capsule to protect the payload from the acidity of the stomach, combined with muco-adhesive nanoparticles to encourage deposition within the lower intestine.

Insulin dosed using this system to rats had a bioavailability of around nine per cent, suggesting that, at least in principle, this approach could provide an oral alternative to insulin injections for treating diabetes. It should also be noted that several other oral insulin products have been developed and failed to get beyond early-stage testing.
Dr Khutoryanskiy is still looking at oral delivery, though for live materials such as bacteria and living cells, and not for medicines.

The team has already developed an encapsulated formulation of bacteria that releases probiotic bacteria into the intestine to improve GI health and subsequent work will look at the possibility of combining this with muco-adhesive materials to improve retention times. Further down the line, the aim is to extend this research to explore its potential to deliver vaccines, providing an oral alternative to injections.

Meanwhile, the research team is looking beyond oral delivery to see how muco-adhesive principles can be applied to other organ systems.

Ocular delivery
Away from the GI tract, one of the most compelling applications of muco-adhesion is in ocular drug delivery, which, like the GI tract, is particularly challenging because of the defence mechanisms of the eye, such as tear fluids, blinking and the extremely low permeability of ocular membranes to drugs.

Liquids and semi-solid dosage forms, such as gels, are already used to deliver drugs to the eye, but delivery efficiency could be improved though the use of materials that stick to the cornea or conjunctiva, potentially improving retention times and drug release.

“We're looking at materials that are both muco-adhesive and also improve permeation of drugs through the ocular membranes,” Dr Khutoryanskiy stated.

Typically, more than 95 per cent of a drug delivered via a conventional eye drop formulation will not be absorbed, which is a huge waste of material and can make it very hard to achieve drug concentrations within the eye that reach therapeutic levels. Dr Khutoryanskiy's lab is looking at using hydrogel materials, which have liquid form in the fridge but form a gel when administered into the relatively warm environment of the eye.

There are commercially-available polymers that can provide this in situ gelling, but they tend to cause ocular irritation and can be uncomfortable for patients.

“What we are looking for is a material that provides improved drug retention but does not cause any local damage or irritation to the eye,” he explained.

One particular project addressed by Dr Khutoryanskiy's team gives a clear example of the potential for this type of approach. There is a condition called keratoconus in which the structure of the cornea degenerates and changes from its normal round shape to a cone.

Treatment for the condition can be quite unpleasant, with the surgeon scraping off the ocular epithelium under local anaesthetic in order to allow a drug called riboflavin to be instilled into the eye to saturate the cornea. The cornea is then irradiated with ultraviolet light, with the riboflavin helping to improve the structural integrity of the cornea under these conditions.

“We are trying to develop a formulation that would avoid the scraping of the epithelium,” noted Dr Khutoryanskiy.

Muco-penetration
Meanwhile, Dr Khutoryanskiy's work has recently taken his team beyond the realm of finding materials that can stick to mucosal tissues into a much more difficult area; materials that are not necessarily muco-adhesive but have greater ability to penetrate mucosal barriers.

A new project is looking at muco-adhesive silica nanoparticles that will stick to mucosal cells, and also nanoparticles that can penetrate through the mucous layer. At the moment, the focus is on developing nanoparticles linked to polyethylene glycol ('PEGylated') that appear to have this muco-penetrating ability.

Silica-based nanoparticles are somewhat limited in their applications because silica itself is non-biodegradeable and so would only be suitable for topical applications, including ocular and, perhaps, vaginal delivery. However, other penetrating materials could open up fascinating new areas of research, such as for delivery to the lung.

“If you want to deliver a drug to the lung, it is not desirable to have it stick to the upper airways, as this can mean that some of the dose is diverted to the stomach through swallowing and not all reaches the target tissue,” he continued.

“In these cases, you need to have a dosage form that penetrates the mucus rather than sticking to it, because mucus in the upper airways is a moving blanket designed to clear foreign material from the lung.”

A huge opportunity would be the development of muco-penetrating formulations that could allow delivery of genes to lung epithelial cells, potentially opening the door to an effective treatment for the common genetic disorder cystic fibrosis, although work in this area remains at a very early stage.

One limitation to this type of research is that the list of materials that are approved for delivery to the lungs, and indeed the eyes, is actually quite limited and this has, to some extent, put a brake on the development of new therapies based on novel materials and excipients.

Companies that develop excipients argue that the lack of an excipient master file in Europe, which can be cited by drugmakers without having to incorporate data on the excipient into a marketing application for a new product, is holding back innovation in this area.

“Even assuming a new material passes approval stages, the pharma industry still faces the challenge of manufacturing it on a commercial scale, which is a completely different from making it in the lab, and persuading customers to adopt it,” Khutoryanskiy concluded.

The Author
Phil Taylor is a freelance journalist specialising in the pharmaceutical industry