Julien Lamps, Product Manager, Lonza10.14.20
Orally administered medications are hands down, the world’s preferred way to take medications. According to Kiplinger, of the top 15 selling drugs in 2017, 8 out of 15 were oral solid dose (OSD) formulations, including the top seller.1
Despite the rise of parenterally administered biologics, many patients find injections stressful and inconvenient. For developers, OSD forms remain the preferred administration route due to their cost-effectiveness, relative ease of manufacturing and the wide availability of patient-friendly dosing options.
For these reasons, there continues to be an increasing number of oral dose forms being approved and in development. In 2018, 53% of the new molecular entities (NMEs) approved by the FDA were OSDs. This portion of OSD approvals was higher than the previous two years (50% in 2017 and 32% in 2016).2
In addition, although compressed tablet forms currently dominate OSD drugs overall, encapsulated therapeutics are a near second. This is largely driven by the fact that encapsulating active ingredients is seen as a reliable route for administering highly potent APIs as well as other compounds.
In 2018, approximately 25% of new chemical entities (NCEs) were considered to be “potent,” a trend largely attributed to the fact that about one-third of all drug candidates being developed are oncology treatments.3,4 Of the 31 solid-dose oncological NMEs approved in 2018, seven were capsules.
The rise of HPMC capsules
Today, gelatin remains the most popular capsule material. Gelatin-based hard capsules offer traditional benefits and are supported by data to demonstrate compatibility. For a time, there were few alternatives that could offer the same characteristics. However, advances in materials science and organic chemistry are providing pharma’s drug developers with capsule materials that are derived from non-animal sources. These materials offer the same required performance, are compatible with APIs and drug products and cater to the growing patient demand for clean-label products.
Hydroxy Propyl Methyl Cellulose (HPMC) capsules are becoming more popular in the marketplace. HPMC-based capsules show great promise as a potential alternative to gelatin-based formulations. Currently, HPMC-based capsules are widely preferred in clinical trials, and for many investigational NMEs, because they have the added flexibility to accommodate a vast array of drug products and formulations incompatible with gelatin capsules.4
The need to deliver the potent APIs now under development is contributing to a shift towards encapsulating these formulations in HPMC-based capsules. However, there are other factors driving HPMC capsule demand, including:
The benefits of HPMC capsules
When solid oral dosage forms were developed 10 to 20 years ago, the most common capsule material was gelatin, which remains popular today. This occasionally led to concerns around flexibility of hygroscopic formulations, as the plasticity of the shell was not maintained due to water exchanges between components.
Modern HPMC capsules help to resolve this issue, offering a comparable dissolution profile to historical gelatin, while not mechanically suffering from the water exchanges.
As a base material, HPMC offers higher moisture tolerance which helps to stabilize formulations and mitigates the challenges associated with APIs and excipients that are moisture sensitive.
Due to the nature of HPMC, these capsules have lower moisture content than gelatin alternatives, which need more water to be plasticized and malleable. This low amount of water in shell will prevent hygroscopic API from accessing water and increase both their chemical and physical stability and subsequently their shelf life.
The HPMC polymer can also withstand a wider range of temperature variation and fluctuation in storage and transit, meaning there is less chance for brittleness or breakage.
Although gelatin capsules remain a strong candidate for new formulations, advancements in HPMC capsule technology are leading to broader compatibility with the more complex drug products being developed today. For example, there are emerging HPMC capsule technologies that eliminate gelling agents and provide for a standard, reliable alternative for delivering the next-generation of drug products.6 This results primarily from ion and pH independent dissolution behavior when using different dissolution media.
Supporting medicine administration
To develop an innovative oral delivery system without using a gelling agent, HPMC-based capsules have been optimized to stabilize formulation performance even in low humidity and moisture conditions, as well as when using various dissolution media.
Composed of just HPMC and water with no gelling agent, Vcaps Plus HPMC capsules offer a consistent, pH-independent release of API and a more effective option relative to other HPMC capsules using gelling systems.
