Who would disagree that one of the key challenges of pharmaceutical scientists today is developing bioavailable oral dosage forms for poorly soluble compounds? Over the years, various approaches have led to a number of success stories in this area. These successes came in part due to the establishment of new scientific collaborations, new tools and enhanced knowledge.
In vitro tissue culture testing became a somewhat useful tool for screening bioavailability of new molecules. Peyer's patches, tight junctions and absorption enhancers became widely used targets and mechanisms for enhancing oral absorption. Practical nanoparticle and amorphous formulation systems were developed . A fruitful collaboration among formulation scientists, biologists and chemists was nurtured . The anatomy and physiology of the gastrointestinal tract was incorporated into the knowledge base of the various scientific disciplines involved in drug research and development and an agreed upon classification system for drug molecules that ranks drugs according to their probability of having poor bioavailability (BCS ) was established. It appears though, that another challenge for pharmaceutical scientists has been steadily progressing over the past several years; development of drugs and delivery systems for undruggable targets.
In vitro tissue culture testing became a somewhat useful tool for screening bioavailability of new molecules. Peyer's patches, tight junctions and absorption enhancers became widely used targets and mechanisms for enhancing oral absorption. Practical nanoparticle and amorphous formulation systems were developed . A fruitful collaboration among formulation scientists, biologists and chemists was nurtured . The anatomy and physiology of the gastrointestinal tract was incorporated into the knowledge base of the various scientific disciplines involved in drug research and development and an agreed upon classification system for drug molecules that ranks drugs according to their probability of having poor bioavailability (
The term “undruggable” means different things to different researchers but when used in the context of drug discovery it mostly refers to drug targets that range form not easily to impossibly difficult to access by conventional therapeutic agents. There may be no enzyme to inhibit, no surface receptor that exists or is suitably specific, no really efficient way of treating the disease except by inhibiting the synthesis of the target protein within the cell. The figures usually quoted are that approximately 70 -80% of potential drug targets are undruggable. The implications are clear; there is a vast untapped “gold mine” for treatment of disease. If this hurdle is eliminated, the impact on pharmacotherapeutics could be huge. Cancer is an area for which reaching undruggable targets may be the most rewarding. One example is TGF-β which is a growth factor over expressed in certain tumor cells. Over expression of TGF in tumors leads to immnunosuppression and effectively allows the tumor to become more invasive as well as less likely to be eliminated by the immune system. Inhibiting its synthesis, specifically in tumor cells, would decrease their lethality. Many other examples exist.
There are variety of methodologies use to reach undruggable targets. Lipid systems (nanoparticles, liposomes), polymeric systems, lipidated peptides , and stapled peptides (AILERON Therapeutics) are among them. The field is in it early stages if one considers the usual timeframe needed for drug development. It seems, very likely that undruggable target research will continue and grow. The goal of reaching three to four times the therapeutic targets we can reach today is an almost irresistible one for those in serious pursuit of treating disease.
In light of the new challenge of “drugging the undruggable”, the present paradigm for pharmaceutical scientists must change throughout R&D , not just for the molecular biologist. Knowledge of intracellular trafficking mechanims should be given high priority by all disciplines. The challenges of cellular uptake and targeting must be understood and a multidisciplinary approach must be taken to solve the various issues. The barrier of endosomal release, for instance, could be examined by scientists who have achieved success in increasing bioavailability of poorly absorbed compounds. Molecular biologists, drug delivery experts and formulators must seriously join forces. Bioavailability itself, must not be limited to comparitive blood levels but to the amount and time course for a drug to be taken up by the cells and reache its intracellular target.
As with oral absorption enhancement, collaborative scientific efforts, development of new tools in research and development and expansion of the relative knowledge base to all involved disciplines will be critical. The challenges are formidable, the re-think process a challenge itself, but the rewards promise to be great for patients and researchers alike.
Drawings compiled from::
As with oral absorption enhancement, collaborative scientific efforts, development of new tools in research and development and expansion of the relative knowledge base to all involved disciplines will be critical. The challenges are formidable, the re-think process a challenge itself, but the rewards promise to be great for patients and researchers alike.
Drawings compiled from::
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