The Soft Side of Drug Delivery

December 2015 saw the launch of The Medicine Maker Innovation Awards, which recognized some of the most exciting technologies of 2015. Catalent’s OptiShell softgel technology was one of 10 winners.

At first glance, a new type of softgel may not seem like a startling innovation, but softgels are an important and proven drug delivery tool, particularly for poorly water-soluble drugs (of which there are an increasing number). The judges of the 2015 Innovation Awards praised the OptiShell technology for its focus on natural ingredients (plant-based rather than gelatin) and its ability to encapsulate higher melting point fill formulations.

Keith Tanner, manager of technology development at Catalent, was one of the first scientists assigned to work on OptiShell. Here, he shares the developmental story behind the innovation and explains why it was so important for the company to develop a non-gelatin based softgel.

The Softgel Story

As told by Keith Tanner

In 1998, I was given a new project at Catalent: find a non-animal alternative to gelatin that can be used to make softgels. The project was prompted by the outbreak of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CJD) in the late 1980s and early 1990s. At the time, Catalent was very reliant on gelatin for its softgels, particularly bovine gelatin derived from bone, and there were concerns that the prions that cause BSE could be passed to humans through gelatin. It has since been proven that the gelatin manufacturing process destroys these prions, but at the time it was a big concern in Europe – and there was the potential for future restrictions on gelatin. To be on the safe side, Catalent wanted to find an alternative. Apart from the concerns around BSE, there were also other advantages to replacing gelatin. Gelatin is prone to fluctuations in price and quality – with the quality aspect being particularly worrying for the pharma industry. Indeed, simply changing supplier can mean that you are suddenly working with a completely different gelatin. In addition, gelatin is prone to cross-linking, particularly the high-bloom grades, which can lead to the gelatin becoming insoluble and interfering with a softgel drug’s shelf life. 

When we were given the project brief, I understood the benefits of replacing gelatin but, at the same time, I remember me and my colleagues staring at one another – we knew it wouldn’t be easy. Despite its disadvantages, gelatin is a very versatile polymer with good elastic properties and it usually behaves well in manufacturing. In that sense, it would be hard to beat. Fortunately, we were given a broad canvas to work with and we had the freedom to investigate different production methods, such as radio frequency sealing, reciprocating plates and other forms of encapsulation. We decided, however, that a hermetically sealed envelope using the traditional rotary die process would economically be the best process, which meant that our gelatin alternative would have to possess suitable elastic film strength, as well as being sealable with heat and pressure. We also needed a high solids loading; you can’t use high levels of water to form a shell because the capsule will lack strength. We needed to look for polymers that could be typically loaded at 40-50 percent in solution without developing unmanageable process viscosities.

A big challenge was simply the fact that there are a lot of polymers out there to test! Many polymers are excellent gelling agents (too good in some cases). We reviewed all the natural polymers on paper and in the lab, and we did extensive testing of films derived from these natural polymers (using them alone and in combination with each other). I began to look at vegetable-derived alternatives, but many ingredients were excluded on the basis of functionality – often being too poorly elastic, developing high viscosity, requiring high water contents or exhibiting poor film strength. During this time, it really felt as if we’d looked at everything you could think of. As we’d anticipated at the start of the project, finding that perfect gelatin replacement was difficult. Despite the frustrations, I never thought it would be impossible. I knew that we would eventually find something functional – it was just a case of using the right materials in the right amounts.

A big concern when you work on a cutting-edge project is that the revelation may come too late – what if another softgel company gets there first? You never know what competitors are working on and whether someone will beat you to the finish line. Patents can give you an idea, but they are not published for eighteen months after being filed. (As it turned out, it was actually about another 10 or so years before anyone else came out with a gelatin alternative, so I didn’t have anything to worry about after all!)

Starch serendipity

The breakthrough in the project came when a colleague dropped a packet of starch on my desk. He’d been to a trade show and knew about my project, so he brought me a sample just in case it turned out to be useful. The starch was exactly what I needed. On its own, it was ineffective. It formed great films and we could make it seal, but we couldn’t process it on our encapsulation machines. By combining it with a polymer (a certain type of carrageenan), we were able to duplicate similar properties to gelatin. We looked at other starches too, from potato, tapioca, and rice, but it was the sample that had landed on my desk that gave the highest loading of solid into a liquid without too much viscosity.

