Oral delivery of drugs remains a preferred route, and innovation in this field is at its most creative. Dr Sarah Houlton looks at some of the interesting options under development
If a drug can be formulated in an oral dosage form, then patient acceptance is likely to be much higher than if it has to be administered via injection. However, it can be difficult to create oral formulations for certain products, perhaps because the drug will be destroyed before it reaches the bloodstream or its target site, or because it is too insoluble. A high dose can also require very large tablets or capsules that are hard to swallow. Numerous creative formulations are already available that can overcome some of these issues, but it remains an area that is ripe for innovation.
Ohio-based Aprecia has been working in the field for more than a decade, and at the beginning of August, the FDA approved its lead product – the first ever dosage form to be created using 3D printing. The product is a formulation of the anti-epilepsy drug levetiracetam that will be marketed under the brand name Spritam. Levetiracetam is the active in UCB Pharma’s Keppra, which is now off patent, but the new formulation is designed to give extremely rapid dissolution and thus absorption of the high doses required.
The company’s technology has its roots in the powder-liquid 3D printing technique developed by scientists at MIT in Cambridge, MA, US in the late 1980s. Their original aim was to create a way of making prototypes very rapidly. In contrast to the now-familiar 3D printing technique of fused deposition modelling that uses plastic extrusion, this method uses an aqueous fluid to knit together many layers of powder.
The porous nature of the tablets allows them to disintegrate extremely quickly on contact with liquid as the bonds created in the water-soluble matrix during the printing process break apart
The required shape is first created on a computer, and this is used to generate a slicing algorithm that splits the shape up into layers. These layers are then printed one at a time, with each layer starting off as a thin spread of powder on a powder bed; droplets of the binder liquid are placed precisely to join those particles that are in the correct location to form the object. The powder bed is then lowered slowly so the next layer can be added, and so on until the shape is complete. The final step is a heat treatment and the removal of any unbound powder.
MIT licensed the technology to various companies working in different fields, from car parts to tissue engineering. Aprecia has the licence for pharmaceutical applications, and used the technique to develop its ZipDose technology platform. The dosage forms are created by the sequential spreading of thin layers of powdered active mixed with food-safe ingredients, which are knitted together by droplets of aqueous binder placed at specific points to give the desired matrix. It allows very porous tablet structures to be created, in contrast to traditional tablets manufactured using compression, or those made via hot melt extrusion.
The porous nature of the tablets allows them to disintegrate extremely quickly on contact with liquid as the bonds created in the water-soluble matrix during the printing process break apart. The absence of traditional compression excipients that increase bulk means doses of up to 1,000mg can be incorporated in a standard sized tablet, and the company says taste-masking agents can also be included. The tablets will disintegrate in 10 seconds in a sip of liquid, far faster than could be achieved via compression for a high dose tablet. The technology should be of particular benefit in improving compliance for those who struggle to swallow large tablets, such as the very young, the elderly and the infirm.
The now-approved formulation of levetiracetam is being followed up by several other, as yet undisclosed, high dose drugs. Aprecia’s initial focus is on drugs to treat conditions of the central nervous system, where the need for formulations that are easy to take to improve compliance is particularly high.
A whole range of other innovative oral delivery forms are also being investigated. For example, a novel capsule is being developed by scientists at Purdue University. This capsule is designed to deliver drugs to the large intestine, rather than the stomach and small intestine where oral formulations are more commonly taken up. Potential applications, the team says, include Crohn’s disease, colon cancer and irritable bowel syndrome. It could also have potential in Clostridium difficile infections, where the ‘good’ bacteria that fight off infections in the colon are lost, and treatment can be effected via transplanting faeces from a healthy person to replace these bacteria. Freeze-dried microbes delivered via a smart capsule would be a rather less unpleasant form of therapy.
Figure 1: A smart capsule is being developed at Purdue University
Image courtesy of Purdue University
The new form of capsule being investigated by Babak Ziaie’s Purdue team takes the type of technology already routinely applied to smart capsules used for endoscopy and biopsy, and puts a drug delivery spin on it. For example, Given Imaging’s PillCam is widely used to make images of otherwise hard to reach areas in the gastrointestinal tract. However, these types of capsules are not ideal for long term drug delivery, as they need to be tracked in real time using fluoroscopy or gamma rays, neither of which is realistic outside a hospital setting. They also present health risks if used repeatedly. In addition, an RF transmitter has to be triggered when the capsule reaches the correct part of the GI tract – again, reasonably straightforward in a clinic, but not when the patient is going about their normal day-to-day business, given the unpredictable nature of the timing of gut functions. The capsule also needs a power source, which greatly adds to the cost and patient risk.