Studies have shown that Vcaps Plus HPMC capsules deliver consistent disintegration and dissolution properties which helps optimize product performance. Moreover, gelatin-free HPMC capsules are suitable for moisture-sensitive ingredients, provide product stability and reduce risk of cross-linking.
For example, Capsugel Vcaps Plus capsules, composed of HPMC without gelling agent, are exhibiting a fully pH-independent performance, as shown in Graph 1. This feature is addressing patient compliance concern, as it permits patients to take medication under fasted as well as under fed conditions.
Graph 1. In vitro dissolution of caffeine in Capsugel Vcaps Plus capsules.
Specific grades of HPMC are also the ideal tool for targeting release in the gastrointestinal tract (GI) tract. Targeting dispersion to occur along a specific point in the GI tract is proving to be an effective delivery strategy for certain therapeutics.6 Depending on the capsule’s film composition, this control can be relatively precise.
The enteric version of capsules manufactured with Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS) and HPMC can be utilized to greatly simplify and accelerate prototype development and rapid in-vivo testing of products requiring targeted delivery to the upper GI tract. For example, they eliminate coating system preparation and application steps; allow rapid screening and optimization of enteric performance; remove dependency of enteric functionality with process variability; and obviate the need for process development of the enteric coating step, process scale-up and validation.
References
Julien Lamps is Product Manager of Capsules and Health Ingredients at Lonza. He graduated from Ecole Nationale Supérieure de Chimie de Lille with an engineering degree in chemistry in 2004. Julien joined the company 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 Capsugel Quality mindset. He specialized in coordinating new product introductions to develop innovative offers around modified release profiles and also inhalation products.
Despite the rise of parenterally administered biologics, many patients find injections stressful and inconvenient. For developers, OSD forms remain the preferred administration route due to their cost-effectiveness, relative ease of manufacturing and the wide availability of patient-friendly dosing options.
For these reasons, there continues to be an increasing number of oral dose forms being approved and in development. In 2018, 53% of the new molecular entities (NMEs) approved by the FDA were OSDs. This portion of OSD approvals was higher than the previous two years (50% in 2017 and 32% in 2016).2
In addition, although compressed tablet forms currently dominate OSD drugs overall, encapsulated therapeutics are a near second. This is largely driven by the fact that encapsulating active ingredients is seen as a reliable route for administering highly potent APIs as well as other compounds.
In 2018, approximately 25% of new chemical entities (NCEs) were considered to be “potent,” a trend largely attributed to the fact that about one-third of all drug candidates being developed are oncology treatments.3,4 Of the 31 solid-dose oncological NMEs approved in 2018, seven were capsules.
The rise of HPMC capsules
Today, gelatin remains the most popular capsule material. Gelatin-based hard capsules offer traditional benefits and are supported by data to demonstrate compatibility. For a time, there were few alternatives that could offer the same characteristics. However, advances in materials science and organic chemistry are providing pharma’s drug developers with capsule materials that are derived from non-animal sources. These materials offer the same required performance, are compatible with APIs and drug products and cater to the growing patient demand for clean-label products.
Hydroxy Propyl Methyl Cellulose (HPMC) capsules are becoming more popular in the marketplace. HPMC-based capsules show great promise as a potential alternative to gelatin-based formulations. Currently, HPMC-based capsules are widely preferred in clinical trials, and for many investigational NMEs, because they have the added flexibility to accommodate a vast array of drug products and formulations incompatible with gelatin capsules.4
The need to deliver the potent APIs now under development is contributing to a shift towards encapsulating these formulations in HPMC-based capsules. However, there are other factors driving HPMC capsule demand, including:
- Clean label, animal protein-free alternative to gelatin – addresses dietary and ethical concerns;
- Processability and structural integrity; and
- Source reliability and quality.
