Manufacturing
HPMC and the Value of Vegetarian Hard Capsules
Oral solid dose (OSD) products continue to be the preferred drug delivery form for active pharmaceutical ingredients (APIs) for drug developers, due to their cost-effectiveness, comparative ease of manufacturing, and availability of patient-friendly dosing options. Of the 38 small molecule new molecular entities (NMEs) approved by the US Food and Drug Administration in 2019, 26 were OSDs1. In addition, the secondary manufacturing of OSD branded products carried out by contract manufacturing organisations (CMOs) accounted for $7.2 billion (USD) of market revenue in North America in 20182. Likewise, the small molecule outsourcing market is predicted to reach more than $69 billion by 20243. All of this demonstrates the continuing prevalence of OSD delivery. Compressed tablets currently dominate the OSD market, but hard capsules are becoming an increasingly attractive alternative. This is, in part, due to the reliability of encapsulation as a delivery method for medicines, including highly potent oncology APIs, which often have more complicated delivery requirements to ensure safety and efficacy. For patients, capsules are familiar, offer taste masking and good swallowability, making them preferable to more invasive dosage formulations. In this article with International Pharmaceutical Industry, Julien Lamps, Product Manager at Lonza Capsules and Health Ingredients discusses the various advantages of selecting a hard capsule over a tablet formulation. Julien also shares insight into how the introduction of hydroxypropyl methylcellulose (HPMC) alternatives could see the scales start to tip as developers look for ways to not only optimise their products but also meet consumer demand for vegetarian-friendly medicines. Hard Capsules: Improving Patient Compliance and Optimising Performance Patients may be reluctant or unwilling to 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY
take medications that taste or smell bad, are difficult to swallow, or have the potential for adverse side-effects. With this in mind, compliance with a treatment regimen is fostered by the development of userfriendly dosage forms. Hard capsules are an attractive option for patients because, in addition to masking taste and smell, they can also decrease pill burden due to less frequent dosing and better release timing. This is achieved through the use of rapid, controlled, and extended-release formulations. Gaining more control over the release profile of a drug, for example by using pelletised API, can prevent dose dumping and may also reduce side-effects. Drug developers have found that encapsulated multi-pellet technology allows for increased flexibility and more effective handling of controlled-release APIs. It can even allow combinations of pellets containing different APIs within the same capsule, meaning multiple drugs can be delivered simultaneously in different doses, hence further reductions in dose frequency can be achieved. These formulations, including multipleunit pellet systems4, extrusion-spheronised APIs3, and fixed-dose combination systems5, also exhibit more reproducible pharmacokinetic and pharmacodynamic behaviours when compared to traditional formulations. Due to this combination of potential improvements in patient compliance and therapeutic efficacy, demand for hard capsules to encapsulate pelletised APIs is continuing to rise. Polymer Preference: The Need for a Vegetarian Alternative to Hard Gelatin Capsules While hard capsules have traditionally been made from gelatin, this polymer can be challenging to use with hydroscopic or moisture-sensitive molecules. Derived from animal by-products, gelatin capsules are susceptible to cross-linking reactions that may interfere with dissolution and have a relatively high water content to maintain pliability. This can lead to water exchange between the shell and the encapsulated API and excipients.
In addition to the impact polymer selection can have on product performance, an increasing number of patients are unwilling to ingest animal products for social or cultural reasons and are seeking medications that can be classed as vegetarian or vegan. In order to meet this demand, pharmaceutical companies are investing in drug delivery innovation to develop compatible vegetarian alternatives that are just as safe and effective. Recent advances in material science have allowed companies to develop alternative capsule polymers that have the benefits of gelatin capsules – swallowability, ease of manufacture, and cost-effectiveness – while offering patients a capsule derived from a non-animal source. Achieving Improved Dissolution and Compatibility: The Application of HPMC Currently, one of the best alternatives to gelatin is hydroxypropyl methylcellulose (HPMC), a polymer derived from the cellulose found in trees. HPMC is also less chemically reactive and absorbs water to a lesser degree than gelatin6. The low moisture content of HPMC capsules reduces water exchange between the capsule and the encapsulated formulation which in some cases can improve chemical and physical stability, increase shelf-life, and alleviate challenges with including hygroscopic APIs and excipients in the formulation. HPMC shells are also stable at a wide range of temperatures, which makes them easy to store and transport. With the increasing number of highly potent APIs in development with more complex requirements in terms of formulation, manufacturers are exploring the use of HPMC-based capsules as a potential alternative to traditional gelatin capsules and have so far experienced very positive results. In fact, HPMC capsules are now often preferred in clinical trials for investigational NMEs due to their ability to encapsulate a wide range of drug products and excipients7. The ongoing improvements in HPMC capsule technology have meant drug developers are able to take advantage of their dissolution parameters and their Winter 2020 Volume 12 Issue 4