Ziaie’s team is taking a different approach and applying engineering to the problem – using a pre-charged capacitor in combination with a magnetic reed switch, a spring-loaded cap, a nichrome wire and a nylon fuse. The patient wears, or has implanted, a permanent magnet near the desired delivery site, and when the capsule gets close to it the reed switch will close, thus discharging the capacitor through the wire. This melts the nylon fuse, which opens the cap, and releases the drug. The strategy both removes the need for real-time tracking, and simplifies the issue of timing. The team says it is particularly suitable for releasing drugs at the ileocecal valve, where the small and large intestines meet, and a magnet worn on a belt could provide the trigger. The capacitor is much smaller than a battery, and as only a small amount of power in a single hit is required to operate the device, this is sufficient.
An erodible barrier layer is wrapped round the outside of a core that contains the drug itself. This barrier is engineered to erode at a controlled rate, and when sufficiently eroded the drug is released
Strathclyde University spin-out Bio-Images Drug Delivery, currently based at the Glasgow Royal Infirmary, is working on an erosion-based controlled release technology for tablets. Oralogik allows drug release to happen at a pre-defined time, with none escaping before the pulse. It involves an erodible barrier layer wrapped round the outside of a core that contains the drug itself. This barrier is engineered to erode at a controlled rate, and when sufficiently eroded the drug is released. The release time can be set at anywhere between two and eight hours after the tablet is taken by altering the excipient ratios.
The company claims that, as the barrier layer around the outside works independently of the core, it could also be applied to the majority of drugs, with only limited additional development being required. Furthermore, the release can be made either sustained or pulsed, depending on requirements. The barrier layer can also be film-coated, providing the opportunity for a bolus dose to be released very quickly, followed by the drug in the tablet’s core at a later time. The two APIs within a tablet formulated like this do not need to be the same, allowing for drug combinations with different delivery requirements to be combined into a single dosage form.
An alternative strategy is being pioneered by Aquarius BioTechnologies, which was formed to commercialise technology developed at Rutgers University, and which was acquired by Matinas BioPharma earlier this year. The idea is to incorporate drug molecules within a series of solid lipid sheets in a multilayer spiral crystalline structure, with no aqueous space within the spiral. This process, which they term encochleation because of the cochlear-shaped spirals it creates, is achieved by stirring calcium and soy-derived phosphatidylserine with the active, causing it to be enveloped, and resulting in a nano-sized drug formulation. This structure protects the API as it passes through the gastro-intestinal tract. After absorption, the cochleate particles are taken up by the macrophages in the bloodstream, where the lower levels of calcium cause the spirals to open and release the drug.
Figure 2: Schematic showing a cochleate formulation
Image courtesy of Aquarius BioTechnologies
The company has several anti-infective product formulations in the pipeline. The furthest advanced is CAmB, now referred to as MAT2203 after the acquisition. This is an encochleated form of the antifungal agent amphotericin B, and it is in the clinic. Amphotericin B is a broad spectrum antifungal with significant side-effects that is currently available only as an intravenous formulation as it is not normally orally available. In a Phase Ia single dose, double blind, dose escalating pharmacokinetic trial in 48 healthy volunteers, the product performed well in safety and tolerability terms, and no adverse events were reported. Encochleated versions of amikacin, capreomycin and atovaquone are in preclinical development, and the company is also looking at its potential to enhance tissue penetration of antiretroviral drugs.
A different multilayer formulation is being developed by Jerusalem, Israel-based Intec Pharma. The Accordion pill comprises multiple planar layers of pharmaceutical-grade biodegradable polymeric films, which are folded up, concertina-style, and enclosed within a standard-sized capsule. When the capsule shell dissolves in the stomach, the structure inside unfolds, and releases the drug slowly in the upper part of the gastro-intestinal tract. It is retained within the stomach for up to 12 hours, and once it exits the stomach it is degraded within the intestine. The pill can be engineered with one or more different actives, and can be used to combine both immediate and controlled release delivery in a single dosage form.
