Unlike injections, most standard tablets fail consistently to deliver effective blood levels – resulting in wasted money and dissatisfied patients
Most drugs do not work for every person or for any one person on every dose occasion. Pain relieving tablets commonly provide acceptable pain relief on only 60% of occasions. The world’s most prescribed migraine tablet provides complete pain relief at two hours on only one quarter of occasions. Research shows that when people take tablets, the peak blood levels of the drug can vary by several hundred percent – a huge amount of variation given the high value placed on consistency and product effectiveness.
The failure of a drug formulation can result from:
- genetic factors specific to an individual which alters the way they process or respond to the drug, or
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physiological factors which can vary significantly during each day for every individual which influence release of drug from a formulation and may result in inadequate delivery.
The quantitative impact of physiological factors is best evaluated by looking at the variability in drug absorption data for each patient when administered the same product under the same conditions on different occasions, (intra-subject variability). The effect of genetic factors is specific to each patient and will be seen as differences in absorption and effect between patients (inter-subject variability).
A patient’s gastric pH and motility changes continually throughout the day according to the intake of food and the volume and type of food eaten. If a patient takes a tablet at the time when they have high gastric motility and a gastric pH which favours the solubility of the drug, the drug dissolves from the tablet and empties into the small intestine quickly leading to rapid absorption and high blood levels of the drug.
As almost all drugs area absorbed through the intestinal wall, not through the stomach, it is only when the drug dissolves rapidly and empties from the stomach rapidly that rapid absorption from the small intestine can occur.
If a tablet is taken when the stomach is resting (low motility) or at a pH not favourable to drug solubility the drug will not dissolve quickly and empty into the intestine, resulting in slow absorption and low peak blood levels.
Slow absorption is a problem, as low peak blood levels may mean that the drug fails to achieve full effect on that occasion. Slow absorption will also result in delayed onset of action.
One way to overcome this variability in drug effectiveness is through injections.
Injecting a drug usually produces high blood levels as the delays and variability seen with oral administration caused by conditions in the stomach are avoided. For example the migraine drug, sumatriptan, when taken orally is only half as effective as the same drug given by injection under the skin. The drug when injected achieves higher blood levels on more occasions delivering double the efficacy of the tablet. But injections are expensive, painful and more risky than tablets. So oral formulations which can achieve consistent absorption and high blood levels at each dose occasion delivering an effective dose to more patients at each dose occasion will improve efficacy and will be preferred over injections.
Furthermore, slow absorption means that drug action is delayed. Rapid absorption increases the speed of action, which is critical if a patient is taking a tablet to treat a migraine, to relieve nausea, to help achieve an erection or to relieve a Parkinsonian spasm.
An Australian company Imaginot has developed a technology which enhances oral delivery performance so that the drug will reach effective levels on most occasions on which it is taken.
The technology enabled tablet is intended to be swallowed whole with a glass of water. The technology works by utilising inert tablet ingredients which drive extremely rapid dissolution of the drug, blowing the tablet apart and creating the right pH for optimal drug solubility in the patient’s stomach. Dissolved drug empties into the small intestine where the high drug concentration drives absorption and then distribution in the body. The technology takes advantage of the fact that liquids empty from the stomach rapidly whether the patient is fasted or has recently ingested food.
For most drugs this new formulation approach will mean rapid absorption independent of gastric pH and motility at the time of dosing, leading to both improved effectiveness and earlier onset of drug action.
The technology offers the convenience, consistency and speed of an injection without the added pain, risk and costs. It provides an unsurpassed solution with the potential to revolutionise how drugs are administered across the world.
Compared to existing technology, based on the evidence to date, Imaginot believes
- that 90% of patients will achieve high blood levels of the drug earlier (20-30 minutes after dosing compared with 1 hour or more for standard tablets and orally disintegrating tablets / ODT’s) and
- that for many drugs the technology will achieve an increase in effective dose occasions of between 50 and 100%
Public & Private Payers demand improved comparative efficacy to ensure re-imbursement
One of the world’s leading CRO’s, Quintiles reports “a cacophony of calls for comparative effectiveness research (CER) requires companies introducing new drugs to demonstrate their new drug improves healthcare outcomes ”.
Indeed a failure to show that a new drug is better than an existing standard is likely to lead to insurers (reimbursers) electing to reimburse the new drug only when the existing standard drug fails, substantially limiting prospects for the new drug.
This push is increasing the pressure for drug companies to optimise both the drug and its formulation to extract every possible advantage in comparison to existing therapies. Enabling drug delivery technologies will be part of the solution for pharmaceutical companies.
Imaginot is poised to provide the new formulation “operating system” enabling improved efficacy and reduced time to peak action
Imaginot has supporting clinical evidence on the effectiveness of its proprietary SurgeDose® (SD) technology on three drugs paracetamol, lornoxicam and diclofenac so it is well positioned to provide a key enabling drug delivery technology to companies developing new drugs.
The focus for Imaginot is on marketing this technology to enable and enhance the effectiveness of new drugs being developed and to enable and enhance the effectiveness of drugs which have recently been approved.
Importantly the SurgeDose® technology, when applied to new drugs as they transition from preclinical to clinical development has virtually no additional cost or time delay implications. In this instance the SurgeDose® technology can be employed as one of the preferred formulation strategies and compared to the best alternative formulations in the normal phase I testing program. The resulting improved efficacy and reduced time to action will assist companies to gain maximum reimbursement and uptake by clinicians and patients.
When the technology is used to improve recently approved drugs ( to build market share or extend lifecycles), typically within a couple of years of approval of the drug, the 505 (b) (2) NDA and sNDA regulatory pathways apply with timeframes and costs substantially reduced in comparison with NDA’s.
Imaginot has established a number of important partnerships which further validate the technology and facilitate evaluation of its merits.
- Imaginot is working with Abbott in India to develop five SurgeDose® products in that market. The first was launched in September 2011 with a second product launch planned. The clinical results from these first two drugs are outstanding.
- Secondly Imaginot has a partnership with a global contract services and research company, Piramal Healthcare. Piramal and Imaginot are offering to undertake, for partner companies development programs showing how Imaginot’s SurgeDose® technology compares in human trials to the partner’s best existing alternative formulation.
Imaginot has patents granted in Canada, Australia and USA with applications pending in Canada, USA, Japan, Europe and India. These patents extend to at least 2024 and may extend beyond this date.
Imaginot intends to monetise its investment in technology by making technology available as a new standard in formulation performance. The company will provide multiple partners with access to the technology at low cost based on single digit royalties with the quantum determined by the magnitude of the PK and PD performance improvements.
The use of operating systems such as Android® by third party device makers is commonplace in the mobile communications industry. Drug delivery technologies are the pharmaceutical equivalent of operating systems in mobile communications. It no longer makes sense for pharmaceutical companies to spend years optimising their own formulations; instead these are outsourced to contract formulators or companies with proprietary systems providing the desired delivery profiles. As examples Catalent has established its Zydus® technology as a leader in orally disintegratable tablets and Elan Drug Technologies established its oral controlled release (OCR) technology as a leader in controlled release. Imaginot is positioned to set a new standard for consistent oral absorption.