By December 1998, we were making benchtop prototypes and everything was working well. Next, we needed to test the material on the encapsulation machine – it worked and we had our first prototypes manufactured on our pilot encapsulation machine. It was early, rough progress, but we were very proud of our achievement. Our spirits weren’t even dampened by a colleague who, when I showed him the prototypes, said, “Do the seals always look that bad?”

In fairness, the capsule seals on the first prototypes were weaker than gelatin seals, which did concern me. However, we managed to address the problem and improve the sealing strength by refining the process, fine tuning the composition ratios and working with suppliers to customize the properties of the raw materials to meet our needs. In addition, there was the shell mass to consider. The gelatin formulations are around 12,000-15,000 centipoise, but our new shell was significantly higher, which meant that we couldn’t use traditional gravity delivery into the machine. We tried conventional pumping, but that didn’t work either. The main problem was that it needed to be at above 85 °C to form encapsulation ribbons – and the equipment we had wasn’t made with that in mind.

Gluing it all together

We eventually sought inspiration from the adhesive equipment industry because viscous glues often need to be delivered at high temperatures using a “melt-on-demand” process – you only melt what you need (the rest remains in the solid form). We took a similar approach with our polymer and since we’re only melting perhaps an hour ahead of time, we don’t have any degradation issues. Of course, even though the process and equipment were inspired by the adhesives industry, they were obviously engineered to meet higher pharmaceutical standards.

By now, we had the polymer and the process, and everything was very refined. Our global affiliates wanted the product as soon as possible because concerns around BSE were rife, particularly in the UK. Commercial manufacturing and roll out in the UK started quickly – around mid-2000 – and other countries soon followed. The product was called Vegicaps. It was the first natural, GMO free, plant-based shell on the global market. At first, its main use was in nutraceutical and topical cosmetic products.

Finding form for pharma

So where does OptiShell come into this? As soon as the Vegicaps capsules were launched, we went back to the lab to explore the future potential of the shell and how it compared with traditional gelatin softgels. We noticed that the new softgel could be filled at high temperatures. Gelatin softgels can be filled at 37–40 °C before the shell distorts, but our shell was stable up to 70 °C, which opens up the possibility to encapsulate high viscosity liquids and semi-solid formulations, which is a real breakthrough for solubility or bioavailability challenges. In addition, our shell was more resistant to alkaline formulations. We can encapsulate fill formulations with a pH of 12 with excellent stability over three years. Gelatin, on the other hand, is destroyed by acidic or particularly alkaline formulations. Gelatin is also prone to cross-linking, especially in the presence of reactive species such as peroxides and aldehydes; severe cross-linking renders the shell insoluble. Unlike geltain, we found that we could prevent our shell from cross-linking; this is an important feature and means that an OptiShell product will retain the same dissolution characteristics throughout its shelf life.

Finally, the shell is natural. And though this fact doesn’t provide benefits in terms of formulation, it is useful from a marketing point of view. I mentioned earlier that the prions responsible for BSE are destroyed in the manufacturing process for gelatin so there isn’t a health issue with gelatin. However, since 2000 there has been increasing focus on natural ingredients and non-animal derivatives. Some countries also have rules against gelatin; for example Japan won’t allow bovine-derived gels in the country. We’ve designed OptiShell and chosen the ingredients carefully so that it can be used in all geographic regions. Finally, non-gelatin shells don’t have an odor, which is a plus for consumers.

Of course, we had to do a lot of work to refine Vegicaps into OptiShell, which is designed to take advantage of all the properties mentioned above. It was a long journey (and I can’t give you all the details for obvious reasons) but OptiShell finally launched in 2015. Overall, it is compatible with a wider range of excipients and can be used to encapsulate a range of highly viscous and semi-solid formulations (which facilitates extended release).

Since the launch, OptiShell has already been well adopted by the industry; for example, in June 2016, the FDA approved the first non-gelatin Rx softgel product, which uses a hot fill semi solid matrix in an OptiShell format as its delivery platform. We’ve seen a lot of interest in the technology, which is exciting for me to witness given that I’ve been working on the project since the very beginning! I’m looking forward to learning what else lies ahead for the technology.