Drug Delivery
Drug delivery systems have evolved over time and have become increasingly sophisticated yet more user-friendly, allowing drugs to be administered more reliably and easily. NDDS has seen a foray of transformations such as microencapsulation, epithelial and transdermal delivery, nanoparticles, liposomal vesicles etc.

Carrier-mediated drug delivery has emerged as a powerful methodology for the treatment of various pathologies. The therapeutic index of traditional and novel drugs is enhanced via the increase of specificity due to targeting of drugs to a particular tissue, cell or intracellular compartment, the control over release kinetics, the protection of the active agent or a combination of the above.

The global market for advanced drug delivery systems was more than €37.9 billion in 2000 and is estimated to grow and reach €75B by 2005 (i.e., controlled release €19.8B, needle-less injection €0.8B, injectable/implantable polymer systems €5.4B, transdermal €9.6B, trans-nasal €12.0B, pulmonary €17.0B, trans-mucosal €4.9B, rectal €0.9B, liposomal drug delivery €2.5B, cell/gene therapy €3.8B, miscellaneous €1.9B). Developments within this market are continuing at a rapid pace, especially in the area of alternatives to injected macromolecules, as drug formulations seek to cash in on the €6.2B worldwide market for genetically engineered protein and peptide drugs and other biological therapeutics.
Oral Drug Delivery System
 
Overview
The choice of a delivery route is driven by patient acceptability, the properties of the drug (such as its solubility), access to a disease location, or effectiveness in dealing with the specific disease. The most important drug delivery route is the peroral route. An increasing number of drugs are protein and peptide based. They offer the greatest potential for more effective therapeutics, but they do not easily cross mucosal surfaces and biological membranes; they are easily denatured or degraded, prone to rapid clearance in the liver and other body tissues and require precise dosing. At present, protein drugs are usually administered by injection, but this route is less pleasant and also poses problems of oscillating blood drug concentrations. So, despite the barriers to successful drug delivery that exist in the gastrointestinal tract (i.e., acid-induced hydrolysis in the stomach, enzymatic degradation throughout the gastrointestinal tract by several proteolytic enzymes, bacterial fermentation in the colon), the peroral route is still the most intensively investigated as it offers advantages of convenience and cheapness of administration, and potential manufacturing cost savings. We are currently developing several proprietary Novel Drug Delivery Technologies for the oral delivery of peptides and proteins. Right now, we have separate delivery systems for Insulin, IgG and IgG-Fc fusion molecules, as well as a generic system for peptides and proteins.
Oral delivery of Insulin

Challenges
With the advent of rDNA technology, combined with advances in the large-scale production of recombinant proteins, there is an ever-increasing list of pharmaceutical products that are available for administration to patients. Unfortunately, however the administration of these molecules must generally be via sub-cutaneous injection either once, twice or thrice weekly, depending upon the molecule and dose, or, in the case of insulin, up to four times daily. The administration of these molecules via the sub-cutaneous route has many disadvantages, including pain and swelling at the site of injection, highly variable intra and inter-subject variability in dosing, stimulation of an immune response, and large fluctuations in the serum profile of the sub-cutaneously administered drugs.

Administration of these proteins via alternative routes has previously been precluded by the very low bioavailability of these molecules when given orally, transdermally, or via pulmonary administration. Despite this, there are obvious benefits to oral delivery of the afore-mentioned molecules, including the ability to maintain a flatter serum profile of the administered protein, an increase in patient comfort, an increase in patient compliance, decreased in intra and inter-subject variability, and the possibility of achieving site directed targeting of the active agent to the intestinal wall for conditions such as Crohn’s disease, and gastro-intestinal cancer. As such the oral administration of proteins would be regarded as much more “patient friendly” and clearly more desirable than sub-cutaneous administration.

Whilst the oral route of administration is a highly desirable route of administration, the gastro-intestinal tract poses a number of physical and chemical barriers to successful administration of therapeutic agents. Firstly, the intestinal tract is specifically designed to degrade proteins, and thus orally administered therapeutics must withstand both the gastric acidity encountered in the stomach as well as attack by endogenous intestinal enzymes such as trypsin, pepsin and chymotrypsin, without losing activity. Secondly, in addition to surviving the harsh milieu of the intestine, the orally administered material must still be transported across the gastrointestinal mucosal epithelial cells, enter the blood stream and move to the site where activity is required. Thirdly, uptake and transport must be relatively efficient to ensure that the majority of the dosage administered is taken up from the gut, rather than be excreted at the end of the alimentary canal. Failure to over-come these obstacles is the main reason why many compounds have been shown to be ineffective or exhibit low or variable potency when administered orally.


Scientific Rationale
Our scientists at Transgene have discovered a previously undescribed transporter in the intestine of mammals, including humans. The use of this transport system has several advantages over the previously described vitamin B12 and transferrin uptake systems, the main ones being that the uptake capacity is relatively high, it is suitable for conjugation to other molecules, and it is relatively low cost.
The current technology combines to of our in-house technologies. Firstly, the specific targeting provides a means of uptake of the administered pharmaceutical from the intestine to the circulation. Secondly, our scientists have developed several formulation systems employing a proprietary transporter system, forming a targeted nanolattice. This is required to increase the dose deliverable, and to protect the peptides and proteins from proteolysis in the intestine, thus enabling proteins to be administered orally to vertebrates without the need for injection.

Transdermal Drug Delivery System

Overview
here is a need for the development of new drug delivery system that will improve the therapeutic efficacy and safety of drugs by precise (i.e. site specific), spatial and temporal placement within the body, thereby reducing both the size and number of doses. New drug delivery systems are also essential for the delivery of novel, genetically engineered peptide or protein drugs to their site of action, without incurring significant immunogenicity or biological inactivation.

One of the methods most often utilized has been transdermal delivery - meaning transport of therapeutic substances through the skin for systemic effect.

Transdermal drug delivery avoids problems such as gastrointestinal irritation, metabolism, variations in delivery rates and interference due to the presence of food. It is also suitable for unconscious patients. The technique is generally non-invasive and aesthetically acceptable, and can be used to provide local delivery over several days.


Scientific Rationale
The advantage of our transdermal delivery system will be delayed release, plus the ability to target APCs in the skin. We have developed a proprietary transdermal delivery using a proprietary water-in-oil micro-emulsion.

Using our patented transdermal delivery platform, we have initiated the program to deliver its novel fusion protein drug as a therapeutic vaccine against AIDS. Successful delivery of the protein is monitored by direct measurement of the appearance of the specific fusion protein in serum, and also by measuring specific anti-V3 antibodies in V3 vaccinated mice.

Additionally, the number of antigen-producing cells is measured by performing plaque assay.
 
 
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