Session 3 Delivery Systems

Delivery of Bioactives to Possums

I Tucker1, G Butt2, B McLeod3

1School of Pharmacy, 2Department of Physiology, University of Otago and 3AgReserach, Invermay

Abstract

Bioactives can be delivered to an animal by various routes: oral, injections, skin, nose, lung, mouth, eye, and other orifices such as rectal, vaginal, or aural delivery. For many of these routes (e.g. the skin or transdermal), only highly potent and hence low dose drugs can be delivered. About 90 percent of material put into the eye drains through the nasalacrimal duct and may be absorbed from the intestine. Mucous membranes (e.g. mouth) have mucosal associated lympoid tissue and so maybe sites for mucosal immunisation. The oral route is the most commonly used route, usually because of its convenience, and is arguably the most suitable route for delivery to possums. Delivery systems should fulfil a number of functions. They should make the bioactive convenient to use, put it in a form attractive to possums, maintain the stability of the bioactive in the field and in the gastrointestinal tract, deliver the bioactive to a particular region in the gastrointestinal tract, perhaps enhance its absorption and also be capable of influencing the biological response. Various types of degradation can occur on storage and in the field. These include physical degradation such as aggregation, chemical degradation due to moisture, oxygen and light and microbial degradation. The type of bioactive in use and formulation of this bioactive will determine its rate of degradation. Within the gastrointestinal tract the bioactive may be exposed to acid secretions of the stomach, metabolising enzymes in various regions of the intestinal lumen and in the brush border. It is important to understand the distribution of these enzymes and how they might be inhibited so that appropriate formulations can be designed to maintain stability. It is important to consider formulation issues at an early stage of development of a bioactive to ensure that it is capable of being formulated to achieve a biological response.

Routes of Delivery

The aim of this paper is to give a general overview of some of the formulation and delivery issues which must be addressed to ensure bioactives delivered to possums have the desired efficacy.

Bioactives can be delivered to an animal by various routes: oral, injections, skin (transdermal), nose, lung, mouth (buccal/sublingual), eye, and other orifices such as the rectal, vaginal and aural. The oral route is arguably the most appropriate route for delivery in the field but it is worth discussing the alternatives. Injections are clearly unacceptable for delivery to possums in the field. Delivery through the skin or transdermal delivery on the other hand is potentially viable. Pour-ons and spot-ons are used for both farm animals and companion animals and could be applicable for possums. The skin is a formidable barrier to delivery of bioactives and so transdermal delivery is probably only viable for highly potent (low dose) small organic molecules. It is probably unsuitable for hydrophylic drugs such as peptides and proteins, although there is current research on the development of transdermal vaccines.

The nasal route is a potential pathway for delivery of peptide and protein bioactives to possums. Work in rats and humans has shown that small proteins (e.g. insulin MW5000) is absorbed through the nasal epithelium provided permeation enhancers (e.g. bile salts) are co-administered. Interestingly, a Japanese group has shown that peptides can be delivered directly to the cerebral spinal fluid using nasal delivery. This suggests that the nasal route might be used for delivery of bioactives which might not cross the blood brain barrier and so not be available to the brain if other routes, such as oral, were used for systemic delivery.

The lungs provide an enormous surface area for absorption and so delivery of bioactives via the pulmonary route may be possible. However a major issue to be addressed is to ensure that the aerosol comprises particles of the appropriate size (2-3m for humans) since large particles would impinge on the back of the throat, whereas particles too fine will be expired without deposition in the lungs. The particle size required in possums is probably unknown.

The buccal and sublingual tissues of the mouth provide a potential route for delivery of bioactives. However the surface area of these membranes is relatively small so that it is only suitable for highly potent drugs. Having said that, the lymphoid tissue of the nasopharanx provides a potential site for mucosal immunisation.

In excess of 90 percent of material put into the eye drains into the nasoglacrimal duct and maybe subsequently absorbed from the intestine. Some bioactives administered to the eye are absorbed through the conjunctival tissue into the systamic circulation so that the ocular route is a potential delivery pathway, although, once again, it would only be suitable for highly potent drugs.

It is unlikely that other orifices such as the rectal, vaginal and ear would be suitable for delivery of bioactives to possums in the field.

Functions of the Delivery System

Bioactives compounds cannot be used in their pure form but must be converted through the process of formulation to usable products or delivery systems. The delivery system has a number of functions: convenience of use, attractiveness to the possum, maintenance of stability of the bioactive, targeting delivery of the bioactive, enhancing absorption, influencing the biological response. Some of these topics are discussed below.

