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 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

Figure 1

compatibility with many NMEs, including highly potent compounds. HPMC capsules that are produced without the need for a gelling agent provide ion- and pHindependent dissolution performance in a range of media, meaning patients will experience the same therapeutic efficacy in fasted or fed conditions. This is shown in Figure 1.8

As a result, these improvements in dissolution can lead to enhanced patient compliance simply because the patient has less to worry about in terms of timing their dose routine. Additionally, ongoing innovations in HPMC capsule film solutions can also allow for enteric protection and rapid release in a specific section of the GI tract, effecting targeted delivery for some therapeutics9 and further bolstering the potential application of HPMC capsules.

Another potential application for HPMC capsules is for use in inhalation devices for pulmonary delivery. The prevalence of this dosage form continues to grow because of the potential improvements in bioavailability by avoiding the first pass liver and providing a more direct delivery route when targetting diseases such as asthma and chronic obstructive pulmonary disease (COPD).

As pharmaceutical manufacturers look to develop cost-effective, patient-friendly, and effective treatments for respiratory conditions, as well as explore inhalation delivery for a number of central nervous system (CNS) diseases, the demand for capsule-based dry powder inhalants is increasing. The low moisture content of HPMC capsules makes them ideal for the type of hygroscopic or water-sensitive APIs used in dry powder inhalers, though electrostatic properties between the formulation and the capsule shell also have to be taken into account throughout the development process8 . Final Thought Ongoing developments in polymer science and engineering have paved the way for HPMC to become a viable alternative to gelatin-based capsules for certain formulations, providing more options when it comes to optimising product performance. In addition, the increased prominence being placed on consumer preference and the high demand for affordable inhalation medications are bolstering demand for capsules that are compatible with moisture-sensitive molecules. However, polymer selection is a critical part of ensuring product success and the decision between gelatin and HPMC should only be made with access to the right expertise. Chosen correctly, a polymer can enhance efficacy and reduce adverse side-effects as well as overcome certain formulation challenges. REFERENCES

1. FDA. 2019. Novel Drug Approvals for 2019. Accessed at https://www.fda.gov/drugs/newdrugs-fda-cders-new-molecular-entitiesand-new-therapeutic-biological-products/ novel-drug-approvals-2019 2. Persistence Market Research. 2018. Global Market Study on Oral Solid Dosage Contract Manufacturing: Tablets Dosage Form to Register Significant Revenue Growth Through 2028. Accessed at https://www. persistencemarketresearch.com/marketresearch/oral-solid-dosage-contractmanufacturing-market.asp 3. Ravetti S, Hergert LY, Sparo MD et al. 2016. Challenges in Protein Formulation Focused on Extrusion-Spheronization Process. Int J Pharma Research Rev 2016; Visiongain. 2020. Pharmaceutical Contract Manufacturing Market 2019-2020. Accessed at https://www. visiongain.com/report/pharmaceuticalcontract-manufacturing-market-2019-2029/ 4. Panda SK, Parida KR, Roy H et al. A Current Technology for Modified Release Drug Delivery System: Multiple-Unit Pellet System (MUPS). Int J Pharm Sci Health Care 2013;3(6):51–63. 5. Moon C and Oh E. Rationale and strategies for formulation development of oral fixed dose combination drug products. J Pharma Investigation 2016;46:615–631. 6. Pinto JT, Wutscher T, Stankovic-Brandl M et al. Evaluation of the Physico-mechanical Properties and Electrostatic Charging Behavior of Different Capsule Types for Inhalation Under Distinct Environmental Conditions. AAPS PharmSciTech 2020;21(4):128. 7. Al-Tabakha MM. HPMC capsules: current status and future prospects. J Pharm Pharm Sci 2010;13(3):428–42. 8. Bordes-Picard F and Lamps J. “Advanced Capsule Technologies: Dry Powder Inhalers to Target Disease.” ONdrugDelivery, August 2020;110:54–57. 9. Lynch M. Technology boosts access to biologics and insulin via oral delivery. BioPharma Reporter. 2019. Accessed 8 October 2020. https://www.biopharmareporter.com/Article/2019/03/18/Oraldelivery-of-biologics

Julien Lamps

Julien Lamps graduated from Ecole Nationale Supérieure de Chimie de Lille with an engineering degree in chemistry in 2004. Julien joined Lonza CHI as a Quality Assurance Engineer in the Colmar plant in 2011. In this role he worked at the interphase of operations and customers within the well-known Lonza Quality Mindset. He specialised in coordinating new product introductions to develop innovative offers around modified release profiles and also inhalation products. He is now Product Manager for Lonza CHI’s Capsule Delivery Solutions business unit focusing on inhalation and HPMC portfolios.