Ciclosporin, a potent immunosuppressant, was once a drug that displayed low and unpredictable oral absorption, until a novel delivery system revolutionised its therapeutic potential.

It’s a story with which the pharmaceutical industry is all too familiar: a highly potent ingredient is discovered, but it possesses unfavourable absorption properties. Screening for new chemical entities often results in the rapid identification of compounds possessing excellent pharmacodynamic attributes, but less promising pharmacokinetics. In fact, it’s estimated that 40-70% of new drug candidates are insufficiently soluble in aqueous media.

"Pharma companies are looking for more selective and more potent drugs. To some extent, they have already picked the low-hanging fruit, and finding a tractable target is getting more difficult," says Professor Colin Pouton, head of pharmaceutical biology at Australia’s Monash University.

Pouton, who researches delivery systems for poorly water-soluble drugs (PWSDs), says high-throughput screening has also tended to identify relatively low-affinity compounds that need improving by chemical modification. These new properties make drugs bind to their corresponding receptors more effectively, but often simultaneously reduce their solubility in water.

And these types of pharmaceutical can be a real problem if the therapeutic is to be administered orally. The performance of drugs taken this way is dependent on oral bioavailability: the amount of compound that reaches the systemic circulation after absorption in the gut. If a drug is poorly water soluble, its bioavailability is likely to be meagre too, resulting in low efficacy, high inter-individual variability and, consequently, an unpredictable response. It’s a major reason for lengthy drug development programmes or failing to reach the market.

"The aim is to design a product that works well when adminstered to a fasted stomach."

"Poor water solubility is often detrimental to oral drug delivery as, in nearly all cases, a drug must be in solution for it to be absorbed into the bloodstream from the GI tract," explains Dr Hywel Williams, a senior scientist at Capsugel.

Williams, who develops and emulates bioavailability enhancement technologies, says patterns in physicochemical properties for new drug candidates suggest this trend towards low-water-solubility compounds is not going to go away.

Lipid-based drug delivery systems

As a result, there is a real need for formulation strategies that can overcome this bioavailability problem and provide drugs with robust and reproducible exposure after oral administration.

A lipid-based drug delivery system (LBDDS), where a drug is encapsulated or dissolved in lipid excipients, is one of the technologies designed to address such a challenge. The theory behind these delivery vehicles stems from the observation that drugs with poor oral bioavailability often have improved delivery when taken with food. The human body has developed myriad systems for dealing with the absorption of lipid molecules, so it’s possible to apply this understanding to improving the pharmacokinetic properties of
disadvantaged pharmaceuticals.

"Many poorly water-soluble drugs have higher bioavailability when taken with a meal, particularly one that’s fat-rich," says Pouton. "But pharmaceutical companies want to produce a dosage form that works equally well whether the food is taken with a meal or not. The aim is to design a product that works well when administered to a fasted stomach."

This well-known enhanced bioavailability effect in the fed state suggests the beneficial role lipids can have on drug absorption. The stimulation of biliary secretion can promote drug solubilisation within the GI tract. LBDDSs are designed to mimic this effect with the drug dissolving within colloidal lipid structures and bypassing the dissolution step usually required when the compound is administered in its default crystalline state.

"The key concept is to present the drug in solution so that the slow dissolution step for PWSD is avoided," explains Pouton. "The drug is dissolved in a system that disperses in the stomach or intestine as a colloidal dispersion."

Provided the drug stays in its lipid solution in the gut, the API will present itself in the lumen for absorption into the blood. But it’s not the only way the vehicles can improve absorption.

"This mechanism addresses a drug’s physical obstacles to oral bioavailability, but, unlike many other approaches, lipid formulations also have the capacity to overcome biological obstacles," says Williams.

These may include increasing intestinal membrane permeability by inhibiting efflux transporters (such as P-glycoprotein) or major drug metabolism enzymes (like CYP3A4).

Types and categorisation

There are different types of lipid-based formulations. So, in 2000, Pouton proposed an effective categorisation (refined in 2006) called the lipid formulation classification system (LFCS). It consists of four broad categories. The systems range from simple oily solutions (type I) to self-emulsifying vehicles that either contain purely hydrophobic components (type II) or possess some water-soluble features (type III). Type IV devices are essentially oil-free formulations made of surfactants and co-solvents.

Many vehicles in the type III category belong to a class of LBDDSs called self-microemulsifying drug delivery systems (SMEDDSs). SMEDDSs have garnered particular interest in recent years and it’s by this formulation that ciclosporin is now administered under the brand name Neoral. This type of system allows a much finer dispersion of the pharmaceutical into the GI tract, resulting in better dose linearity and a reduction in intrasubject variability.

Williams says the type of formulation selected for product development is dependent on several factors, such as the physicochemical properties of the compound and its biopharmaceutical needs. At Capsugel, he employs an in silico selection process to determine the optimal technology according to the drug’s properties, which, he says, speeds up development and ensures better in vivo performance.