The company says a high drug loading of up to 550mg is possible in a single capsule, and more than 30 clinical studies looking at its safety and efficacy have already been carried out. It is particularly appropriate, they say, for use with drugs that have a narrow absorption window because of poor colonic absorption, and those with poor solubility. There is also potential with APIs where local action in the stomach and upper GI tract is desired, or which present adverse events further down the tract.
Its furthest advanced product, AP-CDLD, is a formulation of carbidopa/levodopa. Phase II trials showed that it gives improved control of Parkinson’s disease symptoms. The protocol for a Phase III trial comparing its effectiveness in patients with advanced Parkinson’s disease with a conventional immediate release levodopa product, Sinemet IR, was recently agreed with the FDA. Phase II trials have also been completed with AP-ZP, a formulation of the hypnotic drug zaleplon, in which gastric retention gives a significantly prolonged absorption phase and reduced variability via delivery to the upper GI tract. The company recently signed a development agreement with an unnamed major pharmaceutical company, and at the beginning of August announced the pricing of an IPO designed to raise funding for the Phase III trial of AP-CDLD.
Protein-based therapeutics are notoriously difficult to deliver orally, thanks to their poor pharmacokinetics and the propensity of peptide bonds to break down in the acid environment of the stomach
Another company at the IPO stage – closed at the end of July – is Neos Therapeutics, which is working on novel oral extended release formulations to treat ADHD, in both orally dissolving tablet and oral liquid suspension formats, and believes its technology should be applicable to other drugs. To create the formulations, it takes resin microparticles which it loads with the active via an ion exchange process, before applying a coating that gives a modified release profile.
These particles are sufficiently robust to withstand compression tableting when mixed with suitable excipients to create extended release orally dissolving tablets. Alternatively, in combination with suspension excipients, they can be used to make a liquid suspension formulation. Either way, and importantly for products designed for children, taste-masking technology can be incorporated into the dosage forms, and the extended release profile can allow for once-a-day dosing. NDAs have been filed with the FDA for orally dissolving tablet forms of both methylphenidate and amphetamine, and a liquid form of amphetamine is in clinical development.
Protein-based therapeutics are notoriously difficult to deliver orally, thanks to their poor pharmacokinetics and the propensity of peptide bonds to break down in the acid environment of the stomach, destroying the active before it can enter the bloodstream. This means injection or infusion predominate for the delivery of protein therapeutics such as monoclonal antibodies, with the inevitable impact on patient acceptance.
One potential alternative method is being developed by Rani Therapeutics, based in San Jose, CA, which recently entered into a collaboration with Novartis to investigate the delivery of some of the Swiss company’s biologics. Rani describes its technology as a ‘robotic pill’, and it is currently in the preclinical stage of development. The idea is to use the digestive system itself to activate the delivery mechanism, rather than relying on a power source or electronics. The company’s investors include Google’s venture capital unit.
Figure 3: Rani Therapeutics, the startup formed at InCube Labs, aims to commercialise the robot pill. Taken orally the pill is designed to safely inject drugs in the small intestine. Once it reaches the intestine, the acid eats through the outer layer and dissolves a tiny valve separating compartments filled with citric acid and sodium bicarbonate. On mixing these produce CO2, which inflates a balloon-like structure and pushes the drug-filled sugar microneedles into the wall of the intestine. The needles detach from the pill and slowly disssolve. The remaining components of the pill are expelled from the body.
Image courtesy of InCube Labs
The capsule shell is designed to dissolve in the small intestine, where the environment is less acidic and therefore more compatible with protein-based therapeutics. Inside the capsule are two separate compartments, one containing citric acid and the other sodium bicarbonate. The valve separating the two also dissolves in the small intestine, and the carbon dioxide formed when they react inflates a small ‘balloon’ bearing tiny ‘needles’ made of sugar into the walls of the intestine. These needles also contain the biologic drug, which is released into the intestine wall as they dissolve.
While some drugs will always need to be delivered parenterally, there is a huge amount of market potential for innovative dosage forms that give successful oral delivery. If they give significantly better compliance or enable more accurate delivery to the target site, then they may well gain at least some degree of market acceptance, despite the added cost.