The benefits of HPMC capsules
When solid oral dosage forms were developed 10 to 20 years ago, the most common capsule material was gelatin, which remains popular today. This occasionally led to concerns around flexibility of hygroscopic formulations, as the plasticity of the shell was not maintained due to water exchanges between components.
Modern HPMC capsules help to resolve this issue, offering a comparable dissolution profile to historical gelatin, while not mechanically suffering from the water exchanges.
As a base material, HPMC offers higher moisture tolerance which helps to stabilize formulations and mitigates the challenges associated with APIs and excipients that are moisture sensitive.
Due to the nature of HPMC, these capsules have lower moisture content than gelatin alternatives, which need more water to be plasticized and malleable. This low amount of water in shell will prevent hygroscopic API from accessing water and increase both their chemical and physical stability and subsequently their shelf life.
The HPMC polymer can also withstand a wider range of temperature variation and fluctuation in storage and transit, meaning there is less chance for brittleness or breakage.
Although gelatin capsules remain a strong candidate for new formulations, advancements in HPMC capsule technology are leading to broader compatibility with the more complex drug products being developed today. For example, there are emerging HPMC capsule technologies that eliminate gelling agents and provide for a standard, reliable alternative for delivering the next-generation of drug products.6 This results primarily from ion and pH independent dissolution behavior when using different dissolution media.
Supporting medicine administration
To develop an innovative oral delivery system without using a gelling agent, HPMC-based capsules have been optimized to stabilize formulation performance even in low humidity and moisture conditions, as well as when using various dissolution media.
Composed of just HPMC and water with no gelling agent, Vcaps Plus HPMC capsules offer a consistent, pH-independent release of API and a more effective option relative to other HPMC capsules using gelling systems.
Studies have shown that Vcaps Plus HPMC capsules deliver consistent disintegration and dissolution properties which helps optimize product performance. Moreover, gelatin-free HPMC capsules are suitable for moisture-sensitive ingredients, provide product stability and reduce risk of cross-linking.
For example, Capsugel Vcaps Plus capsules, composed of HPMC without gelling agent, are exhibiting a fully pH-independent performance, as shown in Graph 1. This feature is addressing patient compliance concern, as it permits patients to take medication under fasted as well as under fed conditions.
Graph 1. In vitro dissolution of caffeine in Capsugel Vcaps Plus capsules.
Specific grades of HPMC are also the ideal tool for targeting release in the gastrointestinal tract (GI) tract. Targeting dispersion to occur along a specific point in the GI tract is proving to be an effective delivery strategy for certain therapeutics.6 Depending on the capsule’s film composition, this control can be relatively precise.
The enteric version of capsules manufactured with Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS) and HPMC can be utilized to greatly simplify and accelerate prototype development and rapid in-vivo testing of products requiring targeted delivery to the upper GI tract. For example, they eliminate coating system preparation and application steps; allow rapid screening and optimization of enteric performance; remove dependency of enteric functionality with process variability; and obviate the need for process development of the enteric coating step, process scale-up and validation.
References
- https://www.kiplinger.com/slideshow/investing/T027-S001-the-15-all-time-best-selling-prescription-drugs/index.html
- https://www.futuremarketinsights.com/reports/oral-solid-dosage-pharmaceutical-formulation-market
- https://www.pharmamanufacturing.com/articles/2019/solid-dose-under-hyped-but-not-under-represented/
- http://www.samedanltd.com/uploads/pdf/white_paper/9908ae04a14145d662675ac2eb0e0e5c.pdf
- https://www.ncbi.nlm.nih.gov/pubmed/21092714
- https://www.ncbi.nlm.nih.gov/pubmed/19900518
Julien Lamps is Product Manager of Capsules and Health Ingredients at Lonza. He graduated from Ecole Nationale Supérieure de Chimie de Lille with an engineering degree in chemistry in 2004. Julien joined the company 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 Capsugel Quality mindset. He specialized in coordinating new product introductions to develop innovative offers around modified release profiles and also inhalation products.