"These formulation types may be liquid or semi-solid at room temperature. Semi-solid formulations are often explored if there is a need for a more sustained drug release profile or if there are significant physical/chemical stability concerns," he explains.

Within the delivery system, the API may be present in a dissolved or suspended form, and the most popular formulation options are liquid-filled soft capsules or gelatine hard capsules. Williams says developing lipid formulations that contain only dissolved drugs is often more desirable, and, while suspensions can be effective, spray-dried dispersion formulations should also be considered.

He and his colleagues have been looking to expand their company’s capabilities in lipid multiparticulates (LMPs). These vehicles are particularly versatile as they provide immediate or sustained release and can be contained in sachets and capsules.

"LMPs combine some of the advantages of lipid formulations with the well-known benefits of multiparticulates, such as low inter and intrasubject variability," says Williams.

Dangers of drug precipitation

Martin Kuentz, professor of pharmaceutical technology at the University of Applied Sciences and Arts Northwestern Switzerland (FHNW) is similarly enthusiastic about the advantages LBDDSs and associated new technology can bring to some compounds. However, he is keen to point out that not all poorly water-soluble drugs are likely to benefit from the vehicles.

"Most people think if something is poorly soluble in water, then you can dissolve it in oil, but that is not necessarily true," he says. "There are some compounds that are poorly soluble because of a high melting point. They do not apply so well for lipid-based delivery."

"LMPs combine some of the advantages of lipid formulations with the well-known benefits of multiparticulates, such as low inter and intrasubject variability. "

Kuentz has been working with LBDDSs for many years. He now leads a research group at FHNW that focuses on oral lipid-based formulations. The researchers look at the dispersion characteristics of the drug candidate in simulated intestinal fluids, and use an enzymatic assay to see what happens to the formulation during digestion. It’s a method that reveals a significant difficulty of the application of such delivery systems.

"There is often drug supersaturation generated in the intestinal lumen," he says. "This typically evolves in the course of formulation dispersion and digestion."

The process can lead to drug precipitation. And, once a pharmaceutical precipitates in crystalline form, it is generally assumed that redissolution is too slow compared with intestinal transit time, and will therefore result in incomplete absorption.

"You start with the drug in solution as opposed to a tablet. But it’s unfavourable if you don’t keep it in there," says Kuentz. "Drug precipitation is a consequence of rather high drug supersaturation, so much higher concentrations are reached than equilibrium solubility. This is a double-edged sword. The good thing is that higher concentration means more absorption usually, but unfortunately it is also the main driver for precipitations."

He thinks further research must be undertaken for a more rational basis to designing lipid-based formulations. Some groups are now focusing on ways to prevent this precipitation during digestion.

"The inclusion of polymers to slow down crystallisation looks very interesting," says Pouton. "This could be a formulation additive, but also hard capsules made of the appropriate polymers can have the same effect."

Another setback with the systems is the industry’s slow application and development of the technologies.

"Most new drugs are poorly water soluble and lipids are a key technology to formulate them, so you should have a lot of new lipid-based delivery systems coming to the market. As a matter of fact, there are not that many products that have got there," says Kuentz.

He thinks he knows one culprit for this underexploitation: costs. In order to manufacture the liquid-filled soft capsules the vehicles are usually encased in, pharmaceutical companies often have to go to an external producer, which will clearly result in a higher price tag than undertaking the task in-house.

But Kuentz believes the industry needs to realise that the expenditure might in fact balance out.

"If you can get a drug with a lipid formulation to a higher bioavailability than before, you can have a lower dose," he says. "Therefore, I think this concern might be countered by making a higher bioavailability format that uses less drug, which gives you lower costs for the final drug product."

Williams agrees that there is a sense of unfamiliarity when it comes to developing liquid and semi-solid formulations. While knowledge of formulation techniques has improved enormously over the past decade, it’s taking a while to filter through. But his team at Capsugel want to ensure the industry does not overlook the LBDDS option.

"With more efficient capsule filling and sealing, and a greater understanding of how to develop and test lipid formulations, it is likely the industry will look more to lipid formulations to solve their product needs," he says.

Stability appears to be another worry, though. This property is very drug-specific and, unfortunately, very little data exists to give formulators confidence. There have been incidences in the past where surfactant impurities have been associated with chemical degradation of the drug. But, while Kuentz understands the industry’s fear for long-term instability, he believes increased knowledge is the remedy.

"If you formulate a lipid-based system in a proper way, this should not happen. It’s often just a hurdle for inexperienced formulators," he insists.

"My personal view is that lipid-based delivery is a really wonderful tool because it works in so many cases. If, in the future, the pharmaceutical industry becomes more courageous about going down this route, I think this will be very beneficial for the companies themselves."