The perennial problem for pharmacists is whether they choose the easy way to dose or select the most effective method. It is far simpler to administer medicine by mouth than to inject it, which is why the majority of the highest-selling drugs in Europe and the US are orally dosed. But this form of administration must be hydrophilic enough to dissolve in aqueous solutions, while remaining hydrophobic (the hydrogen bond that allows substances to be absorbed through liquid) enough to cross cell membranes. Drugs in Class II of the Biopharmaceutics Classification System, which have high intestinal permeability but low water solubility, pose a particular problem. This class includes treatments for diabetes, anti-androgens, anti-inflammatories for arthritis patients and seizure medications, as well as many of the newest drugs to recently hit the market.
Researching lipid-based formulations
Low-solubility drugs can be absorbed more easily if they are formulated with lipids instead of water-based excipients. These formulations currently account for 2–4% of available drugs, such as Accutane, Marinol and Sandimmune. They have been on the market since the mid-2000s, when they enjoyed a moment in the limelight – though there has been less demand for them during the intervening years. Since then, René Holm, scientific director and head of drug product development, parenterals and liquids at Janssen Belgium, has focused on lipid-based formulations. His latest research – which was presented at the ninth Global Drug Delivery & Formulation Summit in March 2017 – discusses lipid-based suspension, a delivery system that has flown even further under the industry’s radar.
“Quite often, the perception when you work with lipid-based formulations is that it’s a prerequisite that the active pharmaceutical ingredients (API) solubilise in the formulations, so it’s a true solution, in order to give the positive benefits of the lipid-based systems. We tried to challenge that,” Holm explains. “We saw on several occasions that suspension in lipids worked very well.”
Holm and two masters students used cinnarazine and fenofibrate – two compounds with high solubility in lipids – as the active ingredients for their research. They tested them in five groups of varying doses and lipid types, keeping the amount of lipid in each dose constant, since changing it would also change the gastric response. The APIs were combined with lipid excipients in varying degrees of solution, ranging from 100% solubilised to 75%, 50% and finally 25% solubilised with the rest suspended in the excipient, which delivered a dose four times as high as that in the first group. The lipid solvents varied between long-chain and medium-chain triglycerides, as well as long-chain and medium-chain monoglycerides, and castor oil.
“What we noted was, not so much for the long-chain triglyceride, but in particular for the long-chain monoglyceride, the relative amount that was absorbed with only 25% in solution was the same as when everything was in solution,” adds Holm. “Basically, we saw the bioconversion of the excipient facilitating a higher absorption.”
Those findings went against the way that formulations usually behave outside of the digestive system. Normally, medium-chain triglycerides and monoglycerides exhibit higher solubility than long-chain lipids. Exactly how this works forms the next topic of Holm’s research. “I honestly do not fully understand the mechanism’s absorption,” he states. “We need to gain more systematic knowledge of the classes of excipients that can facilitate this, and the loadings that provide sufficient absorption.”
Ostwald ripening
It has already been proved that lipid-based formulations increase gastric bioavailability because they induce a food response. When the body detects the presence of lipids, the gall bladder releases bile salts and gastric emptying slows down. The time taken to pass through the small intestine remains the same, so the API has more time to dissolve, which increases the potential solubility and effectiveness of low-solubility drugs.
Long-chain lipids had the highest solubility in the digestive system, suggesting that they were the best choice for bioavailability. The researchers also came across some of common pitfalls of lipid formulations, such as Ostwald ripening, a phenomenon seen in water-in-oil emulsions, where small suspended particles dissolve into the solvent before redepositing onto larger particles over time.
“In principle, Ostwald ripening can occur in lipid suspension as well. In practice, I don’t see it,” says Holm. “If Ostwald ripening is less of an issue in lipid suspensions, it means that the approach could be used as an alternative drug delivery system for compounds, where enabling technologies are needed to drive the bioavailability.” That could prove to be beneficial to manufacturers, but commercialising these findings is still a long way off.
Lipids and potential commercialisation
Holm is cautious about the possible commercial applications of lipid-based suspensions, but he believes that they could be useful in toxicology, where researchers often need to deliver very high doses to find the danger point of a drug. They also require drugs that are simple to dose when testing on animals outside of the lab. “Lipid suspension is a means to administer a dose that is higher than the solubility, while still maintaining the dose-proportional advantage of the enabling effect from the lipids, so it is just another option over going for very complex formulation systems, such as amorphous solid dispersions, which add to the cost and complexity of the programmes.”
Manufacturers will first need a motivation to move in that direction after years of focusing on other delivery methods, but Holm says that he sees an opening for lipids. “I personally think that lipid-based formulations have advantages over some of the other systems – for instance, amorphous solid dispersions – on many elements; I think that it takes low investment to develop them,” he explains. “And the physical stability, that’s the huge disadvantage for amorphous solid dispersions.”
Compounds in an amorphous solid dispersion will eventually crystallise out of the solution, but it is hard to predict how long it will take for a given formula. A suspension in a lipid avoids this completely. Using lipids and simultaneously doing away with the need to solubilise could also streamline the development process for oral drug delivery. It would no longer be necessary to always use the form of a compound that demonstrates the highest lipid solubility – and that would open the way for new uses of compounds with low lipid solubility. “You can generate lipophilic salts, you can optimise in sol screening, and instead of increasing the aqueous solubility, you can actually focus on increasing the lipid solubility,” explains Holm.
However, lipids can also exhibit problems with chemical stability. The API is relatively mobile in a liquid lipid formula, which increases the risk of oxidation as it interacts with impurities in the excipient. Those points of failure have contributed to the low visibility of lipid-based formulations in the commercial space. It has created a self-perpetuating cycle in which manufacturers are unlikely to have the right equipment for lipid formulations because of low demand.
“What really limits the commercial use of lipid-based formulation systems is the supply chain,” adds Holm. “The molecules haven’t really fitted into the formulation space… and if a field hasn’t seen any success possibilities for a period of time, then you will look into it less.”
Deemed by Holm as the ‘sleeping beauty’ of pharmaceuticals, lipids lie dormant and await the kiss of life. “There will always be someone who remembers, so if there’s a need, it will pop up again, and I think that’s the phase it is in now.”
A few companies are already selling non-solubilised lipid products. Capsugel’s Prolive, a probiotic nutriceutical that is sold in Brazil, uses a double-capsule system to keep the API and excipient completely separate. The idea is that the outer capsule will be digested first, keeping the probiotic inactive until it reaches the small intestine where it can do its best work. Another possibility on Holm’s radar is chase dosing, in which the excipient is given first and then ‘chased’ with the API in an aqueous solution, aiming for solubilisation in the intestine.
Holm is adamant that there is still a lot to learn about what makes lipid-based suspensions tick. Certainly, lipid-based formulations of any kind face a tough battle to expand commercially. Whether they’re destined to be the next big thing is debatable, but they have the potential to solve problems that no other delivery method can.