Stability on Storage & in the Field

Bioactives, and indeed the delivery system or formulation, can undergo various types of degradations: physical degradation, chemical degradation, microbial degradation.

Physical Degradation

An example of physical degradation is that which might occur for an aerosol type system. A great deal of effort might be put into developing a formulated product comprising suitably sized particles to ensure delivery to the lung. However on storage and exposure to high relative humidities, particles may aggregate leading to substantial changes in the particle size distribution of the product and hence poor efficacy. Other types of physical degradation could include denaturation and aggregation of proteins, caking in suspensions, crumbling of pellets.

Chemical Degradation

Bioactives and products distributed in the field will be exposed to varying levels of moisture (humidity and rain), oxygen and light. This can potentially lead to major chemical degradations of both the bioactive and components of the formulation. In general, proteins such as vaccine antigens will be far less stable than the commonly used small organic toxins (e.g. 1080) and so chemical degradation of these bioactives is going to be more problematic. So, greater efforts will be needed on formulation in attempts to enhance the stability of these bioactives.

Microbial Degradation

Formulations in the field, particularly if exposed to high humidities may become damp and microbial degradation of peptides and proteins and indeed the components of the formulation will become an important issue. It is well known that 1080 in pure water is relatively stable but when 1080 is dissolved in water heavily contaminated with microbial flora its degradation occurs reasonably rapidly (e.g. half life of about 10 days). Microbial degradation of proteins in the field is going to present even greater problems than those for small organic toxins.

Stability in the Gastrointestinal Tract

In addition to degradation in the field, a bioactive may be degraded within the gastrointestinal tract. The bioactive may be exposed to the acid of the stomach (pH1.5-2) and to various enzymes in the small and large intestines. In the paper which follows, we discuss metabolism of two model bioactive compounds in various regions of the intestine of the possum.

Given that degradation of peptide and protein drugs is extensive within the gastrointestinal tract, there is an important function for the delivery system to protect the bioactive in various regions of the gut. For example enteric coats might be used to protect from acid in the stomach or metabolic inhibitors might be included to limit enzyme catalysed degradations within the intestine.

Delivery to the Appropriate Region of the Gut

We have found that metabolism of peptides and proteins in the intestine of the possum varies from region to region (see next paper). This means that there is a role for the formulation to deliver the bioactive to a specific region of the intestine. Various approaches are possible. Some enteric polymers prevent release in the stomach but allow release in the duodenum whereas others release at ileal pHs. By appropriate choice of the enteric polymer, it is possible to delay release of the bioactive to lower regions in the intestine. Other polymers such as azo-cross-linked polymers, will remain intact in the stomach and small intestine, and not dissolve until they are reduced by the microflora in the large intestine. These so-called colonic delivery systems provide a means to deliver peptide or protein to the posterior colon where we have shown that the metabolising enzymes are at far lower levels than in the small intestine.

Enhancing Absorption

Yet another function of the formulation may be to enhance the absorption of drug through the intestinal wall. Hydrophylic drugs such as peptides and proteins are usually poorly absorbed from the gastrointestinal tract, not just due to their metabolism, but because their hydrophylic nature means they penetrate the intestinal epithelium poorly. Potentially, permeation enhancers could be included within formulations to modify the integrity of the epithelium and thereby enhance absorption. These issues are discussed in the next paper.

Conclusions

It is important to understand the physiology of the gastrointestinal tract of the possum so that delivery systems can be designed appropriately. Information required includes: the transition time of materials through the gastrointestinal tract and how this transition time is affected by feeding of the possum and formulation factors such as particle size, density, and surface characteristics of particles. It is also necessary to understand the regional differences in metabolism within the intestine and how this metabolism can be inhibited through the use of metabolic inhibitors. Finally an understanding of the permeability of the intestinal wall to various bioactives is important to provide the scientific basis for the use of permeation enhancers.

It is essential that formulation and delivery issues are considered at an early stage in the development of any potential bioactive. The pharmaceutical industry has recognised this and now incorporate pre-formulation and formulation research into the early phase of the drug discovery process. If this is not done, bioactives will be identified for their potential efficacy but will finally be rejected because of their poor stability in the field or in the gastrointestinal tract and inability to formulate them into stable efficacious products.

Previous PageTable Of ContentsNext Page

Contact for Enquiries

Manager, Strategic Science Team
MAF Biosecurity New Zealand
PO Box 2526
Wellington
NEW ZEALAND

Phone: +64 4 894 0115
Fax: +64 4 894 0731
Contact this person

 
Print this page Print this page




WebSite survey